Phenotypic markers for cell therapy and related methods

Abstract

Provided are methods, compositions and articles of manufacture for use in cell therapy involving the administration of one or more doses of a therapeutic T cell composition, and methods, compositions and articles of manufacture for use in the same. The cells of the T cell composition express recombinant receptors such as chimeric receptors, e.g. chimeric antigen receptors (CARs) or other transgenic receptors such as T cell receptors (TCRs). Features of the embodiments of the present disclosure, including the dose of cells or units of cells administered and / or the phenotype of administered cells, provide various advantages, such as consistent dosing, lower risk of toxicity and / or increased response in subjects administered the T cell compositions.

Description

PHENOTYPIC MARKERS FOR CELL THERAPY AND RELATED METHODSCross-Reference to Related Applications

[0001] This application claims priority from U.S. provisional application 62 / 596,775, filed December 8, 2017, entitled“PHENOTYPIC MARKERS FOR CELL THERAPY ANDRELATED METHODS,” U.S. provisional application No. 62 / 643,165, filed March 14, 2018, entitled“PHENOTYPIC MARKERS FOR CELL THERAPY AND RELATED METHODS,” U.S. provisional application No. 62 / 657,716, filed April 13, 2018, entitled“PHENOTYPIC MARKERS FOR CELL THERAPY AND RELATED METHODS,” and U.S. provisional application No. 62 / 716,967, filed August 9, 2018, entitled“PHENOTYPIC MARKERS FOR CELL THERAPY AND RELATED METHODS,” the contents of which are incorporated by reference in their entirety.Incorporation by Reference of Sequence Listing

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 7350420l4540SeqList.txt, created December 7, 2018, which is 35,461 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.Field

[0003] The present disclosure relates to cell therapy involving the administration of one or more doses of a therapeutic T cell composition, and methods, compositions and articles of manufacture for use in the same. The cells of the T cell composition express recombinant receptors such as chimeric receptors, e.g. chimeric antigen receptors (CARs) or other transgenic receptors such as T cell receptors (TCRs). Features of the embodiments of the present disclosure, including the dose of cells or units of cells administered and / or the phenotype of administered cells, provide various advantages, such as consistent dosing, lower risk of toxicity and / or increased response in subjects administered the T cell compositions.Background

[0004] Various immunotherapy and / or cell therapy methods are available for treating diseases and conditions. For example, adoptive cell therapies (including those involving theadministration of cells expressing chimeric receptors specific for a disease or disorder of interest, such as chimeric antigen receptors (CARs) and / or other recombinant antigen receptors, as well as other adoptive immune cell and adoptive T cell therapies) can be beneficial in the treatment of cancer or other diseases or disorders. Improved approaches are needed. Provided are methods and articles of manufacture that meet such needs.Summary

[0005] Provided herein are therapeutic compositions containing T cells expressing a recombinant receptor, wherein at least at or about, or at or about, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27. In some embodiments, at least at or about, or at or about 50% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor are surface positive for CCR7 and / or CD27. In some embodiments, at least at or about, or at or about 60% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor are surface positive for CCR7 and / or CD27. In some embodiments, at least at or about, or at or about 70% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor are surface positive for CCR7 and / or CD27. In some embodiments, at least at or about, or at or about 80% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor are surface positive for CCR7 and / or CD27.

[0006] In some embodiments, the T cells in the composition and / or expressing the recombinant receptor comprise or consist of CD8+ T cells; the T cells in the composition and / or expressing the recombinant receptor comprise or consist of CD4+ T cells; the T cells in the composition and / or expressing the recombinant receptor comprise or consist of CD8+ and CD4+ T cells; the T cells in the composition and / or expressing the recombinant receptor comprise or consist of at least at or about 30%, 50% 95%, 96%, 97%, 98%, or 99% or 100% CD8+ T cells; the T cells in the composition and / or expressing the recombinant receptor comprise or consist of at least at or about 30%, 50% 95%, 96%, 97%, 98%, or 99% or 100% CD4+ T cells; and / or the T cells in the composition and / or expressing the recombinant receptor comprise or consist ofapproximately 1: 1 or approximately between 1:3 and 3:1 or approximately between 1:2 and 2: 1, CD4+:CD8+ T cells.

[0007] Provided herein are methods, compositions, and articles of manufacture involving or comprising a unit dose of cells based on a defined number, such as a subtype of CD8+T cells or a subtype of CD4+T cells or cells thereof expressing a recombinant receptor, or a ratio of such subtype of CD8+and CD4+T cells. In some embodiments, the total number of T cells in the composition, or the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7. In some embodiments, the total number of T cells in the composition, or the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CD27. In some embodiments, the total number of T cells in the composition, or the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and CD27. In some embodiments, the composition comprises one or more unit doses of cells.

[0008] In some embodiments, the subtype of cells is positive for a cell surface marker, such as a marker of a central memory phenotype and / or in which the cell surface marker is CCR7 and / or CD27. In some embodiments, the provided methods, compositions and articles of manufacture are for use in connection with cell therapy, such as engineered T cell therapy for the treatment of diseases and conditions, including various tumors.

[0009] Provided herein are articles of manufacture. In some embodiments, the provided articles of manufacture includes a container, comprising one or more unit doses of cells, present in one or more therapeutic composition, the unit dose comprising a plurality of CD8+and / or CD4+T cells expressing (optionally engineered to express) a recombinant receptor, wherein a unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express (optionally surface express) C-C chemokine receptor type 7 (CCR7)(receptor+ / CD8+ / CCR7+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 (receptor+ / CD4+ / CCR7+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+cells and / or receptor+ / CD4+ / CCR7+cells to another subset of cells in the composition; and instructions for administering to a subject having a disease or condition, the therapeutic composition, optionally one or more unit doses thereof and / or a volumecorresponding to such one or more of unit doses.

[0010] Provided herein are articles of manufacture. In some embodiments, the provided articles of manufacture includes a container, comprising one or more unit doses of cells, presentin one or more therapeutic composition, the unit dose comprising a plurality of CD8+and / or CD4+T cells expressing (optionally engineered to express) a recombinant receptor, wherein a unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express (optionally surface express) cluster of differentiation 27 (CD27)(receptor+ / CD8+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CD27 (receptor+ / CD4+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells and / or a defined ratio ofreceptor+ / CD8+ / CD27+cells and / or receptor+ / CD4+ / CD27+cells to another subset of cells in the composition; and instructions for administering to a subject having a disease or condition, the therapeutic composition, optionally one or more unit doses thereof and / or a volumecorresponding to such one or more of unit doses.

[0011] Also provided herein are therapeutic compositions. In some embodiments, the therapeutic composition comprises T cells expressing a recombinant receptor, wherein at least at or about, or at or about, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition (or of the total number of T cells in the composition expressing the recombinant receptor), are surface positive for CCR7 and / or CD27, optionally wherein: the T cells in the composition and / or expressing the recombinant receptor comprise or consist of CD8+T cells; the T cells in the composition and / or expressing the recombinant receptor comprise or consist of CD4+T cells; the T cells in the composition and / or expressing the recombinant receptor comprise or consist of CD8+and CD4+T cells; the T cells in the composition and / or expressing the recombinant receptor comprise or consist of at least at or about 30%, 50% 95%, 96%, 97%, 98%, or 99% or 100% CD8+T cells; the T cells in the composition and / or expressing the recombinant receptor comprise or consist of at least at or about 30%, 50% 95%, 96%, 97%, 98%, or 99% or 100% CD4+T cells; the T cells in the composition and / or expressing the recombinant receptor comprise or consist of approximately 1: 1 or approximately between 1:3 and 3: 1 or approximately between 1:2 and 2: 1, CD4+:CD8+T cells.

[0012] In some embodiments, the unit dose of cells comprises any of the therapeutic compositions described herein.

[0013] In some embodiments, the unit dose of cells comprises a defined number ofCD8+ / CCR7+cells; and / or wherein the unit dose of cells comprises a defined number of CD4+ / CCR7+cells. In some embodiments, the unit dose of cells comprises a defined number of CD8+ / CD27+cells; and / or wherein the unit dose of cells comprises a defined number ofCD4+ / CD27+cells. In some embodiments, the unit dose of cells comprises a defined number of CD8+ / CCR7+ / CD27+cells; and / or wherein the unit dose of cells comprises a defined number of CD4+ / CCR7+ / CD27+cells.

[0014] In some embodiments, the unit dose or composition comprises between at or about 1 x 10 and at or about 1 x 10 , between at or about 5 x 10 and at or about 1 x 10 , or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cells that express the recombinant receptor (receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+cells, total receptor+ / CD4+ / CCR7+cells, totalreceptor+ / CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells, each inclusive, and / or the unit dose or composition comprises no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 107, no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, totalreceptor+ / CD8+ / CCR7+cells, total receptor+ / CD4+ / CCR7+cells, total receptor+ / CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells.

[0015] In some embodiments, the unit dose comprises at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD8+ / CCR7+cells or totalreceptor+ / CD8+ / CD27+cells and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x106, 9 x 106, or 1 x 107total receptor+ / CD4+ / CCR7+cells or total receptor+ / CD4+ / CD27+. In some embodiments, the unit dose comprises between at or about 3 x 106and at or about 2.5 x107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+cells or total receptor+ / CD8+ / CD27+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD4+ / CCR7+cells or total receptor+ / CD4+ / CD27+, each inclusive. In some embodiments, at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose arereceptor+ / CD8+ / CCR7+or receptor+ / CD8+ / CD27+; or at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD4+ / CCR7+or receptor+ / CD4+ / CD27+.

[0016] In some embodiments, the unit dose of cells or composition comprises a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells, which ratio optionally is or is approximately 1:1 or is between approximately 1:3 and approximately 3:1.

[0017] In some embodiments, the unit dose of cells or composition comprises a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells, which ratio optionally is or is approximately 1:1 or is between approximately 1:3 and approximately 3:1. In someembodiments, the defined number or ratio is further based on expression or absence of expression of CCR7 and / or CD45RA on the cells. In some embodiments, the defined number of cells further express or do not express CCR7 and / or CD45RA, optionally wherein the defined number of cells further are CCR7+or CD45RA cells.

[0018] In some embodiments, the defined number or ratio is further based on expression or absence of expression of CD27 and / or CD45RA on the cells. In some embodiments, the defined number of cells further express or do not express CD27 and / or CD45RA, optionally wherein the defined number of cells further are CD27+or CD45RA- cells. In some embodiments, the defined number further comprises cells that express or do not express CD27 and / or CD45RA, optionally wherein the defined number further comprises CD27+or CD45RA cells. In some embodiments, the unit dose of cells or composition comprises a defined number ofreceptor+ / CD8+ / CCR7+ / CD27+cells and / or rcccp tor+ / C D8+ / CCR7+ / C D45RA cells. In some embodiments, the unit dose of cells or composition comprises a defined number ofreceptor+ / CD4+ / CCR7+ / CD27+cells and / or rcccp tor+ / C D4+ / CCR7+ / C D45RA cells.

[0019] In some embodiments, at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD8+ / CCR7+ / CD27+,receptor+ / CD8+ / CCR7+ / CD45RA , receptor+ / CD4+ / CCR7+ / CD27+or receptor+ / CD4+ / CCR7+ / CD45RA .

[0020] Also provided herein are articles of manufacture, that include: a container, comprising one or more unit doses of cells, present in one or more therapeutic composition, the unit dose comprising a plurality of CD8+and / or CD4+T cells expressing, optionally engineered to express, a recombinant receptor, wherein a unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express CCR7 and CD27(receptor+ / CD8+ / CCR7+ / CD27+cells) and / or a defined number of recombinant receptor expressing CD4+T cells that express CCR7 and CD27 (receptor+ / CD4+ / CCR7+ / CD27+cells)and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells and / orreceptor+ / CD4+ / CCR7+ / CD27+cells to another subset of cells in the composition; and instructions for administering to a subject having a disease or condition, the therapeutic composition, optionally one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses. In some embodiments, the unit dose of cells comprises a defined number of CD8+ / CCR7+ / CD27+cells. In some embodiments, the unit dose of cells comprises a defined number of CD4+ / CCR7+ / CD27+cells. In some embodiments, the unit dose comprises between at or about 1 x 10 and at or about 1 x 10 , between at or about 5 x 10 and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cells that express the recombinant receptor (receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+ / CD27+cells, or totalreceptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive. In some embodiments, the unit dose comprises no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, total receptor+ / CD8+ / CCR7+ / CD27+cells, or total receptor+ / CD4+ / CCR7+ / CD27+cells.

[0021] In some embodiments, the unit dose comprises at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor7CD87CCR7+ / CD27+cells and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107totalreceptor+ / CD4+ / CCR7+ / CD27+cells. In some embodiments, the unit dose comprises between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+ / CD27+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107totalreceptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive. In some embodiments, at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose arereceptor+ / CD8+ / CCR7+ / CD27+or receptor7CD47CCR7+ / CD27+.

[0022] In some embodiments, the unit dose of cells comprises a defined ratio ofreceptor+ / CD8+ / CCR7+ / CD27+cells to receptor7CD47CCR7+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

[0023] In some embodiments, the defined number or ratio is further based on expression or absence of expression of CD45RA on the cells. In some embodiments, the defined number of cells further express or do not express CD45RA, optionally wherein the defined number of cells further are CD45RA cells. In some embodiments, the defined number further comprises cells that express or do not express CD45RA, optionally wherein the defined number further comprises CD45RA cells.

[0024] In some embodiments, among a plurality of articles or unit doses or compositions, optionally produced according to the same method, the number or ratio of cells that express CCR7 (CCR7+cells) in the unit dose varies by no more than 40%, by no more than 30%, by no more than 20%, by no more than 10% or by no more than 5%.

[0025] In some embodiments, the unit dose or number of cells expressing the recombinant receptor comprises between at or about 1 x 105 and at or about 5 x 108, between at or about 1 x 10 and at or about 1 x 10 , between at or about 5 x 10 and at or about 1 x 10 , or between at or about 1 x 106and at or about 1 x 107total CD3+cells that express the recombinant receptor (receptor+ / CD3+cells) or total CD3+cells, each inclusive. In some embodiments, the unit dose or number of cells expressing the recombinant receptor comprises no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105totalreceptor+ / CD3+cells or total CD3+cells.

[0026] In some embodiments, the total number of CD3+cells, total number ofreceptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number of receptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number of receptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number of receptor+ / CD4+ / CCR7+ / CD27+cells, total number of rcccptor+ / CD8+ / CCR7+ / CD45RA cells and / orrcccptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that are live or viable.In some embodiments, the total number of CD3+cells, total number of receptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number of receptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number of receptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number of receptor7CD47CCR7+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD45RA cells and / or receptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that do not express an apoptotic marker and / or is the totalnumber of such cells that are apoptotic marker negative ( ), wherein the apoptotic marker is Annexin V or activated Caspase 3.

[0027] In some embodiments, the instructions specify administering a plurality of unit doses contained in a plurality of separate compositions. In some embodiments, the plurality of separate compositions comprise a first composition comprising one of the CD8+T cells and the CD4+T cells and a second composition comprising the other of the CD8+T cells and the CD4+T cells.In some embodiments, the first composition comprises the CD8+T cells. In some embodiments, the first composition comprises the CD4+T cells.

[0028] In some embodiments, the instructions specify administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses and the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses, no more than 2 hours, no more than 1 hour, no more than 30 minutes, no more than 15 minutes, no more than 10 minutes or no more than 5 minutes apart or simultaneously.

[0029] In some embodiments, the instructions specify administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses, prior to administering the composition containing CD4+cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses. In some embodiments, the instructions specify administering the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses, prior to administering the composition containing CD8+cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.

[0030] In some embodiments, the recombinant receptor is or comprises a chimeric receptor and / or a recombinant antigen receptor. In some embodiments, the recombinant receptor is capable of binding to a target antigen that is associated with, specific to, and / or expressed on a cell or tissue of a disease, disorder or condition. In some embodiments, the disease, disorder or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or a cancer. In some embodiments, the target antigen is a tumor antigen.

[0031] In some embodiments, the target antigen is selected from among anbό integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-l), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44,CD44v6, CD44v7 / 8, CD138, CD171, epidermal growth factor protein (EGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRF5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O- acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), G Protein Coupled Receptor 5D (GPCR5D), Her2 / neu (receptor tyrosine kinase erbB2), Her3 (erb-B3), Her4 (erb- B4), erbB dimers, Human high molecular weight- melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HFA-AI), Human leukocyte antigen A2 (HFA-A2), IF- 22 receptor alpha(IF-22Ra), IF- 13 receptor alpha 2 (IF-l3Ra2), kinase insert domain receptor (kdr), kappa light chain, Fl cell adhesion molecule (F1CAM), CE7 epitope of Fl-CAM, Feucine Rich Repeat Containing 8 Family Member A (FRRC8A), Fewis Y,Melanoma-associated antigen (MAGE)-Al, MAGE- A3, MAGE-A6, mesothelin, c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D(NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Fike Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-l), a pathogen- specific antigen, or an antigen associated with a universal tag, and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV or other pathogens.

[0032] In some embodiments, the recombinant receptor is or comprises a functional non- TCR antigen receptor or a TCR or antigen-binding fragment thereof. In some embodiments, the recombinant receptor is a chimeric antigen receptor (CAR).

[0033] In some embodiments, the recombinant receptor comprises an extracellular domain comprising an antigen-binding domain. In some embodiments, the antigen-binding domain is or comprises an antibody or an antibody fragment thereof, which optionally is a single chain fragment. In some embodiments, the fragment comprises antibody variable regions joined by a flexible linker. In some embodiments, the fragment comprises an scFv.

[0034] In some embodiments, the recombinant receptor comprises an intracellular signaling region. In some embodiments, the intracellular signaling region comprises an intracellularsignaling domain. In some embodiments, the intracellular signaling domain is or comprises a primary signaling domain, a signaling domain that is capable of inducing a primary activation signal in a T cell, a signaling domain of a T cell receptor (TCR) component, and / or a signaling domain comprising an immunoreceptor tyrosine-based activation motif (IT AM). In some embodiments, the intracellular signaling domain is or comprises an intracellular signaling domain of a CD3 chain, optionally a CD3-zeta ^ϋ3z) chain, or a signaling portion thereof.

[0035] In some embodiments, the recombinant receptor further comprises a transmembrane domain disposed between the extracellular domain and the intracellular signaling region. In some embodiments, the intracellular signaling region further comprises a costimulatory signaling domain. In some embodiments, the costimulatory signaling domain comprises an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. In some embodiments, the costimulatory signaling domain comprises an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof. In some embodiments, the costimulatory signaling domain is between the transmembrane domain and the intracellular signaling domain.

[0036] In some embodiments, the T cells are primary T cells obtained from a subject. In some embodiments, the T cells are autologous to the subject. In some embodiments, the T cells are allogeneic to the subject.

[0037] Also provided herein are methods of treatment. In some embodiments, the methods of treatment involve administering to a subject having a disease or condition one or more unit doses of any therapeutic composition described herein or a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor and / or a volume corresponding to such unit doses. In some embodiments, the unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express C-C chemokine receptor type 7 (CCR7) (receptor+ / CD8+ / CCR7+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 (receptor+ / CD4+ / CCR7+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+cells and / or receptor+ / CD4+ / CCR7+cells to another subset of cells in the composition; and / or among a group of subjects treated according to the method, the number or ratio of cells that express CCR7 (CCR7+cells) in the unit dose varies by no more than 40%, by no more than 30%, by no more than 20%, by no more than 10% or by no more than 5%.

[0038] Also provided herein are methods of treatment. In some embodiments, the methods of treatment involve administering to a subject having a disease or condition one or more unit doses of a therapeutic composition described herein or a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor and / or a volume corresponding to such unit doses, optionally wherein: the unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express cluster of differentiation 27 (CD27) (receptor+ / CD8+ / CD27+cells) and / or a defined number ofrecombinant receptor-expressing CD4+T cells that express CD27 (receptor+ / CD4+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CD27+cells and / or receptor+ / CD4+ / CD27+cells to another subset of cells in the composition; and / or among a group of subjects treated according to the method, the number or ratio of cells that express CD27 (CD27+cells) in the unit dose varies by no more than 40%, by no more than 30%, by no more than 20%, by no more than 10% or by no more than 5%.

[0039] In some embodiments, the unit dose of cells comprises a defined number ofCD8+ / CD27+cells. In some embodiments, the unit dose of cells comprises a defined number of CD4+ / CD27+cells.

[0040] In some embodiments, the unit dose of cells comprises a defined number ofCD8+ / CCR7+cells. In some embodiments, the unit dose of cells comprises a defined number of CD4+ / CCR7+cells. In some embodiments, the unit dose comprises between at or about 1 x 105and at or about 1 x 10 , between at or about 5 x 10 and at or about 1 x 10 , or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cells that express the recombinant receptor (receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+cells, total receptor+ / CD4+ / CCR7+cells, totalreceptor+ / CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells, each inclusive. In some embodiments, the unit dose comprises no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 107, no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, totalreceptor+ / CD8+ / CCR7+cells, total receptor+ / CD4+ / CCR7+cells, total receptor+ / CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells.

[0041] In some embodiments, the unit dose comprises at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD8+ / CCR7+cells or totalreceptor+ / CD8+ / CD27+cells and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x106, 9 x 106, or 1 x 107total receptor+ / CD4+ / CCR7+cells or total receptor+ / CD4+ / CD27+. In some embodiments, the unit dose comprises between at or about 3 x 106and at or about 2.5 x107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+cells or total receptor+ / CD8+ / CD27+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD4+ / CCR7+cells or total receptor+ / CD4+ / CD27+, each inclusive. In some embodiments, at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose arereceptor+ / CD8+ / CCR7+or receptor+ / CD8+ / CD27+; or at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD4+ / CCR7+or receptor+ / CD4+ / CD27+.

[0042] In some embodiments, the unit dose of cells comprises a defined ratio ofreceptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

[0043] In some embodiments, the defined number or ratio is further based on expression or absence of expression of CD27 and / or CD45RA on the cells. In some embodiments, the unit dose of cells comprises a defined number of receptor+ / CD8+ / CCR7+ / CD27+cells and / or rcccptor+ / CD8+ / CCR7+ / CD45RA cells. In some embodiments, the unit dose of cells comprises a defined number of receptor+ / CD4+ / CCR7+ / CD27+cells and / orrcccptor+ / CD4+ / CCR7+ / CD45RA cells. In some embodiments, the unit dose of cells comprises a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1. In some embodiments, the defined number or ratio is further based on expression or absence of expression of CCR7 and / or CD45RA on the cells. In some embodiments, at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose arereceptor+ / CD8+ / CCR7+ / CD27+or rcccptor+ / CD8+ / CCR7+ / CD45RA .

[0044] In some embodiments, also provided are methods of treatment, wherein the methods involve administering to a subject having a disease or condition one or more unit doses of any compositions described herein.

[0045] In some embodiments, the unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express CCR7 and CD27(receptor+ / CD8+ / CCR7+ / CD27+cells) and / or a defined number of recombinant receptor expressing CD4+T cells that express CCR7 and CD27 (receptor+ / CD4+ / CCR7+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells and / orreceptor+ / CD4+ / CCR7+ / CD27+cells to another subset of cells in the composition; and among a group of subjects treated according to the method, the number or ratio of cells that express CCR7 (CCR7+cells) in the unit dose varies by no more than 40%, by no more than 30%, by no more than 20%, by no more than 10% or by no more than 5%.

[0046] Also provided herein are methods of treatment, wherein the methods involve administering to a subject having a disease or condition a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor and / or a volume corresponding to such unit doses. In some embodiments, the unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express CCR7 and CD27 (receptor+ / CD8+ / CCR7+ / CD27+cells) and / or a defined number of recombinant receptor expressing CD4+T cells that express CCR7 and CD27 (receptor+ / CD4+ / CCR7+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells and / orreceptor+ / CD4+ / CCR7+ / CD27+cells to another subset of cells in the composition; and among a group of subjects treated according to the method, the number or ratio of cells that express CCR7 (CCR7+cells) in the unit dose varies by no more than 40%, by no more than 30%, by no more than 20%, by no more than 10% or by no more than 5%.

[0047] In some embodiments, the unit dose of cells comprises a defined number ofCD8+ / CCR7+ / CD27+cells. In some embodiments, the unit dose of cells comprises a defined number of CD4+ / CCR7+ / CD27+cells. In some embodiments, the unit dose comprises between at or about 1 x 10 and at or about 1 x 10 , between at or about 5 x 10 and at or about 1 x 10 , or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cell that express the recombinant receptor(receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+ / CD27+cells, or totalreceptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive. In some embodiments, the unit dose comprises no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, total receptor+ / CD8+ / CCR7+ / CD27+cells, or total receptor+ / CD4+ / CCR7+ / CD27+cells.

[0048] In some embodiments, the unit dose comprises at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor7CD87CCR7+ / CD27+cells; and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107totalreceptor+ / CD4+ / CCR7+ / CD27+cells. In some embodiments, the unit dose comprises between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+ / CD27+cells; and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107totalreceptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive. In some embodiments, at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose arereceptor+ / CD8+ / CCR7+ / CD27+or receptor7CD47CCR7+ / CD27+.

[0049] In some embodiments, the unit dose of cells comprises a defined ratio ofreceptor+ / CD8+ / CCR7+ / CD27+cells to receptor7CD47CCR7+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

[0050] In some embodiments, the defined number or ratio is further based on expression or absence of expression of CD45RA on the cells. In some embodiments, the defined number or ratio is further based on the number of CD45RA cells. In some embodiments, the defined number of cells further express or do not express CD45RA, optionally wherein the defined number of cells further are CD45RA cells.

[0051] In some embodiments, the unit dose comprises between at or about 1 x 105and at or about 5 x 108, between at or about 1 x 105 and at or about 1 x 108, between at or about 5 x 105 and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD3+cells that express the recombinant receptor (receptor+ / CD3+cells) or total CD3+cells, each inclusive.In some embodiments, the unit dose comprises no more than about 5 x 10 , no more than about1 x 108 , no more than about 5 x 107 , no more than about 1 x 107 , no more than about 5 x 106 , nomore than about 1 x 106, or no more than about 5 x 105total receptor+ / CD3+cells or total CD3+cells.

[0052] In some embodiments, the total number of CD3+cells, total number ofreceptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number of receptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number of receptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number of receptor+ / CD4+ / CCR7+ / CD27+cells, total number of rcccptor+ / CD8+ / CCR7+ / CD45RA cells and / orrcccptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that are live or viable.In some embodiments, the total number of CD3+cells, total number of receptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number of receptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number of receptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number of receptor+ / CD4+ / CCR7+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD45RA cells and / or rcccptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that do not express an apoptotic marker and / or is the total number of such cells that are apoptotic marker negative O, wherein the apoptotic marker is Annexin V or activated Caspase 3.

[0053] In some embodiments, the method involves administering a plurality of unit doses contained in a plurality of separate compositions.

[0054] In some embodiments, the plurality of separate compositions comprise a first composition comprising one of the CD8+T cells and the CD4+T cells and a second composition comprising the other of the CD8+T cells and the CD4+T cells. In some embodiments, the first composition comprises the CD8+T cells. In some embodiments, the first composition comprises the CD4+T cells.

[0055] In some embodiments, the method involves administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses and the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses, no more than 2 hours, no more than 1 hour, no more than 30 minutes, no more than 15 minutes, no more than 10 minutes or no more than 5 minutes apart or simultaneously.

[0056] In some embodiments, the method involves administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding tosuch one or more of unit doses, prior to administering the composition containing CD4+cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.In some embodiments, the method involves administering the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses, prior to administering the composition containing CD8+cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.

[0057] In some embodiments, the recombinant receptor is or comprises a chimeric receptor and / or a recombinant antigen receptor. In some embodiments, the recombinant receptor is capable of binding to a target antigen that is associated with, specific to, and / or expressed on a cell or tissue of a disease, disorder or condition. In some embodiments, the disease, disorder or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or a cancer. In some embodiments, the target antigen is a tumor antigen.

[0058] In some embodiments, the target antigen is selected from among anbό integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-l), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD138, CD171, epidermal growth factor protein (EGFR), , type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O- acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), G Protein Coupled Receptor 5D (GPRC5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb- B4), erbB dimers, Human high molecular weight- melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HLA-A1), Human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha(IL-22Ra), IL-13 receptor alpha 2 (IL-l3Ra2), kinase insert domain receptor (kdr), kappa light chain, Ll cell adhesion molecule (Ll-CAM), CE7 epitope of Ll-CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y,Melanoma-associated antigen (MAGE)-Al, MAGE- A3, MAGE-A6, mesothelin, c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D(NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, aprostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-l), a pathogen- specific antigen, or an antigen associated with a universal tag, and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV or other pathogens.

[0059] In some embodiments, the recombinant receptor is or comprises a functional non- TCR antigen receptor or a TCR or antigen-binding fragment thereof. In some embodiments, the recombinant receptor is a chimeric antigen receptor (CAR).

[0060] In some embodiments, the recombinant receptor comprises an extracellular domain comprising an antigen-binding domain. In some embodiments, the antigen-binding domain is or comprises an antibody or an antibody fragment thereof, which optionally is a single chain fragment. In some embodiments, the fragment comprises antibody variable regions joined by a flexible linker. In some embodiments, wherein the fragment comprises an scFv.

[0061] In some embodiments, the recombinant receptor comprises an intracellular signaling region. In some embodiments, the intracellular signaling region comprises an intracellular signaling domain. In some embodiments, the intracellular signaling domain is or comprises a primary signaling domain, a signaling domain that is capable of inducing a primary activation signal in a T cell, a signaling domain of a T cell receptor (TCR) component, and / or a signaling domain comprising an immunoreceptor tyrosine-based activation motif (IT AM). In some embodiments, the intracellular signaling domain is or comprises an intracellular signaling domain of a CD3 chain, optionally a CD3-zeta ^ϋ3z) chain, or a signaling portion thereof.

[0062] In some embodiments, the recombinant receptor further comprises atransmembrane domain disposed between the extracellular domain and the intracellular signaling region. In some embodiments, the intracellular signaling region further comprises a costimulatory signaling domain. In some embodiments, the costimulatory signaling domain comprises an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. In some embodiments, the costimulatory signaling domain comprises an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof. In some embodiments, the costimulatory signaling domain is between the transmembrane domain and the intracellular signaling domain.

[0063] In some embodiments, the T cells are primary T cells obtained from a subject. In some embodiments, the T cells are autologous to the subject. In some embodiments, the T cells are allogeneic to the subject.

[0064] Also provided herein are methods of determining a dose unit of engineered T cells for treating a subject. In some embodiments, the method comprises assessing, in a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor, the number, percentage or ratio of T cells that express the recombinant receptor and CCR7 (receptor+ / CCR7+). In some embodiments, the method comprises, based on the number, percentage or ratio of receptor+ / CCR7+cells, determining one or more unit doses of cells for administration to a subject having a disease or conditions, wherein the unit dose comprises a defined number of recombinant receptor-expressing CD8+T cells that express C-C chemokine receptor type 7 (CCR7) (receptor+ / CD8+ / CCR7+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 (receptor+ / CD4+ / CCR7+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+cells and / or receptor+ / CD4+ / CCR7+cells to another subset of cells in the composition.

[0065] Also provided herein are methods of determining a dose unit of engineered T cells for treating a subject. In some embodiments, the method involves (a) assessing, in a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor, the number, percentage or ratio of T cells that express the recombinant receptor and CD27 (receptor+ / CD27+); and (b) based on the number, percentage or ratio of receptor+ / CD27+cells, determining one or more unit doses of cells for administration to a subject having a disease or conditions, wherein the unit dose comprises a defined number of recombinant receptor-expressing CD8+T cells that express cluster of differentiation 27 (CD27) (receptor+ / CD8+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CD27 (receptor+ / CD4+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells and / or a defined ratio ofreceptor+ / CD8+ / CD27+cells and / or receptor+ / CD4+ / CD27+cells to another subset of cells in the composition.

[0066] Also provided herein are methods of producing a composition comprising a unit dose of a T cell composition. In some embodiments, the method comprises assessing, in a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor, the number, percentage or ratio of T cells that express the recombinantreceptor and CCR7 and CD27 (receptor+ / CCR7+ / CD27+). In some embodiments, the method comprises filling a container with all or a portion of the composition and optionally another solution to achieve a unit dose of the T cell composition, wherein the unit dose comprises a defined number of recombinant receptor-expressing CD8+T cells that express C-C chemokine receptor type 7 (CCR7) (receptor+ / CD8+ / CCR7+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 (receptor+ / CD4+ / CCR7+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+cells and / or receptor+ / CD4+ / CCR7+cells to another subset of cells in the composition. In some embodiments, the method comprises filling a container with all or a portion of the composition and optionally another solution to achieve a unit dose of the T cell composition, wherein the unit dose comprises a defined number of recombinant receptor expressing CD8+T cells that express cluster of differentiation 27 (CD27)(receptor+ / CD8+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CD27 (receptor+ / CD4+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells and / or a defined ratio ofreceptor+ / CD8+ / CD27+cells and / or receptor+ / CD4+ / CD27+cells to another subset of cells in the composition.

[0067] Also provided herein are methods of producing a therapeutic composition comprising a unit dose of a T cell composition. In some embodiments, the method comprises filling a container with all or a portion of a T cell composition, the T cell composition comprising T cells comprising a recombinant receptor that specifically binds an antigen associated with a disease or condition, to achieve a unit dose of the T cell composition, wherein the unit dose comprises a defined number of recombinant receptor-expressing CD8+T cells that express C-C chemokine receptor type 7 (CCR7) (receptor+ / CD8+ / CCR7+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 (receptor+ / CD4+ / CCR7+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+cells and / or receptor+ / CD4+ / CCR7+cells to another subset of cells in the composition.

[0068] Also provided herein are methods of producing a therapeutic composition comprising a unit dose of a T cell composition. In some embodiments, the method comprises filling a container with all or a portion of a T cell composition, the T cell composition comprising T cells comprising a recombinant receptor that specifically binds an antigen associated with a disease or condition, to achieve a unit dose of the T cell composition, wherein the unit dose comprises adefined number of recombinant receptor-expressing CD8+T cells that express cluster of differentiation 27 (CD27) (receptor+ / CD8+ / CD27+cells) and / or a defined number ofrecombinant receptor-expressing CD4+T cells that express CD27 (receptor+ / CD4+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CD27+cells and / or receptor+ / CD4+ / CD27+cells to another subset of cells in the composition.

[0069] In some embodiments, the unit dose of cells comprises a defined number ofCD8+ / CCR7+cells. In some embodiments, the unit dose of cells comprises a defined number of CD4+ / CCR7+cells.

[0070] In some embodiments, the unit dose comprises between at or about 1 x 105and at or about 1 x 108, between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cell that express the recombinant receptor (receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+cells, total receptor+ / CD4+ / CCR7+cells, total receptor+ / CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells, each inclusive. In some embodiments, the unit dose comprises no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, total receptor+ / CD8+ / CCR7+cells, total receptor+ / CD4+ / CCR7+cells, total receptor+ / CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells.

[0071] In some embodiments, the unit dose comprises at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD8+ / CCR7+cells or totalreceptor+ / CD8+ / CD27+cells and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x106, 9 x 106, or 1 x 107total receptor+ / CD4+ / CCR7+cells or total receptor+ / CD4+ / CD27+. In some embodiments, the unit dose comprises between at or about 3 x 106and at or about 2.5 x107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+cells or total receptor+ / CD8+ / CD27+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD4+ / CCR7+cells or total receptor+ / CD4+ / CD27+, each inclusive. In some embodiments, at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose arereceptor+ / CD8+ / CCR7+or receptor+ / CD8+ / CD27+; or at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD4+ / CCR7+or receptor+ / CD4+ / CD27+.

[0072] In some embodiments, the unit dose of cells comprises a defined ratio ofreceptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

[0073] In some embodiments, the unit dose further comprises a defined number of cells comprising cells that express or do not express CD27 and / or CD45, optionally wherein the unit dose further comprises a defined number of cells comprising CD27+or CD45RA- cells.

[0074] In some embodiments, the methods further comprise assessing in the therapeutic composition the number, percentage or ratio of T cells that express or do not express CD27 and / or CD45RA, optionally the number, percentage or ratio of T cells that are CD27+or CD45RA-.

[0075] In some embodiments, the unit dose of cells comprises a defined number of receptor+ / CD8+ / CCR7+ / CD27+cells and / or rcccp tor+ / C D8+ / CCR7+ / C D45RA cells. In some embodiments, the unit dose of cells comprises a defined number ofreceptor+ / CD4+ / CCR7+ / CD27+cells and / or rcccp tor+ / C D4+ / CCR7+ / C D45RA cells.

[0076] In some embodiments, at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD8+ / CCR7+ / CD27+,receptor+ / CD8+ / CCR7+ / CD45RA , receptor+ / CD4+ / CCR7+ / CD27+or receptor+ / CD4+ / CCR7+ / CD45RA .

[0077] Also provided herein are methods of determining a unit dose of engineered T cells for treating a subject. In some embodiments, the method comprises assessing, in a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor, the number, percentage or ratio of T cells that express the recombinant receptor and CCR7 and CD27 (receptor+ / CCR7+ / CD27+). In some embodiments, the method comprises, based on the number, percentage or ratio of receptor+ / CCR7+ / CD27+cells, determining one or more unit doses of cells for administration to a subject having a disease or conditions, wherein the unit dose comprises a defined number of recombinant receptor-expressing CD8+T cells that express CCR7 and CD27 (receptor+ / CD8+ / CCR7+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 and CD27 (receptor+ / CD4+ / CCR7+ / CD27+cells) and / or a defined ratio ofreceptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells and / or receptor+ / CD4+ / CCR7+ / CD27+cells to another subset of cells in the composition.

[0078] Also provided herein are methods of producing a composition comprising a unit dose of a T cell composition. In some embodiments, the method comprises assessing, in a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor, the number, percentage or ratio of T cells that express the recombinant receptor and CCR7 and CD27 (receptor+ / CCR7+ / CD27+). In some embodiments, the method comprises filling a container with all or a portion of the composition and optionally another solution to achieve a unit dose of the T cell composition, wherein the unit dose comprises a defined number of recombinant receptor-expressing CD8+T cells that express CCR7 and CD27 (receptor+ / CD8+ / CCR7+ / CD27+cells) and / or a defined number of recombinant receptor expressing CD4+T cells that express CCR7 and CD27 (receptor+ / CD4+ / CCR7+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells and / orreceptor+ / CD4+ / CCR7+ / CD27+cells to another subset of cells in the composition.

