Articles of manufacture and methods for treatment using adoptive cell therapy

Abstract

To provide adoptive cell therapy involving the administration of certain doses of cells for treating diseases and conditions such as particular B cell malignancies, and related methods, compositions, uses and articles of manufacture.SOLUTION: Cells for treating diseases generally express recombinant receptors such as chimeric antigen receptors (CARs). In some embodiments, the methods are for treating subjects with non-Hodgkin lymphoma (NHL). In some embodiments, the methods are for treating subjects with relapsed or refractory NHL. Also provided are articles of manufacture and prophylactic treatments in connection with adoptive therapy methods.SELECTED DRAWING: Figure 31A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 514,774, entitled "ARTICLES OF MANUFACTURE AND METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY," filed June 2, 2017; U.S. Provisional Patent Application No. 62 / 515,530, entitled "ARTICLES OF MANUFACTURE AND METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY," filed June 5, 2017; and U.S. Provisional Patent Application No. 62 / 521,366, entitled "ARTICLES OF MANUFACTURE AND METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY," filed June 16, 2017. U.S. Provisional Patent Application No. 62 / 527,000, filed June 29, 2017, entitled "ARTICLES OF MANUFACTURE AND METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY," U.S. Provisional Patent Application No. 62 / 549,938, filed August 24, 2017, entitled "ARTICLES OF MANUFACTURE AND METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY," U.S. Provisional Patent Application No. 62 / 580,425, filed November 1, 2017, entitled "ARTICLES OF MANUFACTURE AND METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY," U.S. Provisional Patent Application No. 62 / 593,871, filed December 1, 2017, entitled "ARTICLES OF MANUFACTURE AND METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY," U.S. Provisional Patent Application No. 62 / 596, filed December 8, 2017, entitled "METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY"This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 614,957, filed January 8, 2018, entitled "ARTICLES OF MANUFACTURE AND METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY," filed January 8, 2018, the contents of each of which are incorporated by reference in their entirety.

[0002] INCORPORATION-BY-REFERENCE TO SEQUENCE LISTING This application is filed with an electronic Sequence Listing, which is provided in a file entitled 735042012140SeqList.txt, created on June 1, 2018, and is 35,306 bytes in size. The information in the electronic Sequence Listing is incorporated by reference in its entirety.

[0003] Field In some aspects, the present disclosure relates to adoptive cell therapy, which involves the administration of a dose of cells to treat subjects with diseases and conditions (e.g., certain B-cell malignancies), as well as related methods, compositions, uses, and articles of manufacture. The cells generally express a recombinant receptor (e.g., a chimeric antigen receptor (CAR)). In some embodiments, the disease or condition is non-Hodgkin's lymphoma (NHL), e.g., relapsed or refractory NHL or a particular NHL subtype; in some embodiments, the subject is a particular group or subset of NHL subjects, e.g., subjects who have undergone multiple therapies or subjects with a poor prognosis. [Background technology]

[0004] background A variety of immunotherapy and / or cell therapy methods are available for treating disease and pathology.For example, adoptive cell therapy (including the administration of cells that express chimeric receptors, such as chimeric antigen receptors (CAR) and / or other recombinant antigen receptors, specific to the disease or disorder of interest, and other adoptive immune cell therapy and adoptive T cell therapy) can be beneficial in the treatment of cancer or other diseases or disorders.There is a need for improved approaches.The present invention provides methods and uses that meet such needs. Summary of the Invention

[0005] overview Provided herein are methods, uses, compositions, formulations, and articles of manufacture for treating a subject having or suspected of having a disease or condition (e.g., cancer or tumor, optionally a B-cell malignancy, such as NHL or ALL or CLL, or a subtype thereof). The methods and other embodiments generally involve administering to the subject T cells, generally modified T cells, such as those that express or include a recombinant receptor, such as a chimeric antigen receptor (CAR) or TCR.

[0006] In some embodiments, the dose of cells or cells administered in association with any of the provided methods, compositions, articles of manufacture and uses are CD4 + T cells or their subtypes or phenotypes (e.g., modified or recombinant receptor-expressing CD4 + T cells) and / or CD8 + T cells or subtypes thereof (e.g., modified or recombinant receptor-expressing CD4 + In some embodiments, the CD8 + In some embodiments, the cells or subtypes or phenotypes are present in a particular dose or amount or number; in ... + The cells or subtypes or phenotypes are present in a particular dose or amount or number. +cells or their subtypes or phenotypes and CD4 + The cells or subtypes or phenotypes thereof are present in the article, composition, or combination or administered in the method at a defined ratio (e.g., 1:1 or about 1:1, or 1:3 or about 1:3 to 3:1 or about 3:1). In some embodiments, the dose or administration comprises or is a specific amount or number of one of the populations of cells, which is a defined ratio or a ratio that occurs naturally, such as in the blood of the subject from which the cells are derived, or a ratio that exists without selection or control for a specific ratio.

[0007] In some embodiments, CD4 + T cells (or subsets thereof) and CD8 + T cells (or a subset thereof) individually comprise a receptor that specifically binds to a target antigen expressed by or a cell or tissue of the disease or condition and / or a target antigen associated with the disease or condition.

[0008] In some embodiments, CD4 + and CD8 + The cells may be administered and / or formulated together, eg, in a single formulation and / or in a single container.

[0009] In some embodiments, the dose of CD4 + cells and CD8 + Separate administrations of cells are given and / or in separate formulations or containers, each containing an individual CD4 + cells or CD4 + A separate formulation or container in which the modified cells are concentrated (e.g., at least a certain percentage (%), e.g., at least 80%, 85%, 90%, or 95%, or more, of CD4 + Preparations containing cells and / or greater than 10% or greater than 5% CD8 + T cell-free formulation) and CD8 + cells or CD8 +A separate formulation or container in which the modified cells are enriched (e.g., at least a particular percentage (%), e.g., at least 80%, 85%, 90%, or 95%, or more, of CD8 + Preparations containing cells and / or greater than 10% or greater than 5% CD4 + T cell-free formulations) are included.

[0010] In some aspects, the administering comprises administering a plurality of separate compositions, the plurality of separate compositions comprising CD4 + T cells and CD8 + a first composition comprising one of a CD4 T cell and a CD4 + T cells and CD8 + In certain embodiments of any of the provided methods, the second composition comprises a CD4 T cell. + T cell-containing receptors and / or CD8 + The receptor contained on the T cell includes a recombinant receptor-expressing T cell and / or a CD4 + T cells and / or CD8 + The T cells are genetically modified to express the receptor.

[0011] In some embodiments of any of the provided methods, the administration of the first composition and the administration of the second composition occur on the same day, about 0 to about 12 hours apart, about 0 to about 6 hours apart, or about 0 to about 2 hours apart; and / or the start of administration of the first composition and the start of administration of the second composition occur about 1 minute to about 1 hour apart, or about 5 minutes to about 30 minutes apart. In certain embodiments of any of the provided methods, the first composition and the second composition are administered 2 hours or less, 1 hour or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less apart.