[0079] Also provided herein are methods of producing a therapeutic composition comprising a unit dose of a T cell composition. In some embodiments, the method comprises filling a container with all or a portion of a T cell composition, the T cell composition comprising T cells comprising a recombinant receptor that specifically binds an antigen associated with a disease or condition, to achieve a unit dose of the T cell composition, wherein the unit dose comprises a defined number of recombinant receptor-expressing CD8+T cells that express CCR7 and CD27 (receptor+ / CD8+ / CCR7+ / CD27+cells) and / or a defined number of recombinant receptor expressing CD4+T cells that express CCR7 and CD27 (receptor+ / CD4+ / CCR7+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells and / orreceptor+ / CD4+ / CCR7+ / CD27+cells to another subset of cells in the composition.

[0080] In some embodiments, the unit dose of cells comprises a defined number ofCD8+ / CCR7+ / CD27+cells. In some embodiments, the unit dose of cells comprises a defined number of CD4+ / CCR7+ / CD27+cells.

[0081] In some embodiments, the unit dose comprises between at or about 1 x 105and at or about 1 x 108, between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cell that express the recombinant receptor (receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+ / CD27+cells, or total receptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive. In some embodiments, the unit dose comprises no more than about 1 x 10 , no more than about 5 x 107, no more than about 1 x 107, no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, total receptor+ / CD8+ / CCR7+ / CD27+cells, or total receptor+ / CD4+ / CCR7+ / CD27+cells.

[0082] In some embodiments, the unit dose comprises at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD8+ / CCR7+ / CD27+cells and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107totalreceptor+ / CD4+ / CCR7+ / CD27+cells. In some embodiments, the unit dose comprises between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+ / CD27+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107totalreceptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive. In some embodiments, at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose arereceptor+ / CD8+ / CCR7+ / CD27+or receptor+ / CD4+ / CCR7+ / CD27+.

[0083] In some embodiments, the unit dose of cells comprises a defined ratio ofreceptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

[0084] In some embodiments, the unit dose further comprises a defined number of cells comprising cells that express or do not express CD45, optionally wherein the unit dose further comprises a defined number of cells comprising CD45RA- cells. In some embodiments, the method further comprises assessing in the therapeutic composition the number, percentage or ratio of T cells that express or do not express CD45RA, optionally the number, percentage or ratio of T cells that are CD45RA-.

[0085] Also provided are methods for generating a cell composition comprising genetically engineered cells. In some embodiments, the method involves providing, from a biologicalsample from a subject, an input composition comprising a target percentage of CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a target percentage of CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA. In some embodiments, the method involves introducing, into the input composition, a polynucleotide encoding a recombinant receptor. In some embodiments, the method involves stimulating the cells in the input composition, prior to, during and / or subsequent to said introducing, wherein stimulating comprises incubating the cells in the presence of one or more stimulating agents, said stimulating results in activation and / or proliferation of the cells. In some embodiments, the method produces an output composition comprising a defined ratio of recombinant receptor expressing (receptor+) CD8+T cells that express or do not express CCR7, CD27 and / orCD45RA to receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / orCD45RA, and / or a defined ratio of receptor+ / CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA to another subset of cells in the composition.

[0086] Also provided are methods for generating a cell composition comprising genetically engineered cells. In some embodiments, the method involves introducing, into an input composition, a polynucleotide encoding a recombinant receptor, wherein the input composition comprises a target percentage of CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a target percentage of CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA provided from a biological sample from a subject, and the input composition is stimulated, prior to, during and / or subsequent to said introducing by incubating the cells in the presence of one or more stimulating agents, said stimulation results in activation and / or proliferation of the cells; and wherein the method produces an output composition comprising a defined ratio of recombinant receptor-expressing (receptor+) CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA to receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a defined ratio of receptor+ / CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA to another subset of cells in the composition.

[0087] Also provided are methods for generating a cell composition comprising genetically engineered cells. In some embodiments, the method involves isolating, from a biological sample obtained from a subject, a target number of CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a target number of CD4+T cells that express or do not expressCCR7, CD27 and / or CD45RA, thereby generating an input composition. In some embodiments, the method involves introducing, into the input composition, a polynucleotide encoding a recombinant receptor. In some embodiments, the method involves stimulating the cells in the input composition, prior to, during and / or subsequent to said introducing, wherein stimulating comprises incubating the cells in the presence of one or more stimulating agents, said stimulating results in activation and / or proliferation of the cells. In some embodiments, the method produces an output composition comprising a defined ratio of recombinant receptor expressing (receptor+) CD8+T cells that express or do not express CCR7, CD27 and / orCD45RA to receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a defined ratio of receptor+ / CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA to another subset of cells in the composition.

[0088] Also provided are methods for generating a cell composition comprising genetically engineered cells. In some embodiments, the method involves introducing, into an input composition, a polynucleotide encoding a recombinant receptor, wherein the input composition is generated by isolating, from a biological sample obtained from a subject, a target number of CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a target number of CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA, and the input composition is stimulated, prior to, during and / or subsequent to said introducing by incubating the cells in the presence of one or more stimulating agents, said stimulation results in activation and / or proliferation of the cells; and wherein the method produces an output composition comprising a defined ratio of recombinant receptor-expressing (receptor+) CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA to receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a defined ratio ofreceptor+ / CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA to another subset of cells in the composition.

[0089] In some embodiments, the input composition comprises a target percentage of CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a target percentage of CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA.

[0090] In some embodiments, the input composition comprises a target percentage of CD4+ / CCR7+, CD4+ / CD27+, CD4+ / CCR7+ / CD27+, CD4+ / CCR7+ / CD45RA-,CD4+ / CCR7+ / CD45RA+, CD8+ / CCR7+, CD8+ / CD27+, CD8+ / CCR7+ / CD27+,CD8+ / CCR7+ / CD45RA- and / or CD8+ / CCR7+ / CD45RA+cells.

[0091] In some embodiments, the output composition comprises a defined ratio of receptor+ / CD8+ / CCR7+, receptor+ / CD8+ / CD27+, receptor+ / CD8+ / CCR7+ / CD27+,receptor+ / CD8+ / CCR7+ / CD45RA- and / or receptor+ / CD8+ / CCR7+ / CD45RA+cells, to receptor+ / CD4+ / CCR7+, receptor+ / CD4+ / CD27+, receptor+ / CD4+ / CCR7+ / CD27+,receptor+ / CD4+ / CCR7+ / CD45RA- and / or receptor+ / CD4+ / CCR7+ / CD45RA+cells; or a defined ratio of receptor+ / CD8+ / CCR7+, receptor+ / CD8+ / CD27+, receptor+ / CD8+ / CCR7+ / CD27+, receptor+ / CD8+ / CCR7+ / CD45RA- and / or receptor+ / CD8+ / CCR7+ / CD45RA+cells and / or receptor+ / CD4+ / CCR7+, receptor+ / CD4+ / CD27+, receptor+ / CD4+ / CCR7+ / CD27+,receptor+ / CD4+ / CCR7+ / CD45RA- and / or receptor+ / CD4+ / CCR7+ / CD45RA+cells to another subset of cells in the composition.

[0092] In some embodiments, the methods also involve determining one or more unit doses of a T cell composition for administration to a subject having a disease or condition, wherein the unit dose comprises all or a portion of the output composition that comprises: a defined number of recombinant receptor-expressing CD8+T cells that express C-C chemokine receptor type 7 (CCR7) (receptor+ / CD8+ / CCR7+cells) and / or a defined number of recombinant receptor expressing CD4+T cells that express CCR7 (receptor+ / CD4+ / CCR7+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+cells and / or receptor+ / CD4+ / CCR7+cells to another subset of cells in the composition; a defined number of recombinant receptor-expressing CD8+T cells that express cluster of differentiation 27 (CD27) (receptor+ / CD8+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CD27 (receptor+ / CD4+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CD27+cells and / or receptor+ / CD4+ / CD27+cells to another subset of cells in the composition; or a defined number of recombinant receptor-expressing CD8+T cells that express CCR7 and CD27 (receptor+ / CD8+ / CCR7+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 and CD27 (receptor+ / CD4+ / CCR7+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells and / or a defined ratio ofreceptor+ / CD8+ / CCR7+ / CD27+cells and / or receptor+ / CD4+ / CCR7+ / CD27+cells to another subset of cells in the composition.

[0093] In some embodiments, the unit dose of cells comprises a defined number ofCD8+ / CCR7+cells, CD4+ / CCR7+cells, CD8+ / CD27+cells, CD4+ / CD27+cells,CD8+ / CCR7+ / CD27+cells and / or CD4+ / CCR7+ / CD27+cells.

[0094] In some embodiments, the unit dose comprises between at or about 1 x 105and at or about 1 x 108, between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107, each inclusive, total receptor+ / CD8+cells or total receptor+ / CD4+cells, total receptor+ / CD8+ / CCR7+cells, total receptor+ / CD4+ / CCR7+cells, totalreceptor+ / CD8+ / CD27+cells, total receptor+ / CD4+ / CD27+cells, totalreceptor+ / CD8+ / CCR7+ / CD27+cells, or total receptor+ / CD4+ / CCR7+ / CD27+cells.

[0095] In some embodiments, the unit dose comprises at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD8+ / CCR7+cells or totalreceptor+ / CD8+ / CD27+cells; and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD4+ / CCR7+cells or total receptor+ / CD4+ / CD27+; and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD8+ / CCR7+ / CD27+cells and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD4+ / CCR7+ / CD27+cells.

[0096] In some embodiments, the unit dose comprises between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+cells or total receptor+ / CD8+ / CD27+cells; and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107totalreceptor+ / CD4+ / CCR7+cells or total receptor+ / CD4+ / CD27+, and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+ / CD27+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive.

[0097] In some embodiments, at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD8+ / CCR7+or receptor+ / CD8+ / CD27+;and / or at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD4+ / CCR7+or receptor+ / CD4+ / CD27+; and / or at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose arereceptor+ / CD8+ / CCR7+ / CD27+or receptor+ / CD4+ / CCR7+ / CD27+.

[0098] In some embodiments, the unit dose of cells comprises a defined ratio ofreceptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1; and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1; and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

[0099] In some embodiments, the unit dose further comprises a defined number of cells comprising cells that express or do not express CD45, optionally wherein the unit dose further comprises a defined number of cells comprising CD45RA- cells. In some embodiments, the unit dose of cells comprises a defined number of receptor+ / CD4+ / CCR7+ / CD45RA- cells and / or receptor+ / CD8+ / CCR7+ / CD45RA- cells.

[0100] In some embodiments, at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD4+ / CCR7+ / CD45RA- orreceptor+ / CD8+ / CCR7+ / CD45RA-.

[0101] In some embodiments, the methodsfurther comprise, prior to the providing or isolating, determining the number, number per volume, number per weight, and / or percentage of the CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA.

[0102] In some embodiments, the one or more stimulating agent is capable of activating T cells, CD4+T cells and / or CD8+T cells; is capable of inducing a signal through a TCR complex; and / or is capable of inducing proliferation of T cells, CD4+T cells and / or CD8+T cells.

[0103] In some embodiments, the one or more stimulating agent comprises a primary agent that binds to a member of a TCR complex, optionally that specifically binds to CD3. In some embodiments, the one or more stimulating agent further comprises a secondary agent thatspecifically binds to a T cell costimulatory molecule. In some embodiments, the costimulatory molecule is selected from the group consisting of CD28, CD137 (4-l-BB), 0X40, or ICOS. In some embodiments, the primary and secondary agents comprise antibodies, optionally wherein the one or more stimulating agent comprises incubation with an anti-CD3 antibody and an anti- CD28 antibody. In some embodiments, the one or more stimulating agents are present on the surface of a solid support, optionally a bead. In some embodiments, the one or more stimulating agent is selected from the group consisting of CD3-binding molecules; CD28-binding molecules; recombinant IL-2; recombinant IL-15; and recombinant IL-7, a vaccine comprising an antigen specifically recognized by the antigen receptor, and an anti-idiotype antibody that specifically binds the antigen receptor or combinations thereof.

[0104] In some embodiments, the therapeutic composition is any of the compositions described herein.

[0105] In some embodiments, the method further comprises administering to a subject having a disease or condition, the therapeutic composition, optionally one or more unit doses thereof and / or a volume corresponding to such one or more of the unit doses.

[0106] In some embodiments, among a group of subjects treated according to the method, the number or ratio of cells that express CCR7 (CCR7+cells) in the unit dose varies by no more than 40%, by no more than 30%, by no more than 20%, by no more than 10% or by no more than 5%.

[0107] In some embodiments, the unit dose comprises between at or about 1 x 105and at or about 5 x 108, between at or about 1 x 105 and at or about 1 x 108, between at or about 5 x 105 and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD3+cells that express the recombinant receptor (receptor+ / CD3+cells) or total CD3+cells, each inclusive.In some embodiments, the unit dose comprises no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD3+cells or total CD3+cells.

[0108] In some embodiments, the total number of CD3+cells, total number ofreceptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number of receptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number of receptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number of receptor+ / CD4+ / CCR7+ / CD27+cells, total number of rcccptor+ / CD8+ / CCR7+ / CD45RA cells and / orrcccptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that are live or viable.In some embodiments, the total number of CD3+cells, total number of receptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number of receptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number of receptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number of receptor+ / CD4+ / CCR7+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD45RA cells and / or rcccptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that do not express an apoptotic marker and / or is the total number of such cells that are apoptotic marker negative O, wherein the apoptotic marker is Annexin V or activated Caspase 3.

[0109] In some embodiments, the method involves administering a plurality of unit doses contained in a plurality of separate compositions.

[0110] In some embodiments, the plurality of separate compositions comprise a first composition comprising one of the CD8+T cells and the CD4+T cells and a second composition comprising the other of the CD8+T cells and the CD4+T cells. In some embodiments, the first composition comprises the CD8+T cells. In some embodiments, the first composition comprises the CD4+T cells.

[0111] In some embodiments, the method involves administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses and the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses, no more than 2 hours, no more than 1 hour, no more than 30 minutes, no more than 15 minutes, no more than 10 minutes or no more than 5 minutes apart or simultaneously.

[0112] In some embodiments, the method involves administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses, prior to administering the composition containing CD4+cells or one or more unit doses thereof and / or a volume corresponding to such one or more of the unit doses. In some embodiments, the method involves administering the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses, prior to administering the composition containing CD8+cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.

[0113] In some embodiments, the recombinant receptor is or comprises a chimeric receptor and / or a recombinant antigen receptor. In some embodiments, the recombinant receptor iscapable of binding to a target antigen that is associated with, specific to, and / or expressed on a cell or tissue of a disease, disorder or condition. In some embodiments, the disease, disorder or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or a cancer. In some embodiments, the target antigen is a tumor antigen.

[0114] In some embodiments, the target antigen is selected from among anbό integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-l), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD138, CD171, epidermal growth factor protein (EGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O- acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), G Protein Coupled Receptor 5D (GPRC5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb- B4), erbB dimers, Human high molecular weight- melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HLA-A1), Human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha(IL-22Ra), IL-13 receptor alpha 2 (IL-l3Ra2), kinase insert domain receptor (kdr), kappa light chain, Ll cell adhesion molecule (Ll-CAM), CE7 epitope of Ll-CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y,Melanoma-associated antigen (MAGE)-Al, MAGE- A3, MAGE-A6, mesothelin, c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D(NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-l), a pathogen- specific antigen, or an antigen associated with a universal tag, and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV or other pathogens.

[0115] In some embodiments, the recombinant receptor is or comprises a functional non- TCR antigen receptor or a TCR or antigen-binding fragment thereof. In some embodiments, the recombinant receptor is a chimeric antigen receptor (CAR). In some embodiments, the recombinant receptor comprises an extracellular domain comprising an antigen-binding domain. In some embodiments, the antigen-binding domain is or comprises an antibody or an antibody fragment thereof, which optionally is a single chain fragment. In some embodiments, the fragment comprises antibody variable regions joined by a flexible linker. In some embodiments, the fragment comprises an scFv.

[0116] In some embodiments, the recombinant receptor comprises an intracellular signaling region. In some embodiments, the intracellular signaling region comprises an intracellular signaling domain. In some embodiments, the intracellular signaling domain is or comprises a primary signaling domain, a signaling domain that is capable of inducing a primary activation signal in a T cell, a signaling domain of a T cell receptor (TCR) component, and / or a signaling domain comprising an immunoreceptor tyrosine-based activation motif (IT AM). In some embodiments, the intracellular signaling domain is or comprises an intracellular signaling domain of a CD3 chain, optionally a CD3-zeta ^ϋ3z) chain, or a signaling portion thereof.

[0117] In some embodiments, the recombinant receptor further comprises a transmembrane domain disposed between the extracellular domain and the intracellular signaling region.

[0118] In some embodiments, the intracellular signaling region further comprises a costimulatory signaling domain. In some embodiments, the costimulatory signaling domain comprises an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. In some embodiments, the costimulatory signaling domain comprises an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof. In some embodiments, the costimulatory signaling domain is between the transmembrane domain and the intracellular signaling domain.

[0119] In some embodiments, the T cells are primary T cells obtained from a subject. In some embodiments, the T cells are autologous to the subject. In some embodiments, the T cells are allogeneic to the subject.

[0120] In some aspects of any of the embodiments provided herein, the cells in a provided therapeutic composition or a unit dose are associated with certain functional attributes, including certain recombinant receptor (e.g. CAR)- dependent activities that depend on an activity or presence of the recombinant receptor, e.g. an activity induced or mediated in the presence of antigen recognized by the recombinant receptor. In some embodiments, a functional attributeincludes production of higher levels of a cytokine, e.g., IL-2. In some aspects of any of the embodiments provided herein, the functional attribute includes production of lower levels of a cytokine, e.g., IFNy or IL-13. In some embodiments, the higher or lower levels of such cytokines are with reference to a reference composition in which is contained a non-defined number of cells of a particular phenotype and / or in which cells of a particular phenotype are not at a particular defined ratio according to embodiments provided herein. In some embodiments, a reference composition is one in which is contained a greater frequency or number of T cells having an effector or differentiated phenotype.

[0121] In some aspects, upon administration of a therapeutic composition or a unit dose to one of a group of subjects according to any of the embodiments provided herein, a plurality of subjects among the group of subjects exhibits one or more features associated with increased efficacy, persistence and / or reduced toxicity following the administration. In someembodiments, a plurality of subjects among the group of subjects is likely to exhibit and / or is associated with, pharmacokinetic parameters, reduced likelihood of development of a toxicity or an adverse event, and / or a particular response, efficacy or survival outcome. In some embodiments, the subject is a subject suspected of having a disease or condition. In some embodiments, the one or more features are improved compared to a similar group of subjects treated with the reference composition in which is contained a non-defined number of cells of a particular phenotype and / or in which cells of a particular phenotype are not at a particular defined ratio according to embodiments provided herein. In some embodiments, a reference composition is one in which is contained a greater frequency or number of T cells having an effector or differentiated phenotype.

[0122] In some aspects, upon administration of a therapeutic composition or a unit dose to one of a group of subjects according to any of the embodiments provided herein, a plurality of subjects among the group of subjects is likely to exhibit and / or is associated with particular pharmacokinetic parameters, such as maximum (peak) plasma concentration (Cmax), the peak time ( i.e . when maximum plasma concentration (Cmax) occurs; Tmax), the minimum plasma concentration (i.e. the minimum plasma concentration between doses of a therapeutic agent, e.g., CAR+T cells; Cmin), the elimination half-life (Ti / 2) and area under the curve (i.e. the area under the curve generated by plotting time versus plasma concentration of the therapeutic agent CAR+T cells; AUC). In some aspects, upon administration of a therapeutic composition or a unit dose, a plurality of subjects among the group is likely to exhibit or is associated with increased maximum (peak) plasma concentration (Cmax) of the administered cells. In some embodiments,long term persistence of cells of the therapeutic composition or unit dose are observed in a plurality of subjects among the group.

[0123] In some aspects, upon administration of a therapeutic composition or a unit dose to one of a group of subjects according to any of the embodiments provided herein, a plurality of subjects among the group of subjects is likely to exhibit and / or is associated with a reduced likelihood of development of a toxicity or an adverse event, such as cytokine release syndrome (CRS) or severe CRS (sCRS) or neurotoxicity (NT) or severe NT (sNT).

[0124] In some aspects, upon administration of a therapeutic composition or a unit dose to one of a group of subjects according to any of the embodiments provided herein, a plurality of subjects among the group of subjects is likely to exhibit and / or is associated with a particular response, efficacy or survival outcome, such as partial response (PR) or partial remission, complete response (CR) or complete remission, progression-free survival (PFS), objective response (OR), overall survival (OS), event-free survival (EFS), increased duration of response (DOR) or increased survival rate. In some aspects, upon administration of a therapeutic composition or a unit dose, a plurality of subjects among the group is likely to exhibit or is associated with increased progression-free survival (PFS).

[0125] In some embodiments of any of the provided embodiments, the methods and / or uses and / or administration of a unit dose of cells according to the articles of manufacture, achieve certain outcomes and / or are associated with certain reduced risks of toxicity, e.g., in the population of subjects treated according to the methods or according to information provided in the article of manufacture. In some aspects, at least 35%, at least 40% at least 50%, or at least 60%, of subjects treated according to the method achieve a complete response (CR) or complete remission, progression-free survival (PFS), objective response (OR), overall survival (OS), event-free survival (EFS), or a response that is durable for greater than 3 months, greater than 6 months or greater than 12 months. In certain embodiments of any of the provided methods, greater than or greater than about 50% of the subjects treated according to the method do not exhibit a grade 3 or greater cytokine release syndrome (CRS) or a grade 3 or greaterneurotoxicity. In some embodiments, such subjects do not exhibit early onset CRS and / or neurotoxicity, such as do not exhibit onset of CRS earlier than 3 days following initiation of the administration and / or do not exhibit onset of neurotoxicity earlier than 5 days following initiation of the administration. In some embodiments of any of the provided methods, greater than or greater than about 30%, 35%, 40%, or 50% of the subjects treated according to the method do not exhibit any grade of cytokine release syndrome (CRS) or neurotoxicity.

[0126] Also provided are output compositions produced by any of the methods described herein.

[0127] Also provided are unit doses determined or produced by any of the methods described herein.

[0128] Also provided are pharmaceutical compositions comprising any of the unit doses described herein. In some embodiments, the pharmaceutical compositions also include a pharmaceutical carrier.

[0129] Also provided are methods of treatment, comprising administering to a mammalian subject all or a portion of any of the output compositions, unit doses or pharmaceutical compositions described herein.

[0130] Also provided are uses of all or a portion of any of the output compositions, unit doses or pharmaceutical compositions described herein for treating cancer.

[0131] Also provided are uses of all or a portion of any of the output compositions, unit doses or pharmaceutical compositions described herein in the manufacture of a medicament for treating cancer.

[0132] Also provided are all or a portion of any of the output compositions, unit doses or pharmaceutical compositions described herein for use in treating cancer.

[0133] Provided herein are therapeutic cell compositions containing T cells expressing a recombinant receptor that binds to an antigen, wherein, following stimulation with a stimulatory agent: at least at or about, or at or about, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing the recombinant receptor are able to produce a cytokine selected from interleukin 2 (IL-2) and / or TNF-alpha; and / or at least at or about, or at or about, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in the composition expressing the recombinant receptor are polyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha. In some embodiments, at least at or about, or at or about, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing the recombinant receptor are able to produce a cytokine selected from interleukin 2 (IL-2) and / or TNF-alpha. In some embodiments, at least at or about, or at or about, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in the composition expressing the recombinant receptor are polyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha. In some embodiments, at least at or about, or at or about, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in the composition expressing the recombinant receptor are polyfunctional for producing the cytokines interferon-gamma (IFN- gamma), interleukin 2 (IL-2) and TNF-alpha.

[0134] In some embodiments, the stimulatory agent is a non-specific or non-antigen- dependent T cell stimulatory agent. In some embodiments, the non-specific or non-antigen dependent T cell stimulatory agent is a polyclonal stimulatory agent. In some embodiments, the non-specific or non-antigen dependent stimulatory agent comprises PMA / ionomycin, anti- CD3 / anti-CD28, phytohemagglutinin (PHA) or concanavalin A (ConA). In some embodiments, the non-specific or non-antigen dependent T cell stimulatory agent comprises PMA / ionomycin. In some embodiments, the stimulatory agent specifically binds the recombinant receptor, optionally wherein the stimulatory agent is an antigen-specific stimulatory reagent and / or contains the antigen or a portion thereof specifically recognized by the recombinant receptor. In some embodiments, production of the cytokines is measured in an intracellular cytokine assay.

[0135] In some embodiments, the composition contains at least at or about, or at or about, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27, optionally further negative for surface expression of CD45RA.

[0136] In some embodiments, the T cells are primary cells obtained from a subject. In some embodiments, the subject has a cancer, optionally wherein the cancer is a leukemia or a lymphoma. In some embodiments, the subject is a subject that, at the time of obtaining the cells, is identified or known to have a high tumor burden. In some embodiments, the subject has high tumor burden if a sum of product dimensions (SPD) of a tumor in the subject is above at or about 30 cm , 40 cm , 50 cm , 60 cm or 70 cm ; and / or the subject has high tumor burden if C reactive protein (CRP) in a biological sample, optionally a serum sample, from the subject is above at or about 5 miligrams per liter, 10 miligrams per liter, 15 miligrams per liter, 20 miligrams per liter, 25 miligrams per liter, 30 miligrams per liter, 40 miligrams per liter or 50 miligrams per liter. In some embodiments, the subject has high tumor burden if the SPD of a tumor in the subject is above at or about 50 cm . In some embodiments, the subject has high tumor burden if the CRP is above at or about 20 miligrams per liter in the biological sample.

[0137] In some embodiments, the therapeutic cell composition is enriched in CD4+ T cells and / or at least at or about 60%, at least at or about 70%, at least at or about 80%, at least at orabout 90%, at least at or about 95%, at least at or about 97% of the total recombinant receptor+cells in the engineered composition, or between about 60% and 99%, between about 75% and 99%, between about 85% and 99%, or between about 90% and 99%, each inclusive, of the total cells in the composition are CD4+. In some embodiments, the therapeutic cell composition is enriched in CD3+ T cell, is enriched in CD4+ and CD8+ T cells and / or at least at or about 60%, at least at or about 70%, at least at or about 80%, at least at or about 90%, at least at or about 95%, at least at or about 97% of the total recombinant receptor+cells in the engineered composition, or between about 60% and 99%, between about 75% and 99%, between about 85% and 99%, or between about 90% and 99%, each inclusive, of the total cells in the composition are CD3+ or CD4+and CD8+. In some embodiments, the therapeutic cell composition contains CD4+ and CD8+ T cells at a ratio of CD4+ to CD8+ T cells that is between approximately 1:3 and approximately 3:1, optionally between approximately 1:2 and 2:1.

[0138] In some embodiments, the recombinant receptor is or contains a chimeric receptor and / or a recombinant antigen receptor. In some embodiments, the recombinant receptor is capable of binding to a target antigen that is associated with, specific to, and / or expressed on a cell or tissue of a disease, disorder or condition. In some embodiments, the disease, disorder or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or a cancer. In some embodiments, the target antigen is a tumor antigen. In some embodiments, the target antigen is selected from among anb6 integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-l), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138, CD171, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), glypican-3 (GPC3), G Protein Coupled Receptor 5D (GPRC5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight- melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HLA-A1), Human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha(IL-22Ra), IL-13 receptor alpha 2 (IL-l3Ra2), kinase insert domain receptor (kdr), kappa light chain, Ll cell adhesion molecule (Ll-CAM), CE7 epitope of Ll-CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)- Al, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72), Tyrosinase related protein 1 (TRP1, also known as TYRP1 or gp75), Tyrosinase related protein 2 (TRP2, also known as dopachrome tautomerase, dopachrome delta-isomerase or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-l), a pathogen-specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV or other pathogens.

[0139] In some embodiments, the recombinant receptor is or contains a functional non- TCR antigen receptor or a TCR or antigen-binding fragment thereof. In some embodiments, the recombinant receptor is a chimeric antigen receptor (CAR). In some embodiments, the recombinant receptor contains an extracellular domain containing an antigen-binding domain and an intracellular signaling region containing an intracellular signaling domain. In some embodiments, the antigen-binding domain is or contains an antibody or an antibody fragment thereof, which optionally is a single chain fragment. In some embodiments, the fragment contains antibody variable regions joined by a flexible linker. In some embodiments, the fragment comprises an scFv. In some embodiments, the intracellular signaling domain is or contains a primary signaling domain, a signaling domain that is capable of inducing a primary activation signal in a T cell, a signaling domain of a T cell receptor (TCR) component, and / or a signaling domain containing an immunoreceptor tyrosine-based activation motif (IT AM). In some embodiments, the intracellular signaling domain is or contains an intracellular signaling domain of a CD3 chain, optionally a CD3-zeta ^ϋ3z) chain, or a signaling portion thereof. In some embodiments, the recombinant receptor further contains a transmembrane domain disposed between the extracellular domain and the intracellular signaling region. In some embodiments, the intracellular signaling region further contains a costimulatory signalingdomain. In some embodiments, the costimulatory signaling domain contains an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. In some embodiments, the costimulatory signaling domain contains an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof. In some embodiments, the costimulatory signaling domain is between the transmembrane domain and the intracellular signaling domain.

[0140] In some embodiments, the T cells are primary T cells obtained from a subject. In some embodiments, the T cells are autologous to the subject.

[0141] Provided herein are articles of manufacture, including a container containing a therapeutic cell composition described herein, and instructions for administering to a subject having a disease or condition, the therapeutic cell composition, optionally one or more unit doses thereof and / or a volume corresponding to such one or more unit doses. In some embodiments, the instructions specify administering a plurality of unit doses contained in a plurality of separate compositions. In some embodiments, the plurality of separate compositions contain a first composition containing the therapeutic cell composition containing one of CD8+T cells and CD4+T cells and a second composition containing the other of the CD8+T cells and the CD4+T cells, said second composition containing cells expressing the recombinant receptor or a recombinant receptor specific for the antigen or for a cell expressed by the disease or condition optionally wherein the second composition is any composition described herein. In some embodiments, the instructions specify administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses and the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses within no more than 48 hours apart, within no more than 36 hours apart, within no more than 24 hours apart, within no more than 12 hours apart, within no more than 6 hours apart, within no more than 2 hours apart, within no more than 1 hour apart or simultaneously. In some embodiments, the instructions specify administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses, prior to administering thecomposition containing CD4+cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.

[0142] Provided herein are methods of treatment, the method including administering to a subject having a disease or condition one or more unit doses of a therapeutic cell composition described herein. In some embodiments, the therapeutic composition is a first therapeutic cellcomposition containing one of CD8+ T cells and CD4+ T cells and the one or more units doses further contains a second therapeutic cell composition containing the other of the CD8+ T cells and CD4+ cells, said second composition containing cells expressing the recombinant receptor or a recombinant receptor specific for the antigen or for a cell expressed by the disease or condition, optionally wherein the second composition is any composition described herein.

[0143] In some embodiments, at least at or about, or at or about, 40%, 50%, 60%, 70%,80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the second therapeutic cell composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27, optionally further negative for surface expression of CD45RA. In some embodiments, the second therapeutic cell composition is enriched in CD8+ T cells and / or at least at or about 60%, at least at or about 70%, at least at or about 80%, at least at or about 90%, at least at or about 95%, at least at or about 97% of the total recombinant receptor+cells in the engineered composition, or between about 60% and 99%, between about 75% and 99%, between about 85% and 99%, or between about 90% and 99%, each inclusive, of the total cells in the composition are CD8+.

[0144] In some embodiments, the first therapeutic composition and second therapeutic composition are administered within at or about 48 hours, within at or about 36 hours, within at or about 24 hours, within at or about 12 hours, within at or about 6 hours, within at or about 2 hours or within at or about 1 hour of each other. In some embodiments, the second therapeutic cell composition containing the CD8+ T cells is administered before the first composition containing CD4+ T cells. In some embodiments, the one or more unit dose of cells contains a defined ratio of CD4+ to CD8+ T cells, which ratio is or is approximately 1:3 and approximately 3:1, optionally that is or is approximately 1:2 and 2:1, optionally that is or is about 1:1.

[0145] Provided herein are methods for treatment of a subject, the method including (A) assaying an engineered cell composition containing T cells expressing a recombinant receptor for a factor indicative of the function or phenotype of engineered cells in the composition, the factor selected from (i) the percentage of T cells expressing the recombinant receptor that are surface positive for CCR7 and / or CD27, and optionally surface negative for CD45RA; and / or (ii) the percentage of CD4+ T cells expressing the recombinant receptor that are able to produce IL-2, TNF-alpha, and / or IFN-gamma following stimulation with a stimulatory agent; and (B) administering to a subject having a disease or condition a therapy, the administering selected from: (1) if a factor indicative of the function or phenotype of cells of the engineered T cellcomposition is at or above a threshold value, administering to the subject one or more unit doses of cells of an engineered cell composition containing T cells expressing a recombinant receptor; or (2) if the factor indicative of the function or phenotype of cells of the engineered T cell composition is below a threshold value of the factor, administering a therapy selected from (a) one or more unit doses of cells of the engineered cell composition and an agent capable of increasing expansion, proliferation or efficacy of T cells of the engineered cell composition in the subject, (b) an increased dose of cells of the engineered cell composition, optionally increased compared to the one or more unit dose administered to a similarly situated subject having the same disease or condition but exhibiting the threshold value of the factor or greater; or (c) an alternative therapeutic treatment for treating the disease or condition other than one or more unit doses of the engineered cell composition, wherein the threshold value of the factor is selected from (i) at or about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27; and / or (ii) at or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing the recombinant receptor are able to produce interleukin 2 (IL-2) or TNF-alpha following stimulation with a stimulatory agent; and / or (iii) at or about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in thecomposition expressing the recombinant receptor are polyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF- alpha following stimulation with a stimulatory agent.

[0146] Provided herein are methods for treatment of a subject, the methods including administering to a subject having a disease or condition a therapy, the administering selected from: (1) if a factor indicative of a function or phenotype of cells of an engineered cell composition containing T cells expressing a recombinant receptor is at or above a threshold value, administering to the subject one or more unit doses of cells of the engineered T cell composition; or (2) if the factor indicative of the function or phenotype of cells of the engineered T cell composition is below a threshold value of the factor, administering a therapy selected from (a) one or more unit doses of cells of the engineered cell composition and an agent capable of increasing expansion, proliferation or efficacy of T cells of the engineered cell composition in the subject, (b) an increased dose of cells of the engineered cell composition, optionally increased compared to the one or more unit doses administered to a similarly situatedsubject having the same disease or condition but exhibiting the threshold value of the factor or greater; or (c) an alternative therapeutic treatment for treating the disease or condition other than a dose of the engineered cell composition, wherein the threshold value of the factor is selected from (i) at or about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27; and / or (ii) at or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing the recombinant receptor are able to produce interleukin 2 (IL-2) or TNF-alpha following stimulation with a stimulatory agent; and / or (iii) at or about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in thecomposition expressing the recombinant receptor are polyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF- alpha following stimulation with a stimulatory agent.

[0147] In some embodiments, cells of the cell composition are autologous to the subject. In some embodiments, at least 35%, at least 40 %, at least 50%, at least 60% or at least 70%, or at least 75% of the subjects treated according to the method achieve progression free survival for at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months or at least 12 months following administration of the one or more unit doses. In some embodiments, at least 35%, at least 40 %, at least 50%, at least 60% or at least 70% , or at least 75% of the subjects treated according to the method do not achieve disease progression for at least at or about 3 months, at least at or about 4 months, at least at or about 5 months, at least at or about 6 months, at least at or about 9 months or at least at or about 12 months following administration of the one or more unit doses. In some embodiments, subjects treated according to the method achieve a pharmacokinetic property of cells of the cell composition in a biological sample, optionally a blood or serum sample, that is improved, on average, compared to a group of similarly situated subjects having the same disease or condition and administered a similar dose of an autologous cell composition comprising T cells expressing the recombinant receptor but in which the factor indicative of function or phenotype of cells is below the threshold value. In some embodiments, the pharmacokinetic property is the total exposure over time (AUC) or peak number of cells in the biological sample.

[0148] Provided herein are methods of predicting likelihood of response to a therapeutic T cell composition, the method including: (a) assaying an engineered cell composition containingT cells expressing a recombinant receptor for a factor indicative of the function or phenotype of engineered cells in the composition, the factor selected from (i) the percentage of T cells expressing the recombinant receptor that are surface positive for CCR7 and / or CD27, and optionally surface negative for CD45RA; and / or (ii) the percentage of CD4+ T cells expressing the recombinant receptor that are able to produce IL-2, TNF-alpha, and / or IFN-gamma following stimulation with a stimulatory agent; and (b) determining the likelihood of response following administration of a cell therapy containing a dose of the engineered cells, wherein if the factor is at or above a threshold value identifying the subject as likely to achieve a durable response or progression free survival, optionally for at least 3 months, following administration the therapy; or if the factor is below a threshold value identifying the subject as not likely to exhibit a durable response or progression free survival to the therapy, wherein the threshold value of the factor is selected from: (i) at or about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27; and / or (ii) at or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing the recombinant receptor are able to produce interleukin 2 (IL-2) or TNF-alpha following stimulation with a stimulatory agent; and / or (iii) at or about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in the composition expressing the recombinant receptor are polyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF- alpha following stimulation with a stimulatory agent.

[0149] In some embodiments, cells of the cell composition are autologous to the subject. In some embodiments, if the subject is identified as likely to achieve a durable response or progression free survival to the therapy, administering to the subject one or more unit doses of cells of the engineered T cell composition. In some embodiments, the one or more unit doses contain between at or about 1 x 10 and at or about 5 x 10 , between at or about 1 x 10 and at or about 1 x 108, between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total T cells that express the recombinant receptor (receptor+ / T cells) or total T cells, each inclusive. In some embodiments, the one or more unit doses contains no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 107, no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / T cells or total T cells. In some embodiments, the threshold value of the factor isat or about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27. In some embodiments, the threshold value of the factor is at or about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27. In some embodiments, the threshold value of the factor is at or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing the recombinant receptor are able to produce a cytokine selected from interleukin 2 (IL-2) and / or TNF-alpha. In some embodiments, the threshold value of the factor is at or about, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+T cells in the composition expressing the recombinant receptor are polyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL- 2) and TNF-alpha. In some embodiments, the threshold value of the factor is at or about, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in the composition expressing the recombinant receptor are polyfunctional for producing the cytokines interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha.

[0150] In some embodiments, if the subject is identified as not likely to achieve a durable response or progression free survival, administering to the subject a therapy selected from (a) a dose of cells of the engineered cell composition and an agent capable of increasing expansion, proliferation or efficacy of T cells of the engineered cell composition in the subject, (b) an increased dose of cells of the engineered cell composition, optionally increased compared to a dose administered to a similarly situated subject having the same disease or condition but exhibiting a likelihood of achieving progression free survival or a durable response to the cell therapy; or (c) an alternative therapeutic treatment for treating the disease or condition other than a dose of the engineered cell composition.