[0012] In certain embodiments of any of the provided embodiments, the first composition is CD4 + In some embodiments of any of the provided methods, the first composition comprises CD8 T cells. +In certain embodiments of any of the provided methods, the dose of cells comprises a defined ratio of recombinant receptor-expressing CD4 T cells. In certain embodiments of any of the provided methods, the initiation of administration of the first composition occurs before the initiation of administration of the second composition. In certain embodiments of any of the provided methods, the dose of cells comprises a defined ratio of recombinant receptor-expressing CD4 T cells. + Cells and recombinant receptor-expressing CD8 + cells, and / or defined ratios of CD4 + Cells and CD8 + cells, optionally at a ratio of 1:1 or about 1:1 or about 1:3 to about 3:1; and / or CD4 receptor-containing cells in one of the first and second compositions. + T cells and CD8 T cells containing the receptor in the other of the first and second compositions. + and T cells in a defined ratio, optionally 1:1 or about 1:1 or about 1:3 to about 3:1; and / or CD4 T cells containing the receptor administered in the first and second compositions. + T cells and CD8 containing the receptor + and T cells at a defined ratio, optionally 1:1 or about 1:1, or about 1:3 to about 3:1. In some embodiments of any of the provided methods, the defined ratio is 1:1 or about 1:1. In certain embodiments of any of the provided methods, the dose of T cells is administered to the subject as a single dose, or only once within a two-week, one-month, three-month, six-month, one-year, or longer period. In certain embodiments of any of the provided methods, the dose of T cells is administered as a double dose comprising a first dose of T cells and a subsequent dose of T cells, wherein one or both of the first and second doses constitute administration of the plurality of compositions of T cells. In some embodiments of any of the provided methods, the subsequent dose is administered at least about 7 days or at least about 14 days after initiation of administration of the first dose of cells, but before about 28 days after initiation of administration of the first dose of cells.

[0013] In certain embodiments of any of the methods or embodiments provided, the dose of cells is 1 x 10 5 Or about 1 x 10 5 ~5×108 Or about 5 x 10 8 1 x 10 total recombinant receptor-expressing T cells or total T cells 5 Or about 1 x 10 5 ~1×10 8 Or about 1 x 10 8 5 x 10 total recombinant receptor-expressing T cells or total T cells 5 Or about 5 x 10 5 ~1×10 7 Or about 1 x 10 7 1 x 10 total recombinant receptor-expressing T cells or total T cells 6 Or about 1 x 10 6 ~1×10 7 Or about 1 x 10 7 In certain embodiments of any of the provided methods, the dose of T cells comprises 1 x 10 total recombinant receptor-expressing T cells or total T cells, each inclusive. 8 ≤1 x 10 whole recombinant receptor-expressing T cells or whole T cells 7 ≤0.5 x 10 total recombinant receptor-expressing T cells or total T cells 7 ≤1 x 10 whole recombinant receptor-expressing T cells or whole T cells 6 ≤0.5 x 10 total recombinant receptor-expressing T cells or total T cells 6 In some embodiments of any of the provided methods, the dose of T cells comprises administering 5×10 or less whole recombinant receptor-expressing T cells or whole T cells. 7 Or about 5 x 10 7 ~1×10 8 Or about 1 x 10 8 recombinant receptor-expressing T cells, each inclusive of both endpoints.

[0014] In certain embodiments of any of the provided methods, the recombinant receptor specifically binds to an antigen associated with the disease or condition, or to an antigen expressed in cells in the environment of a lesion associated with the disease or condition. In certain embodiments of any of the provided methods, the disease or condition is cancer. In some embodiments of any of the provided methods, the disease or condition is myeloma, leukemia, or lymphoma.In certain embodiments of any of the provided methods, the antigen is selected from the group consisting of ROR1, B-cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), tEGFR, Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, anti-folate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, EGFR vIII, folate-binding protein (FBP), FCRL5, FCRH5, fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, kinase insert domain receptor (kdr), kappa light chain, Lewis Y, L1 cell adhesion molecule (L1-CAM), melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, melanoma preferentially expressed antigen (PRAME), survivin, TAG72, B7-H6, IL-13 receptor alpha 2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, bispecific antigen, cancer-testis antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, oncofetal antigen, ROR 1, TAG72, VEGF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms' tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, G protein-coupled receptor 5D (GPCR5D), or a pathogen-specific antigen. In certain embodiments of any of the provided methods, the antigen is CD19.

[0015] In some embodiments of any of the provided methods, the disease or condition is a B-cell malignancy and / or is acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin's lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL). In particular embodiments of any of the provided methods, the disease or condition is NHL, and the NHL is selected from the group consisting of aggressive NHL, diffuse large B-cell lymphoma (DLBCL), NOS (not otherwise specified) (de novo and indolent transformed), primary mediastinal large B-cell lymphoma (PMBCL), T-cell / histiocytocyte-rich large B-cell lymphoma (TCHRBCL), Burkitt's lymphoma, mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B).

[0016] In some embodiments of any of the provided methods, the recombinant receptor comprises an extracellular domain containing an antigen-binding domain. In some embodiments, the antigen-binding domain is or comprises an antibody or an antibody fragment thereof, optionally a single-chain fragment. In specific embodiments of any of the provided methods, the fragment comprises antibody variable regions linked by a flexible linker. In some embodiments, the fragment comprises an scFv. In some embodiments of any of the provided methods, the recombinant receptor also comprises a spacer and / or hinge region.

[0017] In certain embodiments of any of the provided methods, the recombinant receptor comprises an intracellular signaling region. In some embodiments of any of the provided methods, the intracellular signaling region comprises an intracellular signaling domain. In some embodiments of any of the provided methods, the intracellular signaling domain is or comprises a primary signaling domain, a signaling domain capable of inducing a primary activation signal in a T cell, a signaling domain that is a T cell receptor (TCR) component, and / or a signaling domain containing an immunoreceptor tyrosine-based activation motif (ITAM). In some embodiments, the intracellular signaling domain is or comprises the intracellular signaling domain of a CD3 chain (optionally the CD3-zeta (CD3ζ) chain) or a signaling portion thereof.

[0018] In certain embodiments of any of the provided methods, the recombinant receptor also comprises a transmembrane domain disposed between the extracellular domain and the intracellular signaling region.

[0019] In some embodiments of any of the provided methods, the intracellular signaling region also comprises a costimulatory signaling region. In some embodiments, the costimulatory signaling region comprises the intracellular signaling domain of a T cell costimulatory molecule, or a signaling portion thereof. In specific embodiments of any of the provided methods, the costimulatory signaling region comprises the intracellular signaling domain of CD28, 4-1BB, or ICOS, or a signaling portion thereof. In some embodiments, the costimulatory signaling region is located between the transmembrane domain and the intracellular signaling region.