[0151] In some embodiments, the method includes administration of a therapy containing a dose of cells of the engineered cell composition and an agent capable of increasing expansion, proliferation or efficacy of T cells of the engineered cell composition in the subject, wherein the agent is an anti-idiotype antibody or antigen-binding fragment thereof specific to the CAR, an immune checkpoint inhibitor, a modulator of a metabolic pathway, an adenosine receptor antagonist, a kinase inhibitor, an anti-TGFp antibody or an anti-TGFpR antibody or a cytokine.In some embodiments, the agent is administered prior to, concurrently or after the administration of the therapeutic T cell composition.

[0152] In some embodiments, the subject is a subject that, at the time of the assaying and / or prior to the administering, is identified or known to have a high tumor burden. In some embodiments, the subject has high tumor burden if a sum of product dimensions (SPD) of a tumor in the subject is above at or about 30 cm , 40 cm , 50 cm , 60 cm or 70 cm ; and / or the subject has high tumor burden if C reactive protein (CRP) in a biological sample, optionally a serum sample, from the subject is above at or about 5 miligrams per liter, 10 miligrams per liter, 15 miligrams per liter, 20 miligrams per liter, 25 miligrams per liter, 30 miligrams per liter, 40 miligrams per liter or 50 miligrams per liter. In some embodiments, the subject has high tumor burden if the SPD of a tumor in the subject is above at or about 50 cm . In some embodiments, the subject has high tumor burden if the CRP is above at or about 20 miligrams per liter in the biological sample.

[0153] In some embodiments, the stimulatory agent is a non-specific or non-antigen- dependent T cell stimulatory agent. In some embodiments, the non-specific or non-antigen dependent T cell stimulatory agent is a polyclonal stimulatory agent. In some embodiments, the the non-specific or non-antigen dependent stimulatory agent contains PMA / ionomycin, anti- CD3 / anti-CD28, phytohemagglutinin (PHA) or concanavalin A (ConA). In some embodiments, the non-specific or non-antigen dependent T cell stimulatory agent contains PMA / ionomycin. In some embodiments, the stimulatory agent specifically binds the recombinant receptor, optionally wherein the stimulatory agent is an antigen- specific stimulatory reagent and / or comprises the antigen or a portion thereof specifically recognized by the recombinant receptor. In some embodiments, production of the cytokines is measured in an intracellular cytokine assay.

[0154] In some embodiments, the recombinant receptor is or contains a chimeric receptor and / or a recombinant antigen receptor. In some embodiments, the recombinant receptor is capable of binding to a target antigen that is associated with, specific to, and / or expressed on a cell or tissue of a disease, disorder or condition. In some embodiments, the disease, disorder or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or a cancer. In some embodiments, the target antigen is a tumor antigen. In some embodiments, the target antigen is selected from among anb6 integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif ChemokineLigand 1 (CCL-l), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138, CD171, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), glypican-3 (GPC3), G Protein Coupled Receptor 5D (GPRC5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight- melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HLA-A1), Human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha(IL- 22Ra), IL-13 receptor alpha 2 (IL-l3Ra2), kinase insert domain receptor (kdr), kappa light chain, Ll cell adhesion molecule (Ll-CAM), CE7 epitope of Ll-CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)- Al, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specificantigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72), Tyrosinase related protein 1 (TRP1, also known as TYRP1 or gp75), Tyrosinase related protein 2 (TRP2, also known as dopachrome tautomerase, dopachrome delta-isomerase or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-l), a pathogen-specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV or other pathogens.

[0155] In some embodiments, the recombinant receptor is or comprises a functional non- TCR antigen receptor or a TCR or antigen-binding fragment thereof. In some embodiments, the recombinant receptor is a chimeric antigen receptor (CAR). In some embodiments, the recombinant receptor contains an extracellular domain containing an antigen-binding domain and an intracellular signaling region containing an intracellular signaling domain. In some embodiments, the antigen-binding domain is or contains an antibody or an antibody fragmentthereof, which optionally is a single chain fragment. In some embodiments, the fragment contains antibody variable regions joined by a flexible linker. In some embodiments, the fragment comprises an scFv. In some embodiments, the intracellular signaling domain is or contains a primary signaling domain, a signaling domain that is capable of inducing a primary activation signal in a T cell, a signaling domain of a T cell receptor (TCR) component, and / or a signaling domain containing an immunoreceptor tyrosine-based activation motif (IT AM). In some embodiments, the intracellular signaling domain is or contains an intracellular signaling domain of a CD3 chain, optionally a CD3-zeta ^ϋ3z) chain, or a signaling portion thereof. In some embodiments, the recombinant receptor further contains a transmembrane domain disposed between the extracellular domain and the intracellular signaling region. In some embodiment, the intracellular signaling region further contains a costimulatory signaling domain. In some embodiments, the costimulatory signaling domain contains an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. In some embodiments, the costimulatory signaling domain contains an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof. In some embodiments, the costimulatory signaling domain is between the transmembrane domain and the intracellular signaling domain.

[0156] In some embodiments, the T cells are primary T cells obtained from a subject. In some embodiments, the T cells are autologous to the subject.

[0157] Provided herein are methods of producing a therapeutic T cell composition, including (a) incubating an input composition under stimulating conditions, thereby generating a stimulated composition, wherein the input composition containing a defined number of T cells that do not express an apoptotic marker (apoptotic marker negative O); and (b) introducing a recombinant receptor into cells from the stimulated composition thereby generating an engineered cell composition, wherein the introducing includes contacting the cells of the stimulated composition with an agent comprising a polynucleotide encoding the recombinant receptor. In some embodiments, the apoptotic marker negative T cells are or contain apoptotic marker negative CD3+cells, apoptotic marker negative CD8+cells, apoptotic marker negative CD4+ cells, or apoptotic marker negative CD8+ cells and apoptotic marker negative CD4+ cells. In some embodiments, the apoptotic marker is Annexin V. In some embodiments, the apoptotic marker is activated Caspase 3. In some embodiments, the defined number of T cells contains at least 50 x 106of the apoptotic marker negative T cells, optionally apoptotic marker negative CD4+ and / or apoptotic marker negative CD8+ T cells. In some embodiments, the definednumber of T cells contains at least 100 x 106of the apoptotic marker negative T cells, optionally apoptotic marker negative CD4+ and / or apoptotic marker negative CD8+ T cells. In some embodiments, the defined number of T cells includes between at or about 100 x 106and at or about 500 x 106apoptotic marker negative T cells, optionally apoptotic marker negative CD4+ and / or apoptotic marker negative CD8+ T cells. In some embodiments, the defined number of T cells includes at or about 300 x 106, apoptotic marker negative T cells, optionally apoptotic marker negative CD4+ and / or apoptotic marker negative CD8+ T cells.

[0158] In some embodiments, the percentage of apoptotic marker negative T cells as a percentage of the total T cells in the input composition is greater than or greater than about 70%, greater than or greater than about 80%, greater than or greater than about 90%, or greater than or greater than about 95%. In some embodiments, prior to the incubating, isolating, selecting or enriching apoptotic marker negative T cells, optionally apoptotic marker negative CD4+ and / or apoptotic marker negative CD8+ T cells from a biological sample.

[0159] Provided herein are methods of producing a therapeutic T cell composition, the method including (a) isolating, selecting or enriching, from a biological sample, a population of T cells that do not express an apoptotic marker (apoptotic marker negative O), optionally apoptotic marker negative CD4+ and / or apoptotic marker negative CD8+ T cells, thereby obtaining an input composition; (b) incubating the input composition under stimulating conditions, thereby generating a stimulated composition; and (c) introducing a recombinant receptor into cells from the stimulated composition thereby generating an engineered cell composition, wherein the introducing comprises contacting the cells of the stimulated composition with an agent comprising a polynucleotide encoding the recombinant receptor.

[0160] In some embodiments, the biological sample primary T cells obtained from a subject. In some embodiments, the subject is a human subject. In some embodiments, the biological sample is or contains a whole blood sample, a buffy coat sample, a peripheral bloodmononuclear cell (PBMC) sample, an unfractionated T cell sample, a lymphocyte sample, a white blood cell sample, an apheresis product, or a leukapheresis product. In someembodiments, the biological sample contains an apheresis product or a leukapheresis product. In some embodiments, the T cells are isolated, selected or enriched from the biological sample no more than 36 hours after it is obtained from a subject. In some embodiments, the biological sample is cryofozen in the presence of a cryoprotectant no more than 36 hours after it is obtained from the subject and thawed prior to isolating, selecting or enriching the cells, optionally wherein the cryofrozen sample is thawed immediately prior to or within not more than 6 hours,no more than 4 hours, no more than 2 hours or no more than 1 hour prior to the isolating, selecting or enriching the cells.

[0161] In some embodiments, the incubation is performed in the presence of one or more cytokines, optionally in a serum free medium. In some embodiments, the one or more cytokines are selected from recombinant IL-2, recombinant IL-7, and / or recombinant IL-15. In some embodiments, the one or more cytokines comprise: between 10 and 200 IU / mL recombinant IL- 2; between 100 IU / mL and 1,000 IU / mL recombinant IL-7; and / or between 10 and 200 IU / mL recombinant IL-15. In some embodiments, the stimulatory reagent contains a primary agent that specifically binds to a member of a TCR complex, optionally that specifically binds to CD3, optionally wherein the primary agent is an antibody or an antigen-binding fragment thereof. In some embodiments, the stimulatory reagent further contains a secondary agent that specifically binds to a T cell costimulatory molecule, optionally wherein the costimulatory molecule is selected from CD28, CD137 (4-l-BB), 0X40, or ICOS, optionally wherein the secondary agent is an antibody or an antigen-binding fragment thereof. In some embodiments, the stimulatory reagent includes incubation with an anti-CD3 antibody and an anti-CD28 antibody, or an antigen-binding fragment thereof. In some embodiments, the primary agent and / or secondary agent are present on the surface of a solid support. In some embodiments, the solid support is or comprises a bead. In some embodiments, the primary agent and secondary agent areimmobilized or reversibly bound on the surface of an oligomeric particle reagent comprising a plurality of streptavidin or streptavidin mutein molecules.

[0162] In some embodiments, the input composition is incubated under stimulating conditions for between 12 hours and 36 hours, inclusive, optionally at or about 24 hours. In some embodiments, the contacting is carried out by viral transduction, optionally with a retroviral vector, optionally a lentiviral vector.

[0163] In some embodiments, the method further includes cultivating the engineered composition under conditions to promote proliferation and / or expansion of the engineered cells, thereby producing an output composition comprising the engineered T cells. In some embodiments, the cultivating is performed in the presence of one or more cytokines, optionally in a serum free medium. In some embodiments, the one or more cytokines are selected from recombinant IL-2, recombinant IL-7, and / or recombinant IL-15. In some embodiments, the one or more cytokines contains: between 50 and 400 IU / mL recombinant IL-2; between 100 IU / mL and 2,000 IU / mL recombinant IL-7; and / or between 50 and 400 IU / mL recombinant IL-15.

[0164] In some embodiments, the input composition contains CD4+ T cells and CD8+ T cells at a ratio of between 2:1 and 1:2 CD4+ to CD8+ T cells; or the input composition contains apoptotic marker negative CD4+ T cells and apoptotic marker negative CD 8+ T cells at a ratio of between 2:1 and 1:2 CD4+ to CD8+ T cells. In some embodiments, the CD4+ T cell and CD8+ T cells are separately selected, isolated or enriched from the same biological sample or a sample therefrom and combined prior to the incubating. In some embodiments, the recombinant receptor is a chimeric antigen receptor (CAR).

[0165] In some embodiments, the output composition contains at least at or about 40%,50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27; and / or at least at or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing therecombinant receptor are able to produce interleukin 2 (IL-2) or TNF-alpha following stimulation with a stimulatory agent; and / or at least at or about 10%, 15%, 20%, 25%, 30%,40%, 50%, 60% or more of the total number of CD4+ T cells in the composition expressing the recombinant receptor are polyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha following stimulation with a stimulatory agent. In some embodiments, the stimulatory agent is a non specific or non-antigen-dependent T cell stimulatory agent. In some embodiments, the non specific or non-antigen dependent T cell stimulatory agent is a polyclonal stimulatory agent. In some embodiments, the non-specific or non-antigen dependent stimulatory agent comprises PMA / ionomycin, anti-CD3 / anti-CD28, phytohemagglutinin (PHA) or concanavalin A (ConA).In some embodiments, the non-specific or non-antigen dependent T cell stimulatory agent contains PMA / ionomycin. In some embodiments, the stimulatory agent specifically binds the recombinant receptor, optionally wherein the stimulatory agent is an antigen- specific stimulatory reagent and / or contains the antigen or a portion thereof specifically recognized by the recombinant receptor. In some embodiments, production of the cytokines is measured in an intracellular cytokine assay.Brief Description of the Drawings

[0166] FIG. 1A shows the number of CD3+CAR+T cells present in CAR T cellcompositions for administration at DL1 and DL2. FIG. IB shows the number of CD4+CAR+and CD8+CAR+cells, CD4+CAR+TNF-a+cells and CD8+CAR+TNF-a+, CD4+CAR+CCR7+cells and CD8+CAR+CCR7+cells present in CAR T cell compositions for administration at DL1 and DL2. FIG. 1C shows the number of CD4+CAR+and CD8+CAR+cells, CD4+CAR+CCR7+cells and CD8+CAR+CCR7+cells present in CAR T cell compositions for administration at DL1 and DL2.

[0167] FIG. 2 depicts the median (iquartiles) number of CAR-expressing CD3+cells / pL blood, assessed by flow cytometry using an antibody specific for a truncated receptor (CD3, circle; N=87); or median (iquartiles) number of copies integrated CAR transgene / pg genomic DNA, assessed by quantitative polymerase chain reaction (qPCR) using primers specific for a woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) present in the vector encoding the CAR (qPCR, square; N=85) in blood samples from 87 subjects that have been administered anti-CDl9 CAR-expressing cells. The cutoff for CAR+cell detection in flow cytometry was set at > 25 events in the CAR+gate, and limit of detection for qPCR was > 12.5 copies of CAR transgene per pg of genomic DNA.

[0168] FIG. 3A shows a plot of percentage CCR7+cells (among CD4+CAR+and CD8+CAR+cell populations) against pharmacokinetic parameters of CD4+CAR+cells and CD8+CAR+cells, respectively (as indicated by AUC0-28of CD4+CAR+or AUC0-28of CD8+CAR+cells in blood for subjects administered the cell therapy). Each dot represents an individual patient, with shading of individual dots indicating whether the patient received dose level 1 (DL1) or dose level 2 (DL2). FIG. 3B shows similar plots, indicated separately for subjects observed to exhibit high (in this assessment, indicated by a sum of the products of diameters (SPD) value of greater than or equal to 50 cm ) or low (SPD value of less than 50 cm ) pre treatment tumor burden (assessed at the time of pre-treatment lymphodepleting chemotherapy). FIG. 3C depicts a plot of the number of CD4+CAR+CCR7+cells and CD8+CAR+CCR7+cells against AUCo-28of CD4+CAR+or AUCo-28of CD8+CAR+cells in blood for subjects administered the cell therapy), with the correlation coefficients and associated p-values. FIGS. 3D-3J, depict plots of the percentage CCR7+or CCR7+CD27+CD4+or CD8+CAR+T cells against pharmacokinetic parameters (AUCo-28and Cmax) of CD4+CAR+T cells (FIGS. 3 A, 3D- 3F) and CD8+CAR+T cells (FIGS. 3G-3J), with the correlation coefficients and associated p- values.

[0169] FIGS. 4A-4B depict a plot of the percentage of CCR7+CD27+cells amongCD4+CAR+cells against IFNy (FIG. 4A) and IL-2 (FIG. 4B) secretion by the CD4+CAR+composition upon stimulation with the antigen recognized by the CAR (CD 19).

[0170] FIGS. 5A-5B depict a plot of the percentage of CCR7+CD27+cells amongCD8+CAR+cells against IL-5 (FIG. 5A) and IL-13 (FIG. 5B) secretion by the CD4+CAR+composition upon stimulation with the antigen recognized by the CAR (CD 19).

[0171] FIGS. 6A-6D show the Kaplan-Meier survival curves for subjects who were administered CAR+T cell compositions, divided into groups that were administeredcompositions containing a percentage of CCR7+CD27+CAR+T cells among CD4+CAR+T cells (FIG. 6A for progression free survival, FIG. 6C for duration of response) and among CD8+CAR+T cells (FIG. 6B for progression free survival, FIG. 6D for duration of response) that is above or below a certain threshold level.

[0172] FIGS. 7A-7B show boxplots depicting the percentage of CCR7+CD27+cells among CD4+CAR+cells (FIG. 7A) or IFNy secretion by CD4+CAR+cells (FIG. 7B) in cellcompositions administered to for subjects as a function of whether the subject went on to develop cytokine release syndrome (CRS; grade 0 vs. grade 1 or higher). FIGS. 7C-7D show boxplots depicting the percentage of CCR7+CD27+cells among CD4+CAR+cells (FIG. 7C) or IFNy secretion by CD4+CAR+cells (FIG. 7D) in cell compositions administered to for subjects as a function of whether the subject went on to develop neurotoxicity (NT; grade 0-2 vs. grade 3 or higher).

[0173] FIG. 8A shows an exemplary multiparameter phenotype analysis based on a t- distributed stochastic neighbor embedding (tSNE). FIG. 8B shows an exemplary flow cytometry plot for a cell subtype identified from the analysis (within the boundary of the shape drawn on FIG. 8A) for CCR7 and CD27 expression.

[0174] FIGS. 9A-9C show exemplary partial least squares-discriminant analysis (PLS-DA) assessment of phenotypic and functional attributes (FIG. 9A) and transcriptomic (FIG. 9B) and epigenomic analyses (FIG. 9C) to identify variables that discriminate between subjects that exhibited complete response (CR) and subjects that exhibited progressive disease (PD) or partial response (PR), at 6 months after administration of the CAR+T cell composition.

[0175] FIG. 10A shows a plot of the frequency of CD4+CCR7+CD27+cells in pre engineering compositions against the frequency of CD4+CAR+CCR7+CD27+cells in the engineered cell compositions (Spearman’s rank-order correlation coefficient: 0.591). FIG. 10B shows a plot of the frequency of CD8+CCR7+CD27+cells in pre-engineering compositions andthe frequency of CD8+CAR+CCR7+CD27+cells in the engineered cell compositions (Spearman’s rank-order correlation coefficient: 0.357).

[0176] FIGS. 11A-11D depict results from CAR+ T cell compositions generated from exemplary expanded and non-expanded processes involving a bead-based stimulatory reagent (Bead) and incubation in basal media (Bead-Basal Media), or an oligomeric stimulatory reagent (Oligomer). FIG. 11 A depicts the percentage of CD4+ and CD8+ T cells positive for both CCR7 and CD27. FIG. 11B depicts the percentage of CCR7+CD27+cells for CD4+CAR+T cells. FIG. 11C depicts the percentage of CCR7+CD27+cells for CD8+CAR+T cells. FIG. 11D displays the percentage of CCR7+ CD27+ cells generated from a representative donor from an exemplary expanded process at various days during the process of manufacture, including activation at day l(activation dl), transduction at day 2 (transduction d2), and at various timed after initiation of cultivation (d4 INOC+2, d6 INOC+4, d7 INOC+5).

[0177] FIG. 12 shows the T cell clonality of the isolated CD4+ and CD8+ T cellcompositions before engineering and of the CD4+ and CD8+ therapeutic CAR+T cell compositions after engineering (Shannon index applied).

[0178] FIGS. 13A and 13B show progression free survival curves (Cox Proportional Hazard (top) and optimal split (bottom)) for patients with a“high” or“low” percentage of cells producing IL-2 or TNFa, respectively, in CD4+ / CAR+T cells of the therapeutic composition as determined using maximally selected rank statistics.

[0179] FIG. 14 shows the relationship of clinical outcome to baseline sum of the products of diameters (SPD) and baseline C-reactive protein (CRP) levels in subjects exhibiting a complete response (CR) (triangles) or loss of response / no response (circles)) at 6 months.

[0180] FIG. 15 shows the percentage of IL-2 / CD4+ / CAR+ cells in therapeutic T cell compositions generated from high baseline SPD / CRP subjects exhibiting a complete response (CR) (triangles; 1) or loss of response / no response (circles; 0)) at 6 months.

[0181] FIG. 16 shows progression free survival curves for exemplary tertile cut-off values for cells positive for the apoptotic marker activated caspase 3 in the input compositions.

[0182] FIG. 17 shows the percent of cells positive for apoptotic marker activated caspase 3 caspase 3 in enriched input T cells compositions as a function of age of the starting apheresis sample, i.e. samples varying in the length of time (e.g. in hours) between apheresis and its further processing before enrichment of T cells. The left plot shows the percentage ofCD4+ / activated caspase 3+ cells and the right plot shows the percentage of CD8+ / activated caspase 3+ cells.Detailed Description

[0183] Provided herein are methods, compositions, and articles of manufacture for use in connection with cell therapy, such as engineered T cell therapy for the treatment of diseases and conditions, including various tumors. The provided embodiments relate to therapeutic T cell compositions containing engineered T cells such as those engineered to express recombinant proteins such as expressing recombinant receptors designed to recognize and / or specifically bind to molecules associated with the disease or condition and result in a response, such as an immune response against such molecules upon binding to such molecules. The receptors may include chimeric receptors, e.g., chimeric antigen receptors (CARs), and other transgenic antigen receptors including transgenic T cell receptors (TCRs).

[0184] The provided embodiments in some aspects relate to aspects in which cell phenotypes, e.g., the presence and / or expression of a surface marker, and / or the absence or lack of expression of a surface marker, is related to function or activity of the therapeutic T cell composition, pharmacokinetic parameters, e.g., exposure or maximum cell concentration, risk of the likelihood of developing a toxicity, such as cytokine release syndrome (CRS) orneurotoxicity (NT) and / or an outcome of the cell therapy, e.g., response to the cell therapy, in a subject administered the T cell composition and / or may provide information about the potency of the therapeutic T cell composition. In some aspects, the provided embodiments are based on the observation that certain cell phenotypes, e.g., expression of one or more surface markers, production of one or more cytokines are associated with pharmacokinetic parameters, likelihood of response and / or likelihood of developing a toxicity. In some embodiments, the expression and / or absence of expression of cell surface markers such as C-C chemokine receptor type 7 (CCR7), CD27 and CD45RA or combinations thereof in the T cell composition foradministration, e.g., drug composition, are positively or negatively correlated withpharmacokinetic parameters and / or response or toxicity outcomes. In some aspects, it is observed herein that phenotype and functional attributes associated with a less differentiated T cell product or of a product enriched in naive-like or central memory T cell subsets correlate with or exhibit a relationship with improved pharmacokinetic properties or responses, such as durability of response and / or progression free survival, following administration to a subject.

[0185] Aspects of the provided embodiments also relate to administering or providing a unit dose containing a number, ratio, percentage and / or proportion of cells, that is a function of the number of cells of a certain phenotype, such as a phenotype indicative of a cell population,including for use in connection with dosing of the therapeutic T cell composition. In some aspects, the provided embodiments allow for consistent dosing and / or administration. In some aspects, the provided embodiments may be used to assess the likelihood of a certain outcome and / or value of a certain pharmacokinetic parameter, risk of toxicity and / or response, potency or efficacy of the cell therapy. In some aspects, the provided methods can control, ameliorate or reduce the risk of toxicity in a subject administered a dose of the therapeutic T cell composition, while ensuring potency of the T cell composition. Also provided are articles of manufacture containing the cells and designed for administration according to such dosing regimens.

[0186] In some embodiments, the provided methods, doses, unit doses, compositions, and articles of manufacture are based on observations that it can be advantageous to take into account certain phenotypes, e.g., expression of surface markers, and combinations thereof when determining appropriate dose of cell therapy and / or releasing or generating cell compositions for therapy. In certain available methods, doses are based on numbers of particular cell types, such as those engineered to exhibit a particular activity, such as those positive for an engineered receptor. For example, in certain available methods and doses, dose is based upon an observed or suspected relationship between the number (or number per patient weight) of viable engineered T cells, or of a subset thereof, such as of viable, cytotoxic (e.g., CD8+) engineered T cells. In various contexts, such numbers can have a relationship with efficacy and / or safety outcomes, such as response and / or risk of toxicities, such as neurotoxicity, cerebral edema and CRS. Provided herein are embodiments based on the observation that nonetheless, such metrics in some contexts do not consistently adequately associate with pharmacological parameters in the subject, risk of toxicities, CRS or NT, particularly without taking into account other variables. Accordingly, approaches for defining dose and evaluating product for release that rely on such metrics alone may not be entirely satisfactory. For example, such approaches may in some contexts fail to reach a certain therapeutic range or window, for safe and effective cell therapy. Provided herein are methods (including treatment, dosing, dose-determination and assay methods), therapeutic compositions, and articles of manufacture that address such shortcomings.

[0187] In some aspects, the provided embodiments permit the administration of a controlled and consistent dose of cells, thereby minimizing variation in efficacy and / or safety outcomes in the subjects. In some aspects, controlling the dose of cells based on a defined number, ratio, percentage and / or proportions of particular subset of cells, e.g., based on cell phenotypes, permit the understanding of the impact of a subset of cells having particular phenotypes on the health,potency and / or efficacy of the cells contained in the therapeutic compositions. Such approaches can be used to determine and / or calculate consistent and precise effective doses of the cells in the cell therapy and / or control the pharmacokinetic parameters of the cell therapy. Provided are methods of determining such doses, including unit doses for administration, based on the number, ratio, percentage and / or proportions of cells expressing particular surface markers and / or having particular phenotypes, articles of manufacture and kits containing doses determined using such methods and instructions for administration, and related methods of treatment. In some aspects, the provided embodiments allow the identification of attributes of cells in the engineered cell composition and potential association with pharmacokinetics (PK) and clinical outcomes such as response and toxicity, based on the consistency and tight control of the number of CD4+and CD8+CAR+T cells, and optionally subsets thereof that are CCR7+, CD27+and / or CD45RA-, in the therapeutic composition for administration in subjects. Such consistency and tight control of the total number of CAR+cells in the cell composition for administration can provide the basis for strategies to assess and control other aspects of the cells in the engineered cell composition for administration.

[0188] In some aspects, the provided embodiments permits the administration of CAR+T cell compositions that exhibit low variability, are pure and contain a precise dose, allowing identification of relationships between various cell attributes and clinical outcomes, such as response and toxicity. In some aspects, the provided embodiments are based on the observation that cell populations expressing markers associated with certain phenotypes, such as a less differentiated phenotype, exhibit certain functional profiles (e.g., cytokine production). In some aspects, CCR7+CD27+CD4+CAR T cells produce reduced IFNy and increased IL-2, and, in some aspects, CCR7+CD27+CD8+CAR T cells produce reduced IL-5 and IL-13, such as upon antigen-specific stimulation of the CAR. In some embodiments, administered cell compositions containing CAR+T cells in which a certain percentage of cells in the composition exhibit a less differentiated state and / or are CCR7+CD27+are associated with desirable or improved pharmacokinetic parameters, safety events and increased durable response, such as compared to compositions containing a lower percentage of such cell populations.

[0189] All publications, including patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are hereinincorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference.

[0190] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.I. DOSES AND DOSE DETERMINATION IN THERAPEUTIC T CELLCOMPOSITIONS

[0191] Provided herein are methods, compositions, and articles of manufacture for use in connection with cell therapy, such as engineered T cell therapy for the treatment of diseases and conditions, including various tumors. The provided embodiments relate to methods of determining a dose for administration to a subject, related methods of treatment, compositions containing doses of cells and related article of manufacture and kits. The provided embodiments in some aspects relate to aspects in which cell phenotypes, e.g., the presence and / or expression of a surface marker, the absence or lack of expression of a surface marker and / or the ability to produce one or more cytokines (e.g. IL-2), of the cells in the composition for administration, is related to, correlated with or associated with values or measurements of pharmacokinetic parameters, e.g., exposure or maximum cell concentration. In some aspects, the phenotypes and / or parameters are also related to correlated with or associated with activity and / or function of the cells and / or the likelihood of developing a toxicity, such as cytokine release syndrome (CRS) or neurotoxicity (NT) and / or an outcome of the cell therapy, e.g., response to the cell therapy, in a subject administered the T cell composition, such as durability of response and progression free survival.

[0192] In some aspects, the provided embodiments, involve determining and / oradministering a dose of the cell composition, e.g., one or more unit doses of a cell composition and / or a volume corresponding to such unit doses. In some aspects, the dose of cells is enriched for, e.g. has a high or relatively high percentage of, biologically active engineered T cells having a particular phenotype. In some aspects, the dose is based upon the number of biologically active engineered T cells having a particular phenotype. In some aspects, biologically active refers to a property of cells not programmed to undergo cell death, e.g., non-apoptotic cells or cells not showing indications of entry into an apoptotic pathway. In some aspects, dose is based upon number of biologically active engineered CD8+T cells having a particular phenotype, and / or, where dose is based upon total numbers of biologically active engineered T cells having a particular phenotype.

[0193] In some embodiments, the methods ensure that a unit dose encompasses a relatively consistent numbers, proportion, ratio and / or percentage of engineered cells having a particular phenotype in one or more particular compositions. In some aspects, the consistency is associated with or related to a relatively consistent activity, function, pharmacokinetic parameters, toxicity outcome and / or response outcome. In some embodiments, the percentage of engineered cells capable of consistent activity, function, pharmacokinetic parameters, toxicity outcome, and / or response outcome (e.g., durable response, durable progression free survival) is or includes at least at or about, or at or about, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of engineered cells (e.g., T cells) in the composition or of the total number of engineered cells (e.g., T cells) in the composition expressing the recombinant receptor, surface positive for CCR7 and / or CD27, optionally further negative for surface expression of CD45RA. In some embodiments, the engineered cells (e.g., T cells) are further negative for an apoptotic marker, such as activated caspase 3 or annexin V. In some embodiments, the percentage of engineered cells capable of consistent activity, function, pharmacokinetic parameters, toxicity outcome, and / or response outcome (e.g., durable response, durable progression free survival) is or includes at least at or about, or at or about, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the total number of engineered cells (e.g., T cells) in the composition or of the total number of engineered cells (e.g., T cells) in the composition expressing the recombinant receptor, negative for markers of apoptosis (e.g., caspase-3, annexin V). In some embodiments, the percentage of engineered cells capable of consistent activity, function, pharmacokinetic parameters, toxicity outcome, and / or response outcome (e.g., durable response, durable progression free survival) is or includes at least at or about, or at or about, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of engineered CD4+ T cells in the composition or the total number of engineered CD4+ T cells expressing the recombinant receptor capable of producing a cytokine selected from interleukin 2 (IL-2) and / or TNF-alpha. In someembodiments, the percentage of engineered cells capable of consistent activity, function, pharmacokinetic parameters, toxicity outcome, and / or response outcome (e.g., durable response, durable progression free survival) is or includes at least at or about, or at or about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of engineered CD4+ T cells in the composition or the total number of engineered CD4+ T cells expressing the recombinant receptor are polyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha. In someembodiments, the engineered cells of the composition capable of consistent activity, function, pharmacokinetic parameters, toxicity outcome, and / or response outcome (e.g., durable response, durable progression free survival) are or include one or more phenotypes described herein. Thus, in some embodiments, the percentage of engineered cells capable of consistent activity, function, pharmacokinetic parameters, toxicity outcome, and / or response outcome (e.g., durable response, durable progression free survival) is or includes a combination of percentages of phenotypes. In some embodiments, the composition to be used as a therapeutic composition is selected based on the percentage of cells including one or more phenotypes in the composition (e.g., output composition).

[0194] In some aspects, in a plurality of subjects, compositions and / or doses, the numbers, proportion, ratio and / or percentage, are relatively consistent, e.g., the number or ratio of cells that have a particular phenotype, e.g., express CCR7 (CCR7+) and / or have the ability to produce one or more cytokines, in the composition or unit dose, varies by no more than 40%, by no more than 30%, by no more than 20%, by no more than 10% or by no more than 5%. In some aspects the number or ratio of cells that have a particular phenotype, e.g., express CCR7 (CCR7+) and / or the ability to produce one or more cytokines, in the composition or unit dose, varies by no more than 20% or no more than 10% or no more than 5% from an average of said number or ratio in a plurality of T cell compositions produced by the process and / or varies from such average by no more than one standard deviation or varies by no more than 20% or no more than 10% or no more than 5% among a plurality of T cell compositions or doses determined.

[0195] In some embodiments, the methods involve determining and / or administering one or more unit doses of cells, e.g., engineered T cells expressing a recombinant receptor such as a CAR. In some aspects, the methods involve administering one or more unit doses of cells in which the one or more unit doses of cells are enriched in, and / or contain a high or relatively high percentage of cells having a particular phenotype, such as particular surface marker phenotype and / or indicating functional activity, such as the ability to produce one or more cytokines. In some aspects, the unit dose is determined based on the number, percentage, ratio, frequency and / or proportion of a particular subset of engineered T cells, e.g., cells having a particular phenotype, such as particular surface marker phenotype and / or indicating functional activity, such as the ability to produce one or more cytokines. In some embodiments, an engineered or therapeutic cell composition can be produced by a method that results in an output composition containing or enriched for cells having such phenotypes or functional attributes, such as compared to the starting material or input composition used to generate the engineered outputcomposition. Exemplary phenotype and functional attributes of cells of an engineered or therapeutic cell composition, such as an output composition produced in accord with methods for generating engineered cells, including in one or more unit doses of any such composition, are described herein.

[0196] In some aspects, the cell marker includes markers indicative of cell health, viability and / or apoptotic state of the cells. In some aspects, exemplary markers include CD3, CD4,CD8, CCR7, CD27, CD45RA, annexin V, or activated caspase 3. In some aspects, exemplary markers include CCR7, CD27 and / or CD45RA. In some aspects, exemplary markers include CCR7 and / or CD27. In some aspects, an exemplary marker is CCR7. In some aspects, an exemplary marker is CD27.

[0197] In some aspects, the provided methods also involve assessing the therapeutic composition for cell phenotypes, e.g., expression of the markers, e.g. CD3, CD4, CD8, CCR7, CD27, CD45RA, annexin V, or activated caspase 3. In some embodiments, the phenotype includes antigen- specific functions. In some embodiments, the phenotype includes production or secretion of a cytokine, e.g., upon stimulation with an antigen that the recombinant receptor, e.g., CAR, specifically binds and / or recognizes. In some embodiments, the phenotype includes production of cytokines, e.g., cytokines associated with particular cell types, such as cytokines associated with Thl, Th2, Thl7 and / or Treg subtypes.

[0198] In some aspects, the provided methods involve determining a suitable dose, e.g., one or more unit doses of a therapeutic composition containing engineered T cells for administration to a subject having a disease or condition. In some aspects, the methods also involve assessing the number, percentage, ratio, frequency and / or proportion of a particular subset of engineered T cells, e.g., cells having a particular phenotype, such as particular surface marker phenotype, in a therapeutic composition containing engineered T cells. In some embodiments, the provided methods involve assessing, in a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor, the number, percentage or ratio of T cells that express the recombinant receptor and CCR7 (receptor+ / CCR7+).

[0199] In some embodiments, the provided methods involve assessing, in a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor, the number, percentage or ratio of T cells that express or do not express CD27 and / or CD45RA. Other exemplary phenotypic markers for assessment and / or methods for assessment are described below, e.g., in Section LA. In some aspects, the unit dose can be determined based on any of the assessments. In some aspects, the methods also involveassessing the number, percentage, ratio, frequency and / or proportion of the cells expressing the recombinant receptor (e.g., CAR) or a surrogate marker of the recombinant receptor. The doses, e.g., one or more unit doses, can be determined based on the assessment for the number, percentage, ratio, frequency and / or proportion any of the phenotypic markers described herein.A. Determining Cell Phenotypes

[0200] In some embodiments, cell phenotypes, or the level or percentage of such phenotypes in a composition of cells, correlate to or are associated with activity and / or function of the cells and / or the likelihood of developing a toxicity, such as cytokine release syndrome (CRS) or neurotoxicity (NT) and / or an outcome of the cell therapy, e.g., response to the cell therapy, in a subject administered the T cell composition, such as durability of response and progression free survival. In some embodiments, compositions including cells with specific phenotypes, and, more particularly, percentages of cells with such specific phenotypes, correlate with clinical outcomes, such as durable response and / or progression free survival. In some embodiments, the phenotype is determined by assessing the presence or absence of one or more specific molecules, including surface molecules and / or molecules that may accumulate or be produced by the cells or a subpopulation of cells within a T cell composition. In some embodiments, the phenotype, directly or inversely, indicates or is indicative of a biological activity of the cells or of a population of cells within the T cell composition. In some embodiments, phenotype may include cell activity, such as production of a factor (e.g., cytokine) in response to a stimulus. In certain embodiments, assessment of a cell composition is performed to identify, detect, or quantify a phenotype of the cell composition. In particular embodiments, a measurement of a cell composition is performed to identify, detect, or quantify the presence, absence, degree of expression or level of a specific molecule.

[0201] It is contemplated that the phenotype of the cell composition (e.g., engineered T cell composition) can, in some cases, depend upon many factors, including, but not limited to, the phenotype of the starting cellular material (e.g., apheresis product or leukapheresis product) used to generate the cell composition and the phenotype of the cellular material undergoing processing to generate the cell composition. Thus, in some embodiments, phenotype is assessed in cells of the starting material and / or the material undergoing processing to generate the cell composition, as well as the final cell composition.

[0202] In some embodiments, the phenotype is indicative of viability of a cell. In some embodiments, the phenotype is indicative of absence of apoptosis, absence of early stages ofapoptosis or absence of late stages of apoptosis. In some embodiments, the phenotype is the absence of a factor indicative of absence of apoptosis, early apoptosis or late stages of apoptosis. In some embodiments, the phenotype is a phenotype of a sub-population or subset of T cells, such as recombinant receptor-expressing T cells (e.g. CAR+T cells), CD8+T cells, or CD4+T cells. In some embodiments, the phenotype is a phenotype of cells that are not activated and / or that lack or are reduced for or low for expression of one or more activation marker. In some embodiments, the phenotype is a phenotype of cells that are not exhausted and / or that lack or are reduced for or low for expression of one or more exhaustion markers.

[0203] In some embodiments, the phenotype is indicated by the presence, absence, or level of expression in a cell of one or more specific molecules, such as certain surface markers indicative of the phenotype, e.g., surface proteins, intracellular markers indicative of the phenotype, or nucleic acids indicative of the phenotype or other molecules or factors indicative of the phenotype. In some embodiments, the phenotype is or comprises a positive or negative expression of the one or more of specific molecules. In some embodiments, the specific molecules include, but are not limited to, a surface marker, e.g., a membrane glycoprotein or a receptor; a marker associated with apoptosis or viability; or a specific molecule that indicates the status of an immune cells, e.g., a marker associated with activation, exhaustion, or a mature or naive phenotype. In some embodiments, any known method for assessing or measuring, counting, and / or quantifying cells based on specific molecules can be used to determine the number of cells of the phenotype.

[0204] In some embodiments, a phenotype is or includes a positive or negative expression of one or more specific molecules in a cell. In some embodiments, the positive expression is indicated by a detectable amount of the specific molecule in the cell. In certain embodiments, the detectable amount is any detected amount of the specific molecule in the cell. In particular embodiments, the detectable amount is an amount greater than a background, e.g., background staining, signal, etc., in the cell. In certain embodiments, the positive expression is an amount of the specific molecule that is greater than a threshold, e.g., a predetermined threshold. Likewise, in particular embodiments, a cell with negative expression of a specific molecule may be any cell not determined to have positive expression, or is a cell that lacks a detectable amount of the specific molecule or a detectable amount of the specific molecule above background. In some embodiments, the cell has negative expression of a specific molecule if the amount of the specific molecule is below a threshold. One of skill in the art will understand how to define a threshold to define positive and / or negative expression for a specific molecule as a matter ofroutine skill, and that the thresholds may be defined according to specific parameters of, for example, but not limited to, the assay or method of detection, the identity of the specific molecule, reagents used for detection, and instrumentation.

[0205] Examples of methods that can be used to detect a specific molecule and / or analyze a phenotype of the cells include, but are not limited to, biochemical analysis; immunochemical analysis; image analysis; cytomorphological analysis; molecule analysis such as PCR, sequencing, high-throughput sequencing, determination of DNA methylation; proteomics analysis such as determination of protein glycosylation and / or phosphorylation pattern;genomics analysis; epigenomics analysis (e.g., ChIP-seq or ATAC-seq); transcriptomics analysis (e.g., RNA-seq); and any combination thereof. In some embodiments, the methods can include assessment of immune receptor repertoire, e.g., repertoire of T cell receptors (TCRs). In some aspects, determination of any of the phenotypes can be assessed in high-throughput, automated and / or by single-cell-based methods. In some aspects, large-scale or genome-wide methods, can be used to identify one or more molecular signatures. In some aspects, large-scale or genome-wide methods, can be used to identify molecular signatures that are associated with outcomes of therapy, e.g., efficacy and safety, or pharmacokinetic parameters. In some aspects, one or more molecular signatures, e.g., expression of specific RNA or proteins in the cell, can be determined. In some embodiments, molecular features of the phenotype analyzed by image analysis, PCR (including the standard and all variants of PCR), microarray (including, but not limited to DNA microarray, MMchips for microRNA, protein microarray, cellular microarray, antibody microarray, and carbohydrate array), sequencing, biomarker detection, or methods for determining DNA methylation or protein glycosylation pattern. In particular embodiments, the specific molecule is a polypeptide, i.e. a protein. In some embodiments, the specific molecule is a polynucleotide.

[0206] In some embodiments, positive or negative expression of a specific molecule is determined by incubating cells with one or more antibodies or other binding agent that specifically bind to one or more surface markers expressed or expressed (marker+) at a relatively higher level (markerhlgh) on the positively or negatively selected cells, respectively. In particular embodiments, the positive or negative expression is determined by flow cytometry,immunohistochemistry, or any other suitable method for detecting specific markers.

[0207] In particular embodiments, expression of a specific molecule is assessed with flow cytometry. Flow cytometry is a laser- or impedance-based, biophysical technology employed in cell counting, cell sorting, biomarker detection and protein engineering, by suspending cells in astream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and chemical characteristics of up to thousands of particles per second.

[0208] The data generated by flow-cytometers can be plotted in a single dimension, to produce a histogram, or in two-dimensional dot plots or even in three dimensions. The regions on these plots can be sequentially separated, based on fluorescence intensity, by creating a series of subset extractions, termed“gates.” Specific gating protocols exist for diagnostic and clinical purposes especially in relation to immunology. Plots are often made on logarithmic scales. Because different fluorescent dyes' emission spectra overlap, signals at the detectors have to be compensated electronically as well as computationally. Data accumulated using the flow cytometer can be analyzed using software, e.g., JMP (statistical software), WinMDI, Flowing Software, and web-based Cytobank), Cellcion, FCS Express, FlowJo, FACSDiva, CytoPaint (aka Paint-A-Gate), VenturiOne, CellQuest Pro, Infinicyt or Cytospec.

[0209] Flow Cytometry is a standard technique in the art and one of skill would readily understand how to design or tailor protocols to detect one or more specific molecules and analyze the data to determine the expression of one or more specific molecules in a population of cells. Standard protocols and techniques for flow cytometry are found in Loyd“FlowCytometry in Microbiology; Practical Flow Cytometry by Howard M. Shapiro; Flow Cytometry for Biotechnology by Larry A. Sklar, Handbook of Flow Cytometry Methods by J. Paul Robinson, et ah, Current Protocols in Cytometry, Wiley-Liss Pub, Flow Cytometry in Clinical Diagnosis, v4, (Carey, McCoy, and Keren, eds), ASCP Press, 2007, Ormerod, M.G. (ed.) (2000) Flow Cytometry -A practical approach. 3rd edition. Oxford University Press, Oxford, UK, Ormerod, M.G. (1999) Flow Cytometry. 2nd edition. BIOS Scientific Publishers, Oxford., and Flow Cytometry -A basic introduction. Michael G. Ormerod, 2008.

[0210] In some embodiments, cells are sorted by phenotype for further analysis. In some embodiments, cells of different phenotypes within the same cell composition are sorted by Fluorescence-activated cell sorting (FACS). FACS is a specialized type of flow cytometry that allows for sorting a heterogeneous mixture of cells into two or more containers, one cell at a time, based upon the specific light scattering and fluorescent characteristics of each cell. It is a useful scientific instrument as it provides fast, objective and quantitative recording of fluorescent signals from individual cells as well as physical separation of cells of particular interest.

[0211] In some embodiments, the phenotype includes the number of total T cells or the number of total CD3+T cells. In particular embodiments, a T cell composition, e.g., a therapeutic T cell composition that contains cells that express a recombinant receptor or a CAR, may include one or more different subtypes of T cells. In some embodiments, the phenotype is or includes the identity of a T cell subtype. Different populations or subtypes of T cells include, but are not limited to effector T cells, helper T cells, memory T cell, Regulatory T cells, naive T cells, CD4+cells, and CD8+T cells. In certain embodiments, a T cell sub-type may be identified by detecting the presence or absence of a specific molecule. In certain embodiments, the specific molecule is a surface marker that can be used to identify a T cell subtype.

[0212] In some embodiments, the phenotype is positive or high level expression of one or more specific molecule that are surface markers, e.g., CD3, CD4, CD8, CD28, CD62L, CCR7, CD27, CD 127, CD4, CD8, CD45RA, and / or CD45RO. In certain embodiments, the phenotype is a surface marker of T cells or of a subpopulation or subset of T cells, such as based on positive surface marker expression of one or more surface markers, e.g., CD3+, CD4+, CD8+, CD28+, CD62L+, CCR7+, CD27+, CDl27+, CD4+, CD8+, CD45RA+, and / or CD45RO+. In some embodiments, the phenotype is positive or high level expression of one or more specific molecule that are surface markers, e.g., C-C chemokine receptor type 7 (CCR7), Cluster of Differentiation 27 (CD27), Cluster of Differentiation 28 (CD28), and Cluster of Differentiation 45 RA (CD45RA). In certain embodiments, the phenotype markers include CCR7, CD27,CD28, CD44, CD45RA, CD62L, and L-selectin. In some embodiments, the phenotype is negative or the absence of expression of one or more specific molecule that are surface markers, e.g., CD3, CD4, CD8, CD28, CD62L, CCR7, CD27, CD127, CD4, CD8, CD45RA, and / or CD45RO. In certain embodiments, the phenotype is a surface marker of T cells or of a subpopulation or subset of T cells, such as based on the absence of surface marker expression of one or more surface markers, e.g., CD3 , CD4 , CD8-, CD28 , CD62L , CCR7 , CD27 , CD 127 , CD4 , CD8 , CD45RA , and / or CD45RO . In some embodiments, the phenotype is negative or the absence of expression of one or more specific molecule that are surface markers, e.g., C-C chemokine receptor type 7 (CCR7), Cluster of Differentiation 27 (CD27), Cluster ofDifferentiation 28 (CD28), and Cluster of Differentiation 45 RA (CD45RA). In certain embodiments, the phenotype markers include CCR7, CD27, CD28, CD44, CD45RA, CD62L, and L-selectin.

[0213] In certain embodiments, the phenotype is or includes positive or negative expression of CD27, CCR7 and / or CD45RA. In some embodiments, the phenotype is CCR7+. In someembodiments, the phenotype is CD27+. In some embodiments, the phenotype is CCR7+ / CD27+. In some embodiments, the phenotype is CD45RA . In some embodiments, the phenotype is CCR7+ / CD45RA . In some embodiments, the phenotype is CD27+ / CD45RA . In some embodiments, the phenotype is CCR7+ / CD27+ / CD45RA .

[0214] In certain embodiments, the surface marker indicates expression of a recombinant receptor, e.g., a CAR. In particular embodiments, the surface marker is expression of the recombinant receptor, e.g. CAR, which, in some aspects, can be determined using an antibody, such as an anti-idiotype antibody. In some embodiments, the surface marker that indicates expression of the recombinant receptor is a surrogate marker. In particular embodiments, such a surrogate marker is a surface protein that has been modified to have little or no activity. In certain embodiments, the surrogate marker is encoded on the same polynucleotide that encodes the recombinant receptor. In some embodiments, the nucleic acid sequence encoding the recombinant receptor is operably linked to a nucleic acid sequence encoding a marker, optionally separated by an internal ribosome entry site (IRES), or a nucleic acid encoding a self cleaving peptide or a peptide that causes ribosome skipping, such as a 2A sequence, such as a T2A (e.g., SEQ ID NOS: 6 and 17), a P2A (e.g., SEQ ID NOS: 18 and 19) , a E2A (e.g., SEQ ID NO: 20) or a F2A (e.g., SEQ ID NO: 21). Extrinsic marker genes may in some cases be utilized in connection with engineered cells to permit detection or selection of cells and, in some cases, also to promote cell suicide.

[0215] Exemplary surrogate markers can include truncated cell surface polypeptides, such as a truncated human epidermal growth factor receptor 2 (tHER2), a truncated epidermal growth factor receptor (EGFRt, exemplary EGFRt sequence set forth in SEQ ID NO:7 or 16) or a prostate-specific membrane antigen (PSMA) or modified form thereof. EGFRt may contain an epitope recognized by the antibody cetuximab (Erbitux®) or other therapeutic anti-EGFR antibody or binding molecule, which can be used to identify or select cells that have been engineered with the EGFRt construct and a recombinant receptor, such as a chimeric antigen receptor (CAR), and / or to eliminate or separate cells expressing the receptor. See U.S. Patent No. 8,802,374 and Liu et ah, Nature Biotech. 2016 April; 34(4): 430-434). In some aspects, the marker, e.g. surrogate marker, includes all or part (e.g., truncated form) of CD34, a NGFR, or epidermal growth factor receptor (e.g., tEGFR). In some embodiments, the nucleic acid encoding the marker is operably linked to a polynucleotide encoding for a linker sequence, such as a cleavable linker sequence, e.g., T2A. For example, a marker, and optionally a linker sequence, can be any as disclosed in PCT Pub. No. WO2014031687. For example, the markercan be a truncated EGFR (tEGFR) that is, optionally, linked to a linker sequence, such as a T2A cleavable linker sequence. An exemplary polypeptide for a truncated EGFR ( e.g . tEGFR) comprises the sequence of amino acids set forth in SEQ ID NO: 7 or 16 or a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 7 or 16.

[0216] In some embodiments, the marker is or comprises a fluorescent protein, such as green fluorescent protein (GFP), enhanced green fluorescent protein (EGFP), such as super-fold GFP, red fluorescent protein (RFP), such as tdTomato, mCherry, mStrawberry, AsRed2, DsRed or DsRed2, cyan fluorescent protein (CFP), blue green fluorescent protein (BFP), enhanced blue fluorescent protein (EBFP), and yellow fluorescent protein (YFP), and variants thereof, including species variants, monomeric variants, and codon-optimized and / or enhanced variants of the fluorescent proteins. In some embodiments, the marker is or comprises an enzyme, such as a luciferase, the lacZ gene from E. coli, alkaline phosphatase, secreted embryonic alkaline phosphatase (SEAP), chloramphenicol acetyl transferase (CAT). Exemplary light-emitting reporter genes include luciferase (luc), b-galactosidase, chloramphenicol acetyltransferase (CAT), b-glucuronidase (GETS) or variants thereof.

[0217] In certain embodiments, the phenotype comprises expression, e.g. surface expression, of one or more of the surface markers CD3, CD4, CD8, and / or a recombinant receptor (e.g. CAR) or its surrogate marker indicating or correlating to expression of a recombinant receptor (e.g. CAR).

[0218] In particular embodiments, the phenotype is identified by the expression of one or more specific molecules that are surface markers. In certain embodiments, the phenotype is or includes positive or negative expression of CD3, CD4, CD8, and / or a recombinant receptor, e.g. a CAR. In certain embodiments, the recombinant receptor is a CAR. In particular embodiments the phenotype comprises CD3+ / CAR+, CD4+ / CAR+, and / or CD8+ / CAR+.

[0219] In certain embodiments, the phenotype is or includes positive or negative expression of CD27, CCR7 and / or CD45RA, and / or a recombinant receptor, e.g. a CAR. In some embodiments, the phenotype is CCR7+ / CAR+. In some embodiments, the phenotype isCD27+ / CAR+. In some embodiments, the phenotype is CCR7+ / CD27+ / CAR+. In some embodiments, the phenotype is CD45RA 7CAR+. In some embodiments, the phenotype is CCR7+ / CD45RA7CAR+. In some embodiments, the phenotype is CD27+ / CD45RA 7CAR+. In some embodiments, the phenotype is CCR7+ / CD27+ / CD45RA 7CAR+.

[0220] In some embodiments, the phenotype is viability. In certain embodiments, the phenotype is the positive expression of a marker that indicates that the cell undergoes normal functional cellular processes and / or has not undergone or is not under the process of undergoing necrosis or programmed cell death. In some embodiments, viability can be assessed by the redox potential of the cell, the integrity of the cell membrane, or the activity or function ofmitochondria. In some embodiments, viability is the absence of a specific molecule associated with cell death, or the absence of the indication of cell death in an assay.

[0221] In some embodiments, the phenotype is or comprises cell viability. In certain embodiments, the viability of cells can be detected, measured, and / or assessed by a number of means that are routine in the art. Non-limiting examples of such viability assays include, but are not limited to, dye uptake assays (e.g., calcein AM assays), XTT cell viability assays, and dye exclusion assays (e.g., trypan blue, Eosin, or propidium dye exclusion assays). Viability assays are useful for determining the number or percentage (e.g., frequency) of viable cells in a cell dose, a cell composition, and / or a cell sample. In particular embodiments, the phenotype comprises cell viability along with other features, e.g., recombinant receptor expression.

[0222] In certain embodiments, the phenotype is or includes cell viability, viable CD3+, viable CD4+, viable CD8+, viable CD3+ / CAR+, viable CD4+ / CAR+, viable CD8+ / CAR+, viable CD4+ / CCR7+ / CAR+, viable CD8+ / CD27+ / CAR+, viable CD4+ / CD27+ / CAR+, viableCD8+ / CCR7+ / CD27+ / CAR+, viable CD4+ / CCR7+ / CD27+ / CAR+, viable CD8+ / CCR7+ / CD45RA / CAR+or viable CD4+ / CCR7+ / CD45RA or a combination thereof.

[0223] In particular embodiments, the phenotype is or includes an absence of apoptosis and / or an indication the cell is undergoing the apoptotic process. Apoptosis is a process of programmed cell death that includes a series of stereotyped morphological and biochemical events that lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and global mRNA decay. Apoptosis is a well characterized process, and specific molecules associated with various stages are well known in the art.

[0224] In some embodiments, the phenotype is the absence of an early stage of apoptosis, and / or an absence of an indicator and / or a specific molecule associated with an early stage of apoptosis. In the early stages of apoptosis, changes in the cellular and mitochondrial membrane become apparent. Biochemical changes are also apparent in the cytoplasm and nucleus of the cell. For example, the early stages of apoptosis can be indicated by activation of certain caspases, e.g., 2, 8, 9, and 10. In particular embodiments, the phenotype is the absence of a latestage of apoptosis, and / or an absence of an indicator and / or a specific molecule associated with a late stage of apoptosis. The middle to late stages of apoptosis are characterized by further loss of membrane integrity, chromatin condensation and DNA fragmentation, and includebiochemical events such as activation of caspases 3, 6, and 7.

[0225] In certain embodiments, the phenotype is the negative expression of one or more factors associated with apoptosis, including pro-apoptotic factors known to initiate apoptosis, e.g., members of the death receptor pathway, activated members of the mitochondrial (intrinsic) pathway, such as Bcl-2 family members, e.g., Bax, Bad, and Bid, and caspases. In some embodiments, the phenotype is a negative or low amount of a marker of apoptosis. In certain embodiments, the phenotype is the negative expression of a marker of apoptosis. In certain embodiments, the phenotype is the absence of an indicator, e.g., an Annexin V molecule, which will preferentially bind to cells undergoing apoptosis when incubated with or contacted to a cell composition. In some embodiments, the phenotype is or includes the expression of one or more markers that are indicative of an apoptotic state in the cell.

[0226] In some embodiments, the phenotype is the negative (or low) expression of a specific molecule that is a marker for apoptosis. Various apoptosis markers are known to those of ordinary skill in the art and include, but are not limited to, an increase in activity of one or more caspases i.e. an activated caspase (e.g., an active caspase), an increase in PARP cleavage, activation and / or translocation of Bcl-2 family proteins, members of the cell death pathway, e.g., Fas and FADD, presence of nuclear shrinkage (e.g., monitored by microscope) and presence of chromosome DNA fragmentation (e.g., presence of chromosome DNA ladder) or with apoptosis assays that include TUNEL staining, and Annexin V staining.

[0227] Caspases are enzymes that cleave proteins after an aspartic acid residue, the term is derived from“cysteine-aspartic acid proteases.” Caspases are involved in apoptosis, thus activation of caspases, such as caspase-3 is indicative of an increase or revival of apoptosis. In certain embodiments, caspase activation can be detected by methods known to the person of ordinary skill. In some embodiments, an antibody that binds specifically to an activated caspase (i.e., binds specifically to the cleaved polypeptide) can be used to detect caspase activation. In another example, a fluorochrome inhibitor of caspase activity (FLIC A) assay can be utilized to detect caspase-3 activation by detecting hydrolysis of acetyl Asp-Glu-Val-Asp 7-amido-4- methylcoumarin (Ac-DEVD-AMC) by caspase-3 (i.e., detecting release of the fluorescent 7- amino-4-methylcoumarin (AMC)). FLIC A assays can be used to determine caspase activation by a detecting the product of a substrate processed by multiple caspases (e.g., FAM-VAD-FMKFLICA). Other techniques include The CASPASE-GLO® caspase assays (PROMEGA) that use luminogenic caspase-8 tetrapeptide substrate (Z-LETD-aminoluciferin), the caspase-9 tetrapeptide substrate (Z-LEHD-aminoluciferin), the caspase-3 / 7 substrate (Z-DEVD- aminoluciferin), the caspase-6 substrate (Z-VEID-aminoluciferin), or the caspase-2 substrate (Z- VD V AD- aminoluciferin) .

[0228] In certain embodiments, the phenotype is or includes negative expression of activated caspase-l, activated caspase-2, activated caspase-3, activated caspase-7, activated caspase-8, activated caspase-9, activated caspase- 10 and / or activated caspase- 13 in a cell. In particular embodiments, the phenotype is or includes activated caspase 3-. In some embodiments, the proform (zymogen cleaved) form of a caspase, such as any above, also is a marker indicating the presence of apoptosis. In some embodiments, the phenotype is or includes the absence of or negative expression of a proform of a caspase, such as the proform of caspase-3.

[0229] In some embodiments, the marker of apoptosis is cleaved the Poly ADP-ribose polymerase 1 (PARP). PARP is cleaved by caspase during early stages of apoptosis. Thus, detection of a cleaved PARP peptide is a marker for apoptosis. In particular embodiments, the phenotype is or includes positive or negative expression of cleaved PARP.

[0230] In some embodiments, the marker of apoptosis is a reagent that detects a feature in a cell that is associated with apoptosis. In certain embodiments, the reagent is an annexin V molecule. During the early stages of apoptosis the lipid phosphatidylserine (PS) translocates from the inner to the outer leaflet of the plasma membrane. PS is normally restricted to the internal membrane in healthy and / or non-apoptotic cells. Annexin V is a protein thatpreferentially binds phosphatidylserine (PS) with high affinity. When conjugated to a fluorescent tag or other reporter, Annexin V can be used to rapidly detect this early cell surface indicator of apoptosis. In some embodiments, the presence of PS on the outer membrane will persist into the late stages of apoptosis. Thus in some embodiments, annexin V staining is an indication of both early and late stages of apoptosis. In certain embodiments, an Annexin, e.g. Annexin V, is tagged with a detectable label and incubated with, exposed to, and / or contacted with cells of a cell composition to detect cells that are undergoing apoptosis, for example by flow cytometry. In some embodiments, fluorescence tagged annexins, e.g., annexin V, are used to stain cells for flow cytometry analysis, for example with the annexin- V / 7- A AD assay.Alternative protocols suitable for apoptosis detection with annexin include techniques and assays that utilize radiolabeled annexin V. In certain embodiments, the phenotype is or includes negative staining by annexin, e.g. annexin V-. In particular embodiments, the phenotype is orincludes the absence of PS on the outer plasma membrane. In certain embodiments, the phenotype is or includes cells that are not bound by annexin e.g. annexin V. In certain embodiments, the cell that lacks detectable PS on the outer membrane is annexin V-. In particular embodiments, the cell that is not bound by annexin V- in an assay, e.g., flow cytometry after incubation with labeled annexin V, is annexin V-.

[0231] In particular embodiments, the phenotype is annexin V , annexin V CD3+, annexin V-CD4+, annexin V- CD8+, annexin V-CD3+ / CAR+, annexin V- CD4+ / CAR+, annexin V- CD8+ / CAR+, activated caspase 3 activated caspase 3 CD3+, activated caspase 37CD4+, activated caspase 3 / CD8+, activated caspase 37CD3+ / CAR+, activated caspase 37CD47CAR+, activated caspase 37CD87CAR+, annexin V7CD47CCR77CAR+, annexin V7CD87CD277CAR+, annexin V- / CD47CD277CAR+, annexinV7CD 87CCR7 CD277C AR+, annexin V- / CD47CCR77CD277CAR+, annexinV7CD87CCR77CD45RA / CAR+or annexin V- / CD47CCR77CD45RA ; activated caspase 37CD47CCR77CAR+, activated caspase 3- / CD87CD277CAR+, activated caspase37CD47CD277CAR+, activated caspase 37CD87CCR77CD277CAR+, activated caspase 37CD47CCR77CD277CAR+, activated caspase 37CD87CCR77CD45RA 7CAR+or activated caspase 37CD47CCR77CD45RA or a combination thereof.

[0232] Particular embodiments contemplate that cells positive for expression of a marker for apoptosis are undergoing programmed cell death, show reduced or no immune function, and have diminished capabilities if any to undergo activation, expansion, and / or bind to an antigen to initiate, perform, or contribute to an immune response or activity. In particular embodiments, the phenotype is defined by negative expression for an activated caspase and / or negative staining with annexin V.

[0233] In certain embodiments, the phenotype is or includes activated caspase 3 (caspase 3 ) and / or annexin V .

[0234] Among the phenotypes are the expression or surface expression of one or more markers generally associated with one or more sub-types or subpopulations of T cells, or phenotypes thereof. T cell subtypes and subpopulations may include CD4+and / or of CD8+T cells and subtypes thereof that may include naive T (TN) cells, effector T cells (TEEE), memory T cells and sub-types thereof, such as stem cell memory T (TSCM), central memory T (TCM), effector memory T (TEM), TEMRA cells or terminally differentiated effector memory T cells, tumor-infiltrating lymphocytes (TIL), immature T cells, mature T cells, helper T cells, cytotoxic T cells, mucosa-associated invariant T (MAIT) cells, naturally occurring and adaptive regulatoryT (Treg) cells, helper T cells, such as TH1 cells, TH2 cells, TH3 cells, TH17 cells, TH9 cells, TH22 cells, follicular helper T cells, alpha / beta T cells, and delta / gamma T cells.

[0235] In some aspects, among the phenotypes include expression or markers or functions, e.g. antigen- specific functions such as cytokine secretion, that are associated with a less differentiated cell subset or a more differentiated subset. In some embodiments, the phenotypes are those associated with a less differentiated subset, such as one or more of CCR7+, CD27+and interleukin-2 (IL-2) production. In some aspects, less differentiated subsets can also be related to therapeutic efficacy, self-renewal, survival functions or graft- versus-host disease. In some embodiments, the phenotypes are those associated with a more differentiated subset, such as one or more of interferon-gamma (IFN-g) or IL-13 production. In some aspects, more differentiated subsets can also be related to senescence and effector function.

[0236] In some embodiments, the phenotype is or includes a phenotype of a memory T cell or memory T cell subset exposed to their cognate antigen. In some embodiments the phenotype is or includes a phenotype of a memory T cell (or one or more markers associated therewith), such as a TCM cell, a TEMcell, or a TEMRA cell, a TSCM cell, or a combination thereof. In particular embodiments, the phenotype is or includes the expression of one or more specific molecules that is a marker for memory and / or memory T cells or subtypes thereof. In some aspects, exemplary phenotypes associated with TCMcells can include one or more of CD45RA , CD62L+, CCR7+and CD95+. In some aspects, exemplary phenotypes associated with TEMcells can include one or more of CD45RA , CD62L , CCR7 and CD95+.

[0237] In particular embodiments, the phenotype is or includes the expression of one or more specific molecules that is a marker for naive T cells.

[0238] In some embodiments, the phenotype is or includes a memory T cell or a naive T cell. In certain embodiments, the phenotype is the positive or negative expression of one or more specific molecules that are markers for memory. In some embodiments, the memory marker is a specific molecule that may be used to define a memory T cell population.

[0239] In some embodiments, the phenotype is or includes a phenotype of or one or more marker associated with a non-memory T cell or sub-type thereof; in some aspects, it is or includes a phenotype or marker(s) associated with a naive cell. In some embodiments, the phenotype is CCR7+ / CD27+ / CD28+ / CD45RA+. In certain embodiments, the phenotype is or includes CCR7+ / CD45RA+. In some embodiments, the phenotype is or includes a phenotype of a central memory T cell. In particular embodiments, the phenotype is or includesCCR7+ / CD27+ / CD28+ / CD45RA_. In some embodiments, the phenotype is or includesCCR7 CD27+ / CD28+ / CD45RA-. In certain embodiments, the phenotype is or includes that of a TEMRA cell or a TSCM cell. In certain embodiments, the phenotype is or includes CD45RA+. In particular embodiments, the phenotype is or includes CCR77CD277CD287CD45RA+. In some embodiments, the phenotype is or includes one of CD27+ / CD28+, CD277CD28+, CD27+ / CD28_, or CD277CD287 In some embodiments, the phenotype is CCR7+ / CD27+ / CD45RA+. In certain embodiments, the phenotype is or includes CCR7+ / CD45RA+. In particular embodiments, the phenotype is or includes CCR7+ / CD27+ / CD45RA_. In some embodiments, the phenotype is or includes CCR77CD277CD45RA7 In certain embodiments, the phenotype is or includes CD45RA+. In particular embodiments, the phenotype is or includes CCR77CD277 CD45RA+.

[0240] In some embodiments the phenotype is or includes any of the foregoing phenotypic properties and further includes the expression of a recombinant receptor, such as phenotype associated with a memory T cell or memory subtype and that expresses a CAR, or a phenotype associated with a naive cell that expresses a CAR. In certain embodiments, the phenotype is or includes that of a central memory T cell or stem central memory T cell that expresses a CAR. In particular embodiments, the phenotype is or includes that of an effector memory cell that expresses a CAR. In some embodiments, the phenotype is or includes that of a TEMRA cell that expresses a CAR. In particular embodiments, the phenotype is or includesCAR+ / CCR7+ / CD27+ / CD28+ / CD45RA_; CAR+ / CCR77CD277CD287CD45RA ;CAR7CCR77CD277CD287CD45RA+; CAR7CD277CD28+; CAR7CD277CD28+;CAR7CD277CD28-; or CAR7CD277CD287 In particular embodiments, the phenotype is or includes CAR7CCR77CD277CD45RA ; CAR7CCR77CD277CD45RA ;CAR7CCR77CD277CD287CD45RA+; CAR7CD27+; CAR+ / CD27 ; CAR7CD277CD28 ; or CAR7CD277CD28 .

[0241] In certain embodiments, the phenotype is or includes a phenotype of a T cell that is negative for a marker of apoptosis. In certain embodiments, the phenotype is or includes a naive cell that is negative for a marker of apoptosis. In some embodiments, the marker of apoptosis is activated caspase 3. In some embodiments, the marker of apoptosis is positive staining by annexin V.

[0242] In particular embodiments, the phenotype is or includes that of a memory T cell or subtype thereof that is negative for a marker of apoptosis that expresses a CAR. In particular embodiments, the phenotype is or includes that of a memory T cell or particular subtype that is negative for a marker of apoptosis that expresses a CAR. In certain embodiments, the phenotype is or includes a naive cell that is negative for a marker of apoptosis that expresses aCAR. In certain embodiments, the phenotype is or includes that of a central memory T cell or TSCM cell or naive cell that is negative for a marker of apoptosis that expresses a CAR. In particular embodiments, the phenotype is or includes that of an effector memory cell that is negative for a marker of apoptosis that expresses a CAR. In certain embodiments, the phenotype is or includes annexin V CAR+ / CCR7+ / CD27+ / CD28+ / CD45RA_; annexinV7CAR+ / CCR77CD27+ / CD28+ / CD45RA_; annexinV7CAR7CCR77CD277CD287CD45RA+; annexin V7CAR7CD277CD28+; annexinV7CAR7CD277CD28+; annexin V7CAR7CD277CD28 ; or annexinV7CAR7CD277CD287 In certain embodiments, the phenotype is or includes activated caspase 37CAR7CCR77CD277CD287CD45RA-; activated caspase37CAR7CCR77CD277CD287CD45RA-; activated caspase37CAR7CCR77CD277CD287CD45RA+; activated caspase 37CAR7CD277CD28+; activated caspase 37CAR7CD277CD28+; activated caspase 37CAR7CD277CD28-; or activated caspase 37CAR7CD277CD287 In certain embodiments, the phenotype is or includes annexin V7CAR7CCR77CD277CD45RA-; annexin V7CAR7CCR77CD277CD45RA ; annexin V7CAR7CCR77CD277CD45RA+; annexin V7CAR7CD277CD28+; annexinV7CAR7CD277CD28+; annexin V7CAR7CD27+; or annexin V7CAR7CD277 In certain embodiments, the phenotype is or includes activated caspase37CAR7CCR77CD277CD45RA-; activated caspase 37CAR7CCR77CD277CD45RA ; activated caspase 37CAR7CCR77CD277CD45RA+; activated caspase37CAR7CD277CD28+; activated caspase 37CAR7CD277CD28+; activated caspase37CAR7CD27+; or activated caspase 37CAR7CD277

[0243] In particular embodiments, the phenotype is or includes CD277CD28+,CD277CD28+, CD277CD28-, CD277CD28-, or a combination thereof. In some embodiments, the phenotype is or includes CAR7CD277CD28+, CAR7CD277CD28+, CAR7CD277CD28 , CAR7CD277CD28-, or a combination thereof. In certain embodiments, the phenotype is or includes activated caspase 37CAR7CD277CD28+, activated caspase 37CAR7CD277CD28+, activated caspase 37CAR7CD277CD28-, activated caspase 37CAR7CD277CD28-, or a combination thereof. In particular embodiments, the phenotype is or includes annexinV7CAR7CD277CD28+, annexin V7CAR7CD277CD28+, annexin V / CAR7CD277CD28 , annexin V7CAR7CD277CD28-, or a combination thereof. In particular embodiments, the phenotype is or includes CD27+, CD27-, CD27+, CD27-, or a combination thereof. In some embodiments, the phenotype is or includes CAR7CD27+, CAR7CD27-, CAR7CD27+,CAR+ / CD27-, or a combination thereof. In certain embodiments, the phenotype is or includes activated caspase 3 CAR+ / CD27+, activated caspase 37CAR+ / CD27_, activated caspase 37CAR+ / CD27+, activated caspase 37CAR+ / CD27_, or a combination thereof. In particular embodiments, the phenotype is or includes annexin V7CAR+ / CD27+, annexin V7CAR+ / CD27_, annexin V7CAR7CD27+, annexin V7CAR7CD27-, or a combination thereof.

[0244] In particular embodiments, the phenotype is or includes CCR77CD28+,CCR77CD28+, CCR77CD287 CCR77CD287 or a combination thereof. In someembodiments, the phenotype is or includes CAR7CCR77CD28+, CAR7CCR77CD28+, CAR7CCR77CD28-, CAR7CCR77CD28-, or a combination thereof. In certain embodiments, the phenotype is or includes activated caspase 37CAR7CCR77CD28+, activated caspase 37CAR7CCR77CD28+, activated caspase 37CAR7CCR77CD28-, activated caspase37CAR7CCR77CD28-, or a combination thereof. In particular embodiments, the phenotype is or includes annexin V7CAR7CCR77CD28+, annexin V7CAR7CCR77CD28+, annexin V7CAR7CCR77CD287 annexin V7CAR7CCR77CD287 or a combination thereof. In particular embodiments, the phenotype is or includes CCR7+, CCR7-, CCR7+, CCR7-, or a combination thereof. In some embodiments, the phenotype is or includes CAR7CCR7+, CAR7CCR7-, CAR7CCR7+, CAR7CCR7-, or a combination thereof. In certain embodiments, the phenotype is or includes activated caspase 37CAR7CCR7+, activated caspase37CAR7CCR7-, activated caspase 37CAR7CCR7+, activated caspase 37CAR7CCR7-, or a combination thereof. In particular embodiments, the phenotype is or includes annexinV7CAR7CCR7+, annexin V7CAR7CCR77 annexin V7CAR7CCR7+, annexinV7CAR7CCR7-, or a combination thereof.

[0245] In some embodiments, the phenotype is or includes positive or negative expression of a marker of exhaustion. In certain embodiments, the phenotype is or includes positive or negative expression of a specific molecule that is associated with exhaustion. In certain embodiments, the specific molecule is any molecule that is associated with exhaustion or a quality associated with exhaustion, e.g., poor effector function or inhibitory receptor expression. In particular embodiments, the phenotype is positive or negative expression of an immune checkpoint inhibitor. In particular embodiments, marker of exhaustion is CTLA-4, FOXP3, PD- 1, TIGIT, LAB-3, 2B4, BTLA, TIM3, VISTA, or CD96, or a combination thereof. In certain embodiments, the phenotype is the positive or negative expression of CTLA-4, FOXP3, PD-l, TIGIT, LAB-3, 2B4, BTLA, TIM3, VISTA, or CD96, or a combination thereof. In particular embodiments, the phenotype is positive or negative expression of PD1 and / or FOXP3.

[0246] In some embodiments, the phenotype is or includes positive or negative expression of an exhaustion marker in a CD3+cell that expresses a recombinant receptor or a CAR. In particular embodiments, the phenotype is or includes positive or negative expression of an exhaustion marker in a CD4+cell that expresses a recombinant receptor or a CAR. In some embodiments, the phenotype is or includes positive or negative expression of an exhaustion marker and CD3+and positive expression of a recombinant receptor or a CAR. In particular embodiments, the phenotype is or includes positive or negative expression of an exhaustion marker in a CD4+cell that expresses a recombinant receptor or a CAR. In some embodiments, the phenotype is or includes positive or negative expression of an exhaustion marker in a CD8+cell that expresses a recombinant receptor or a CAR. In particular embodiments, the exhaustion marker is one or more of CTLA-4, FOXP3, PD-l, TIGIT, LAB-3, 2B4, BTLA, TIM3, VISTA, or CD96. In particular embodiments, the exhaustion marker is PD1 and / or FOXP3.

[0247] In particular embodiments, the phenotype is or includes PD1 / CD3+, PD1 / CD4+, PDl7CD8+, PDl7CD3+ / CAR+, PD 17CD47C AR+, PD 17CD87C AR+, PDl7annexin V , PDl7annexin V7CD3+, PDl7annexin V7CD4+, PDl7annexin V7CD8+, PDl7annexin V / CD37CAR+, PDl7annexin V7CD47CAR+, PDl7annexin V7CD87CAR+, PDl7activated caspase 3 PDl7activated caspase 37CD3+, PDl7activated caspase 37CD4+, PDl7activated caspase 37CD8+, PDl7activated caspase 37CD37CAR+, PDl7activated caspase37CD47CAR+, PDl7activated caspase 37CD87CAR+, or a combination thereof.

[0248] In certain embodiments, the phenotype is or includes FOXP37CD3+, FOXP3_CD4+, FOXP37CD8+, FOXP37CD37CAR+, FOXP37CD47CAR+, FOXP37CD87CAR+,FOXP37annexin V , FOXP37annexin V7CD3+, FOXP37annexin V7CD4+, FOXP37annexin V7CD8+, FOXP37annexin V / CD37CAR+, FOXP37annexin V7CD47CAR+,FOXP37annexin V7CD87CAR+, FOXP37activated caspase 37 FOXP37activated caspase 37CD3+, FOXP37activated caspase 37CD4+, FOXP37activated caspase 37CD8+,FOXP37activated caspase 37CD37CAR+, FOXP37activated caspase 37CD47CAR+,FOXP37activated caspase 37CD87CAR+, or a combination thereof.

[0249] In certain embodiments, the phenotype is the negative expression of a specific molecule that is associated with T cell activation. In some embodiments, the phenotype is or includes the negative expression of one or more of a specific molecule that is an activation marker. In general, T cell activation requires two simultaneous signals. The first is binding of the T cell receptor complex (TCR) to a major histocompatibility complex (MHC) molecule carrying a peptide antigen. The second is provided by the binding of the co- stimulatory receptorCD28 to proteins in the surface of the APC, such as B7-2 or B7-1. In certain embodiments, the specific molecule is associated with TCR activation, e.g., is activated, altered, or expressed as a result of T cell activation. In some embodiments, the specific molecule is associated with activation of a CD28 receptor, e.g., a molecule that is activated, altered, or expressed as a result of T cell activation.

[0250] In particular embodiments, the phenotype is or includes the negative expression of one or more of a specific molecule that is an activation marker. In certain embodiments, the activation marker is one or more of CD25, CD26, CD27, CD28, CD30, CD71, CD154, CD40L, CD127, LAG3, Ki67, or a combination thereof. In certain embodiments, the phenotype is the negative or positive expression of one or more of CD25, CD26, CD27, CD28, CD30, CD71, CD154, CD40L, CD127, LAG3, or Ki67. In certain embodiments, the phenotype is or includes the expression of CD25, CD 127, LAG3, Ki67, or a combination thereof.