[0020] In certain embodiments of any of the provided methods, the recombinant receptor is a chimeric antigen receptor (CAR), wherein optionally, the recombinant receptor is a chimeric antigen receptor (CAR), and optionally, the CAR comprises an extracellular antigen recognition domain that specifically binds to an antigen and an intracellular signaling domain comprising an ITAM, optionally, the intracellular signaling domain comprises the intracellular domain of the CD3-zeta (CD3ζ) chain; and / or the CAR further comprises a costimulatory signaling region optionally comprising the signaling domain of CD28 or 4-1BB.

[0021] In some embodiments, the article of manufacture comprises a recombinant CD4 receptor-expressing + a container (e.g., a vial) containing a composition comprising T cells and administering the CD4 T cells to a subject having a disease or condition; + and instructions for administering the composition of CD4 T cells. + The composition of T cells expresses a recombinant receptor, CD8 + or administered as a plurality of compositions together with a composition containing T cells, or + All or part of T cells and CD8 expressing recombinant receptors + In some embodiments, the article of manufacture is administered as a unit dose of cells comprising a composition comprising T cells. + a container (e.g., a vial) containing a composition comprising CD8 T cells and administering the composition to a subject having a disease or condition; + and instructions for administering the composition of CD8 T cells. + The composition of T cells expresses a recombinant receptor, CD4 + or administered as a plurality of compositions together with a composition containing T cells, or + All or part of T cells and CD8 expressing recombinant receptors + The composition comprising the T cells is administered as a unit dose of cells.

[0022] In some of any of the embodiments, the CAR comprises, in order, an antigen-specific scFv, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule (optionally being or including 4-1BB), and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule (optionally being or including a CD3 zeta signaling domain), optionally further comprising a spacer between the transmembrane domain and the scFv.

[0023] In some of any of the embodiments, the CAR comprises, in order, an scFv specific for an antigen, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule (optionally being or including a 4-1BB signaling domain), and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule (optionally being a CD3 zeta signaling domain).

[0024] In some of any of the embodiments, the CAR comprises or consists of, in order, an antigen-specific scFv, a spacer, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule (optionally a 4-1BB signaling domain), and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule (optionally being or including a CD3 zeta signaling domain).

[0025] In some aspects, the spacer (a) comprises or consists of all or a portion of an immunoglobulin hinge, or a modified form thereof, or comprises about 15 amino acids or less and does not include the CD28 or CD8 extracellular region; (b) comprises or consists of all or a portion of an immunoglobulin hinge (optionally an IgG4 hinge), or a modified form thereof, and / or comprises about 15 amino acids or less and does not include the CD28 or CD8 extracellular region; or (c) is 12 amino acids or about 12 amino acids in length and / or comprises or consists of all or a portion of an immunoglobulin (optionally an IgG4) hinge, or a modified form thereof; or (d) the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO: or (e) a polypeptide spacer having the formula X1PPX2P, wherein X1 is glycine, cysteine, or arginine and X2 is cysteine ​​or threonine; and / or the costimulatory domain has or consists of a sequence encoded by SEQ ID NO:34, or a variant of any of the foregoing having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto; or (f) a polypeptide spacer having the formula X1PPX2P, wherein X1 is glycine, cysteine, or arginine and X2 is cysteine ​​or threonine; and / or NO:12, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto; and / or the primary signaling domain comprises SEQ ID NO:13 or 14 or 15, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto;and / or the scFv comprises the CDRL1 sequence of RASQDISKYLN (SEQ ID NO: 35), the CDRL2 sequence of SRLHSGV (SEQ ID NO: 36), and / or the CDRL3 sequence of GNTLPYTFG (SEQ ID NO: 37), and / or the CDRH1 sequence of DYGVS (SEQ ID NO: 38), the CDRH2 sequence of VIWGSETTYYNSALKS (SEQ ID NO: 39), and / or the CDRH3 sequence of YAMDYWG (SEQ ID NO: 40). or the scFv comprises the heavy chain variable region of FMC63 and the light chain variable region of FMC63, and / or the CDRL1 sequence of FMC63, the CDRL2 sequence of FMC63, the CDRL3 sequence of FMC63, the CDRH1 sequence of FMC63, the CDRH2 sequence of FMC63, and the CDRH3 sequence of FMC63, or binds to the same epitope as or competes for binding with any of the foregoing, and optionally the scFv comprises, in order, V; H , a linker (optionally comprising SEQ ID NO:24), and V L and / or the scFv comprises a flexible linker and / or comprises the amino acid sequence shown as SEQ ID NO:24.

[0026] In some embodiments, the spacer comprises or consists of SEQ ID NO:1, the costimulatory domain comprises SEQ ID NO:12 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto, the transmembrane domain is that of CD28 or comprises SEQ ID NO:9 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto, and the scFv comprises the binding domain or CDRs or V of FMC63. H and V Land the primary signaling domain comprises SEQ ID NO:13, 14 or 15 and / or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto.

[0027] In some embodiments, the spacer comprises or consists of SEQ ID NO:30, the costimulatory domain comprises SEQ ID NO:12 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto, the transmembrane domain is that of CD28 or comprises SEQ ID NO:9 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto, and the scFv comprises the binding domain or CDRs or V of FMC63. H and V L and the primary signaling domain comprises SEQ ID NO:13, 14 or 15 and / or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto.

[0028] In some embodiments, the spacer comprises or consists of SEQ ID NO:31, the costimulatory domain comprises SEQ ID NO:12 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto, the transmembrane domain is that of CD28 or comprises SEQ ID NO:9 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto, and the scFv comprises the binding domain or CDRs or V of FMC63. H and V L and the primary signaling domain comprises SEQ ID NO:13, 14 or 15 and / or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto.

[0029] In some embodiments, the spacer comprises or consists of SEQ ID NO:33, the costimulatory domain comprises SEQ ID NO:12 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto, the transmembrane domain is that of CD28 or comprises SEQ ID NO:9 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto, and the scFv comprises the binding domain or CDRs or V of FMC63. H and V Land the primary signaling domain comprises SEQ ID NO:13, 14 or 15 and / or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto.

[0030] In some embodiments, the spacer comprises or consists of SEQ ID NO:34, the costimulatory domain comprises SEQ ID NO:12 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto, the transmembrane domain is that of CD28 or comprises SEQ ID NO:9 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto, and the scFv comprises the binding domain or CDRs or V of FMC63. H and V L and the primary signaling domain comprises SEQ ID NO:13, 14 or 15 and / or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto.

[0031] In some embodiments of any of the provided articles of manufacture, CD4 + Recombinant receptors and CD8 expressed by cells + The recombinant receptors expressed by the T cells are the same or different. In certain embodiments of any of the provided articles of manufacture, the vial contains 10 x 10 6 or about 10 x 10 6 More than 15 x 10 T cells or recombinant receptor-expressing T cells 6 or about 15 x 10 6More than 25 x 10 T cells or recombinant receptor-expressing T cells 6 or about 25 x 10 6 The recombinant T cells may contain more than one T cell or recombinant receptor-expressing T cells.

[0032] In certain embodiments of any of the provided articles of manufacture, the vial contains about 10 million / ml to about 70 million / ml, about 10 million / ml to about 50 million / ml, about 10 million / ml to about 25 million / ml, about 10 million / ml to about 15 million / ml, 15 million / ml to about 70 million / ml, about 15 million / ml to about 50 million / ml, about 15 million / ml to about 25 million / ml, about 25 million / ml to about 70 million / ml, about 25 million / ml to about 50 million / ml, and about 50 million / ml to about 70 million / ml. In some embodiments of any of the provided articles of manufacture, the composition further comprises a cryoprotectant, and / or the article further comprises instructions for thawing the composition prior to administration to a subject.

[0033] In some embodiments of any of the provided articles of manufacture, the composition or compositions comprise at least 2×10 7 or about 2 x 10 7 ~4×10 7 or about 4 x 10 7 CD8 + cells, e.g., about 2 x 10 7 , about 2.5×10 7 , about 3×10 7 , about 3.5×10 7 , or about 4 × 10 7 CD8 + cells, and 2 × 10 7 or about 2 x 10 7 ~4×10 7 or about 4 x 10 7 CD4 + cells, e.g., about 2 x 10 7 , about 2.5×10 7 , about 3×10 7 , about 3.5×10 7 , or about 4 × 10 7 CD4 +In some embodiments, the composition or compositions comprise about 3 x 10 cells, each inclusive. 7 CD8 + cells and approximately 3.5 x 10 7 CD4 + A dose of cells comprising cells.

[0034] In certain embodiments of any of the provided articles of manufacture, the cells of the plurality of compositions are recombinant receptor-expressing CD4 + Cells and recombinant receptor-expressing CD8 + cells, and / or defined ratios of CD4 + Cells and CD8 + In some embodiments of any of the provided articles of manufacture, the plurality of compositions together comprise 1 x 10 cells, optionally at a ratio of about 1:1 or about 1:3 to about 3:1. In certain embodiments of any of the provided articles of manufacture, the specified ratio is 1:1 or about 1:1. In some embodiments of any of the provided articles of manufacture, the plurality of compositions together comprise 1 x 10 cells, optionally at a ratio of about 1:1 or about 1:3 to about 3:1. 5 Or about 1 x 10 5 ~5×10 8 Or about 5 x 10 8 1 x 10 total recombinant receptor-expressing T cells or total T cells 5 ~1×10 8 5 x 10 total recombinant receptor-expressing T cells or total T cells 5 Or about 5 x 10 5 ~1×10 7 Or about 1 x 10 7 1 x 10 total recombinant receptor-expressing T cells or total T cells, or 1 x 10 6 Or about 1 x 10 6 ~1×10 7 Or about 1 x 10 7 In certain embodiments of any of the provided articles of manufacture, the plurality of compositions together comprise a dose of cells comprising 1 x 10 total recombinant receptor-expressing T cells or total T cells, inclusive. 8 ≤1 x 10 whole recombinant receptor-expressing T cells or whole T cells 7 ≤0.5 x 10 total recombinant receptor-expressing T cells or total T cells 7≤1 x 10 whole recombinant receptor-expressing T cells or whole T cells 6 ≤0.5 x 10 total recombinant receptor-expressing T cells or total T cells 6 In certain embodiments of any of the provided articles of manufacture, the plurality of compositions together comprise a dose of cells comprising no more than 5 x 10 total recombinant receptor-expressing T cells or total T cells. 7 Or about 5 x 10 7 pieces~1×10 8 Or about 1 x 10 8 A dose of cells containing recombinant receptor-expressing T cells, each inclusive.

[0035] In some embodiments of any of the provided articles of manufacture, CD4 + Compositions containing T cells and CD8 + The instructions specify that the compositions comprising T cells be administered 0-12 hours apart, 0-6 hours apart, or 0-2 hours apart. + Compositions containing T cells and CD8 + In certain embodiments of any of the provided articles of manufacture, the instructions specify administering the compositions comprising CD4 T cells 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. + The composition comprising T cells is + In some embodiments of any of the provided articles of manufacture, the instructions specify administering the CD8 + The composition comprising T cells is + It is specified that the administration occurs before the administration of the composition containing the cells.

[0036] In certain embodiments of any of the provided articles of manufacture, the recombinant receptor specifically binds to an antigen associated with the disease or condition, or to an antigen expressed in cells in the environment of a lesion associated with the disease or condition. In certain embodiments of any of the provided articles of manufacture, the disease or condition is cancer. In some embodiments of any of the provided articles of manufacture, the disease or condition is myeloma, leukemia, or lymphoma.

[0037] In certain embodiments of any of the provided articles of manufacture, the antigen is selected from the group consisting of ROR1, B-cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), tEGFR, Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, anti-folate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, EGFR vIII, folate-binding protein (FBP), FCRL5, FCRH5, fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, kinase insert domain receptor (kdr), kappa light chain, Lewis Y, L1 cell adhesion molecule (L1-CAM), melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, melanoma preferentially expressed antigen (PRAME), survivin, TAG72, B7-H6, IL-13 receptor alpha 2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, bispecific antigen, cancer-testis antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, oncofetal antigen, ROR 1, TAG72, VEGF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms' tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, G protein-coupled receptor 5D (GPCR5D), or a pathogen-specific antigen. In certain embodiments of any of the provided articles of manufacture, the antigen is CD19.

[0038] In some embodiments of any of the provided articles of manufacture, the disease or condition is a B-cell malignancy and / or is acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin's lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL). In particular embodiments of any of the provided articles of manufacture, the disease or condition is NHL, and the NHL is selected from the group consisting of aggressive NHL, diffuse large B-cell lymphoma (DLBCL), NOS (de novo and indolent transformed), primary mediastinal large B-cell lymphoma (PMBCL), T-cell / histiocytocyte-rich large B-cell lymphoma (TCHRBCL), Burkitt's lymphoma, mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B).

[0039] In certain embodiments of any of the provided articles of manufacture, the T cells are primary T cells obtained from the subject. In some embodiments of any of the provided articles of manufacture, the T cells are autologous to the subject. In certain embodiments of any of the provided articles of manufacture, the T cells are allogeneic to the subject.

[0040] In certain embodiments of any of the provided articles of manufacture, the recombinant receptor is or comprises a functional non-TCR antigen receptor or TCR, or an antigen-binding fragment thereof. In some embodiments, the recombinant receptor is a chimeric antigen receptor (CAR).