[0251] In some embodiments, the phenotype is or includes positive or negative expression of an activation marker in a CD3+cell that expresses a recombinant receptor or a CAR. In particular embodiments, the phenotype is or includes positive or negative expression of activation marker in a CD4+cell that expresses a recombinant receptor or a CAR. In some embodiments, the phenotype is or includes positive or negative expression of activation marker in a CD8+cell that expresses a recombinant receptor or a CAR. In particular embodiments, the activation marker is one or more of CD25, CD26, CD27, CD28, CD30, CD71, CD154, CD40L, CD127, LAG3, or Ki67. In particular embodiments, the activation marker is CD25, CD127, LAG3, Ki67, or a combination thereof.

[0252] In particular embodiments, the phenotype is or includes positive or negative expression of an activation marker and CD3+, CD4+, CD8+, CD3+ / CAR+, CD4+ / CAR+,CD8+ / CAR+, annexin V-, annexin V CD3+, annexin V7CD4+, annexin V7CD8+, annexin V / _CD37CAR+, annexin V7CD47CAR+, annexin V7CD87CAR+, activated caspase 3 activated caspase 37CD3+, activated caspase 37CD4+, activated caspase 3 / CD8+, activated caspase 37CD37CAR+, activated caspase 37 CD47CAR+, activated caspase 37CD87CAR+, or a combination thereof.

[0253] In some embodiments, the phenotype is assessed by a response to a stimulus, for example a stimulus that triggers, induces, stimulates, or prolongs an immune cell function. In certain embodiments, the cells are incubated in the presence of stimulating conditions or a stimulatory agent, the phenotype is or includes the response to the stimulation. In particular embodiments, the phenotype is or includes the production or secretion of a soluble factor inresponse to one or more stimulations. In some embodiments, the phenotype is or includes a lack or production or secretion of a soluble factor in response to one or more stimulations. In certain embodiments, the soluble factor is a cytokine. In some embodiments, the cytokine is IL-2. In some embodiments, the cytokine is TNFa.

[0254] The conditions can include one or more of particular media, temperature, oxygen content, carbon dioxide content, time, agents, e.g., nutrients, amino acids, antibiotics, ions, and / or stimulatory factors, such as cytokines, chemokines, antigens, binding partners, fusion proteins, recombinant soluble receptors, and any other agents designed to activate the cells. In some embodiments, the cells are stimulated and the phenotype is determined by whether or not a soluble factor, e.g., a cytokine or a chemokine, is produced or secreted. In some embodiments, the stimulation is nonspecific, i.e., is not an antigen- specific stimulation. In some embodiments, the stimulation comprises PMA and ionomycin. In some embodiments, cells are incubated in the presence of stimulating conditions or a stimulatory agent for about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 18 hours, about 24 hours, about 48 hours, or for a duration of time between 1 hour and 4 hours, between 1 hour and 12 hours, between 12 hours and 24 hours, or for more than 24 hours.

[0255] In some embodiments, the cells are stimulated with an agent that is an antigen or an epitope thereof that is specific to the recombinant receptor, or is an antibody or fragment thereof that binds to and / or recognizes the recombinant receptor, or a combination thereof. In some embodiments, the recombinant receptor is a CAR, and the agent is an antigen or an epitope thereof that is specific to the CAR, or is an antibody or fragment thereof that binds to and / or recognizes the CAR, or a combination thereof. In particular embodiments, the cells are stimulated by incubating the cells in the presence of target cells with surface expression of the antigen that is recognized by the CAR. In certain embodiments, the recombinant receptor is a CAR, and the agent is an antibody or an active fragment, variant, or portion thereof that binds to the CAR. In certain embodiments, the antibody or the active fragment, variant, or portion thereof that binds to the CAR is an anti-idiotypic (anti-ID) antibody.

[0256] In some embodiments, the stimulating conditions or agents include one or more agent, e.g., ligand, which is capable of stimulating or activating an intracellular signaling domain of a TCR complex. In some aspects, the agent turns on or initiates TCR / CD3 intracellular signaling cascade in a T cell. Such agents can include antibodies, such as those specific for a TCR component and / or costimulatory receptor, e.g., anti-CD3, anti-CD28, forexample, bound to a solid support such as a bead, and / or one or more cytokines. In some embodiments, the one or more agents are PM A and ionomycin.

[0257] In particular embodiments, the phenotype is or includes the production or secretion of a cytokine in response to one or more of stimulations. The production and / or the secretion of cytokines contributes to immune responses, and is involved in different processes including the induction of anti- viral proteins and the induction of T cell proliferation. Cytokines are not pre formed factors but are rapidly produced and secreted in response to cellular activation. The production or secretion of cytokines may be measured, detected, and / or quantified by any suitable technique known in the art.

[0258] In certain embodiments, the phenotype is the production of one or more cytokines. In some embodiments, the production of two or more cytokines from the same cell can be indicative of polyfunctional features of such cells. In particular embodiments, the production of one or more cytokines is measured, detected, and / or quantified by intracellular cytokine staining. Intracellular cytokine staining (ICS) by flow cytometry is a technique well- suited for studying cytokine production at the single-cell level. It detects the production and accumulation of cytokines within the endoplasmic reticulum after cell stimulation, allowing for the identification of cell populations that are positive or negative for production of a particular cytokine or for the separation of high producing and low producing cells based on a threshold. In someembodiments, as described above, the stimulation can be performed using nonspecific stimulation, e.g., is not an antigen-specific stimulation. For example, PMA / ionomycin can be used for nonspecific cell stimulation. In some embodiments, the stimulation can be performed by an agent that is an antigen or an epitope thereof that is specific to the recombinant receptor (e.g., CAR), or is an antibody or fragment thereof that binds to and / or recognizes therecombinant receptor, or a combination thereof. ICS can also be used in combination with other flow cytometry protocols for immunephenotyping using cell surface markers or with MHC multimers to access cytokine production in a particular subgroup of cells, making it an extremely flexible and versatile method. Other single-cell techniques for measuring or detecting cytokine production include, but are not limited to ELISPOT, limiting dilution, and T cell cloning.

[0259] In some embodiments, the phenotype is the production of a cytokine, such as following stimulation of the recombinant receptor with an antigen specific to and / or recognized by the recombinant receptor. In particular embodiments, the phenotype is the lack of the production of the cytokine, such as following stimulation of the recombinant receptor with anantigen specific to and / or recognized by the recombinant receptor. In particular embodiments, the phenotype is positive for or is a high level of production of a cytokine. In certainembodiments, the phenotype is negative for or is a low level of production of a cytokine.Cytokines may include, but are not limited to, interleukin-l (IL-l), IL-1 b, IL-2, sIL-2Ra, IL-3, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL 27, IL-33, IL-35, TNF, tumor necrosis factor alpha (TNF-a), CXCL2, CCL2, CCL3, CCL5, CCL17, CCL24, PGD2, LTB4, interferon gamma (IFN-g), granulocyte macrophage colony stimulating factor (GM-CSF), macrophageinflammatory protein (MIR)-Ia, MIR-Ib, Flt-3L, fracktalkine, and / or IL-5. In someembodiments, the phenotype includes production of cytokines, e.g., cytokines associated with particular cell types, such as cytokines associated with Thl, Th2, Thl7 and / or Treg subtypes. In some embodiments, exemplary Thl -related cytokines include IL-2, IFN-g, and transforming growth factor beta (TGF-b), and in some cases are involved in cellular immune responses. In some embodiments, exemplary Th2-related cytokines include IL-4, IL-5, IL-6, IL-10 and IL-13, and in some cases are associated with humoral immunity and anti-inflammatory properties. In some embodiments, exemplary Thl7-related cytokines include IL-17A and IL-17F, and in some cases are involved in recruiting neutrophils and macrophages, e.g., during an inflammatory reaction.

[0260] In some embodiments, the phenotype is or includes the production of a cytokine. In certain embodiments, the phenotype is or includes the production of more than onecytokine(e.g., polyfunctional). In certain embodiments, the phenotype is or includes a lack of a production of one or more cytokines. In certain embodiments, the phenotype is or includes the production, or lack thereof, of one or more of IL-2, IL-5, IL-13, IFN-gamma, or TNF-alpha. In certain embodiments, the phenotype is or includes the production, or lack thereof, of one or more of IL-2, IL-13, IFN-gamma, or TNF-alpha. In some embodiments, the phenotype is the presence of a production, and / or the presence of a high level of production of the cytokine. In some embodiments, the phenotype is a low, reduced, or absent production of a cytokine.

[0261] In some embodiments, the phenotype is or includes the internal (intracellular) production of a cytokine, for example, as assessed in the presence of a stimulatory agent or under stimulatory conditions when secretion is prevented or inhibited. In some embodiments, the stimulatory agent is nonspecific stimulatory agent, e.g., a stimulatory agent that does not bind to an antigen binding domain, for example on a recombinant receptor (e.g., CAR). In some embodimetns, the stimulatory agent is PMA / ionomycin, which can act as a nonspecific stimulatory agent. In some embodiments, the stimulatory agent is a specific stimulatory agent,e.g., is a stimulatory agent that is an antigen or an epitope thereof that is specific to the recombinant receptor (e.g., CAR), or is an antibody or fragment thereof that binds to and / or recognizes the recombinant receptor, or a combination thereof. In particular embodiments, the phenotype is or includes the lack or absence of an internal production of a cytokine. In certain embodiments, the phenotype is or includes the internal amount of one or more cytokines when the production of more than one cytokines as assessed with an ICS assay. In certainembodiments, the phenotype is or includes the internal amount of one or more of IL-2,IL-5, IL- 13, IFN-gamma, or TNF-alpha as assessed with an ICS assay. In some embodiments, the phenotype is or includes a low internal amount or a lack of a detectable amount of one or more cytokines as assessed with an ICS assay. In certain embodiments, phenotype is or includes a low internal amount or a lack of a detectable amount of IL-2, IL-5, IL-13, IFN-gamma, or TNF- alpha as assessed with an ICS assay. In some embodiments, the phenotype includes assessment of multiple cytokines, e.g., by multiplexed assays or assays to assess polyfunctionality (see, e.g., Xue et ah, (2017) Journal for ImmunoTherapy of Cancer 5:85). In some embodiments, the lack of cytokine expression is inversely correlated with or associated with activity and / or function of the cells and / or durability of response and progression free survival. In some embodiments, cells with reduced, minimal or no cytokine production, assessed according to any known method or method described herein, are reduced in the cell composition (e.g., output composition, therapeutic cell composition).

[0262] Particular embodiments contemplate that the phenotype may include the production of a cytokine or a lack of or a low amount of production for a cytokine. This may depend on several factors that include, but are not limited to, the identity of the cytokine, the assay performed to detect the cytokine, and the stimulatory agent or condition used with the assay.For example, in some embodiments it is contemplated that the phenotype is or includes a lack of, or a low level of IL-13 production as indicated by ICS while in some embodiments, the phenotype is or includes production of IFN-gamma as indicated by ICS.

[0263] In some embodiments, the phenotype is or includes production of one or more cytokines and either CD3+, CD4+, CD8+, CD3+ / CAR+, CD4+ / CAR+, CD8+ / CAR+, annexin V, annexin V- CD3+, annexin V-CD4+, annexin V- CD8+, annexin V_CD3+ / CAR+, annexin V- CD4+ / CAR+, annexin V- CD8+ / CAR+, activated caspase 3_, activated caspase 3 CD3+, activated caspase 37CD4+, activated caspase 37CD8+, activated caspase 37CD3+ / CAR+, activated caspase 37CD4+ / CAR+, or activated caspase 37CD8+ / CAR+, or a combination thereof. In particular embodiments, the phenotype is or includes production of one or more cytokines inCD4+ / CAR+and / or CD8+ / CAR+. In some embodiments, the one or more cytokines are IL-2, IFN-gamma, and / or TNF-alpha. In some embodiments, the phenotype is or includes production of IL-2 in CD4+ / CAR+cells. In some embodiments, the phenotype is or includes production of TNF-alpha in CD4+ / CAR+cells. In some embodiments, the phenotype is or includes production of IL-2 and TNF-alpha in CD4+ / CAR+cells. In some embodiments, the phenotype is or includes production of IL-2 and IFN-gamma in CD4+ / CAR+cells. In some embodiments, the phenotype is or includes production of TNF-alpha in CD8+ / CAR+cells. In some embodiments, the phenotype is or includes production of IFN-gamma and TNF-alpha in CD8+ / CAR+cells. In some embodiments, the phenotype is or includes production of IL-2 in activated caspase 3 CD4+ / CAR+cells. In some embodiments, the phenotype is or includes production of TNF- alpha in activated caspase 37CD4+ / CAR+cells. In some embodiments, the phenotype is or includes production of IL-2 and TNF-alpha in activated caspase 37CD4+ / CAR+cells. In some embodiments, the phenotype is or includes production of IL-2 and IFN-gamma in activated caspase 37CD4+ / CAR+cells. In some embodiments, the phenotype is or includes production of TNF-alpha in activated caspase 37CD8+ / CAR+cells. In some embodiments, the phenotype is or includes production of IFN-gamma and TNF-alpha in activated caspase 37CD8+ / CAR+cells. In some embodiments, the phenotype is or includes production of TNF-alpha in annexinV7CD4+ / CAR+cells. In some embodiments, the phenotype is or includes production of IL-2 and TNF-alpha in annexin V7CD4+ / CAR+cells. In some embodiments, the phenotype is or includes production of IL-2 and IFN-gamma in annexin V7CD4+ / CAR+cells. In some embodiments, the phenotype is or includes production of TNF-alpha in annexin V7CD8+ / CAR+cells. In some embodiments, the phenotype is or includes production of IFN-gamma and TNF- alpha in annexin V7CD8+ / CAR+cells. In some embodiments, the phenotypes described in this paragraph are positively correlated with durable response and progression free survival. Thus, in some embodiments, cells including these phenotypes are maximized or increased in the cell composition (e.g., output composition, therapeutic cell composition). In some embodiments, the cell composition includes at least at or about, or at or about, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells, such as engineered CD4 T cells expressing a recombinant receptor (e.g., CAR), in the composition that are capable of producing a cytokine selected from interleukin 2 (IL-2) and / or TNF-alpha. In some embodiments, the cell composition includes at least at or about, or at or about, 10%, 15%, 20%, 25%, 30%, 40% or more, of the total number of CD4+ T cells, such as engineered CD4 T cells expressing a recombinant receptor (e.g., CAR), in the composition polyfunctional forproducing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha.

[0264] In some embodiments, the phenotype is or includes a lack of production of one or more cytokines. In certain embodiments, the phenotype is or includes a lack of a production of one or more cytokines and either CD3+, CD4+, CD8+, CD3+ / CAR+, CD4+ / CAR+, CD8+ / CAR+, annexin V-, annexin V- CD3+, annexin V-CD4+, annexin V- CD8+, annexin V_CD3+ / CAR+, annexin V- CD4+ / CAR+, annexin V- CD8+ / CAR+, activated caspase 3_, activated caspase 3 CD3+, activated caspase 37CD4+, activated caspase 37CD8+, activated caspase37CD3+ / CAR+, activated caspase 37CD4+ / CAR+, or activated caspase 37CD8+ / CAR+, or a combination thereof. In some embodiments, the one or more cytokines are IL-2, IFN-gamma, and / or TNF-alpha. In some embodiments, the phenotype is or includes the lack of production of IL-2 in activated caspase 37CD4+ / CAR+cells. In some embodiments, the phenotype is or includes the lack of production of TNF-alpha in activated caspase 37CD4+ / CAR+cells. In some embodiments, the phenotype is or includes the lack of production of IL-2 and TNF-alpha in activated caspase 37CD4+ / CAR+cells. In some embodiments, the phenotype is or includes the lack of production of IL-2 and IFN-gamma in activated caspase 37CD4+ / CAR+cells. In some embodiments, the phenotype is or includes the lack of production of TNF-alpha in activated caspase 37CD8+ / CAR+cells. In some embodiments, the phenotype is or includes the lack of production of INF-gamma and TNF-alpha in activated caspase 37CD8+ / CAR+cells. In some embodiments, the phenotypes described in this paragraph are negatively correlated with durable response and progression free survival. Thus, in some embodiments, cells including these phenotypes are minimized or reduced in the cell composition (e.g., output composition, therapeutic cell composition). For example, in some embodiments, cells including the phenotype of this paragraph compose less than 2%, 5%, 10%, 15,%, 20,%, or 25% of the total cells in the cell composition (e.g., output composition, therapeutic cell composition).

[0265] In particular embodiments, the phenotype is or includes the presence or absence of an internal amount of one or more of IL-2, IL-13, IFN-gamma, or TNF-alpha as assessed with an ICS assay and one or more specific markers for a subset of cells or cells of a particular cell type. In some embodiments, the phenotype is or includes production, or lack thereof, of one or more of IL-2, IL-13, IFN-gamma, or TNF-alpha and CD4+ / CAR+and / or CD8+ / CAR+. In certain embodiments, the phenotype is or includes production of IL-2 and CD4+ / CAR+and / orCD8+ / CAR+. In some embodiments, the phenotype is or includes a lack of or low production of IL-2 and CD4+ / CAR+and / or CD8+ / CAR+. In some embodiments, the phenotype is or includesproduction of IL-13 and CD4+ / CAR+and / or CD8+ / CAR+. In some embodiments, the phenotype is or includes production of IL-13 and CD4+ / CAR+and / or CD8+ / CAR+. In certain embodiments, the phenotype is or includes the lack of or low production of IL 13 and CD4+ / CAR+and / or CD8+ / CAR+. In some embodiments, the phenotype is or includes production of IFN-gamma and CD4+ / CAR+and / or CD8+ / CAR+. In certain embodiments, the phenotype is or includes production of TNF-alpha and CD4+ / CAR+and / or CD8+ / CAR+. In certain embodiments, the phenotype is or includes a lack of or low production of TNF-alpha and CD4+ / CAR+and / or CD8+ / CAR+.

[0266] Any one or more the phenotypes, alone or in combination, can be assessed or determined in accord with the provided methods. In some embodiments, the phenotype is CD3+, CD3+ / CAR+, CD4+ / CAR+, CD8+ / CAR+, or a combination thereof.

[0267] In certain embodiments, the phenotype is or includes CD3+. In certain embodiments, the phenotype is or includes CD3+ / CAR+. In some embodiments, the phenotype is or includes CD8+ / CAR+. In certain embodiments, the phenotype is or includes CD4+ / CAR+.

[0268] In particular embodiments, the phenotype is or includes Annexin / CD3+ / CAR+. In some embodiments, the phenotype is or includes Annexin CD4+ / CAR+In particularembodiments, the phenotype is Annexin7CD8+ / CAR.

[0269] In particular embodiments, the phenotype is or includes a lack of or a low amount of intracellular IL-2 and CD4+ / CAR+. In particular embodiments, the phenotype is a lack of or a low amount of intracellular IL-13 and CD4+ / CAR+. In some embodiments, the phenotype is a lack of or a low amount of intracellular expression of IL-13 and CD8+ / CAR+cells. In particular embodiments, the phenotype is a lack of or a low amount of intracellular TNF-alphaCD4+ / CAR+.

[0270] In certain embodiments, the phenotype is or includes CD8+ / CAR+. In certain embodiments, the phenotype is or includes annexin7CD8+ / CAR+.

[0271] In some embodiments, the phenotype comprises an indicator of production of one or a combination of cytokines, optionally non-specific to the antigen or the recombinant receptor and / or that is polyclonally produced, wherein the one or more cytokines is IL-2, IL-13, IL-17, IFN-gamma or TNF-alpha. In some embodiments, the indicator of production is measured in an assay, optionally an intracellular cytokine staining assay, comprising incubating a sample of the T cell composition with a polyclonal agent, an antigen-specific agent or an agent that binds the recombinant receptor, optionally CAR. In some embodiments, the agent is or comprises PMA and ionomycin or is or comprises a T cell receptor or T cell receptor complex agonist. In someembodiments, the phenotype comprises negative expression of an activation marker, wherein the activation marker is selected from among CD25, CD 127, LAG3, Ki67 and combinations thereof. In some embodiments, the phenotype comprises negative expression of an exhaustion marker, wherein the exhaustion maker is a PD1 or FOXP3 gene product or a combination thereof. In some embodiments, the phenotype comprises a naive phenotype or a memory phenotype, optionally wherein the memory phenotype comprises a T effector memory phenotype, a T central memory phenotype, or a T effector memory phenotype expressing CD45RA (Temra).

[0272] In some embodiments, the recombinant receptor-dependent (e.g., CAR) activity is a measure of the production or accumulation of a proinflammatory cytokine, optionally, one of or a combination of TNF-alpha, IFN-gamma, and IL-2. In some embodiments, a reference measure is the average of the measure among a plurality, optionally at least 10, at least 15, at least 20, of reference therapeutic T cell compositions comprising the recombinant receptor (e.g., CAR) in which: (i) each of the reference therapeutic T cell compositions has been observed or determined to result in an acceptable safety profile following administration to a subject, optionally wherein the subject has a disease or condition expressing or associated with the antigen; and / or (ii) each of the reference therapeutic T cell compositions has been observed or determined to result in a desired efficacy following administration to a subject, optionally wherein the subject has a disease or condition expressing or associated with the antigen.

[0273] In certain embodiments, a number, multiple, or fraction of cells of a particular phenotype of a cell composition is determined, measured, obtained, detected, observed, and / or identified. In some embodiments, the cell composition is a T cell composition. In certain embodiments, the cell composition contains cells that express a recombinant receptor, e.g., a CAR. In particular embodiments, the cell composition is a therapeutic T composition containing cells that express a recombinant receptor that may be administered to a subject to treat a disease or condition. In certain embodiments, the number of cells of the phenotype is the total amount of cells of the phenotype of the cell composition. In certain embodiments, the number of cells of the phenotype is the total number of cells of the phenotype present in a dose of the cell composition. In particular embodiments, the number of cells of the phenotype is the number of cells of the phenotype present in a sample of the cell composition. In some embodiments, the number of the cells of the phenotype may be expressed as a frequency, ratio, and / or a percentage of cells of the phenotype present in the cell composition, or a dose or a sample thereof.

[0274] In particular embodiments, the number, multiple, or fraction of the cells of a phenotype is transformed, for example to compress the range of relevant values of the number, multiple, or fraction. In some embodiments, the transformation is any application of a deterministic mathematical function to each point in a data set, such as, each data point x is replaced with the transformed value y = f(x), where f is a function. In general, transforms may be applied so that the data appear to more closely meet the assumptions of a statistical inference procedure that is to be applied, or to improve the interpretability or appearance of graphs. In most cases the function that is used to transform the data is invertible, and generally is continuous. The transformation is usually applied to a collection of comparable measurements. Examples of suitable transformations include, but are not limited to, logarithm and square root transformation, reciprocal transformations, and power transformations. In certain embodiments, the number, multiple, or fraction of the cells of a phenotype is transformed by a logarithmic transformation. In certain embodiments, the logarithmic transformation is a common log (logio(x)), a natural log (ln(x)) or a binary log (log2(x)).B. Determining Dosing and Administration

[0275] The therapeutic composition or a dose thereof, in some embodiments contains the cells in amounts effective to treat or prevent the disease or condition, such as a therapeutically effective or prophylactically effective amount. In some embodiments, the composition includes the cells in an amount effective to reduce burden of the disease or condition. In some embodiments, the composition includes cells in an amount that provides more consistent outcome, e.g., response and / or safety outcomes, among a group of subjects administered the composition, and / or more consistent pharmacokinetic parameters. In some embodiments, the composition includes the cells in an amount effective to promote durable response and / or progression free survival. In some aspects, the provided methods involve assessing a therapeutic composition containing T cells for cell phenotypes, and determining doses based on such outcomes.

[0276] In some embodiments, the dose is determined to encompass a relatively consistent number, proportion, ratio and / or percentage of engineered cells having a particular phenotype in one or more particular compositions. In some aspects, the consistency is associated with or related to a relatively consistent activity, function, pharmacokinetic parameters, toxicity outcome and / or response outcome. In some aspects, in a plurality of subjects, compositions and / or doses the numbers, proportion, ratio and / or percentage, are relatively consistent, e.g., thenumber or ratio of cells that have a particular phenotoype, e.g., express CCR7 (CCR7+) or, that produce a cytokine, for example, produce IL-2, TNF-alpha, or IFN-gamma, in the composition or unit dose, varies by no more than 40%, by no more than 30%, by no more than 20%, by no more than 10% or by no more than 5%. In some aspects the number or ratio of cells that have a particular phenotoype, e.g., express CCR7 (CCR7+), in the composition or unit dose, varies by no more than 20% or no more than 10% or no more than 5% from an average of said number or ratio in a plurality of T cell compositions produced by the process and / or varies from such average by no more than one standard deviation or varies by no more than 20% or no more than 10% or no more than 5% among a plurality of T cell compositions or doses determined. In some embodiments, the plurality of subjects includes at least 10 subjects, such as at least 15, at least 20, at least 25, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100 or more subjects.

[0277] In some aspects, the dose, e.g., one or more unit dose(s) is determined based on the number, percentage, ratio, frequency and / or proportion of a particular subset of engineered T cells, e.g., cells having a particular phenotype, such as particular surface marker phenotype. In some aspects, the cell phenotype is determined based on expression and / or absence of expression of particular cell markers, e.g., surface markers. In some aspects, the cell marker includes markers indicative of viability and / or apoptotic state of the cells. In some aspects, exemplary markers include CD3, CD4, CD8, CCR7, CD27, CD45RA, annexin V, or activated caspase 3. In some aspects, an exemplary marker is CCR7. In some aspects, an exemplary marker is CD27. In some aspects, exemplary markers include CCR7 and / or CD27. In some aspects, exemplary markers include CCR7, CD27 and / or CD45RA.

[0278] In some embodiments, provided are methods involving administering to a subject one or more unit doses of a therapeutic T cell composition, such as any described herein and / or any unit dose determined by the methods provided herein.

[0279] In some embodiments, provided are methods involving administering to a subject having a disease or condition a unit dose of a T cell composition comprising cells comprising a recombinant receptor, such as a chimeric antigen receptor (CAR), that specifically binds to an antigen associated with the disease or condition, wherein either a defined number of total recombinant receptor-expressing cells (receptor+) of the therapeutic composition, total CD8+recombinant receptor-expressing cells (receptor+ / CD8+) are administered and / or a unit dose of such cells is administered in which the unit dose contains a defined number, percentage, ratio, frequency and / or proportion of cells with a certain phenotype, e.g., CCR7+ / CD4+, CCR7+ / CD8+,CD27+ / CD4+, CD27+ / CD8+, CD45RA+ / CD4+, CD45RA+ / CD8+, CCR77CD4+, CCR77CD8+, CD277CD4+, CD277CD8+, CD45RA 7CD4+, CD45RA 7CD8+, CCR77CD277CD4+,CCR77CD277CD8+, CCR77CD45RA 7CD4+, CCR77CD45RA 7CD8+, CCR77CD45RA / CD4+, CCR77CD45RA 7CD8+, CCR77CD277CD4+, CCR77CD277CD8+.

[0280] In some embodiments, the unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express C-C chemokine receptor type 7 (CCR7) (receptor7CD87CCR7+cells) and / or a defined number of recombinant receptor expressing CD4+T cells that express CCR7 (receptor7CD47CCR7+cells) and / or a defined ratio of receptor7CD87CCR7+cells to receptor7CD47CCR7+cells and / or a defined ratio of receptor7CD87CCR7+cells and / or receptor7CD47CCR7+cells to another subset of cells in the composition. In some embodiments, the unit dose of cells comprises a defined number of CD87CCR7+cells. In some embodiments, the unit dose of cells comprises a defined number of CD47CCR7+cells. In some embodiments, the defined number or ratio is further based on expression or absence of expression of CD27 and / or CD45RA on the cells.

[0281] In some embodiments, the unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express cluster of differentiation 27 (CD27) (receptor7CD87CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CD27 (receptor7CD47CD27+cells) and / or a defined ratio of receptor7CD87CD27+cells to receptor7CD47CD27+cells and / or a defined ratio of receptor7CD87CD27+cells and / or receptor7CD47CD27+cells to another subset of cells in the composition. In some embodiments, the unit dose of cells comprises a defined number of CD87CD27+cells. In some embodiments, the unit dose of cells comprises a defined number of CD47CD27+cells. In some embodiments, the defined number or ratio is further based on expression or absence of expression of CCR7 and / or CD45RA on the cells.

[0282] In some embodiments, the unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express CCR7 and CD27(receptor7CD87CCR77CD27+cells) and / or a defined number of recombinant receptor expressing CD4+T cells that express CCR7 and CD27 (receptor7CD47CCR77CD27+cells) and / or a defined ratio of receptor7CD8 CCR77CD27+cells to receptor7CD47CCR77CD27+cells and / or a defined ratio of receptor7CD87CCR77CD27+cells and / orreceptor7CD47CCR77CD27+cells to another subset of cells in the composition. In some embodiments, the unit dose of cells comprises a defined number of CD87CCR77CD27+cells.In some embodiments, the unit dose of cells comprises a defined number ofCD4+ / CCR7+ / CD27+cells. In some embodiments, the defined number or ratio is further based on expression or absence of expression of CD45RA on the cells.

[0283] In some embodiments, the number of cells in the unit dose is the number of cells or number of recombinant receptor-expressing or CAR-expressing cells, or number, percentage, ratio, frequency and / or proportion of such cells of a certain phenotype, e.g. cells that express or do not express one or more markers selected from CD3 CD4, CD8, CCR7, CD27, CD45RA, annexin V, or activated caspase 3, that it is desired to administer to a particular subject in a dose, such as a subject from which the cells have been derived. In some embodiments, the number of cells in the unit dose is the number of cells or number of recombinant receptor-expressing or CAR-expressing cells, or number, percentage, ratio, frequency and / or proportion of such cells of a certain phenotype, e.g., CCR7+, CD27+, CD45RA+, CD45RA , CD4+, CD8+, CD3+, apoptosis marker negative (e.g. Annexin V or Caspase 3 ) cells, or cells that are positive or negative for one or more of any of the foregoing.

[0284] In some embodiments, the number of cells in the unit dose is the number of cells or number of recombinant receptor-expressing or CAR-expressing cells, or number, percentage, ratio and / or proportion of such cells of a certain phenotype, e.g., CCR7+ / CD4+, CCR7+ / CD8+, CD27+ / CD4+, CD27+ / CD8+, CD45RA+ / CD4+, CD45RA+ / CD8+, CCR77CD4+, CCR77CD8+, CD277CD4+, CD277CD8+, CD45RA 7CD4+, CD45RA 7CD8+, CCR77CD277CD4+,CCR77CD277CD8+, CCR77CD45RA 7CD4+, CCR77CD45RA 7CD8+, CCR77CD45RA / CD4+, CCR77CD45RA 7CD8+, CCR77CD277CD4+, CCR77CD277CD8+; and apoptosis marker negative (e.g. Annexin V or Caspase 37 cells, that it is desired to administer to a particular subject in a dose, such as a subject from which the cells have been derived. In some embodiments, the unit dose contains a defined number of cells or number of recombinant receptor-expressing or CAR-expressing cells, or number, percentage, ratio and / or proportion of such cells of a certain phenotype e.g., CCR77CD4+, CCR77CD8+, CD277CD4+, CD277CD8+, CD45RA7CD4+, CD45RA7CD8+, CCR77CD4+, CCR77CD8+, CD277CD4+, CD277CD8+, CD45RA 7CD4+, CD45RA 7CD8+, CCR77CD277CD4+, CCR77CD277CD8+,CCR77CD45RA 7CD4+, CCR77CD45RA 7CD8+, CCR77CD45RA 7CD4+, CCR77CD45RA / CD8+, CCR77CD277CD4+, CCR77CD277CD8+; and apoptosis marker negative (e.g. Annexin V or Caspase 3 ) cells, and / or any subset thereof.

[0285] In some embodiments, the unit dose is determined based on the number of cells or cell type(s) and / or a frequency, ratio, and / or percentage of cells or cell types, e.g., individual populations, phenotypes, or subtypes, in the cell composition, such as those with the phenotypesof annexin V7CCR7+ / CAR+; annexin V7CCR7+ / CAR7CD4+; annexin V / CCR77CAR7CD8+; annexin V7CD277CAR+; annexin V7CD277CAR7CD4+; annexin V7CD277CAR7CD8+; annexin V7CCR77CD277CAR+; annexin V7CCR77CD277CAR7CD4+; annexin V / CCR7 CD27 C AR7CD 8+; annexin V / CCR77CD45RA / CAR+; annexin V / CCR77CD45RA / CAR7CD4+; annexin V / CCR77CD45RA / CAR7CD8+; annexin V / CCR7 / CD45RA / CAR+; annexin V / CCR7 / CD45RA / CAR7CD4+; annexin V / CCR7 / CD45RA / CAR7CD8+; annexin V7CCR7 / CD27 / CAR+, annexin V / CCR7 / CD27 / CAR7CD4+;annexin V / CCR7 / CD27 / CAR7CD8+; activated caspase 3 / CCR77CAR+; activated caspase 3 / CCR7 C AR7CD4+; activated caspase 3 / CCR77CAR7CD8+; activated caspase 3 / CD277CAR+; activated caspase 37CD277CAR7CD4+; activated caspase 3 / CD27 C AR7CD 8+; activated caspase 37CCR77CD277CAR+; activated caspase 3 / CCR7 CD27 C AR7CD4+; activated caspase 37CCR77CD277CAR7CD8+; activated caspase 3 / CCR77CD45RA / CAR+; activated caspase 37CCR77CD45RA7CAR7CD4+;activated caspase 3 / CCR77CD45RA / CAR7CD8+; activated caspase 3 / CCR7 / CD45RA / CAR+; activated caspase 3 / CCR7 / CD45RA / CAR7CD4+; activated caspase 3 / CCR7 / CD45RA / CAR7CD8+; activated caspase 3 / CCR7 / CD27 / CAR+; activated caspase 3 / CCR7 / CD27 / CAR7CD4+; and / or activated caspase 3 / CCR7 / CD27 / CAR7CD8+; or a combination thereof.

[0286] In some embodiments, the unit dose comprises between at or about 1 x 105and at or about 1 x 108, between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor7CD8+cells) or total CD4+cell that express the recombinant receptor (receptor7CD4+cells), total receptor7CD87CCR7+cells, total receptor7CD47CCR7+cells, total receptor7CD87CD27+cells, or total receptor7CD47CD27+cells, each inclusive. In some embodiments, the unit dose comprises no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor7CD8+cells or total receptor7CD4+cells, total receptor7CD87CCR7+cells, total receptor7CD47CCR7+cells, total receptor7CD87CD27+cells, or total receptor7CD47CD27+cells.

[0287] In some embodiments, the unit dose comprises between at or about 5 x 105and at or about 5 x 107, between at or about 1 x 106and at or about 1 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor7CD87CCR7+cells or receptor7CD47CCR7+cells, each inclusive. In some embodiments, the unit dose comprises at least or at least about 5 x 10 , 1 x107, 5 x 106, 1 x 106, or at least about 5 x 105total receptor+ / CD8+ / CCR7+cells or receptor+ / CD4+ / CCR7+cells.

[0288] In some embodiments, the unit dose comprises between at or about 5 x 105and at or about 5 x 107, between at or about 1 x 106and at or about 1 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CD27+cells or receptor+ / CD4+ / CD27+cells, each inclusive. In some embodiments, the unit dose comprises at least or at least about 5 x 10 , 1 x 107, 5 x 106, 1 x 106, or at least about 5 x 105total receptor+ / CD8+ / CD27+cells orreceptor+ / CD4+ / CD27+cells.

[0289] In some embodiments, the unit dose comprises at least at or about 1 x 106, 2 x 106, 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD8+ / CCR7+cells and / or at least at or about 1 x 106, 2 x 106, 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD4+ / CCR7+cells, each inclusive. In some embodiments, the unit dose comprises between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD4+ / CCR7+cells, each inclusive.

[0290] In some embodiments, the unit dose comprises at least at or about 1 x 106, 2 x 106, 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD8+ / CD27+cells and / or at least at or about 1 x 106, 2 x 106, 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x106, 9 x 106, or 1 x 107total receptor+ / CD4+ / CD27+cells, each inclusive. In some embodiments, the unit dose comprises unit dose comprises between at or about 3 x 106and at or about 2.5 x107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CD27+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD4+ / CD27+cells, each inclusive.

[0291] In some embodiments, the unit dose comprises between at or about 5 x 105and at or about 5 x 107, between at or about 1 x 106and at or about 1 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+ / CD27+cells orreceptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive. In some embodiments, the unit dose comprises at least or at least at or about 5 x 107, 1 x 107, 5 x 106, 1 x 106, or at least at or about 5 x 105total receptor+ / CD8+ / CCR7+ / CD27+cells or receptor+ / CD4+ / CCR7+ / CD27+cells.

[0292] In some embodiments, the unit dose comprises at least at or about 1 x 106, 2 x 106, 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107totalreceptor+ / CD8+ / CCR7+ / CD27+cells and / or at least at or about 1 x 106, 2 x 106, 3 x 106, 4 x 106,5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive. In some embodiments, the unit dose comprises between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+ / CD27+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive.

[0293] In some embodiments, the unit dose of cells comprises a defined ratio ofreceptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

[0294] In some embodiments, the unit dose of cells comprises a defined ratio ofreceptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

[0295] In some embodiments, the unit dose comprises between at or about 1 x 105and at or about 1 x 108, between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cell that express the recombinant receptor (receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+ / CD27+cells, or total receptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive. In some embodiments, the unit dose comprises no more than at or about 1 x 10 , no more than at or about 5 x 107, no more than at or about 1 x 107, no more than at or about 5 x 106, no more than at or about 1 x 106, or no more than at or about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, total receptor+ / CD8+ / CCR7+ / CD27+cells, or totalreceptor+ / CD4+ / CCR7+ / CD27+cells .

[0296] In some embodiments, the unit dose of cells comprises a defined ratio ofreceptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

[0297] In some embodiments, the unit dose comprises between at or about 1 x 105and at or about 5 x 108, between at or about 1 x 105 and at or about 1 x 108, between at or about 5 x 105 and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD3+cells that express the recombinant receptor (receptor+ / CD3+cells) or total CD3+cells, each inclusive.In some embodiments, the unit dose comprises no more than at or about 5 x 10 , no more than at or about 1 x 10 , no more than at or about 5 x 10 , no more than at or about 1 x 10 , no more than at or about 5 x 106, no more than at or about 1 x 106, or no more than at or about 5 x 105total receptor+ / CD3+cells or total CD3+cells.