[0041] In certain embodiments of any of the provided articles of manufacture, the recombinant receptor comprises an extracellular domain containing an antigen-binding domain. In some embodiments, the antigen-binding domain is or comprises an antibody or antibody fragment (optionally a single-chain fragment) thereof. In some embodiments, the fragment comprises an antibody variable region linked by a flexible linker. In some embodiments, the fragment comprises an scFv.

[0042] In some embodiments of any of the articles of manufacture or methods provided, the recombinant receptor also includes a spacer and / or hinge region.

[0043] In certain embodiments of any of the provided articles of manufacture or methods, the recombinant receptor comprises an intracellular signaling region. In some embodiments, the intracellular signaling region comprises an intracellular signaling domain. In some embodiments of any of the provided articles of manufacture, the intracellular signaling domain is or comprises a primary signaling domain, a signaling domain capable of inducing a primary activation signal in a T cell, a signaling domain that is a T cell receptor (TCR) component, and / or a signaling domain containing an immunoreceptor tyrosine-based activation motif (ITAM). In some embodiments, the intracellular signaling domain is or comprises the intracellular signaling domain of a CD3 chain (optionally the CD3-zeta (CD3ζ) chain) or a signaling portion thereof.

[0044] In certain embodiments of any of the articles of manufacture or methods provided, the recombinant receptor also includes a transmembrane domain located between the extracellular domain and the intracellular signaling region.

[0045] In some embodiments of any of the provided articles of manufacture or methods, the intracellular signaling region also comprises a costimulatory signaling region. In some embodiments, the costimulatory signaling region comprises the intracellular signaling domain of a T cell costimulatory molecule, or a signaling portion thereof. In some embodiments of any of the provided articles of manufacture, the costimulatory signaling region comprises the intracellular signaling domain of CD28, 4-1BB, or ICOS, or a signaling portion thereof. In some embodiments, the costimulatory signaling region is located between the transmembrane domain and the intracellular signaling region.

[0046] In some embodiments, the methods and articles are for treating a subject with non-Hodgkin's lymphoma (NHL) or can treat a subject with non-Hodgkin's lymphoma (NHL). In some aspects, the methods involve, and / or the articles of manufacture specify or include, a formulation that can administer a dose or multiple T cells to the subject. In some aspects, the T cells are T cells that express a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by NHL, such as CD8 + T cells and / or CD4 + Contains T cells.

[0047] In some embodiments, the dose of T cells is 5 x 10 7 Or about 5 x 10 7 pieces~1×10 8 Or about 1 x 10 8 (inclusive) CAR-expressing T cells; the NHL includes diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), NOS (transformed from de novo or indolent lymphoma), or follicular lymphoma grade 3B, and the subject is identified as having or is identified to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0048] In some embodiments of any of the provided embodiments, the method further comprises specifying a treatment for a subject with diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), NOS (transformed from de novo or indolent lymphoma), or follicular lymphoma grade 3B and having ECOG status 0 or 1, or the article of manufacture comprises information specifying a treatment for a subject with diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), NOS (transformed from de novo or indolent lymphoma), or follicular lymphoma grade 3B and having ECOG status 0 or 1. In some embodiments of any of the provided embodiments, the dose of T cells and / or cells administered comprises a defined ratio of CAR-expressing CD4 T cells. + Cells and CAR-expressing CD8 + cells, and / or defined ratios of CD4 + Cells and CD8 + cells, optionally at a ratio of about 1:1 or about 1:3 to about 3:1.

[0049] In some aspects, embodiments are for treating a subject with non-Hodgkin's lymphoma (NHL) and involve administering to the subject a dose of T cells, including T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by the NHL. In some aspects, the dose of T cells comprises a defined ratio of CAR-expressing CD4 + Cells and CAR-expressing CD8 + cells, and / or defined ratios of CD4 + Cells and CD8 + cells, and in some aspects the ratio is about 1: 1 or 1: 1. In some aspects, the NHL comprises diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), NOS (not otherwise specified) (transformed from de novo or indolent lymphoma), or follicular lymphoma grade 3B.

[0050] In certain embodiments of any of the provided embodiments, the subject is identified as having, or is identified as having, or is designated as having an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. In certain embodiments of any of the provided embodiments, the subject is identified as having, or is identified as having, or is designated as having an ECOG status of 0 or 1.

[0051] In some embodiments of any of the provided embodiments, administration of cells via a method and / or use and / or article of manufacture achieves a certain degree of outcome and / or is associated with a certain degree of reduced risk of toxicity, e.g., in a subject population treated according to the method or according to information provided in the article of manufacture. In some aspects, at least 35%, at least 40%, or at least 50% of subjects treated according to the method achieve a complete response (CR) and / or a durable CR; and / or at least 50%, at least 60%, or at least 70% of subjects treated according to the method achieve an objective response (OR) and / or a durable OR. In particular embodiments of any of the provided methods, the response is sustained for more than 3 months or more than 6 months. In some embodiments, at least 40%, at least 50%, at least 60%, or at least 70% of subjects who had or were identified as having double / triple hit lymphoma or relapse after autologous stem cell transplant (ASCT) (optionally relapse within 12 months) at or before administration of the dose of cells achieve an OR, optionally, an OR that is durable for 3 months or more or 6 months or more. In certain embodiments of any of the provided methods, more than or about 50% of subjects treated according to the method do not exhibit Grade 3 or higher cytokine release syndrome (CRS) or Grade 3 or higher neurotoxicity. In some embodiments, such subjects do not exhibit early-onset CRS and / or neurotoxicity.

[0052] Provided herein is a method for assessing the likelihood of response to cell therapy, comprising the steps of: evaluating the level, amount or concentration of one or more analytes in a biological sample, wherein the one or more analytes are selected from ferritin, LDH, CXCL10, G-CSF and IL-10, wherein the biological sample is derived from a subject who is a candidate for cell therapy treatment, and the cell therapy comprises a dose of genetically modified cells that express recombinant receptors; the biological sample is obtained from the subject before the cell therapy is administered, and / or the biological sample does not comprise recombinant receptors and / or the modified cells; and comparing the level, amount or concentration of the analytes in the sample with a threshold level individually, thereby determining the likelihood that the subject will achieve a sustained response to the cell therapy.In some embodiments, the method also comprises administering the cell therapy to the subject if the subject is likely to achieve a response.

[0053] Provided herein is a method for selecting a subject for treatment, the method comprising: evaluating the level, amount or concentration of one or more analytes in a biological sample, wherein the one or more analytes are selected from ferritin, LDH, CXCL10, G-CSF and IL-10, wherein the biological sample is derived from a subject who is a candidate for cell therapy treatment, and the cell therapy comprises a dose of genetically modified cells that express recombinant receptors; the biological sample is obtained from the subject before the cell therapy is administered, and / or the biological sample does not comprise recombinant receptors and / or the modified cells; and selecting subjects who are likely to be successful in treatment based on the results of individually comparing the level, amount or concentration of the analytes in the sample with a threshold level, thereby determining the likelihood that the subject will achieve success in the cell therapy.In some embodiments, the method also comprises administering the cell therapy to the subject who is selected for treatment.