[0298] In some embodiments, the total number of CD3+cells, total number ofreceptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number of receptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number of receptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number of receptor+ / CD4+ / CCR7+ / CD27+cells, total number of rcccptor+ / CD8+ / CCR7+ / CD45RA cells and / orrcccptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that are live or viable.In some embodiments, the total number of CD3+cells, total number of receptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number of receptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number of receptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number of receptor7CD47CCR7+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD45RA cells and / or receptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that do not express an apoptotic marker and / or is the total number of such cells that are apoptotic marker negative O, wherein the apoptotic marker is Annexin V or activated Caspase 3.

[0299] In some embodiments, in any of the composition comprising T cells expressing a recombinant receptor provided herein, at least at or about, or at or about, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition (or of the total number of T cells in the composition expressing the recombinant receptor), are surface positive for CCR7 and / or CD27.

[0300] In some embodiments, in any of the composition comprising T cells expressing a recombinant receptor provided herein, at least at or about, or at or about, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition (or of the total number of T cells in the composition expressing the recombinant receptor), are able to produce a cytokine selected from interleukin 2 (IL-2) and / or TNF-alpha.In some embodiments, the T cell able to produce IL-2 and / or TNF-alpha is a CD4+ T cell.

[0301] In some embodiments, in any of the composition comprising T cells expressing a recombinant receptor provided herein, at least at or about, or at or about, 15%, 20%, 30%, 40%,50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between at or about 15% and at or about 90%, between at or about 20% and at or about 80%, between at or about 30% and at or about 70%, or between at or about 40% and at or about 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD8+ / CCR7+or receptor+ / CD8+ / CD27+.In some embodiments, in any of the composition comprising T cells expressing a recombinant receptor provided herein, at least at or about 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between at or about 15% and at or about 90%, between at or about 20% and at or about 80%, between at or about 30% and at or about 70%, or between at or about 40% and at or about 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD4+ / CCR7+or receptor+ / CD4+ / CD27+. In some embodiments, at least at or about 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between at or about 15% and at or about 90%, between at or about 20% and at or about 80%, between at or about 30% and at or about 70%, or between at or about 40% and at or about 60%, each inclusive, of the total receptor+cells in the unit dose arereceptor+ / CD8+ / CCR7+ / CD27+, receptor+ / CD8+ / CCR7+ / CD45RA ,receptor+ / CD4+ / CCR7+ / CD27+or receptor+ / CD4+ / CCR7+ / CD45RA .

[0302] In some embodiments, in any of the composition comprising T cells expressing a recombinant receptor provided herein, at least at or about 50%, 60%, 70%, 80% or 90% of the total receptor+ / CD8+cells in the composition or unit dose are or the unit dose, or between at or about 50% and at or about 90%, between at or about 60% and at or about 90%, between at or about 70% and at or about 80%, each inclusive, of the total receptor+ / CD8+cells in the composition or the unit dose are receptor+ / CD8+ / CCR7+or receptor+ / CD8+ / CD27+’ or receptor+ / CD8+ / CCR7+ / CD27+. In some embodiments, in any of the composition comprising T cells expressing a recombinant receptor provided herein, at least at or about 50%, 60%, 70%, 80% or 90% of the total receptor+ / CD4+cells in the composition or unit dose are or the unit dose, or between at or about 50% and at or about 90%, between at or about 60% and at or about 90%, between at or about 70% and at or about 80%, each inclusive, of the total receptor+ / CD4+cells in the composition or the unit dose are receptor+ / CD4+ / CCR7+or receptor+ / CD4+ / CD27+’ or receptor+ / CD4+ / CCR7+ / CD27+. receptor+ / CD8+ / CCR7+ / CD27+,receptor+ / CD8+ / CCR7+ / CD45RA , receptor+ / CD4+ / CCR7+ / CD27+or receptor+ / CD4+ / CCR7+ / CD45RA . In some embodiments, at least at or about 50%, 60%, 70%, 80% or 90% of the total receptor+ / CD8+cells in the composition are receptor+ / CD8+ / CCR7+ / CD27+; or at leastat or about 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+ / CD4+cells in the composition are receptor+ / CD4+ / CCR7+ / CD27+.

[0303] In some embodiments, the unit dose comprises between at or about 1 x 105and at or about 1 x 108, between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cell that express the recombinant receptor (receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+cells, total receptor+ / CD4+ / CCR7+cells, total receptor+ / CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells, each inclusive. In some embodiments, the unit dose comprises no more than at or about 1 x 10 , no more than at or about 5 x 10 , no more than at or about 1 x 107, no more than at or about 5 x 106, no more than at or about 1 x 106, or no more than at or about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, totalreceptor+ / CD8+ / CCR7+cells, total receptor7CD4+ / CCR7+cells, total receptor7CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells.

[0304] In some embodiments, the unit dose of cells comprises a defined ratio ofreceptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

[0305] In some embodiments, the unit dose comprises between at or about 1 x 105and at or about 1 x 108, between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cell that express the recombinant receptor (receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+ / CD27+cells, or total receptor7CD47CCR7+ / CD27+cells, each inclusive. In some embodiments, the unit dose comprises no more than at or about 1 x 10 , no more than at or about 5 x 107, no more than at or about 1 x 107, no more than at or about 5 x 106, no more than at or about 1 x 106, or no more than at or about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, total receptor+ / CD8+ / CCR7+ / CD27+cells, or totalreceptor+ / CD4+ / CCR7+ / CD27+cells .

[0306] In some embodiments, the unit dose of cells comprises a defined ratio ofreceptor+ / CD8+ / CCR7+ / CD27+cells to receptor7CD47CCR7+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

[0307] In some embodiments, the provided methods involve administering a dose containing a defined number of cells. In some embodiments, the dose, such as the defined number of cells, such as a defined number of CAR+cells that are CCR7+ / CD4+, CCR7+ / CD8+, CD27+ / CD4+, CD27+ / CD8+, CD45RA7CD4+, CD45RA+ / CD8+, CCR77CD4+, CCR77CD8+, CD27 / CD4+,CD277CD8+, CD45RA 7CD4+, CD45RA 7CD8+, CCR77CD277CD4+, CCR77CD277CD8+, CCR77CD45RA 7CD4+, CCR77CD45RA 7CD8+, CCR77CD45RA 7CD4+, CCR77CD45RA / CD8+, CCR77CD277CD4+, or CCR77CD277CD8+, is between or between about 5.0 x 106and 2.25 x 107, 5.0 x 106and 2.0 x 107, 5.0 x 106and 1.5 x 107, 5.0 x 106and 1.0 x 107, 5.0 x 106and 7.5 x 106, 7.5 x 106and 2.25 x 107, 7.5 x 106and 2.0 x 107, 7.5 x 106and 1.5 x 107, 7.5 x 106and 1.0 x 107, 1.0 x 107and 2.25 x 107, 1.0 x 107and 2.0 x 107, 1.0 x 107and 1.5 x 107, 1.5 x 107and 2.25 x 107, 1.5 x 107and 2.0 x 107, 2.0 x 107and 2.25 x 107. In someembodiments, such dose, such as such defined number of cells refers to the total recombinant- receptor expressing cells in the administered composition. In some aspects, the defined number of recombinant receptor-expressing cells that are administered are cells that are apoptotic marker negative(-) and optionally wherein the apoptotic marker is Annexin V or activated Caspase 3.

[0308] In some embodiments, the dose of cells of the unit dose contains a number of cells, such as a defined number of cells, between at least or at least about 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, 10 x 106and about 15 xlO6recombinant-receptor expressing cells, such as recombinant-receptor expressing cells that are CCR77CD4+, CCR77CD8+, CD277CD4+, CD277CD8+, CD45RA7CD4+, CD45RA7CD8+, CCR77CD4+, CCR77CD8+, CD277CD4+, CD277CD8+, CD45RA 7CD4+, CD45RA 7CD8+, CCR77CD277CD4+, CCR77CD277CD8+, CCR77CD45RA 7CD4+, CCR77CD45RA 7CD8+, CCR77CD45RA 7CD4+, CCR77CD45RA / CD8+, CCR77CD277CD4+, or CCR77CD277CD8+, and / or that are apoptotic marker negative(-) and CD8+, optionally wherein the apoptotic marker is Annexin V or activated Caspase 3.

[0309] In some embodiments, a dose of cells is administered to subjects in accord with the provided methods, and / or with the provided articles of manufacture or compositions. In some embodiments, the size or timing of the doses is determined as a function of the particular disease or condition in the subject. In some cases, the size or timing of the doses for a particular disease in view of the provided description may be empirically determined.

[0310] In some embodiments, the dose of cells comprises between at or about 2 x 105of the cells / kg and at or about 2 x 106of the cells / kg, such as between at or about 4 x 105of the cells / kg and at or about 1 x 106of the cells / kg or between at or about 6 x 105of the cells / kg and at or about 8 x 105of the cells / kg. In some embodiments, the dose of cells comprises no more than 2 x 105of the cells (e.g. antigen-expressing, such as CAR-expressing cells) per kilogram body weight of the subject (cells / kg), such as no more than at or about 3 x 105cells / kg, no more than at or about 4 x 105cells / kg, no more than at or about 5 x 105cells / kg, no more than at orabout 6 x 105cells / kg, no more than at or about 7 x 105cells / kg, no more than at or about 8 x 105cells / kg, no more than at or about 9 x 105cells / kg, no more than at or about 1 x 106cells / kg, or no more than at or about 2 x 106cells / kg. In some embodiments, the dose of cells comprises at least or at least about or at or about 2 x 105of the cells (e.g. antigen-expressing, such as CAR- expressing cells) per kilogram body weight of the subject (cells / kg), such as at least or at least about or at or about 3 x 105cells / kg, at least or at least about or at or about 4 x 105cells / kg, at least or at least about or at or about 5 x 105cells / kg, at least or at least about or at or about 6 x 105cells / kg, at least or at least about or at or about 7 x 105cells / kg, at least or at least about or at or about 8 x 105cells / kg, at least or at least about or at or about 9 x 105cells / kg, at least or at least about or at or about 1 x 106cells / kg, or at least or at least about or at or about 2 x 106cells / kg.

[0311] In certain embodiments, the cells, or individual populations of sub-types of cells, are administered to the subject at a range of at or about 0.1 million to at or about 100 billion cells and / or that amount of cells per kilogram of body weight of the subject, such as, e.g., at or about 0.1 million to at or about 50 billion cells (e.g., at or about 5 million cells, at or about 25 million cells, at or about 500 million cells, at or about 1 billion cells, at or about 5 billion cells, at or about 20 billion cells, at or about 30 billion cells, at or about 40 billion cells, or a range defined by any two of the foregoing values), at or about 1 million to at or about 50 billion cells (e.g., at or about 5 million cells, at or about 25 million cells, at or about 500 million cells, at or about 1 billion cells, at or about 5 billion cells, at or about 20 billion cells, at or about 30 billion cells, at or about 40 billion cells, or a range defined by any two of the foregoing values), such as at or about 10 million to at or about 100 billion cells (e.g., at or about 20 million cells, at or about 30 million cells, at or about 40 million cells, at or about 60 million cells, at or about 70 million cells, at or about 80 million cells, at or about 90 million cells, at or about 10 billion cells, at or about 25 billion cells, at or about 50 billion cells, at or about 75 billion cells, at or about 90 billion cells, or a range defined by any two of the foregoing values), and in some cases at or about 100 million cells to at or about 50 billion cells (e.g., at or about 120 million cells, at or about 250 million cells, at or about 350 million cells, at or about 450 million cells, at or about 650 million cells, at or about 800 million cells, at or about 900 million cells, at or about 3 billion cells, at or about 30 billion cells, at or about 45 billion cells) or any value in between these ranges and / or per kilogram of body weight of the subject. Dosages may vary depending on attributes particular to the disease or disorder and / or patient and / or other treatments. In someembodiments, the dose of cells is a flat dose of cells or fixed dose of cells such that the dose of cells is not tied to or based on the body surface area or weight of a subject.

[0312] In some embodiments, for example, where the subject is a human, the dose includes fewer than about 5 x 10 total recombinant receptor (e.g., CAR)-expressing cells, T cells, or peripheral blood mononuclear cells (PBMCs), e.g., in the range of at or about 1 x 106to at or about 5 x 108such cells, such as at or about 2 x 106, 5 x 106, 1 x 107, 5 x 107, 1 x 108, 1.5 x 108, or 5 x 10 total such cells, or the range between any two of the foregoing values. In some embodiments, for example, where the subject is a human, the dose includes more than at or about 1 x 106total recombinant receptor (e.g., CAR)-expressing cells, T cells, or peripheral blood mononuclear cells (PBMCs) and fewer than at or about 2 x 109total recombinant receptor (e.g., CAR)-expressing cells, T cells, or peripheral blood mononuclear cells (PBMCs), e.g., in the range of at or about 2.5 x 10 to at or about 1.2 x 10 such cells, such as at or about 2.5 x 10 ,5 x 107 , 1 x 108 , 1.5 x 108 total such cells, or the range between any two of the foregoing values.

[0313] In some embodiments, the dose of genetically engineered cells comprises from at or about 1 x 105 to at or about 5 x 108 total CAR-expressing (CAR-expressing) T cells, from at or about 1 x 105 to at or about 2.5 x 108 total CAR-expressing T cells, from at or about 1 x 105 to at or about 1 x 108 total CAR-expressing T cells, from at or about 1 x 105 to at or about 5 x 107 total CAR-expressing T cells, from at or about 1 x 105 to at or about 2.5 x 107 total CAR- expressing T cells, from at or about 1 x 10 to at or about 1 x 10 total CAR-expressing T cells, from at or about 1 x 105to at or about 5 x 106total CAR-expressing T cells, from at or about 1 x105to at or about 2.5 x 106total CAR-expressing T cells, from at or about 1 x 105to at or about1 x 106total CAR-expressing T cells, from at or about 1 x 106to at or about 5 x 108total CAR- expressing T cells, from at or about 1 x 106to at or about 2.5 x 108total CAR-expressing T cells, from at or about 1 x 106to at or about 1 x 108total CAR-expressing T cells, from at or about 1 x106to at or about 5 x 107total CAR-expressing T cells, from at or about 1 x 106to at or about 2.5 x 107total CAR-expressing T cells, from at or about 1 x 106to at or about 1 x 107total CAR-expressing T cells, from at or about 1 x 106to at or about 5 x 106total CAR-expressing T cells, from at or about 1 x 106to at or about 2.5 x 106total CAR-expressing T cells, from at or about 2.5 x 106to at or about 5 x 108total CAR-expressing T cells, from at or about 2.5 x106to at or about 2.5 x 108total CAR-expressing T cells, from at or about 2.5 x 106to at or about 1 x 10 total CAR-expressing T cells, from at or about 2.5 x 10 to at or about 5 x 10 total CAR-expressing T cells, from at or about 2.5 x 106to at or about 2.5 x 107total CAR- expressing T cells, from at or about 2.5 x 106to at or about 1 x 107total CAR-expressing Tcells, from at or about 2.5 x 106to at or about 5 x 106total CAR-expressing T cells, from at or about 5 x 106to at or about 5 x 108total CAR-expressing T cells, from at or about 5 x 106to at or about 2.5 x 10 total CAR-expressing T cells, from at or about 5 x 10 to at or about 1 x 10 total CAR-expressing T cells, from at or about 5 x 106to at or about 5 x 107total CAR- expressing T cells, from at or about 5 x 106to at or about 2.5 x 107total CAR-expressing T cells, from at or about 5 x 106to at or about 1 x 107total CAR-expressing T cells, from at or about 1 x 10 to at or about 5 x 10 total CAR-expressing T cells, from at or about 1 x 10 to at or about 2.5 x 10 8 total CAR-expressing T cells, from at or about 1 x 107 to at or about 1 x 108 total CAR-expressing T cells, from at or about 1 x 107 to at or about 5 x 107 total CAR- expressing T cells, from at or about 1 x 107 to at or about 2.5 x 107 total CAR-expressing T cells, from at or about 2.5 x 107 to at or about 5 x 108 total CAR-expressing T cells, from at or about 2.5 x 107 to at or about 2.5 x 108 total CAR-expressing T cells, from at or about 2.5 x107 to at or about 1 x 108 total CAR-expressing T cells, from at or about 2.5 x 107 to at or about5 x 107 total CAR-expressing T cells, from at or about 5 x 107 to at or about 5 x 108 total CAR- expressing T cells, from at or about 5 x 107 to at or about 2.5 x 108 total CAR-expressing T cells, from at or about 5 x 107 to at or about 1 x 108 total CAR-expressing T cells, from at or about 1 x 108 to at or about 5 x 108 total CAR-expressing T cells, from at or about 1 x 108 to at or about 2.5 x 10 8 total CAR-expressing T cells, from at or about or 2.5 x 108 to at or about 5 x10 total CAR-expressing T cells. In some embodiments, the dose of genetically engineered cells comprises from or from about 2.5 x 107 to at or about 1.5 x 108 total CAR-expressing T cells, such as from or from about 5 x 107 to or to about 1 x 108 total CAR-expressing T cells.

[0314] In some embodiments, the dose of genetically engineered cells comprises at least at or about 1 x 105CAR-expressing cells, at least at or about 2.5 x 105CAR-expressing cells, at least at or about 5 x 105CAR-expressing cells, at least at or about 1 x 106CAR-expressing cells, at least at or about 2.5 x 106CAR-expressing cells, at least at or about 5 x 106CAR-expressing cells, at least at or about 1 x 10 CAR-expressing cells, at least at or about 2.5 x 10 CAR- expressing cells, at least at or about 5 x 107 CAR-expressing cells, at least at or about 1 x 108CAR-expressing cells, at least at or about 1.5 x 10 CAR-expressing cells, at least at or about 2.5 x 108 CAR-expressing cells, or at least at or about 5 x 108 CAR-expressing cells.

[0315] In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 10 to or to about 5 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), from or from about 5 x 10 to or to about 1 x 10 total recombinant receptor-expressing cells,total T cells, or total peripheral blood mononuclear cells (PBMCs) or from or from about 1 x 106to or to about 1 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), each inclusive. In some embodiments, the cell therapy comprises administration of a dose of cells comprising a number of cells at least or at least about 1 x 105total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), such at least or at least 1 x 106, at least or at least about 1 x 10 , at least or at least about 1 x 10 of such cells. In some embodiments, the number is with reference to the total number of CD3+or CD8+, in some cases also recombinant receptor expressing (e.g. CAR+) cells. In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 10 to or to about 5 x 10 CD3 or CD8+total T cells or CD3+or CD8+recombinant receptor-expressing cells, from or from about 5 x 105to or to about 1 x 107CD3+or CD8+total T cells or CD3+or CD8+recombinant receptor-expressing cells, or from or from about 1 x 106to or to about 1 x 107CD3+or CD8+total T cells or CD3+or CD8+recombinant receptor-expressing cells, each inclusive. In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to or to about 5 x 108total CD3+ / CAR+or CD8+ / CAR+cells, from or from about 5 x 105to or to about 1 x 107total CD3+ / CAR+or CD8+ / CAR+cells, or from or from about 1 x 106to or to about 1 x 107total CD3+ / CAR+or CD8+ / CAR+cells, each inclusive.

[0316] In some embodiments, the T cells of the dose include CD4+ T cells, CD8+ T cells or CD4+ and CD8+ T cells.

[0317] In some embodiments, for example, where the subject is human, the CD8+ T cells of the dose, including in a dose including CD4+ and CD8+ T cells, includes between at or about 1 x 106and at or about 5 x 108total recombinant receptor (e.g., CAR)-expressing CD8+cells, e.g., in the range of from at or about 5 x 10 to at or about 1 x 10 such cells, such as 1 x 10 , 2.5 x 107, 5 x 107, 7.5 x 107, 1 x 108, 1.5 x 108, or 5 x 108total such cells, or the range between any two of the foregoing values. In some embodiments, the patient is administered multiple doses, and each of the doses or the total dose can be within any of the foregoing values. In some embodiments, the dose of cells comprises the administration of from or from about 1 x 10 to or to about0.75 x 10 total recombinant receptor-expressing CD8+ T cells, from or from about 1 x 10 to or to about 5 x 10 total recombinant receptor-expressing CD8+ T cells, from or from about 1 x 10 to or to about 0.25 x 10 total recombinant receptor-expressing CD8+ T cells, each inclusive. In some embodiments, the dose of cells comprises the administration of at or about 1x 107, 2.5 x 107, 5 x 107, 7.5 x 107, 1 x 108, 1.5 x 108, 2.5 x 108, or 5 x 108total recombinant receptor-expressing CD8+ T cells.

[0318] In some embodiments, the dose of cells, e.g., recombinant receptor-expressing T cells, is administered to the subject as a single dose or is administered only one time within a period of two weeks, one month, three months, six months, 1 year or more.

[0319] In the context of adoptive cell therapy, administration of a given“dose” encompasses administration of the given amount or number of cells as a single composition and / or single uninterrupted administration, e.g., as a single injection or continuous infusion, and also encompasses administration of the given amount or number of cells as a split dose or as a plurality of compositions, provided in multiple individual compositions or infusions, over a specified period of time, such as over no more than 3 days. Thus, in some contexts, the dose is a single or continuous administration of the specified number of cells, given or initiated at a single point in time. In some contexts, however, the dose is administered in multiple injections or infusions over a period of no more than three days, such as once a day for three days or for two days or by multiple infusions over a single day period.

[0320] Thus, in some aspects, the cells of the dose are administered in a singlepharmaceutical composition. In some embodiments, the cells of the dose are administered in a plurality of compositions, collectively containing the cells of the dose.

[0321] In some embodiments, the term“split dose” refers to a dose that is split so that it is administered over more than one day. This type of dosing is encompassed by the present methods and is considered to be a single dose.

[0322] Thus, the dose of cells may be administered as a split dose, e.g., a split dose administered over time. For example, in some embodiments, the dose may be administered to the subject over 2 days or over 3 days. Exemplary methods for split dosing includeadministering 25% of the dose on the first day and administering the remaining 75% of the dose on the second day. In other embodiments, 33% of the dose may be administered on the first day and the remaining 67% administered on the second day. In some aspects, 10% of the dose is administered on the first day, 30% of the dose is administered on the second day, and 60% of the dose is administered on the third day. In some embodiments, the split dose is not spread over more than 3 days.

[0323] In some embodiments, cells of the dose may be administered by administration of a plurality of compositions or solutions, such as a first and a second, optionally more, each containing some cells of the dose. In some aspects, the plurality of compositions, eachcontaining a different population and / or sub-types of cells, are administered separately or independently, optionally within a certain period of time. For example, the populations or sub- types of cells can include CD8+and CD4+T cells, respectively, and / or CD8+- and CD4+- enriched populations, respectively, e.g., CD4+and / or CD8+T cells each individually including cells genetically engineered to express the recombinant receptor. In some embodiments, the administration of the dose comprises administration of a first composition comprising a dose of CD8+T cells or a dose of CD4+T cells and administration of a second composition comprising the other of the dose of CD4+T cells and the CD8+T cells.

[0324] In some embodiments, the administration of the composition or dose, e.g., administration of the plurality of cell compositions, involves administration of the cell compositions separately. In some aspects, the separate administrations are carried out simultaneously, or sequentially, in any order. In some embodiments, the dose comprises a first composition and a second composition, and the first composition and second composition are administered 0 to 12 hours apart, 0 to 6 hours apart or 0 to 2 hours apart. In some embodiments, the initiation of administration of the first composition and the initiation of administration of the second composition are carried out no more than 2 hours, no more than 1 hour, or no more than 30 minutes apart, no more than 15 minutes, no more than 10 minutes or no more than 5 minutes apart. In some embodiments, the initiation and / or completion of administration of the first composition and the completion and / or initiation of administration of the second composition are carried out no more than 2 hours, no more than 1 hour, or no more than 30 minutes apart, no more than 15 minutes, no more than 10 minutes or no more than 5 minutes apart.

[0325] In some embodiments , the first composition, e.g., first composition of the dose, comprises CD4+T cells. In some embodiments, the first composition, e.g., first composition of the dose, comprises CD8+T cells. In some embodiments, the first composition is administered prior to the second composition. In some embodiments, the second composition, e.g., second composition of the dose, comprises CD4+ T cells. In some embodiments, the second composition, e.g., second composition of the dose, comprises CD8+ T cells.

[0326] In some embodiments, the dose or composition of cells includes a defined or target ratio of CD4+cells expressing a recombinant receptor to CD8+cells expressing a recombinant receptor and / or of CD4+cells to CD8+cells, which ratio optionally is approximately 1:1 or is between approximately 1:3 and approximately 3:1, such as approximately 1:1. In some aspects, the administration of a composition or dose with the target or desired ratio of different cell populations (such as CD4+:CD8+ratio or CAR+CD4+:CAR+CD8+ratio, e.g., 1:1) involves theadministration of a cell composition containing one of the populations and then administration of a separate cell composition comprising the other of the populations, where the administration is at or approximately at the target or desired ratio. In some aspects, administration of a dose or composition of cells at a defined ratio leads to improved expansion, persistence and / or antitumor activity of the T cell therapy.

[0327] In some embodiments, the subject receives multiple doses, e.g., two or more doses or multiple consecutive doses, of the cells. In some embodiments, two doses are administered to a subject. In some embodiments, the subject receives the consecutive dose, e.g., second dose, is administered approximately 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days after the first dose. In some embodiments, multiple consecutive doses are administered following the first dose, such that an additional dose or doses are administered following administration of the consecutive dose. In some aspects, the number of cells administered to the subject in the additional dose is the same as or similar to the first dose and / or consecutive dose. In some embodiments, the additional dose or doses are larger than prior doses.

[0328] In some aspects, the size of the first and / or consecutive dose is determined based on one or more criteria such as response of the subject to prior treatment, e.g. chemotherapy, disease burden in the subject, such as tumor load, bulk, size, or degree, extent, or type of metastasis, stage, and / or likelihood or incidence of the subject developing toxic outcomes, e.g., CRS, macrophage activation syndrome, tumor lysis syndrome, neurotoxicity, and / or a host immune response against the cells and / or recombinant receptors being administered.

[0329] In some aspects, the time between the administration of the first dose and the administration of the consecutive dose is about 9 to about 35 days, about 14 to about 28 days, or 15 to 27 days. In some embodiments, the administration of the consecutive dose is at a time point more than about 14 days after and less than about 28 days after the administration of the first dose. In some aspects, the time between the first and consecutive dose is about 21 days. In some embodiments, an additional dose or doses, e.g. consecutive doses, are administered following administration of the consecutive dose. In some aspects, the additional consecutive dose or doses are administered at least about 14 and less than about 28 days following administration of a prior dose. In some embodiments, the additional dose is administered less than about 14 days following the prior dose, for example, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 days after the prior dose. In some embodiments, no dose is administered less than about 14 days following the prior dose and / or no dose is administered more than about 28 days after the prior dose.

[0330] In some embodiments, the dose of cells, e.g., recombinant receptor-expressing cells, comprises two doses (e.g., a double dose), comprising a first dose of the T cells and a consecutive dose of the T cells, wherein one or both of the first dose and the second dose comprises administration of the split dose of T cells.

[0331] In some embodiments, the dose of cells is generally large enough to be effective in reducing disease burden.

[0332] In some embodiments, the cells are administered at a desired dosage, which in some aspects includes a desired dose or number of cells or cell type(s) and / or a desired ratio of cell types. Thus, the dosage of cells in some embodiments is based on a total number of cells (or number per kg body weight) and a desired ratio of the individual populations or sub-types, such as the CD4+to CD8+ratio. In some embodiments, the dosage of cells is based on a desired total number (or number per kg of body weight) of cells in the individual populations or of individual cell types. In some embodiments, the dosage is based on a combination of such features, such as a desired number of total cells, desired ratio, and desired total number of cells in the individual populations.

[0333] In some embodiments, the populations or sub-types of cells, such as CD8+and CD4+T cells, are administered at or within a tolerated difference of a desired dose of total cells, such as a desired dose of T cells. In some aspects, the desired dose is a desired number of cells or a desired number of cells per unit of body weight of the subject to whom the cells areadministered, e.g., cells / kg. In some aspects, the desired dose is at or above a minimum number of cells or minimum number of cells per unit of body weight. In some aspects, among the total cells, administered at the desired dose, the individual populations or sub-types are present at or near a desired output ratio (such as CD4+to CD8+ratio), e.g., within a certain tolerated difference or error of such a ratio.

[0334] In some embodiments, the cells are administered at or within a tolerated difference of a desired dose of one or more of the individual populations or sub-types of cells, such as a desired dose of CD4+cells and / or a desired dose of CD8+cells. In some aspects, the desired dose is a desired number of cells of the sub-type or population, or a desired number of such cells per unit of body weight of the subject to whom the cells are administered, e.g., cells / kg. In some aspects, the desired dose is at or above a minimum number of cells of the population or sub- type, or minimum number of cells of the population or sub-type per unit of body weight.

[0335] Thus, in some embodiments, the dosage is based on a desired fixed dose of total cells and a desired ratio, and / or based on a desired fixed dose of one or more, e.g., each, of theindividual sub-types or sub-populations. Thus, in some embodiments, the dosage is based on a desired fixed or minimum dose of T cells and a desired ratio of CD4+to CD8+cells, and / or is based on a desired fixed or minimum dose of CD4+and / or CD8+cells.

[0336] In some embodiments, the cells are administered at or within a tolerated range of a desired output ratio of multiple cell populations or sub-types, such as CD4+and CD8+cells or sub-types. In some aspects, the desired ratio can be a specific ratio or can be a range of ratios. For example, in some embodiments, the desired ratio (e.g., ratio of CD4+to CD8+cells) is between at or about 1:5 and at or about 5:1 (or greater than about 1:5 and less than about 5:1), or between at or about 1:3 and at or about 3:1 (or greater than about 1:3 and less than about 3:1), such as between at or about 2:1 and at or about 1:5 (or greater than about 1:5 and less than about 2:1), such as at or about 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9: 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, or 1:5. In some aspects, the tolerated difference is within about 1%, about 2%, about 3%, about 4% about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% of the desired ratio, including any value in between these ranges.

[0337] In particular embodiments, the numbers and / or concentrations of cells refer to the number of recombinant receptor (e.g., CAR)-expressing cells. In other embodiments, the numbers and / or concentrations of cells refer to the number or concentration of all cells, T cells, or peripheral blood mononuclear cells (PBMCs) administered.

[0338] In some aspects, the size of the dose is determined based on one or more criteria such as response of the subject to prior treatment, e.g. chemotherapy, disease burden in the subject, such as tumor load, bulk, size, or degree, extent, or type of metastasis, stage, and / or likelihood or incidence of the subject developing toxic outcomes, e.g., CRS, macrophage activation syndrome, tumor lysis syndrome, neurotoxicity, and / or a host immune response against the cells and / or recombinant receptors being administered.

[0339] In some embodiments, the methods also include administering one or more additional doses of cells expressing a chimeric antigen receptor (CAR) and / or lymphodepleting therapy, and / or one or more steps of the methods are repeated. In some embodiments, the one or more additional dose is the same as the initial dose. In some embodiments, the one or more additional dose is different from the initial dose, e.g., higher, such as 2-fold, 3-fold, 4-fold, 5- fold, 6-fold, 7-fold, 8-fold, 9-fold or lO-fold or more higher than the initial dose, or lower, such as e.g., 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold or lO-fold or more lower thanthe initial dose. In some embodiments, administration of one or more additional doses is determined based on response of the subject to the initial treatment or any prior treatment, disease burden in the subject, such as tumor load, bulk, size, or degree, extent, or type of metastasis, stage, and / or likelihood or incidence of the subject developing toxic outcomes, e.g., CRS, macrophage activation syndrome, tumor lysis syndrome, neurotoxicity, and / or a host immune response against the cells and / or recombinant receptors being administered.C. Methods of Treatment

[0340] Provided herein are methods of treatment, e.g., including administering any of the engineered cells or compositions containing engineered cells described herein, including one or more doses, e.g., a unit doses or any compositions containing one or more unit doses described herein. In some aspects, also provided are methods of administering any of the engineered cells or compositions containing engineered cells or unit doses described herein to a subject, such as a subject that has a disease or disorder. In some aspects, also provided are uses of any of the engineered cells or compositions containing engineered cells described herein for treatment of a disease or disorder. In some aspects, also provided are uses of any of the engineered cells or compositions containing engineered cells or unit doses described herein for the manufacture of a medicament for the treatment of a disease or disorder. In some aspects, also provided are any of the engineered cells or compositions containing engineered cells or unit doses described herein, for use in treatment of a disease or disorder, or for administration to a subject having a disease or disorder.

[0341] The engineered cells expressing a recombinant receptor, such as a chimeric antigen receptor (CAR), or compositions comprising the same, are useful in a variety of therapeutic, diagnostic and prophylactic indications. For example, the engineered cells or compositions comprising the engineered cells are useful in treating a variety of diseases and disorders in a subject. Such methods and uses include therapeutic methods and uses, for example, involving administration of the engineered cells, or compositions containing the same, to a subject having a disease, condition, or disorder, such as a tumor or cancer. In some embodiments, the engineered cells or compositions comprising the same are administered in an...

Claims

WHAT IS CLAIMED:

1. A therapeutic composition comprising T cells expressing a recombinant receptor, wherein at least at or about, or at or about, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in thecomposition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27.

2. The therapeutic composition of claim 1, wherein at least at or about, or at or about 50% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor are surface positive for CCR7 and / or CD27.

3. The therapeutic composition of claim 1, wherein at least at or about, or at or about 60% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor are surface positive for CCR7 and / or CD27.

4. The therapeutic composition of claim 1, wherein at least at or about, or at or about 70% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor are surface positive for CCR7 and / or CD27.

5. The therapeutic composition of claim 1, wherein at least at or about, or at or about 80% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor are surface positive for CCR7 and / or CD27.

6. The therapeutic composition of any of claims 1-5, wherein:the T cells in the composition and / or expressing the recombinant receptor comprise or consist of CD8+T cells;the T cells in the composition and / or expressing the recombinant receptor comprise or consist of CD4+T cells;the T cells in the composition and / or expressing the recombinant receptor comprise or consist of CD8+and CD4+T cells;the T cells in the composition and / or expressing the recombinant receptor comprise or consist of at least at or about 30%, 50% 95%, 96%, 97%, 98%, or 99% or 100% CD8+T cells; the T cells in the composition and / or expressing the recombinant receptor comprise or consist of at least at or about 30%, 50% 95%, 96%, 97%, 98%, or 99% or 100% CD4+T cells; and / orthe T cells in the composition and / or expressing the recombinant receptor comprise or consist of approximately 1:1 or approximately between 1:3 and 3:1 or approximately between 1:2 and 2:1, CD4+:CD8+T cells.

7. A therapeutic composition comprising T cells expressing a recombinant receptor, wherein at least at or about, or at or about, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition, or the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27, optionally wherein:the T cells in the composition and / or expressing the recombinant receptor comprise or consist of CD8+T cells;the T cells in the composition and / or expressing the recombinant receptor comprise or consist of CD4+T cells;the T cells in the composition and / or expressing the recombinant receptor comprise or consist of CD8+and CD4+T cells;the T cells in the composition and / or expressing the recombinant receptor comprise or consist of at least at or about 30%, 50% 95%, 96%, 97%, 98%, or 99% or 100% CD8+T cells; the T cells in the composition and / or expressing the recombinant receptor comprise or consist of at least at or about 30%, 50% 95%, 96%, 97%, 98%, or 99% or 100% CD4+T cells; and / orthe T cells in the composition and / or expressing the recombinant receptor comprise or consist of approximately 1:1 or approximately between 1:3 and 3:1 or approximately between 1:2 and 2:1, CD4+:CD8+T cells.

8. The therapeutic composition of any of claims 1-7, wherein the total number of T cells in the composition, or the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7.

9. The therapeutic composition of any of claims 1-7, wherein the total number of T cells in the composition, or the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CD27.

10. The therapeutic composition of any of claims 1-7, wherein the total number of T cells in the composition, or the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and CD27.

11. The therapeutic composition of any of claims 1-10, wherein the composition comprises one or more unit doses of cells.

12. The therapeutic composition of any of claims 1-11,wherein the unit dose or composition comprises between at or about 1 x 105and at or about 1 x 108, between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cells that express the recombinant receptor (receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+cells, total receptor+ / CD4+ / CCR7+cells, total receptor+ / CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells, each inclusive; and / orwherein the unit dose or composition comprises no more than about 1 x 10 , no more than about 5 x 107, no more than about 1 x 107, no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, total receptor+ / CD8+ / CCR7+cells, total receptor+ / CD4+ / CCR7+cells, totalreceptor+ / CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells.

13. The therapeutic composition of any of claims 1-12, wherein the composition or unit dose comprises at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD8+ / CCR7+cells or total receptor+ / CD8+ / CD27+cells; and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107totalreceptor+ / CD4+ / CCR7+cells or total receptor+ / CD4+ / CD27+.

14. The therapeutic composition of any of claims 1-13, wherein the unit dose or composition comprises between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+cells or total receptor+ / CD8+ / CD27+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD4+ / CCR7+cells or totalreceptor+ / CD4+ / CD27+, each inclusive.

15. The therapeutic composition of any of claims 1-14, wherein at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose or composition, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose or composition are receptor+ / CD8+ / CCR7+or receptor+ / CD8+ / CD27+; or at least 15%,20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose or composition, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose or composition are receptor+ / CD4+ / CCR7+or receptor+ / CD4+ / CD27+.

16. The therapeutic composition of any of claims 1-15, wherein the unit dose or composition comprises a defined number of receptor+ / CD8+ / CCR7+cells andreceptor+ / CD4+ / CCR7+cells or a defined ratio of receptor+ / CD8+ / CCR7+cells toreceptor+ / CD4+ / CCR7+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

17. The therapeutic composition of claim 16, wherein the defined number or ratio of cells further are of CD27+or CD45RA cells.

18. The therapeutic composition of any of claims 1-15, wherein the unit dose or composition comprises a defined number of receptor+ / CD8+ / CD27+cells andreceptor+ / CD4+ / CD27+cells or a defined ratio of receptor+ / CD8+ / CD27+cells toreceptor+ / CD4+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

19. The therapeutic composition of claim 18, wherein the defined number or ratio of cells further are of CCR7+or CD45RA cells.

20. The therapeutic composition of any of claims 1-19, wherein the unit dose or composition comprises a defined number of receptor+ / CD8+ / CCR7+ / CD27+cells and / or rcccptor+ / CD8+ / CCR7+ / CD45RA cells; and / or the unit dose or composition comprises a defined number of receptor+ / CD4+ / CCR7+ / CD27+cells and / or rcccptor+ / CD4+ / CCR7+ / CD45RA cells.

21. The therapeutic composition of any of claims 1-20, wherein at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose or composition, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose or composition are receptor+ / CD8+ / CCR7+ / CD27+, receptor+ / CD8+ / CCR7+ / CD45RA , receptor+ / CD4+ / CCR7+ / CD27+or receptor+ / CD4+ / CCR7+ / CD45RA .