[0054] Provided herein are methods of treatment that involve selecting subjects who are likely to benefit from cell therapy treatment based on the results of determining the likelihood that the subject will achieve benefit from the cell therapy by individually comparing the level, amount, or concentration of one or more analytes in a biological sample to a threshold level, wherein the one or more analytes are selected from ferritin, LDH, CXCL10, G-CSF, and IL-10, wherein the biological sample is derived from a subject who is a candidate for cell therapy treatment, and the cell therapy comprises a dose of genetically modified cells that express a recombinant receptor; the biological sample is obtained from the subject prior to administering the cell therapy, and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and administering the cell therapy to the subject selected for treatment.

[0055] In some embodiments, a subject is more likely to achieve a response if the level, amount, or concentration of one or more of the analytes is below a threshold level, and a subject is less likely to achieve a response if the level, amount, or concentration of one or more of the analytes is above a threshold level.

[0056] In some embodiments, the threshold level is within 25%, 20%, 15%, 10%, or 5% below the median or mean value of the level, amount, or concentration of the analyte in a biological sample obtained from a group of subjects prior to receiving cell therapy, and / or is within a standard deviation below the median or mean value, or is the median or mean value, or is about the median or mean value, wherein each subject in the group is a subject who achieved a response following administration of a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0057] In some embodiments, the threshold level is within 25%, 20%, 15%, 10%, or 5% above the median or mean value of the level, amount, or concentration of the analyte in a biological sample obtained from a group of subjects prior to receiving cell therapy, and / or within a standard deviation above the median or mean value, wherein each subject in the group is a subject that has exhibited stable disease (SD) and / or progressive disease (PD) following administration of a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0058] In some embodiments, the response comprises an objective response. In some embodiments, the objective response comprises a complete response (CR) or a partial response (PR).

[0059] Provided herein are methods for assessing the likelihood of a sustained response to a cell therapy, comprising: assessing the level, amount, or concentration of one or more analytes in a biological sample, wherein the one or more analytes are selected from LDH, ferritin, CRP, D-dimer, SAA-1, IL-6, IL-10, IL-15, IL-16, TNF-α, IFN-γ, MIP-1α, CXCL-10, IL-8, MCP-1, and MIP-1β, wherein the biological sample is derived from a subject who is a candidate for treatment with a cell therapy, and the cell therapy comprises a dose of genetically modified cells expressing a recombinant receptor; wherein the biological sample was obtained from the subject prior to administration of the cell therapy, and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and individually comparing the level, amount, or concentration of the analytes in the sample to a threshold level, thereby determining the likelihood that the subject will achieve a sustained response to the cell therapy.

[0060] In some embodiments, the methods also involve administering the cell therapy to the subject if the subject is likely to achieve a response.

[0061] Provided herein are methods for selecting subjects for treatment, the methods comprising: assessing the level, amount, or concentration of one or more analytes in a biological sample, wherein the one or more analytes are selected from LDH, ferritin, CRP, D-dimer, SAA-1, IL-6, IL-10, IL-15, IL-16, TNF-α, IFN-γ, MIP-1α, CXCL-10, IL-8, MCP-1, and MIP-1β, wherein the biological sample is derived from a subject who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of genetically modified cells expressing a recombinant receptor; the biological sample is obtained from the subject prior to administration of the cell therapy, and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and selecting subjects who are likely to benefit from treatment based on the results of individually comparing the level, amount, or concentration of the analyte in the sample to a threshold level to determine the likelihood that the subject will achieve a sustained response to the cell therapy. In some embodiments, the method also involves administering the cell therapy to a subject selected for treatment.

[0062]

[0009] Provided herein are methods of treatment that involve selecting subjects who are likely to benefit from cell therapy treatment based on the likelihood that the subject will achieve a sustained response to the cell therapy by individually comparing the level, amount, or concentration of one or more analytes in a biological sample to a threshold level, wherein the one or more analytes are selected from LDH, ferritin, CRP, D-dimer, SAA-1, IL-6, IL-10, IL-15, IL-16, TNF-α, IFN-γ, MIP-1α, CXCL-10, IL-8, MCP-1, and MIP-1β, wherein the biological sample is derived from a subject who is a candidate for cell therapy treatment, and the cell therapy comprises a dose of genetically modified cells that express a recombinant receptor; the biological sample was obtained from the subject prior to administering the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and administering the cell therapy to the subject selected for treatment.

[0063] In some embodiments, a subject is more likely to achieve a sustained response if one or more of the analyte level, amount, or concentration is below a threshold level, and a subject is less likely to achieve a sustained response if one or more of the analyte level, amount, or concentration is above a threshold level.

[0064] In some embodiments, the threshold level is within 25%, 20%, 15%, 10%, or 5% below the median or mean value of the level, amount, or concentration of the analyte in a biological sample obtained from a group of subjects prior to receiving cell therapy, and / or is within a standard deviation below the median or mean value, or is the median or mean value, or is about the median or mean value, wherein each subject in the group is a subject who has achieved a sustained response following administration of a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0065] In some embodiments, the threshold level is within 25%, 20%, 15%, 11%, or 5% above the median or mean value of the level, amount, or concentration of the analyte in a biological sample obtained from a group of subjects prior to receiving cell therapy, and / or within a standard deviation above the median or mean value, wherein each subject in the group is a subject who has not achieved a sustained response following administration of a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0066] In some embodiments, a durable response includes a complete response (CR) or partial response (PR) that is sustained for 3 or more months, 4 or more months, 5 or more months, or 6 or more months.

[0067] In some embodiments, a durable response comprises a CR or PR that is sustained for at least 3 months.

[0068] 1. A method of assessing the risk of developing toxicity following administration of a cell therapy, comprising assessing the level, amount, or concentration of one or more analytes in a biological sample from the subject, or a volumetric measure of tumor burden in the subject, wherein the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (a fibrin degradation product), IL-6, IL-8, IL-10, IL-15, IL-16, TNF-α, IFN-α2, MCP-1, MIP-1α, and MIP-1β, wherein: Provided herein are methods involving the steps of: the subject is a candidate for treatment with a cell therapy, the cell therapy optionally comprising a dose or composition of genetically modified cells that express a recombinant receptor; the biological sample is obtained from the subject prior to administration of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and individually comparing the level, amount, or concentration of the analyte in the sample, or the volumetric measurement of tumor burden, to a threshold level, thereby determining the risk of developing toxicity after administration of the cell therapy.

[0069] Provided herein are methods for identifying a subject, the methods comprising: assessing the level, amount, or concentration of one or more analytes in a biological sample from the subject, or the volumetric measurement of tumor burden in the subject, wherein the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (a fibrin degradation product), IL-6, IL-8, IL-10, IL-15, IL-16, TNF-α, IFN-α2, MCP-1, MIP-1α, and MIP-1β, wherein the subject is a candidate for treatment with a cell therapy, optionally comprising a dose or composition of genetically modified cells that express a recombinant receptor; the biological sample is obtained from the subject prior to administration of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and individually comparing the level, amount, or concentration of the analyte in the sample, or the volumetric measurement of tumor burden, to a threshold level, thereby identifying subjects at risk of developing toxicity after administration of cell therapy.

[0070] assessing the level, amount, or concentration of one or more analytes, or a volumetric measure of tumor burden in a biological sample from a subject, wherein the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (a fibrin degradation product), IL-6, IL-8, IL-10, IL-15, IL-16, TNF-α, IFN-α2, MCP-1, MIP-1α, and MIP-1β, and wherein the subject is a candidate for treatment with a cell therapy, optionally comprising a dose or composition of genetically modified cells expressing a recombinant receptor; and wherein the biological sample is obtained from the subject prior to administering the cell therapy. and / or the biological sample does not contain the recombinant receptor and / or the modified cell; and individually comparing the level, amount, or concentration of the analyte or the volumetric measurement of tumor burden in the sample to a threshold level, thereby determining a risk of developing toxicity after administration of the cell therapy; and according to or based on the results of the assessment, administering the cell therapy to the subject, and optionally applying an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the development of, or the risk of, toxicity.

[0071] In some embodiments, the biological sample is a blood sample or a plasma sample.

[0072] In some embodiments, the volumetric measurement of tumor burden is a sum of two-way products (SPD) or is a volumetric measurement based on CT and / or MRI imaging of the body or other imaging modalities. In some embodiments, the volumetric measurement of tumor burden is performed prior to treatment, prior to apheresis, or prior to cell product manufacturing.

[0073] In some embodiments, the methods also involve monitoring the subject for symptoms of toxicity if the subject is administered a cell therapy and the subject is identified as being at risk for developing toxicity.

[0074] In some embodiments, if the level, amount, or concentration of one or more analytes or the volumetric measurement of tumor burden is above a threshold level, the subject is at risk of developing toxicity, and if the level, amount, or concentration of one or more analytes or the volumetric measurement of tumor burden is below a threshold level, the subject has a low risk of developing toxicity.

[0075] In some embodiments, the threshold level is within 25%, 20%, 15%, 10%, or 5% above the median or mean value of the level, amount, or concentration of an analyte in a biological sample, or said volumetric measurement of tumor burden in said biological sample, obtained from a group of subjects prior to receiving cell therapy, and / or is within a standard deviation above said median or mean value, or is said median or mean value, or is about said median or about said mean value, wherein each subject in the group is a subject who has not experienced any toxicity after receiving a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0076] In some embodiments, the threshold level is within 25%, 20%, 15%, 10%, or 5% below the median or mean value of the level, amount, or concentration of an analyte in a biological sample, or said volumetric measurement of tumor burden in said biological sample, obtained from a group of subjects prior to receiving cell therapy, and / or within a standard deviation below said median or mean value, wherein each subject in the group is a subject who developed toxicity after receiving a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0077] In some embodiments, the toxicity is neurotoxicity or CRS.

[0078] In some embodiments, the toxicity is grade 1 or higher neurotoxicity or CRS.

[0079] In some embodiments, the toxicity is severe neurotoxicity, or is grade 2 or higher neurotoxicity, grade 3 or higher neurotoxicity, prolonged neurotoxicity of at least grade 3, or is grade 4 or higher or grade 5 or higher cytotoxicity; or the toxicity is severe CRS, or includes grade 2 or higher, or grade 3 or higher CRS.

[0080] In some embodiments, the toxicity is neurotoxicity, the volumetric measure of tumor burden is SPD, and the one or more analytes are selected from LDH, IL-10, IL-15, IL-16, TNF-α, and MIP-1β.

[0081] In some embodiments, the toxicity is neurotoxicity and one or more analytes are assessed, and the analytes are selected from LDH, ferritin, CRP, IL-6, IL-8, IL-10, TNF-α, IFN-α2, MCP-1, and MIP-1β.

[0082] In some embodiments, the toxicity is neurotoxicity and one or more analytes are assessed, wherein the analytes are selected from IL-8, IL-10, and CXCL10.

[0083] In some embodiments, the neurotoxicity is severe neurotoxicity or grade 3 or higher neurotoxicity.

[0084] In some embodiments, the toxicity is CRS and the one or more analytes or volume measurements of tumor burden are selected from LDH, SPD, CRP, d-dimer, IL-6, IL-15, TNF-α, and MIP-1α.

[0085] In some embodiments, the CRS is severe CRS or CRS of grade 3 or higher.

[0086] In some embodiments, if a subject is identified as being at risk for developing toxicity, (1) an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the development of, or the risk of, toxicity, and (2) a cell therapy are administered to the subject, wherein administration of the agent should occur (i) prior to initiation of administration of the cell therapy to the subject, (ii) within 1, 2, or 3 days of initiation of administration of the cell therapy to the subject, (iii) concurrently with initiation of administration of the cell therapy to the subject, and / or (iv) at the first onset of fever after initiation of administration of the cell therapy to the subject. and / or administering the cell therapy to the subject at a low dose or at a dose that does not carry the risk of developing toxicity or severe toxicity following administration of the cell therapy, or that does not carry the risk of developing toxicity or severe toxicity in a majority of subjects and / or in a majority of subjects having a disease or condition that the subject has or is suspected of having; and / or administering the cell therapy to the subject in an inpatient setting and / or with one or more days of hospitalization, wherein, optionally, otherwise, the cell therapy is administered to the subject on an outpatient basis or without one or more days of hospitalization.

[0087] In some embodiments, the agent or other treatment is an anti-IL-6 antibody or an anti-IL6 receptor antibody.

[0088] In some embodiments, the agent or other treatment is or includes an agent selected from among tocilizumab, siltuximab, clazakizumab, sarilumab, olokizumab (CDP6038), elsilimomab, ALD518 / BMS-945429, sirukumab (CNTO 136), CPSI-2634, ARGX-109, FE301, and FM101.

[0089] In some embodiments, the agent or other treatment is or includes a steroid (optionally dexamethasone).

[0090] In some embodiments, a volume measurement is assessed, the volume measurement being an SPD, and the threshold level is at or about 30 cm 2 , 40 or about 40 cm 2 , 50 or about 50 cm 2 , 60 or about 60 cm 2 , or 70 or about 70 cm 2 In some embodiments, the volume measurement is SPD and the threshold level is 50 cm 2 or about 50 cm 2 is.