22. The therapeutic composition of any of claims 1-21, wherein the unit dose or number of cells expressing the recombinant receptor comprises between at or about 1 x 105and at or about 5 x 10 , between at or about 1 x 10 and at or about 1 x 10 , between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD3+cells that express the recombinant receptor (receptor+ / CD3+cells) or total CD3+cells, each inclusive; and / or the unit dose or number of cells expressing the recombinant receptor comprises no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 107, no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD3+cells or total CD3+cells.

23. The therapeutic composition of any of claims 1-22, wherein the total number of CD3+cells, total number of receptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number of receptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number of receptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number of receptor+ / CD4+ / CCR7+ / CD27+cells, total number o G rcccptor7C D8+ / CC R77CD45 R A cellsand / or receptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that are live or viable.

24. The therapeutic composition of any of claims 1-23, wherein the total number of CD3+cells, total number of receptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number of receptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number of receptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD4+ / CCR7+ / CD27+cells, total number o G rcccp tor+ / C D 8+ / CC R7+ / C D45RA cells and / or rcccptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that do not express an apoptotic marker and / or is the total number of such cells that are apoptotic marker negative O, wherein the apoptotic marker is Annexin V or activated Caspase 3.

25. The therapeutic composition of any of claims 1-29, wherein the recombinant receptor is capable of binding to a target antigen that is associated with, specific to, and / or expressed on a cell or tissue of a disease, disorder or condition.

26. The therapeutic composition of claim 25, wherein the disease, disorder or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or a cancer.

27. The therapeutic composition of any of claim 25 or claim 26, wherein the target antigen is selected from among anb6 integrin (avb6 integrin), B cell maturation antigen(BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer- testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-l), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138, CD171, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), glypican-3 (GPC3), G ProteinCoupled Receptor 5D (GPRC5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight-melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HLA-A1), Human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha(IL-22Ra), IL-13 receptor alpha 2 (IL- l3Ra2), kinase insert domain receptor (kdr), kappa light chain, Ll cell adhesion molecule (Ll- CAM), CE7 epitope of Ll-CAM, Leucine Rich Repeat Containing 8 Family Member A(LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)-Al, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen(PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor- associated glycoprotein 72 (TAG72), Tyrosinase related protein 1 (TRP1, also known as TYRP1 or gp75), Tyrosinase related protein 2 (TRP2, also known as dopachrome tautomerase, dopachrome delta-isomerase or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-l), a pathogen- specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV or other pathogens.

28. The therapeutic composition of any of claims 1-27, wherein the recombinant receptor is a chimeric antigen receptor (CAR).

29. The therapeutic composition of any of claims 1-28, wherein the recombinant receptor comprises an extracellular domain comprising an antigen-binding domain and an intracellular signaling region comprising an intracellular signaling domain, and further comprises a transmembrane domain disposed between the extracellular domain and the intracellular signaling region.

30. The therapeutic composition of claim 28, wherein the antigen-binding domain is or comprises an antibody or an antibody fragment thereof, which optionally is a single chain fragment.

31. The therapeutic composition of claim 30, wherein the fragment comprises an scFv.

32. The therapeutic composition of any of claims 29-31, wherein the intracellular signaling domain is or comprises an intracellular signaling domain of a CD3 chain, optionally a CD3-zeta (€ϋ3z) chain, or a signaling portion thereof.

33. The therapeutic composition of any of claims 29-32, wherein the intracellular signaling region further comprises a costimulatory signaling domain.

34. The therapeutic composition of claim 33, wherein the costimulatory signaling domain comprises an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof.

35. The therapeutic composition of claim 33 or claim 34, wherein the costimulatory signaling domain comprises an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof.

36. The therapeutic composition of any of claims 33-35, wherein the costimulatory signaling domain is between the transmembrane domain and the intracellular signaling domain.

37. The therapeutic composition of any of claims 1-36, wherein the T cells are primary T cells obtained from a subject.

38. The therapeutic composition of any of claims 1-37, wherein the T cells are autologous to the subject.

39. The therapeutic composition of any of claims 1-37, wherein the T cells are allogeneic to the subject.

40. The therapeutic cell composition of any of claims 37-39, wherein the subject has a cancer, optionally wherein the cancer is a leukemia or a lymphoma.

41. The therapeutic cell composition of claim 40, wherein the subject is a subject that, at the time of obtaining the cells, is identified or known to have a high tumor burden.

42. The therapeutic cell composition of claim 41, wherein:the subject has high tumor burden if a sum of product dimensions (SPD) of a tumor in the subject is above at or about 30 cm 2 , 40 cm 2 , 50 cm 2 , 60 cm 2 or 70 cm 2 ; and / orthe subject has high tumor burden if C reactive protein (CRP) in a biological sample, optionally a serum sample, from the subject is above at or about 5 miligrams per liter, 10 miligrams per liter, 15 miligrams per liter, 20 miligrams per liter, 25 miligrams per liter, 30 miligrams per liter, 40 miligrams per liter or 50 miligrams per liter.

43. The therapeutic cell composition of claim 42, wherein the subject has high tumor2burden if the SPD of a tumor in the subject is above at or about 50 cm .

44. The therapeutic cell composition of claim 42 or claim 43, wherein the subject has high tumor burden if the CRP is above at or about 20 miligrams per liter in the biological sample.

45. An article of manufacture, comprising a container comprising a composition of any of claims 1-44, and instructions for administering to a subject having a disease or condition the therapeutic composition, optionally one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.

46. An article of manufacture, comprising:a container, comprising one or more unit doses of cells, present in one or more therapeutic composition, the unit dose comprising a plurality of CD8+and / or CD4+T cells expressing (optionally engineered to express) a recombinant receptor, wherein a unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express (optionally surface express) C-C chemokine receptor type 7 (CCR7) (receptor+ / CD8+ / CCR7+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 (receptor+ / CD4+ / CCR7+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+cells and / or receptor+ / CD4+ / CCR7+cells to another subset of cells in the composition; andinstructions for administering to a subject having a disease or condition the therapeutic composition, optionally one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.

47. An article of manufacture, comprising:a container, comprising one or more unit doses of cells, present in one or more therapeutic composition, the unit dose comprising a plurality of CD8+and / or CD4+T cells expressing (optionally engineered to express) a recombinant receptor, wherein a unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express (optionally surface express) cluster of differentiation 27 (CD27) (receptor+ / CD8+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CD27 (receptor+ / CD4+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CD27+cells and / or receptor+ / CD4+ / CD27+cells to another subset of cells in the composition; andinstructions for administering to a subject having a disease or condition, the therapeutic composition, optionally one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.

48. The article of manufacture of claim 46 or claim 47, wherein the unit dose of cells comprises the composition of any of claims 1-44.

49. A method of treatment, comprising administering to a subject having a disease or condition one or more unit doses of a therapeutic composition of claim 1 or claim 7 or a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor and / or a volume corresponding to such unit doses, optionally wherein:the unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express C-C chemokine receptor type 7 (CCR7) (receptor+ / CD8+ / CCR7+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 (receptor+ / CD4+ / CCR7+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+cells and / or receptor+ / CD4+ / CCR7+cells to another subset of cells in the composition; and / oramong a group of subjects treated according to the method, the number or ratio of cells that express CCR7 (CCR7+cells) in the unit dose varies by no more than 40%, by no more than 30%, by no more than 20%, by no more than 10% or by no more than 5%.

50. The method of claim 49, wherein the unit dose of cells comprises a defined number of CD8+ / CCR7+cells; and / or the unit dose of cells comprises a defined number of CD4+ / CCR7+cells.

51. A method of treatment, comprising administering to a subject having a disease or condition one or more unit doses of a therapeutic composition of claim 1 or claim 7, or a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor and / or a volume corresponding to such unit doses, optionally wherein:the unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express cluster of differentiation 27 (CD27) (receptor+ / CD8+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CD27 (receptor+ / CD4+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CD27+cells and / or receptor+ / CD4+ / CD27+cells to another subset of cells in the composition; and / oramong a group of subjects treated according to the method, the number or ratio of cells that express CD27 (CD27+cells) in the unit dose varies by no more than 40%, by no more than 30%, by no more than 20%, by no more than 10% or by no more than 5%.

52. The method of claim 51, wherein the unit dose of cells comprises a defined number of CD8+ / CD27+cells; and / or the unit dose of cells comprises a defined number of CD4+ / CD27+cells.

53. The method of any of claims 49-52, wherein:the unit dose comprises between at or about 1 x 10 and at or about 1 x 10 , between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cell that express the recombinant receptor (receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+cells, totalreceptor+ / CD4+ / CCR7+cells, total receptor+ / CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells, each inclusive;the unit dose comprises no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 107, no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, totalreceptor+ / CD8+ / CCR7+cells, total receptor7CD4+ / CCR7+cells, total receptor7CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells; and / orthe unit dose comprises at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD8+ / CCR7+cells or total receptor+ / CD8+ / CD27+cells and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107totalreceptor+ / CD4+ / CCR7+cells or total receptor7CD4+ / CD27+.

54. The method of any of claims 49-53, wherein the unit dose comprises between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+cells or total receptor+ / CD8+ / CD27+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD4+ / CCR7+cells or total receptor+ / CD4+ / CD27+, each inclusive.

55. The method of any of claims 49-54, wherein at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD8+ / CCR7+or receptor+ / CD 8+ / CD27+; or at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD4+ / CCR7+or receptor+ / CD4+ / CD27+.

56. The method of any of claims 49, 50 and 53-55, wherein the unit dose of cells comprises a defined number of receptor+ / CD8+ / CCR7+cells and receptor+ / CD4+ / CCR7+cells or a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

57. The method of any of claims 51-55, wherein the unit dose of cells comprises a defined number of receptor+ / CD8+ / CD27+cells and receptor+ / CD4+ / CD27+cells or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

58. The method of claim 56 or claim 57, wherein the unit dose of cells comprises a defined number of receptor+ / CD8+ / CCR7+ / CD27+cells and / orrcccptor+ / CD8+ / CCR7+ / CD45RA cells; and / or the unit dose of cells comprises a defined number of receptor+ / CD4+ / CCR7+ / CD27+cells and / or rcccptor+ / CD4+ / CCR7+ / CD45RA cells.

59. The method of claim 58, wherein at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD8+ / CCR7+ / CD27+or receptor+ / CD8+ / CCR7+ / CD45RA ; and / or at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD4+ / CCR7+ / CD27+or receptor+ / CD4+ / CCR7+ / CD45RA .

60. A method of treatment, the method comprising administering to a subject having a disease or condition one or more unit doses of a composition of claim 1 or claim 7.

61. The method of claim 60, wherein:the unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express CCR7 and CD27 (receptor+ / CD8+ / CCR7+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 and CD27 (receptor+ / CD4+ / CCR7+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells and / or a defined ratio ofreceptor+ / CD8+ / CCR7+ / CD27+cells and / or receptor+ / CD4+ / CCR7+ / CD27+cells to another subset of cells in the composition; andamong a group of subjects treated according to the method, the number or ratio of cells that express CCR7 (CCR7+cells) in the unit dose varies by no more than 40%, by no more than 30%, by no more than 20%, by no more than 10% or by no more than 5%.

62. A method of treatment, the method comprising administering to a subject having a disease or condition a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor and / or a volume corresponding to such unit doses, wherein:the unit dose of cells comprises a defined number of recombinant receptor-expressing CD8+T cells that express CCR7 and CD27 (receptor+ / CD8+ / CCR7+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 and CD27 (receptor+ / CD4+ / CCR7+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells and / or a defined ratio ofreceptor+ / CD8+ / CCR7+ / CD27+cells and / or receptor+ / CD4+ / CCR7+ / CD27+cells to another subset of cells in the composition; andamong a group of subjects treated according to the method, the number or ratio of cells that express CCR7 (CCR7+cells) in the unit dose varies by no more than 40%, by no more than 30%, by no more than 20%, by no more than 10% or by no more than 5%.

63. The method of any of claims 58-62, wherein the unit dose of cells comprises a defined number of CD8+ / CCR7+ / CD27+cells; and / or the unit dose of cells comprises a defined number of CD4+ / CCR7+ / CD27+cells.

64. The method of any of claims 58-63, wherein:the unit dose comprises between at or about 1 x 10 and at or about 1 x 10 , between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cell that express the recombinant receptor (receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+ / CD27+cells, or total receptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive;the unit dose comprises no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 107, no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, totalreceptor+ / CD8+ / CCR7+ / CD27+cells, or total receptor7CD47CCR7+ / CD27+cells; and / orthe unit dose comprises at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD8+ / CCR7+ / CD27+cells; and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD4+ / CCR7+ / CD27+cells.

65. The method of any of claims 58-64, wherein the unit dose comprises between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+ / CD27+cells; and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107totalreceptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive.

66. The method of any of claims 58-65, wherein at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose arereceptor+ / CD8+ / CCR7+ / CD27+or receptor+ / CD4+ / CCR7+ / CD27+.

67. The method of any of claims 58-66, wherein the unit dose of cells comprises a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

68. The method of any of claims 49-67, wherein the defined number of cells further express or do not express CD45RA, optionally wherein the defined number of cells further are CD45RA cells.

69. The method of any of claims 49-68, wherein the unit dose comprises between at or about 1 x 10 and at or about 5 x 10 , between at or about 1 x 10 and at or about 1 x 10 , between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD3+cells that express the recombinant receptor (receptor+ / CD3+cells) or total CD3+cells, each inclusive.

70. The method of any of claims 49-69, wherein the unit dose comprises no more than about 5 x 10 8 , no more than about 1 x 108 , no more than about 5 x 107 , no more than about 1 x 107, no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD3+cells or total CD3+cells.

71. The method of claim 70, wherein the total number of CD3+cells, total number of receptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number of receptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number of receptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number ofreceptor+ / CD4+ / CCR7+ / CD27+cells, total number o G rcccp tor+ / C D 87CC R7+ / C D45RA cells and / or rcccptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that are live or viable.

72. The method of any of claims 49-71, wherein the total number of CD3+cells, total number of receptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number of receptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number ofreceptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number of receptor+ / CD4+ / CCR7+ / CD27+cells, total number o G rcccptor+ / C D8+ / CC R7+ / CD45 R A cells and / or rcccptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that do not express an apoptotic marker and / or is the total number of such cells that are apoptotic marker negative O, wherein the apoptotic marker is Annexin V or activated Caspase 3.

73. The method of any of claims 49-72, comprising administering a plurality of unit doses contained in a plurality of separate compositions.

74. The method of claim 73, wherein the plurality of separate compositions comprise a first composition comprising one of the CD8+T cells and the CD4+T cells and a second composition comprising the other of the CD8+T cells and the CD4+T cells.

75. The method of claim 74, wherein the first composition comprises the CD8+T cells.

76. The method of claim 74, wherein the first composition comprises the CD4+T cells.

77. The method of any of claims 49-76, comprising administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses and the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses no more than 48 hours apart.

78. The method of claim 77, wherein the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses and the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses are administered no more than 36 hours apart, no more than 24 hours apart, no more than 12 hours apart, no more than 6 hours apart, no more than 4 hours apart, no more than 2 hours apart, no more than 1 hour apart or no more than 30 minutes apart.

79. The method of claim 77 or claim 78, wherein the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses and the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses are administered no more than 2 hours, no more than 1 hour, no more than 30 minutes, no more than 15 minutes, no more than 10 minutes or no more than 5 minutes apart or simultaneously.

80. The method of any of claims 73-79, comprising administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses, prior to administering the composition containing CD4+cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.

81. The method of any of claims 73-79, comprising administering the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding tosuch one or more of unit doses, prior to administering the composition containing CD8+cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.

82. A method of determining a unit dose of engineered T cells for treating a subject, the method comprising:(a) assessing, in a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor, the number, percentage or ratio of T cells that express the recombinant receptor and CCR7 (receptor+ / CCR7+);(b) based on the number, percentage or ratio of receptor+ / CCR7+cells, determining one or more unit doses of cells for administration to a subject having a disease or conditions, wherein the unit dose comprises a defined number of recombinant receptor-expressing CD8+T cells that express C-C chemokine receptor type 7 (CCR7) (receptor+ / CD8+ / CCR7+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7(receptor+ / CD4+ / CCR7+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+cells and / or receptor+ / CD4+ / CCR7+cells to another subset of cells in the composition.

83. A method of determining a unit dose of engineered T cells for treating a subject, the method comprising:(a) assessing, in a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor, the number, percentage or ratio of T cells that express the recombinant receptor and CD27 (receptor+ / CD27+); and(b) based on the number, percentage or ratio of receptor+ / CD27+cells, determining one or more unit doses of cells for administration to a subject having a disease or conditions, wherein the unit dose comprises a defined number of recombinant receptor-expressing CD8+T cells that express cluster of differentiation 27 (CD27) (receptor+ / CD8+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CD27(receptor+ / CD4+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CD27+cells and / or receptor+ / CD4+ / CD27+cells to another subset of cells in the composition.

84. A method of producing a composition comprising a unit dose of a T cell composition, the method comprising:(a) assessing, in a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor, the number, percentage or ratio of T cells that express the recombinant receptor and CCR7 and / or CD27 (receptor+ / CCR7+and / or receptor+ / CD27+); and(b) filling a container with all or a portion of the composition and optionally another solution to achieve a unit dose of the T cell composition, wherein the unit dose comprises a defined number of recombinant receptor-expressing CD8+T cells that express C-C chemokine receptor type 7 (CCR7) (receptor+ / CD8+ / CCR7+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 (receptor+ / CD4+ / CCR7+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+cells and / or receptor+ / CD4+ / CCR7+cells to another subset of cells in the composition, or a defined number of recombinant receptor-expressing CD8+T cells that express cluster of differentiation 27 (CD27) (receptor+ / CD8+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CD27(receptor+ / CD4+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CD27+cells and / or receptor+ / CD4+ / CD27+cells to another subset of cells in the composition.

85. A method of producing a therapeutic composition comprising a unit dose of a T cell composition, the method comprising filling a container with all or a portion of a T cell composition, the T cell composition comprising T cells comprising a recombinant receptor that specifically binds an antigen associated with a disease or condition, to achieve a unit dose of the T cell composition, wherein the unit dose comprises a defined number of recombinant receptor expressing CD8+T cells that express C-C chemokine receptor type 7 (CCR7)(receptor+ / CD8+ / CCR7+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 (receptor+ / CD4+ / CCR7+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+cells and / or receptor+ / CD4+ / CCR7+cells to another subset of cells in the composition.

86. A method of producing a therapeutic composition comprising a unit dose of a T cell composition, the method comprising filling a container with all or a portion of a T cell composition, the T cell composition comprising T cells comprising a recombinant receptor thatspecifically binds an antigen associated with a disease or condition, to achieve a unit dose of the T cell composition, wherein the unit dose comprises a defined number of recombinant receptor expressing CD8+T cells that express cluster of differentiation 27 (CD27)(receptor+ / CD8+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CD27 (receptor+ / CD4+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells and / or a defined ratio ofreceptor+ / CD8+ / CD27+cells and / or receptor+ / CD4+ / CD27+cells to another subset of cells in the composition.

87. The method of any of claims 83-86, wherein the unit dose of cells comprises a defined number of CD8+ / CCR7+cells and / or the unit dose of cells comprises a defined number of CD4+ / CCR7+cells.

88. The method of any of claims 82-87, wherein:the unit dose comprises between at or about 1 x 10 and at or about 1 x 10 , between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cell that express the recombinant receptor (receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+cells, total receptor+ / CD4+ / CCR7+cells, total receptor+ / CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells, each inclusive;the unit dose comprises no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 107, no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, totalreceptor+ / CD8+ / CCR7+cells, total receptor+ / CD4+ / CCR7+cells, total receptor+ / CD8+ / CD27+cells, or total receptor+ / CD4+ / CD27+cells; and / orthe unit dose comprises at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD8+ / CCR7+cells or total receptor+ / CD8+ / CD27+cells and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107totalreceptor+ / CD4+ / CCR7+cells or total receptor7CD4+ / CD27+.

89. The method of any of claims 82-88, wherein the unit dose comprises between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+cells or totalreceptor+ / CD8+ / CD27+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD4+ / CCR7+cells or total receptor+ / CD4+ / CD27+, each inclusive.

90. The method of any of claims 82-89, wherein at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD8+ / CCR7+or receptor+ / CD8+ / CD27+; or at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD4+ / CCR7+or receptor+ / CD4+ / CD27+.

91. The method of any of claims 82-90, wherein the unit dose of cells comprises a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

92. The method of any of claims 82-91, wherein the unit dose further comprises a defined number of cells comprising cells that express or do not express CD27 and / or CD45, optionally wherein the unit dose further comprises a defined number of cells comprising CD27+or CD45RA cells .

93. The method of any of claims 82-92, further comprising assessing in the therapeutic composition the number, percentage or ratio of T cells that express or do not express CD27 and / or CD45RA, optionally the number, percentage or ratio of T cells that are CD27+or CD45RA .

94. The method of claim 92 or claim 93, wherein the unit dose of cells comprises a defined number of receptor+ / CD8+ / CCR7+ / CD27+cells and / orrcccptor+ / CD8+ / CCR7+ / CD45RA cells and / or the unit dose of cells comprises a defined number of receptor+ / CD4+ / CCR7+ / CD27+cells and / or receptor+ / CD4+ / CCR7+ / CD45RA cells.

95. The method of any of claims 92-95, wherein at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose arereceptor+ / CD8+ / CCR7+ / CD27+, receptor+ / CD8+ / CCR7+ / CD45RA ,receptor+ / CD4+ / CCR7+ / CD27+or receptor+ / CD4+ / CCR7+ / CD45RA .

96. A method of determining a unit dose of engineered T cells for treating a subject, the method comprising:(a) assessing, in a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor, the number, percentage or ratio of T cells that express the recombinant receptor and CCR7 and CD27 (receptor+ / CCR7+ / CD27+);(b) based on the number, percentage or ratio of receptor+ / CCR7+ / CD27+cells, determining one or more unit doses of cells of cells for administration to a subject having a disease or conditions, wherein the unit dose comprises a defined number of recombinant receptor-expressing CD8+T cells that express CCR7 and CD27 (receptor+ / CD8+ / CCR7+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 and CD27 (receptor+ / CD4+ / CCR7+ / CD27+cells) and / or a defined ratio ofreceptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells and / or receptor+ / CD4+ / CCR7+ / CD27+cells to another subset of cells in the composition.

97. A method of producing a composition comprising a unit dose of a T cell composition, the method comprising:(a) assessing, in a therapeutic composition comprising a plurality of CD8+and / or CD4+T cells engineered to express a recombinant receptor, the number, percentage or ratio of T cells that express the recombinant receptor and CCR7 and CD27 (receptor+ / CCR7+ / CD27+); and(b) filling a container with all or a portion of the composition and optionally another solution to achieve a unit dose of the T cell composition, wherein the unit dose comprises a defined number of recombinant receptor-expressing CD8+T cells that express CCR7 and CD27 (receptor+ / CD8+ / CCR7+ / CD27+cells) and / or a defined number of recombinant receptor expressing CD4+T cells that express CCR7 and CD27 (receptor+ / CD4+ / CCR7+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells and / orreceptor+ / CD4+ / CCR7+ / CD27+cells to another subset of cells in the composition.

98. A method of producing a therapeutic composition comprising a unit dose of a T cell composition, the method comprising filling a container with all or a portion of a T cell composition, the T cell composition comprising T cells comprising a recombinant receptor that specifically binds an antigen associated with a disease or condition, to achieve a unit dose of the T cell composition, wherein the unit dose comprises a defined number of recombinant receptor expressing CD8+T cells that express CCR7 and CD27 (receptor+ / CD8+ / CCR7+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 and CD27 (receptor+ / CD4+ / CCR7+ / CD27+cells) and / or a defined ratio ofreceptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells and / or receptor+ / CD4+ / CCR7+ / CD27+cells to another subset of cells in the composition.

99. The method of any of claims 96-98, wherein the unit dose of cells comprises a defined number of CD8+ / CCR7+ / CD27+cells and / or the unit dose of cells comprises a defined number of CD4+ / CCR7+ / CD27+cells.

100. The method of any of claims 96-99, wherein the unit dose comprises between at or about 1 x 10 and at or about 1 x 10 , between at or about 5 x 10 and at or about 1 x 10 , or between at or about 1 x 106and at or about 1 x 107total CD8+cells that express the recombinant receptor (receptor+ / CD8+cells) or total CD4+cell that express the recombinant receptor(receptor+ / CD4+cells), total receptor+ / CD8+ / CCR7+ / CD27+cells, or totalreceptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive; the unit dose comprises no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD8+cells or total receptor+ / CD4+cells, total receptor+ / CD8+ / CCR7+ / CD27+cells, or totalreceptor+ / CD4+ / CCR7+ / CD27+cells; and / or the unit dose comprises at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor7CD87CCR7+ / CD27+cells and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD4+ / CCR7+ / CD27+cells.

101. The method of any of claims 96-100, wherein the unit dose comprises between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+ / CD27+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107totalreceptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive.

102. The method of any of claims 96-103, wherein at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose arereceptor+ / CD8+ / CCR7+ / CD27+or receptor+ / CD4+ / CCR7+ / CD27+.

103. The method of any of claims 96-102, wherein the unit dose of cells comprises a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells to receptor+ / CD4+ / CCR7+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

104. The method of any of claims 96-103, wherein the unit dose further comprises a defined number of cells comprising cells that express or do not express CD45, optionally wherein the unit dose further comprises a defined number of cells comprising CD45RA- cells .

105. The method of any of claims 96-104, further comprising assessing in the therapeutic composition the number, percentage or ratio of T cells that express or do not express CD45RA, optionally the number, percentage or ratio of T cells that are CD45RA .

106. A method for generating a cell composition comprising genetically engineered cells, the method comprising:i) providing, from a biological sample from a subject, an input composition comprising a target percentage of CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a target percentage of CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA;ii) introducing, into the input composition, a polynucleotide encoding a recombinant receptor; andiii) stimulating the cells in the input composition, prior to, during and / or subsequent to said introducing, wherein stimulating comprises incubating the cells in the presence of one or more stimulating agents, said stimulating results in activation and / or proliferation of the cells; wherein the method produces an output composition comprising a defined ratio of recombinant receptor-expressing (receptor+) CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA to receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a defined ratio of receptor+ / CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA to another subset of cells in the composition.

107. A method for generating a cell composition comprising genetically engineered cells, the method comprising introducing, into an input composition, a polynucleotide encoding a recombinant receptor, wherein the input composition comprises a target percentage of CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a target percentage of CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA provided from a biological sample from a subject, and the input composition is stimulated, prior to, during and / or subsequent to said introducing by incubating the cells in the presence of one or more stimulating agents, said stimulation results in activation and / or proliferation of the cells; and wherein the method produces an output composition comprising a defined ratio of recombinant receptor expressing (receptor+) CD8+T cells that express or do not express CCR7, CD27 and / orCD45RA to receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a defined ratio of receptor+ / CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA to another subset of cells in the composition.

108. A method for generating a cell composition comprising genetically engineered cells, the method comprising:i) isolating, from a biological sample obtained from a subject, a target number of CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a target number of CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA, thereby generating an input composition;ii) introducing, into the input composition, a polynucleotide encoding a recombinant receptor; andiii) stimulating the cells in the input composition, prior to, during and / or subsequent to said introducing, wherein stimulating comprises incubating the cells in the presence of one or more stimulating agents, said stimulating results in activation and / or proliferation of the cells; wherein the method produces an output composition comprising a defined ratio of recombinant receptor-expressing (receptor+) CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA to receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a defined ratio of receptor+ / CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA to another subset of cells in the composition.

109. A method for generating a cell composition comprising genetically engineered cells, the method comprising introducing, into an input composition, a polynucleotide encoding a recombinant receptor, wherein the input composition is generated by isolating, from a biological sample obtained from a subject, a target number of CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a target number of CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA, and the input composition is stimulated, prior to, during and / or subsequent to said introducing by incubating the cells in the presence of one or more stimulating agents, said stimulation results in activation and / or proliferation of the cells; and wherein the method produces an output composition comprising a defined ratio of recombinant receptor-expressing (receptor+) CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA to receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a defined ratio of receptor+ / CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or receptor+ / CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA to another subset of cells in the composition.

110. The method of any of claims 106-109, wherein the input composition comprises a target percentage of CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or a target percentage of CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA.

111. The method of any of claims 106-110, wherein the input composition comprises a target percentage of CD4+ / CCR7+, CD4+ / CD27+, CD4+ / CCR7+ / CD27+, CD4+ / CCR7+ / CD45RA, CD4+ / CCR7+ / CD45RA+, CD8+ / CCR7+, CD8+ / CD27+, CD8+ / CCR7+ / CD27+,CD 8+ / CCR7+ / CD45R A and / or CD8+ / CCR7+ / CD45RA+cells.

112. The method of any of claims 106-111, wherein the output composition comprises a defined ratio of receptor+ / CD8+ / CCR7+, receptor+ / CD8+ / CD27+,receptor+ / CD8+ / CCR7+ / CD27+, receptor+ / CD8+ / CCR7+ / CD45RA_and / orreceptor+ / CD8+ / CCR7+ / CD45RA+cells, to receptor+ / CD4+ / CCR7+, receptor+ / CD4+ / CD27+, receptor+ / CD4+ / CCR7+ / CD27+, receptor+ / CD4+ / CCR7+ / CD45RA_and / orreceptor+ / CD4+ / CCR7+ / CD45RA+cells; ora defined ratio of receptor+ / CD8+ / CCR7+, receptor+ / CD8+ / CD27+,receptor+ / CD8+ / CCR7+ / CD27+, receptor+ / CD8+ / CCR7+ / CD45RA_and / orreceptor+ / CD8+ / CCR7+ / CD45RA+cells and / or receptor+ / CD4+ / CCR7+, receptor+ / CD4+ / CD27+, receptor+ / CD4+ / CCR7+ / CD27+, receptor+ / CD4+ / CCR7+ / CD45RA_and / orreceptor+ / CD4+ / CCR7+ / CD45RA+cells to another subset of cells in the composition.

113. The method of any of claims 106-112, further comprising determining one or more unit doses of a T cell composition for administration to a subject having a disease or conditions, wherein the unit dose comprises all or a portion of the output composition that comprises:a defined number of recombinant receptor-expressing CD8+T cells that express C-C chemokine receptor type 7 (CCR7) (receptor+ / CD8+ / CCR7+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 (receptor+ / CD4+ / CCR7+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+cells and / or receptor+ / CD4+ / CCR7+cells to another subset of cells in the composition;a defined number of recombinant receptor-expressing CD8+T cells that express cluster of differentiation 27 (CD27) (receptor+ / CD8+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CD27 (receptor+ / CD4+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CD27+cells and / or receptor+ / CD4+ / CD27+cells to another subset of cells in the composition; ora defined number of recombinant receptor-expressing CD8+T cells that express CCR7 and CD27 (receptor+ / CD8+ / CCR7+ / CD27+cells) and / or a defined number of recombinant receptor-expressing CD4+T cells that express CCR7 and CD27 (receptor+ / CD4+ / CCR7+ / CD27+cells) and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells toreceptor+ / CD4+ / CCR7+ / CD27+cells and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells and / or receptor+ / CD4+ / CCR7+ / CD27+cells to another subset of cells in the composition.

114. The method of claim 113, wherein the unit dose of cells comprises a defined number of CD8+ / CCR7+cells, CD4+ / CCR7+cells, CD8+ / CD27+cells, CD4+ / CD27+cells, CD8+ / CCR7+ / CD27+cells and / or CD4+ / CCR7+ / CD27+cells.115 The method of claim 113 or claim 114, wherein the unit dose comprises between at or about 1 x 10 and at or about 1 x 10 , between at or about 5 x 10 and at or about 1 x 10 , or between at or about 1 x 106and at or about 1 x 107, each inclusive, total receptor+ / CD8+cells or total receptor+ / CD4+cells, total receptor+ / CD8+ / CCR7+cells, total receptor+ / CD4+ / CCR7+cells, total receptor+ / CD8+ / CD27+cells, total receptor+ / CD4+ / CD27+cells, totalreceptor+ / CD8+ / CCR7+ / CD27+cells, or total receptor7CD47CCR7+ / CD27+cells.

116. The method of any of claims 113-115, wherein:the unit dose comprises at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD8+ / CCR7+cells or total receptor+ / CD8+ / CD27+cells; and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD4+ / CCR7+cells or total receptor+ / CD4+ / CD27+; and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor7CD87CCR7+ / CD27+cells and / or at least about 3 x 106, 4 x 106, 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, or 1 x 107total receptor+ / CD4+ / CCR7+ / CD27+cells; and / orthe unit dose comprises between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+cells or total receptor+ / CD8+ / CD27+cells; and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD4+ / CCR7+cells or total receptor+ / CD4+ / CD27+, and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD8+ / CCR7+ / CD27+cells and / or between at or about 3 x 106and at or about 2.5 x 107, between at or about 4 x 106and at or about 2 x 107, or between at or about 5 x 106and at or about 1 x 107total receptor+ / CD4+ / CCR7+ / CD27+cells, each inclusive.

117. The method of any of claims 113-116, wherein:at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD8+ / CCR7+or receptor+ / CD8+ / CD27+;at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD4+ / CCR7+or receptor+ / CD4+ / CD27+; and / orat least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose are receptor+ / CD8+ / CCR7+ / CD27+or receptor+ / CD4+ / CCR7+ / CD27+.

118. The method of any of claims 113-117, wherein the unit dose of cells comprises a defined ratio of receptor+ / CD8+ / CCR7+cells to receptor+ / CD4+ / CCR7+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1; and / or a defined ratio of receptor+ / CD8+ / CD27+cells to receptor+ / CD4+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1; and / or a defined ratio of receptor+ / CD8+ / CCR7+ / CD27+cells toreceptor+ / CD4+ / CCR7+ / CD27+cells, which ratio optionally is or is approximately 1: 1 or is between approximately 1:3 and approximately 3: 1.

119. The method of any of claims 113-118, wherein the unit dose further comprises a defined number of cells comprising cells that express or do not express CD45, optionally wherein the unit dose further comprises a defined number of cells comprising CD45RA- cells .

120. The method of claim 110, wherein the unit dose of cells comprises a defined number of receptor+ / CD4+ / CCR7+ / CD45RA cells and / or rcccptor+ / CD8+ / CCR7+ / CD45RA cells.

121. The method of any of claims 113-120 wherein at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total receptor+cells in the unit dose, or between about 15% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60%, each inclusive, of the total receptor+cells in the unit dose arereceptor+ / CD4+ / CCR7+ / CD45RA or rcccptor+ / CD8+ / CCR7+ / CD45RA .

122. The method of any of claims 106-121, wherein prior to the providing or isolating, the method comprises determining the number, number per volume, number per weight, and / or percentage of the CD8+T cells that express or do not express CCR7, CD27 and / or CD45RA and / or CD4+T cells that express or do not express CCR7, CD27 and / or CD45RA.

123. The method of any of claims 106-122, wherein the one or more stimulating agent is capable of activating T cells, CD4+T cells and / or CD8+T cells; is capable of inducing a signal through a TCR complex; and / or is capable of inducing proliferation of T cells, CD4+T cells and / or CD8+T cells.

124. The method of any of claims 106-123, wherein the one or more stimulating agent comprises a primary agent that binds to a member of a TCR complex, optionally thatspecifically binds to CD3.

125. The method of claim 124, wherein the one or more stimulating agent further comprises a secondary agent that specifically binds to a T cell costimulatory molecule.

126. The method of claim 125, wherein the costimulatory molecule is selected from the group consisting of CD28, CD137 (4-1BB), 0X40, or ICOS.

127. The method of claiml25 or claim 126, wherein the primary and secondary agents comprise antibodies, optionally wherein the one or more stimulating agent comprises incubation with an anti-CD3 antibody and an anti-CD28 antibody.

128. The method of any of claims 106-127, wherein the one or more stimulating agents are present on the surface of a solid support, optionally a bead.

129. The method of any of claims 106-128, wherein the one or more stimulating agent is selected from the group consisting of CD3-binding molecules; CD28-binding molecules; recombinant IL-2; recombinant IL-15; and recombinant IL-7, a vaccine comprising an antigen specifically recognized by the antigen receptor, and an anti-idiotype antibody that specifically binds the antigen receptor or combinations thereof.

130. The method of any of claims 82-129, wherein the therapeutic composition is a composition according to claim 1 or claim 7.

131. The methods of any of claims 82-130, further comprising administering to a subject having a disease or condition, the therapeutic composition, optionally one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.

132. The method of any of claims 82-131, wherein among a group of subjects treated according to the method, the number or ratio of cells that express CCR7 (CCR7+cells) in the unit dose varies by no more than 40%, by no more than 30%, by no more than 20%, by no more than 10% or by no more than 5%.

133. The method of any of claims 82-132, wherein the unit dose comprises between at or about 1 x 10 and at or about 5 x 10 , between at or about 1 x 10 and at or about 1 x 10 , between at or about 5 x 105and at or about 1 x 107, or between at or about 1 x 106and at or about 1 x 107total CD3+cells that express the recombinant receptor (receptor+ / CD3+cells) or total CD3 cells, each inclusive;82-and / orthe unit dose comprises no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / CD3+cells or total CD3+cells.

134. The method of any of claims 82-133, wherein the total number of CD3+cells, total number of receptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number ofreceptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number of receptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number of receptor+ / CD4+ / CCR7+ / CD27+cells, total number o G rcccptor+ / C D8+ / CC R7+ / CD45 R A cells and / or rcccptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that are live or viable.

135. The method of any of claims 82-134, wherein the total number of CD3+cells, total number of receptor+ / CD3+cells, total number of receptor+ / CD8+cells, total number of receptor+ / CD4+cells, total number of receptor+ / CD8+ / CCR7+cells, total number ofreceptor+ / CD4+ / CCR7+cells, total number of receptor+ / CD8+ / CD27+cells, total number of receptor+ / CD4+ / CD27+cells, total number of receptor+ / CD8+ / CCR7+ / CD27+cells, total number of receptor+ / CD4+ / CCR7+ / CD27+cells, total number o G rcccptor+ / C D8+ / CC R7+ / CD45 R A cells and / or rcccptor+ / CD4+ / CCR7+ / CD45RA cells is the total number of such cells that do not express an apoptotic marker and / or is the total number of such cells that are apoptotic marker negative O, wherein the apoptotic marker is Annexin V or activated Caspase 3.

136. The method of any of claims 131-135, comprising administering a plurality of unit doses contained in a plurality of separate compositions.

137. The method of claim 136, wherein the plurality of separate compositions comprise a first composition comprising one of the CD8+T cells and the CD4+T cells and a second composition comprising the other of the CD8+T cells and the CD4+T cells.

138. The method of claim 137, wherein the first composition comprises the CD8+T cells.

139. The method of claim 137, wherein the first composition comprises the CD4+T cells.

140. The method of any of claims 131-139, comprising administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses and the composition containing CD4+T cells or one or more unitdoses thereof and / or a volume corresponding to such one or more of unit doses no more than 48 hours apart.

141. The method of claim 140, wherein the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses and the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses are administered no more than 36 hours apart, no more than 24 hours apart, no more than 12 hours apart, no more than 6 hours apart, no more than 4 hours apart, no more than 2 hours apart, no more than 1 hour apart or no more than 30 minutes apart.

142. The method of claim 140 or claim 141, wherein the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses and the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses are adminsitered no more than 2 hours, no more than 1 hour, no more than 30 minutes, no more than 15 minutes, no more than 10 minutes or no more than 5 minutes apart or simultaneously.

143. The method of any of claims 136-142, comprising administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses, prior to administering the composition containing CD4+cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.

144. The method of any of claims 136-142, comprising administering the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses, prior to administering the composition containing CD8+cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.

145. The method of any of claims 49-144, wherein the recombinant receptor is capable of binding to a target antigen that is associated with, specific to, and / or expressed on a cell or tissue of a disease, disorder or condition.

146. The method of claim 145, wherein the disease, disorder or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or a cancer.

147. The method of claim 145 or claim 146, wherein the target antigen is selected from among anb6 integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-l), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138, CD171, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), glypican-3 (GPC3), G Protein Coupled Receptor 5D(GPRC5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight-melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HLA-A1), Human leukocyte antigen A2 (HLA- A2), IL-22 receptor alpha(IL-22Ra), IL-13 receptor alpha 2 (IL-l3Ra2), kinase insert domain receptor (kdr), kappa light chain, Ll cell adhesion molecule (Ll-CAM), CE7 epitope of Ll- CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y, Melanoma- associated antigen (MAGE)-Al, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c- Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72),Tyrosinase related protein 1 (TRP1, also known as TYRP1 or gp75), Tyrosinase related protein 2 (TRP2, also known as dopachrome tautomerase, dopachrome delta-isomerase or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-l), a pathogen-specific or pathogen-expressedantigen, or an antigen associated with a universal tag, and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV or other pathogens.

148. The method of any of claims 49-147, wherein the recombinant receptor is a chimeric antigen receptor (CAR).

149. The method of any of claims 48-148, wherein the recombinant receptor comprises an extracellular domain comprising an antigen-binding domain and an intracellular signaling region comprising an intracellular signaling domain, and further comprises a transmembrane domain disposed between the extracellular domain and the intracellular signaling region.

150. The method of claim 149, wherein the antigen-binding domain is or comprises an antibody or an antibody fragment thereof, which optionally is a single chain fragment.

151. The method of claim 150, wherein the fragment comprises an scFv.

152. The method of any of claims 149-151, wherein the intracellular signaling domain is or comprises an intracellular signaling domain of a CD3 chain, optionally a CD3-zeta ^ϋ3z) chain, or a signaling portion thereof.

153. The method of any of claims 149-152, wherein the intracellular signaling region further comprises a costimulatory signaling domain.

154. The method of claim 153, wherein the costimulatory signaling domain comprises an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof.

155. The method of claim 153 or claim 154, wherein the costimulatory signaling domain comprises an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof.

156. The method of any of claims 153-155, wherein the costimulatory signaling domain is between the transmembrane domain and the intracellular signaling domain.

157. The method of any of claims 49-156, wherein the T cells are primary T cells obtained from a subject.

158. The method of any of claims 49-157, wherein the T cells are autologous to the subject.

159. The method of any of claims 49-157, wherein the T cells are allogeneic to the subject.

160. The method of any of claims 157-179, wherein the subject has a cancer, optionally wherein the cancer is a leukemia or a lymphoma.

161. The method of claim 160, wherein the subject is a subject that, at the time of obtaining the cells, is identified or known to have a high tumor burden.

162. The method of claim 161, wherein:the subject has high tumor burden if a sum of product dimensions (SPD) of a tumor in the subject is above at or about 30 cm 2 , 40 cm 2 , 50 cm 2 , 60 cm 2 or 70 cm 2 ; and / orthe subject has high tumor burden if C reactive protein (CRP) in a biological sample, optionally a serum sample, from the subject is above at or about 5 miligrams per liter, 10 miligrams per liter, 15 miligrams per liter, 20 miligrams per liter, 25 miligrams per liter, 30 miligrams per liter, 40 miligrams per liter or 50 miligrams per liter.

163. The method of claim 162, wherein the subject has high tumor burden if the SPD2of a tumor in the subject is above at or about 50 cm .

164. The method of claim 162 or claim 163, wherein the subject has high tumor burden if the CRP is above at or about 20 miligrams per liter in the biological sample.

165. An output composition produced by the method of any of claims 106-164.

166. A unit dose determined or produced by the method of any of claims 82-164.

167. A pharmaceutical composition comprising the unit dose of claim 166.

168. The pharmaceutical composition of claim 167, further comprising apharmaceutical carrier.

169. A method of treatment, comprising administering to a mammalian subject all or a portion of the output composition of claim 165, a unit dose of claim 166 or a pharmaceutical composition of claim 167 or claim 168.

170. Use of all or a portion of the output composition of claim 165, a unit dose of claim 166 or a pharmaceutical composition of claim 167 or claim 168 for treating cancer.

171. Use of all or a portion of the output composition of claim 165, a unit dose of claim 166 or a pharmaceutical composition of claim 167 or claim 168 in the manufacture of a medicament for treating cancer.

172. The output composition of claim 165, a unit dose of claim 166 or apharmaceutical composition of claim 167 or claim 168 for use in treating cancer.

173. A therapeutic cell composition comprising T cells expressing a recombinant receptor that binds to an antigen, wherein, following stimulation with a stimulatory agent:at least at or about, or at or about, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing the recombinant receptor are able to produce a cytokine selected from interleukin 2 (IL-2) and / or TNF-alpha; and / orat least at or about, or at or about, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in the composition expressing the recombinant receptor are polyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha.

174. The therapeutic cell composition of claim 173, wherein at least at or about, or at or about, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing the recombinant receptor are able to produce a cytokine selected from interleukin 2 (IL-2) and / or TNF-alpha.

175. The therapeutic cell composition of any of claims 173-174, wherein at least at or about, or at or about, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in the composition expressing the recombinant receptor are polyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha.

176. The therapeutic cell composition of any of claims 173-175, wherein at least at or about, or at or about, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in the composition expressing the recombinant receptor are polyfunctional for producing the cytokines interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha.

177. The therapeutic cell composition of any of claims 173-176, wherein the stimulatory agent is a non-specific or non-antigen-dependent T cell stimulatory agent.

178. The therapeutic cell composition of claim 177, wherein the non-specific or non antigen dependent T cell stimulatory agent is a polyclonal stimulatory agent.

179. The therapeutic cell composition of any of claims 173-178, wherein the non specific or non-antigen dependent stimulatory agent comprises PMA / ionomycin, anti-CD3 / anti- CD28, phytohemagglutinin (PHA) or concanavalin A (ConA).

180. The therapeutic cell composition of any of claims 177-179, wherein the non specific or non-antigen dependent T cell stimulatory agent comprises PMA / ionomycin.

181. The therapeutic cell composition of any of claims 173-176, wherein the stimulatory agent specifically binds the recombinant receptor, optionally wherein the stimulatoryagent is an antigen- specific stimulatory reagent and / or comprises the antigen or a portion thereof specifically recognized by the recombinant receptor.

182. The therapeutic cell composition of any of claims 173-181, wherein production of the cytokines is measured in an intracellular cytokine assay.

183. The therapeutic cell composition of any of claims 173-182, wherein the composition comprises at least at or about, or at or about, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27, optionally further negative for surface expression of CD45RA.

184. The therapeutic cell composition of any of claims 173-183, wherein the T cells are primary cells obtained from a subject.

185. The therapeutic cell composition of claim 184, wherein the subject has a cancer, optionally wherein the cancer is a leukemia or a lymphoma.

186. The therapeutic cell composition of claim 185, wherein the subject is a subject that, at the time of obtaining the cells, is identified or known to have a high tumor burden.

187. The therapeutic cell composition of claim 186, wherein:the subject has high tumor burden if a sum of product dimensions (SPD) of a tumor in the subject is above at or about 30 cm 2 , 40 cm 2 , 50 cm 2 , 60 cm 2 or 70 cm 2 ; and / orthe subject has high tumor burden if C reactive protein (CRP) in a biological sample, optionally a serum sample, from the subject is above at or about 5 miligrams per liter, 10 miligrams per liter, 15 miligrams per liter, 20 miligrams per liter, 25 miligrams per liter, 30 miligrams per liter, 40 miligrams per liter or 50 miligrams per liter.

188. The therapeutic cell composition of claim 187, wherein the subject has high2tumor burden if the SPD of a tumor in the subject is above at or about 50 cm .

189. The therapeutic cell composition of claim 187 or claim 188, wherein the subject has high tumor burden if the CRP is above at or about 20 miligrams per liter in the biological sample.

190. The therapeutic cell composition of any of claims 173-189, wherein the therapeutic cell composition is enriched in CD4+ T cells and / or at least at or about 60%, at least at or about 70%, at least at or about 80%, at least at or about 90%, at least at or about 95%, at least at or about 97% of the total recombinant receptor+cells in the engineered composition, or between about 60% and 99%, between about 75% and 99%, between about 85% and 99%, or between about 90% and 99%, each inclusive, of the total cells in the composition are CD4+.

191. The therapeutic cell composition of any of claims 173-189, wherein the therapeutic cell composition is enriched in CD3+ T cell, is enriched in CD4+ and CD8+ T cells and / or at least at or about 60%, at least at or about 70%, at least at or about 80%, at least at or about 90%, at least at or about 95%, at least at or about 97% of the total recombinant receptor+cells in the engineered composition, or between about 60% and 99%, between about 75% and 99%, between about 85% and 99%, or between about 90% and 99%, each inclusive, of the total cells in the composition are CD3+ or CD4+and CD8+.

192. The therapeutic cell composition of claim 191, wherein the therapeutic cell composition comprises CD4+ and CD8+ T cells at a ratio of CD4+ to CD8+ T cells that is between approximately 1:3 and approximately 3:1, optionally between approximately 1:2 and 2: 1.

193. The therapeutic composition of any of claims 173-192, wherein the recombinant receptor is or comprises a chimeric receptor and / or a recombinant antigen receptor.

194. The therapeutic composition of any of claims 173-193, wherein the recombinant receptor is capable of binding to a target antigen that is associated with, specific to, and / or expressed on a cell or tissue of a disease, disorder or condition.

195. The therapeutic composition of claim 194, wherein the disease, disorder or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or a cancer.

196. The therapeutic composition of claim 194 or claim 195, wherein the target antigen is a tumor antigen.

197. The therapeutic composition of any of claims 194-196, wherein the target antigen is selected from among anb6 integrin (avb6 integrin), B cell maturation antigen (BCMA), B7- H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-l), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138, CD 171, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG- 2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), glypican-3 (GPC3), G Protein Coupled Receptor 5D (GPRC5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight-melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HLA-A1), Human leukocyte antigen A2 (HLA- A2), IL-22 receptor alpha(IL-22Ra), IL-13 receptor alpha 2 (IL-l3Ra2), kinase insert domain receptor (kdr), kappa light chain, Ll cell adhesion molecule (Ll-CAM), CE7 epitope of Ll- CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y, Melanoma- associated antigen (MAGE)-Al, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c- Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72),Tyrosinase related protein 1 (TRP1, also known as TYRP1 or gp75), Tyrosinase related protein2 (TRP2, also known as dopachrome tautomerase, dopachrome delta-isomerase or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-l), a pathogen-specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV or other pathogens.

198. The therapeutic composition of any of claims 173-197, wherein the recombinant receptor is or comprises a functional non-TCR antigen receptor or a TCR or antigen-binding fragment thereof.

199. The therapeutic composition of any of claims 173-198, wherein the recombinant receptor is a chimeric antigen receptor (CAR).

200. The therapeutic composition of any of claims 173-199, wherein the recombinant receptor comprises an extracellular domain comprising an antigen-binding domain and an intracellular signaling region comprising an intracellular signaling domain.

201. The therapeutic composition of claim 200, wherein the antigen-binding domain is or comprises an antibody or an antibody fragment thereof, which optionally is a single chain fragment.

202. The therapeutic composition of claim 201, wherein the fragment comprises antibody variable regions joined by a flexible linker.

203. The therapeutic composition of claim 201 or claim 202, wherein the fragment comprises an scFv.

204. The therapeutic composition of any of claims 200-203, wherein the intracellular signaling domain is or comprises a primary signaling domain, a signaling domain that is capable of inducing a primary activation signal in a T cell, a signaling domain of a T cell receptor (TCR) component, and / or a signaling domain comprising an immunoreceptor tyrosine-based activation motif (GGAM).

205. The therapeutic composition of any of claims 200-204, wherein the intracellular signaling domain is or comprises an intracellular signaling domain of a CD3 chain, optionally a CD3-zeta (€ϋ3z) chain, or a signaling portion thereof.

206. The therapeutic composition of any of claims 200-205, wherein the recombinant receptor further comprises a transmembrane domain disposed between the extracellular domain and the intracellular signaling region.

207. The therapeutic composition of any of claims 200-206, wherein the intracellular signaling region further comprises a costimulatory signaling domain.

208. The therapeutic composition of claim 207, wherein the costimulatory signaling domain comprises an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof.

209. The therapeutic composition of claim 207 or claim 208, wherein thecostimulatory signaling domain comprises an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof.

210. The therapeutic composition of any of claims 207-209, wherein the costimulatory signaling domain is between the transmembrane domain and the intracellular signaling domain.

211. The therapeutic composition of any of claims 173-210, wherein the T cells are primary T cells obtained from a subject.

212. The therapeutic composition of any of claims 173-211, wherein the T cells are autologous to the subject.

213. An article of manufacture, comprising a container comprising a therapeutic cell composition of any of claims 173-212, and instructions for administering to a subject having a disease or condition, the therapeutic cell composition, optionally one or more unit doses thereof and / or a volume corresponding to such one or more unit doses.

214. The article of manufacture of claim 213, wherein the instructions specify administering a plurality of unit doses contained in a plurality of separate compositions.

215. The article of manufacture of claim 214, wherein the plurality of separate compositions comprise a first composition comprising the therapeutic cell composition comprising one of CD8+T cells and CD4+T cells and a second composition comprising the other of the CD8+T cells and the CD4+T cells, said second composition comprising cells expressing the recombinant receptor or a recombinant receptor specific for the antigen or for a cell expressed by the disease or condition optionally wherein the second composition is a composition of any of claims 1-40.

216. The article of manufacture of claim 215, wherein the instructions specify administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses and the composition containing CD4+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses within no more than 48 hours apart, within no more than 36 hours apart, within no more than 24 hours apart, within no more than 12 hours apart, within no more than 6 hours apart, within no more than 2 hours apart, within no more than 1 hour apart or simultaneously.

217. The article of manufacture of claim 215 or claim 216, wherein the instructions specify administering the composition containing CD8+T cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses, prior to administering the composition containing CD4+cells or one or more unit doses thereof and / or a volume corresponding to such one or more of unit doses.

218. A method of treatment, the method comprising administering to a subject having a disease or condition one or more unit doses of a therapeutic cell composition of any of claims 173-212.

219. The method of claim 218, wherein the therapeutic composition is a first therapeutic cell composition comprising one of CD8+ T cells and CD4+ T cells and the one or more units doses further comprises a second therapeutic cell composition comprising the other of the CD8+ T cells and CD4+ cells, said second composition comprising cells expressing therecombinant receptor or a recombinant receptor specific for the antigen or for a cell expressed by the disease or condition, optionally wherein the second composition is a composition of any of claims 173-212.

220. The method of claim 47, wherein at least at or about, or at or about, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the second therapeutic cell composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27, optionally further negative for surface expression of CD45RA.

221. The method of claim 219 or claim 220, wherein the second therapeutic cell composition is enriched in CD8+ T cells and / or at least at or about 60%, at least at or about 70%, at least at or about 80%, at least at or about 90%, at least at or about 95%, at least at or about 97% of the total recombinant receptor+cells in the engineered composition, or between about 60% and 99%, between about 75% and 99%, between about 85% and 99%, or between about 90% and 99%, each inclusive, of the total cells in the composition are CD8+.

222. The method of claim 221, wherein the first therapeutic composition and second therapeutic composition are administered within at or about 48 hours, within at or about 36 hours, within at or about 24 hours, within at or about 12 hours, within at or about 6 hours, within at or about 2 hours or within at or about 1 hour of each other.

223. The method of claim 221 or claim 222, wherein the second therapeutic cell composition comprising the CD8+ T cells is administered before the first composition comprising CD4+ T cells.

224. The method of any of claims 218-223, wherein the one or more unit dose of cells comprises a defined ratio of CD4+ to CD8+ T cells, which ratio is or is approximately 1:3 and approximately 3:1, optionally that is or is approximately 1:2 and 2:1, optionally that is or is about 1:1.

225. A method for treatment of a subject, the method comprising:(A) assaying an engineered cell composition comprising T cells expressing a recombinant receptor for a factor indicative of the function or phenotype of engineered cells in the composition, the factor selected from (i) the percentage of T cells expressing therecombinant receptor that are surface positive for CCR7 and / or CD27, and optionally surface negative for CD45RA; and / or (ii) the percentage of CD4+ T cells expressing the recombinant receptor that are able to produce IL-2, TNF-alpha, and / or IFN-gamma following stimulation with a stimulatory agent; and(B) administering to a subject having a disease or condition a therapy, the administering selected from:(1) if a factor indicative of the function or phenotype of cells of the engineered T cell composition is at or above a threshold value, administering to the subject one or more unit doses of cells of an engineered cell composition comprising T cells expressing a recombinant receptor; or(2) if the factor indicative of the function or phenotype of cells of the engineered T cell composition is below a threshold value of the factor, administering a therapy selected from (a) one or more unit doses of cells of the engineered cell composition and an agent capable of increasing expansion, proliferation or efficacy of T cells of the engineered cell composition in the subject, (b) an increased dose of cells of the engineered cell composition, optionally increased compared to the one or more unit dose administered to a similarly situated subject having the same disease or condition but exhibiting the threshold value of the factor or greater; or (c) an alternative therapeutic treatment for treating the disease or condition other than one or more unit doses of the engineered cell composition,wherein the threshold value of the factor is selected from(i) at or about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27; and / or(ii) at or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing the recombinant receptor are able to produce interleukin 2 (IL-2) or TNF-alpha following stimulation with a stimulatory agent; and / or(iii) at or about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in the composition expressing the recombinant receptor arepolyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha following stimulation with a stimulatory agent.

226. A method for treatment of a subject, the method comprising administering to a subject having a disease or condition a therapy, the administering selected from:(1) if a factor indicative of a function or phenotype of cells of an engineered cell composition comprising T cells expressing a recombinant receptor is at or above a threshold value, administering to the subject one or more unit doses of cells of the engineered T cell composition; or(2) if the factor indicative of the function or phenotype of cells of the engineered T cell composition is below a threshold value of the factor, administering a therapy selected from (a) one or more unit doses of cells of the engineered cell composition and an agent capable of increasing expansion, proliferation or efficacy of T cells of the engineered cell composition in the subject, (b) an increased dose of cells of the engineered cell composition, optionally increased compared to the one or more unit doses administered to a similarly situated subject having the same disease or condition but exhibiting the threshold value of the factor or greater; or (c) an alternative therapeutic treatment for treating the disease or condition other than a dose of the engineered cell composition,wherein the threshold value of the factor is selected from(i) at or about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27; and / or(ii) at or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing the recombinant receptor are able to produce interleukin 2 (IL-2) or TNF-alpha following stimulation with a stimulatory agent; and / or(iii) at or about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in the composition expressing the recombinant receptor arepolyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha following stimulation with a stimulatory agent.

227. The method of any of claims 218-226, wherein cells of the cell composition are autologous to the subject.

228. The method of any of claims 218-227, wherein at least 35%, at least 40 %, at least 50%, at least 60% or at least 70% , or at least 75% of the subjects treated according to the method achieve progression free survival for at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months or at least 12 months following administration of the one or more unit doses.

229. The method of any of claims 218-228, wherein at least 35%, at least 40 %, at least 50%, at least 60% or at least 70% , or at least 75% of the subjects treated according to the method do not achieve disease progression for at least at or about 3 months, at least at or about 4 months, at least at or about 5 months, at least at or about 6 months, at least at or about 9 months or at least at or about 12 months following administration of the one or more unit doses.

230. The method of any of claims 218-229, wherein subjects treated according to the method achieve a pharmacokinetic property of cells of the cell composition in a biological sample, optionally a blood or serum sample, that is improved, on average, compared to a group of similarly situated subjects having the same disease or condition and administered a similar dose of an autologous cell composition comprising T cells expressing the recombinant receptor but in which the factor indicative of function or phenotype of cells is below the threshold value.

231. The method of claim 230, wherein the pharmacokinetic property is the total exposure over time (AUC) or peak number of cells in the biological sample.

232. A method of predicting likelihood of response to a therapeutic T cellcomposition, the method comprising:(a) assaying an engineered cell composition comprising T cells expressing a recombinant receptor for a factor indicative of the function or phenotype of engineered cells in the composition, the factor selected from (i) the percentage of T cells expressing the recombinant receptor that are surface positive for CCR7 and / or CD27, and optionally surface negative for CD45RA; and / or (ii) the percentage of CD4+ T cells expressing the recombinant receptor thatare able to produce IL-2, TNF-alpha, and / or IFN-gamma following stimulation with a stimulatory agent; and(b) determining the likelihood of response following administration of a cell therapy comprising a dose of the engineered cells, wherein if the factor is at or above a threshold value identifying the subject as likely to achieve a durable response or progression free survival, optionally for at least 3 months, following administration the therapy; or if the factor is below a threshold value identifying the subject as not likely to exhibit a durable response or progression free survival to the therapy,wherein the threshold value of the factor is selected from:(i) at or about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27; and / or(ii) at or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing the recombinant receptor are able to produce interleukin 2 (IL-2) or TNF-alpha following stimulation with a stimulatory agent; and / or(iii) at or about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in the composition expressing the recombinant receptor arepolyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha following stimulation with a stimulatory agent.

233. The method of claim 232, wherein cells of the cell composition are autologous to the subject.

234. The method of claim 232 or claim 233, wherein if the subject is identified as likely to achieve a durable response or progression free survival to the therapy, administering to the subject one or more unit doses of cells of the engineered T cell composition.

235. The method of any of claims 218-231, 233 and 234, wherein the one or more unit doses comprises between at or about 1 x 105 and at or about 5 x 108, between at or about 1 x 105 and at or about 1 x 108, between at or about 5 x 105 and at or about 1 x 107 , or between at orabout 1 x 106and at or about 1 x 107total T cells that express the recombinant receptor(receptor+ / T cells) or total T cells, each inclusive.

236. The method of any of claims 218-231, and 233-235, wherein the one or more unit doses comprises no more than about 5 x 10 , no more than about 1 x 10 , no more than about 5 x 107, no more than about 1 x 107, no more than about 5 x 106, no more than about 1 x 106, or no more than about 5 x 105total receptor+ / T cells or total T cells.

237. The method of any of claims 225-236, wherein the threshold value of the factor is at or about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27; and / or238. The method of any of claims 225-237, wherein the threshold value of the factor is at or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing the recombinant receptor are able to produce a cytokine selected from interleukin 2 (IL-2) and / or TNF-alpha.

239. The method of any of claims 225-238, wherein the threshold value of the factor is at or about, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+T cells in the composition expressing the recombinant receptor are polyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL- 2) and TNF-alpha.

240. The method of any of claims 225-239, wherein the threshold value of the factor is at or about, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+T cells in the composition expressing the recombinant receptor are polyfunctional for producing the cytokines interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha.

241. The method of any of claims 232-240, wherein if the subject is identified as not likely to achieve a durable response or progression free survival, administering to the subject a therapy selected from (a) a dose of cells of the engineered cell composition and an agent capableof increasing expansion, proliferation or efficacy of T cells of the engineered cell composition in the subject, (b) an increased dose of cells of the engineered cell composition, optionally increased compared to a dose administered to a similarly situated subject having the same disease or condition but exhibiting a likelihood of achieving progression free survival or a durable response to the cell therapy; or (c) an alternative therapeutic treatment for treating the disease or condition other than a dose of the engineered cell composition.

242. The method of any of claims 225-231 and 241, wherein the method comprises administration of a therapy comprising a dose of cells of the engineered cell composition and an agent capable of increasing expansion, proliferation or efficacy of T cells of the engineered cell composition in the subject, wherein the agent is an anti-idiotype antibody or antigen-binding fragment thereof specific to the CAR, an immune checkpoint inhibitor, a modulator of a metabolic pathway, an adenosine receptor antagonist, a kinase inhibitor, an anti-TGFp antibody or an anti-TGFpR antibody or a cytokine.

243. The method of claim 242, wherein the agent is administered prior to,concurrently or after the administration of the therapeutic T cell composition.

244. The method of any of claims 218-242, wherein the subject is a subject that, at the time of the assaying and / or prior to the administering, is identified or known to have a high tumor burden.

245. The method of claim 244, wherein:the subject has high tumor burden if a sum of product dimensions (SPD) of a tumor in the subject is above at or about 30 cm 2 , 40 cm 2 , 50 cm 2 , 60 cm 2 or 70 cm 2 ; and / orthe subject has high tumor burden if C reactive protein (CRP) in a biological sample, optionally a serum sample, from the subject is above at or about 5 miligrams per liter, 10 miligrams per liter, 15 miligrams per liter, 20 miligrams per liter, 25 miligrams per liter, 30 miligrams per liter, 40 miligrams per liter or 50 miligrams per liter.

246. The method of claim 245, wherein the subject has high tumor burden if the SPD2of a tumor in the subject is above at or about 50 cm .

247. The method of claim 245 or claim 246, wherein the subject has high tumor burden if the CRP is above at or about 20 miligrams per liter in the biological sample.

248. The method of any of claims 225-247, wherein the stimulatory agent is a non specific or non-antigen-dependent T cell stimulatory agent.

249. The method of claim 248, wherein the non-specific or non-antigen dependent T cell stimulatory agent is a polyclonal stimulatory agent.

250. The method of any of claim 248 or claim 249, wherein the non-specific or non antigen dependent stimulatory agent comprises PMA / ionomycin, anti-CD3 / anti-CD28, phytohemagglutinin (PHA) or concanavalin A (ConA).

251. The method of any of claims 248-250, wherein the non-specific or non-antigen dependent T cell stimulatory agent comprises PMA / ionomycin.

252. The method of any of claims 225-247, wherein the stimulatory agent specifically binds the recombinant receptor, optionally wherein the stimulatory agent is an antigen- specific stimulatory reagent and / or comprises the antigen or a portion thereof specifically recognized by the recombinant receptor.

253. The method of any of claims 225-252, wherein production of the cytokines is measured in an intracellular cytokine assay.

254. The method of any of claims 218-253, wherein the recombinant receptor is or comprises a chimeric receptor and / or a recombinant antigen receptor.

255. The method of any of claims 218-254, wherein the recombinant receptor is capable of binding to a target antigen that is associated with, specific to, and / or expressed on a cell or tissue of a disease, disorder or condition.

256. The method of claim 255, wherein the disease, disorder or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or a cancer.

257. The method of claim 255 or claim 256, wherein the target antigen is a tumor antigen.

258. The method of any of claims 255-257, wherein the target antigen is selected from among anb6 integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-l and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-l), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138, CD171, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrine receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gplOO), glypican-3 (GPC3), G Protein Coupled Receptor 5D(GPRC5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight-melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen Al (HLA-A1), Human leukocyte antigen A2 (HLA- A2), IL-22 receptor alpha(IL-22Ra), IL-13 receptor alpha 2 (IL-l3Ra2), kinase insert domain receptor (kdr), kappa light chain, Ll cell adhesion molecule (Ll-CAM), CE7 epitope of Ll- CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y, Melanoma- associated antigen (MAGE)-Al, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c- Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-l), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72),Tyrosinase related protein 1 (TRP1, also known as TYRP1 or gp75), Tyrosinase related protein2 (TRP2, also known as dopachrome tautomerase, dopachrome delta-isomerase or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-l), a pathogen-specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV or other pathogens.

259. The method of any of claims 218-258, wherein the recombinant receptor is or comprises a functional non-TCR antigen receptor or a TCR or antigen-binding fragment thereof.

260. The method of any of claims 218-259, wherein the recombinant receptor is a chimeric antigen receptor (CAR).

261. The method of any of claims 218-260, wherein the recombinant receptor comprises an extracellular domain comprising an antigen-binding domain and an intracellular signaling region comprising an intracellular signaling domain.

262. The method of claim 261, wherein the antigen-binding domain is or comprises an antibody or an antibody fragment thereof, which optionally is a single chain fragment.

263. The method of claim 262, wherein the fragment comprises antibody variable regions joined by a flexible linker.

264. The method of claim 262 or claim 263, wherein the fragment comprises an scFv.

265. The method of any of claims 261-264, wherein the intracellular signaling domain is or comprises a primary signaling domain, a signaling domain that is capable of inducing a primary activation signal in a T cell, a signaling domain of a T cell receptor (TCR) component, and / or a signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM).

266. The method of claim 265, wherein the intracellular signaling domain is or comprises an intracellular signaling domain of a CD3 chain, optionally a CD3-zeta ^ϋ3z) chain, or a signaling portion thereof.

267. The method of any of claims 261-266, wherein the recombinant receptor further comprises a transmembrane domain disposed between the extracellular domain and the intracellular signaling region.

268. The method of any of claims 261-267, wherein the intracellular signaling region further comprises a costimulatory signaling domain.

269. The method of claim 268, wherein the costimulatory signaling domain comprises an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof.

270. The method of claim 268 or claim 269, wherein the costimulatory signaling domain comprises an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof.

271. The method of claim 269 or claim 270, wherein the costimulatory signaling domain is between the transmembrane domain and the intracellular signaling domain.

272. The method of any of claims 218-271, wherein the T cells are primary T cells obtained from a subject.

273. The method of any of claims 218-272, wherein the T cells are autologous to the subject.

274. A method of producing a therapeutic T cell composition, comprising:(a) incubating an input composition under stimulating conditions, thereby generating a stimulated composition, wherein the input composition comprising a defined number of T cells that do not express an apoptotic marker (apoptotic marker negative O); and(b) introducing a recombinant receptor into cells from the stimulated composition thereby generating an engineered cell composition, wherein the introducing comprises contacting the cells of the stimulated composition with an agent comprising a polynucleotide encoding the recombinant receptor.

275. The method of claim 274, wherein the apoptotic marker negative T cells are or comprise apoptotic marker negative CD3+cells, apoptotic marker negative CD8+cells, apoptotic marker negative CD4+ cells, or apoptotic marker negative CD8+ cells and apoptotic marker negative CD4+ cells.

276. The method of claim 274 or claim 275, wherein the apoptotic marker is Annexin V.

277. The method of claim 274 or claim 275, wherein the apoptotic marker is activated Caspase 3.

278. The method of any of claim 274-276, wherein the defined number of T cells comprises at least 50 x 106of the apoptotic marker negative T cells, optionally apoptotic marker negative CD4+ and / or apoptotic marker negative CD8+ T cells.

279. The method of any of claims 274-278, wherein the defined number of T cells comprises at least 100 x 106of the apoptotic marker negative T cells, optionally apoptotic marker negative CD4+ and / or apoptotic marker negative CD8+ T cells.

280. The method of any of claims 274-279, wherein the defined number of T cells comprises between at or about 100 x 106and at or about 500 x 106apoptotic marker negative T cells, optionally apoptotic marker negative CD4+ and / or apoptotic marker negative CD8+ T cells.

281. The method of any of claims 274-280, wherein the defined number of T cells comprises at or about 300 x 106, apoptotic marker negative T cells, optionally apoptotic marker negative CD4+ and / or apoptotic marker negative CD8+ T cells.

282. The method of any of claims 274-281, wherein the percentage of apoptotic marker negative T cells as a percentage of the total T cells in the input composition is greaterthan or greater than about 70%, greater than or greater than about 80%, greater than or greater than about 90%, or greater than or greater than about 95%.

283. The method of any of claims 274-282, wherein, prior to the incubating, obtaining an input composition comprising the defined number of apoptotic marker negative T cells.

284. The method of any of claims 274-283, wherein, prior to the incubating, isolating, selecting or enriching apoptotic marker negative T cells, optionally apoptotic marker negative CD4+ and / or apoptotic marker negative CD8+ T cells from a biological sample.

285. A method of producing a therapeutic T cell composition, the method comprising:(a) isolating, selecting or enriching, from a biological sample, a population of T cells that do not express an apoptotic marker (apoptotic marker negative O), optionally apoptotic marker negative CD4+ and / or apoptotic marker negative CD8+ T cells, thereby obtaining an input composition.(b) incubating the input composition under stimulating conditions, thereby generating a stimulated composition; and(c) introducing a recombinant receptor into cells from the stimulated composition thereby generating an engineered cell composition, wherein the introducing comprises contacting the cells of the stimulated composition with an agent comprising a polynucleotide encoding the recombinant receptor.

286. The method claim 284 or claim 285, wherein the biological sample primary T cells obtained from a subject.

287. The method of claim 286, wherein the subject is a human subject.

288. The method of any of claims 284-287, wherein the biological sample is or comprises a whole blood sample, a buffy coat sample, a peripheral blood mononuclear cell (PBMC) sample, an unfractionated T cell sample, a lymphocyte sample, a white blood cell sample, an apheresis product, or a leukapheresis product.

289. The method of any of claims 284-288, wherein the biological sample comprises an apheresis product or a leukapheresis product.

290. The method of any of claims 284-289, wherei the T cells are isolated, selected or enriched from the biological sample no more than 36 hours after it is obtained from a subject.

291. The method of any of claims 284-289, wherein the biological sample is cryofozen in the presence of a cryoprotectant no more than 36 hours after it is obtained from the subject and thawed prior to isolating, selecting or enriching the cells, optionally wherein the cryofrozen sample is thawed immediately prior to or within not more than 6 hours, no more than 4 hours, no more than 2 hours or no more than 1 hour prior to the isolating, selecting or enriching the cells.

292. The methods of any of claims 274-291, wherein the incubation is performed in the presence of one or more cytokines, optionally in a serum free medium.

293. The methods of claim 292, wherein the one or more cytokines are selected from recombinant IL-2, recombinant IL-7, and / or recombinant IL-15.

294. The method of claim 293, wherein the one or more cytokines comprise: between 10 and 200 IU / mL recombinant IL-2; between 100 IU / mL and 1,000 IU / mL recombinant IL-7; and / or between 10 and 200 IU / mL recombinant IL-15.

295. The method of any of claims 274-294, wherein the stimulatory reagent comprises a primary agent that specifically binds to a member of a TCR complex, optionally that specifically binds to CD3, optionally wherein the primary agent is an antibody or an antigen binding fragment thereof.

296. The method of claim 295, wherein the stimulatory reagent further comprises a secondary agent that specifically binds to a T cell costimulatory molecule, optionally wherein the costimulatory molecule is selected from CD28, CD137 (4-l-BB), 0X40, or ICOS, optionally wherein the secondary agent is an antibody or an antigen-binding fragment thereof.

297. The method of any of claims 274-296, wherein the stimulatory reagent comprises incubation with an anti-CD3 antibody and an anti-CD28 antibody, or an antigen-binding fragment thereof.

298. The method of any of claims 295-297, wherein the primary agent and / or secondary agent are present on the surface of a solid support.

299. The method of claim 298, wherein the solid support is or comprises a bead.

300. The method of any of claims 295-299, wherein the primary agent and secondary agent are immobilized or reversibly bound on the surface of an oligomeric particle reagent comprising a plurality of streptavidin or streptavidin mutein molecules301. The methods of any of claims 274-300, wherein the input composition is incubated under stimulating conditions for between 12 hours and 36 hours, inclusive, optionally at or about 24 hours.

302. The method of any of claims 274-301, wherein the contacting is carried out by viral transduction, optionally with a retroviral vector, optionally a lentiviral vector.

303. The method of any of claims 274-302, further comprising cultivating the engineered composition under conditions to promote proliferation and / or expansion of the engineered cells, thereby producing an output composition comprising the engineered T cells.

304. The method of claim 303, wherein the cultivating is performed in the presence of one or more cytokines, optionally in a serum free medium.

305. The method of claim 304, wherein the one or more cytokines are selected from recombinant IL-2, recombinant IL-7, and / or recombinant IL-15.

306. The method of claim 304 or 305, wherein the one or more cytokines comprise: between 50 and 400 IU / mL recombinant IL-2; between 100 IU / mL and 2,000 IU / mL recombinant IL-7; and / or between 50 and 400 IU / mL recombinant IL-15.

307. The method of any of claims 274-306, wherein:the input composition comprises CD4+ T cells and CD8+ T cells at a ratio of between 2:1 and 1:2 CD4+ to CD8+ T cells; orthe input composition comprises apoptotic marker negative CD4+ T cells and apoptotic marker negative CD8+ T cells at a ratio of between 2:1 and 1:2 CD4+ to CD8+ T cells.

308. The method of claim 307, wherein the CD4+ T cell and CD8+ T cells are separately selected, isolated or enriched from the same biological sample or a sample therefrom and combined prior to the incubating.

309. The method of any of claims 274-308, wherein the recombinant receptor is a chimeric antigen receptor (CAR).

310. The method of any of claims 303-309, wherein the output composition comprises:at least at or about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor, are surface positive for CCR7 and / or CD27; and / orat least at or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total number of CD4+ T cells in the composition expressing therecombinant receptor are able to produce interleukin 2 (IL-2) or TNF-alpha following stimulation with a stimulatory agent; and / orat least at or about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60% or more of the total number of CD4+ T cells in the composition expressing the recombinant receptor arepolyfunctional for producing two or more cytokines selected from among interferon-gamma (IFN-gamma), interleukin 2 (IL-2) and TNF-alpha following stimulation with a stimulatory agent.

311. The method of claim 310, wherein the stimulatory agent is a non-specific or non- antigen-dependent T cell stimulatory agent.

312. The method of claim 311, wherein the non-specific or non-antigen dependent T cell stimulatory agent is a polyclonal stimulatory agent.

313. The method of claim 311 or claim 312, wherein the non-specific or non-antigen dependent stimulatory agent comprises PMA / ionomycin, anti-CD3 / anti-CD28,phytohemagglutinin (PHA) or concanavalin A (ConA).

314. The method of any of claims 311-313, wherein the non-specific or non-antigen dependent T cell stimulatory agent comprises PMA / ionomycin.

315. The method of claim 310, wherein the stimulatory agent specifically binds the recombinant receptor, optionally wherein the stimulatory agent is an antigen- specific stimulatory reagent and / or comprises the antigen or a portion thereof specifically recognized by the recombinant receptor.

316. The method of any of claims 310-315, wherein production of the cytokines is measured in an intracellular cytokine assay.