[0091] In some embodiments, the one or more analytes are or include LDH and the threshold level is at or about 300 units / liter, 400 units / liter, 500 units / liter, or 600 units / liter, hi some embodiments, the analyte is LDH and the threshold level is at or about 500 units / liter.

[0092] In some embodiments, the recombinant receptor specifically binds to an antigen associated with the disease or condition, or an antigen expressed on cells in the environment of a lesion associated with the disease or condition. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is myeloma, leukemia, or lymphoma. In some embodiments, the disease or condition is a B-cell malignancy and / or is acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin's lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL).

[0093] In some embodiments, the recombinant receptor is a chimeric antigen receptor (CAR). In some embodiments, the modified cell is a T cell, optionally a CD4 + and / or CD8 +In some embodiments, the T cells are primary T cells obtained from the subject or are autologous cells for the subject.

[0094] 1. A method of treating a subject having non-Hodgkin's lymphoma (NHL), comprising administering to the subject a dose of T cells, the T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by the NHL, wherein the dose of T cells is greater than or equal to 5×10 7 Or about 5 x 10 7 pieces~1×10 8 Or about 1 x 10 8 (inclusive) recombinant receptor-expressing T cells, said dose comprising a defined ratio of recombinant receptor-expressing CD4 + Cells and recombinant receptor-expressing CD8 + cells, and / or defined ratios of CD4 + Cells and CD8 + Provided herein are methods comprising: cells, wherein the ratio is about 1:1 or 1:1; wherein the method (1) results in a complete response (CR) in at least 35%, at least 40%, or at least 50% of treated subjects, and / or results in an objective response (OR) in at least 50%, at least 60%, or at least 70% of treated subjects; and (2) results in no more than 50% of subjects experiencing cytokine release syndrome (CRS) greater than Grade 2 and / or neurotoxicity greater than Grade 2.

[0095] In some embodiments of any of the provided methods, at least 40%, at least 50%, at least 60%, at least 70% of subjects who had or were identified as having double / triple hit lymphoma (or high-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements (double / triple hit) with DLBCL histology) or relapse after autologous stem cell transplant (ASCT) at the time of or prior to administration of the dose of cells achieve an OR, and optionally, the OR is durable for 3 months or more or 6 months or more.

[0096] In some embodiments of any of the provided methods, the CR or OR is sustained for more than 3 months or more than 6 months. In particular embodiments of any of the provided methods, more than or about 50% of subjects treated according to the method do not exhibit any grade of cytokine release syndrome (CRS) or neurotoxicity.

[0097] In some embodiments, the CR or OR is sustained for more than 3 months or more than 6 months; at least 20%, at least 25%, at least 35%, at least 40%, or at least 50% of subjects treated according to the method achieve a sustained CR; at least 60%, 70%, 80%, 90%, or 95% of subjects treated with the method and achieving a CR remain in CR or remain in response or remain alive for 3 months or more, 6 months or more, or 9 months or more; and / or at least 60%, 70%, 80%, 90%, or 95% of subjects treated with the method and achieving a CR by 1 month and / or by 3 months remain in CR or remain in response or remain alive for 3 months or more and / or 6 months or more. and / or remain in response, in CR, and / or alive or alive without progression for 9 months or more; and / or at least 50%, at least 60%, or at least 70% of subjects treated according to the method achieve an objective response (OR), optionally with the OR being durable for 3 months or more or 6 months or more, or with the OR being durable for 3 months or more or 6 months or more in at least 60%, 70%, 80%, 90%, or 95% of subjects who achieve OR after treatment with the method remaining in response or alive for 3 months or more and / or 6 months or more.

[0098] In some embodiments, the subject is identified as having or was identified as having lymphoma associated with or with central nervous system (CNS) infiltration at or before administration of the dose of cells; and / or at least 70%, at least 80%, at least 90%, or at least 95% of the subjects treated according to the method and exhibiting or identified as exhibiting lymphoma with CNS infiltration at or before administration of the dose of cells achieve regression of their CNS disease.

[0099] Provided herein is a method for treating a subject with lymphoma, comprising administering a dose of T cells to the subject, the T cells comprising expressing chimeric antigen receptor (CAR) that specifically binds to the target antigen expressed by the lymphoma, wherein the subject's lymphoma is associated with or involves central nervous system (CNS) infiltration.In some aspects, at the time of administering the dose of cells or before administration, the subject comprises brain lesions, optionally temporal lobe brain lesions.In some examples, the lymphoma is a B-cell malignant tumor.In some embodiments, the lymphoma is non-Hodgkin's lymphoma (NHL).

[0100] In some of any such embodiments, at least 35%, at least 40%, or at least 50% of subjects treated according to the method achieve a complete response (CR) or remission of the CNS disease and / or achieve a reduction in or elimination of the CNS disease, and optionally, the CR or remission or reduction or elimination of the CNS disease is sustained for 3 or more months or 6 or more months, or is sustained for 3 or more months or 6 or more months in at least 60%, 70%, 80%, 90%, or 95% of subjects who achieve a CR; and / or at least 60%, 70%, 80%, 90%, or 95% of subjects who achieve a CR or remission or other reduction in the CNS disease by 1 month and / or by 3 months are still in response, still in remission (e.g., CR), or still showing signs of reduction or remission for 3 or more months and / or 6 or more months and / or 9 or more months. and / or at least 50%, at least 60%, or at least 70% of the subjects treated according to the method achieve an objective response (OR) or remission of the CNS disease, wherein optionally, the OR or remission of the CNS disease is sustained for 3 or more months or for 6 or more months, or is sustained for 3 or more months or for 6 or more months in at least 60%, 70%, 80%, 90%, or 95% of the subjects who achieve an OR; and / or at least 60%, 70%, 80%, 90%, or 95% of the subjects who achieve an OR or remission of the CNS disease remain in response or remain alive for 3 or more months and / or for 6 or more months; and / or the size or volume of brain lesions is reduced, optionally by more than at or about 25%, more than 50% or more than about 50%, more than 75% or more than about 75%.In some aspects, the reduction or remission or elimination of the CNS disease is achieved without or without substantial signs or symptoms of toxicity (e.g., neurotoxicity, e.g., severe neurotoxicity, e.g., Grade 2 or greater or Grade 3 or greater neurotoxicity), and / or without toxicity caused by the activation or presence of the cell therapy cells in the subject's brain, and / or without increased levels of toxicity compared to subjects with residual CNS disease and / or subjects treated with the therapy but not exhibiting CNS disease.

[0101] In some embodiments of any of the provided methods, greater than or about 30%, greater than or about 30%, greater than or about 35%, greater than or about 40%, or greater than or about 40%, or greater than or about 50% of the subjects treated according to the method do not exhibit any grade of cytokine release syndrome (CRS) or neurotoxicity. In some embodiments of any of the provided methods, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least about 90%, or at least 95% of the subjects treated according to the method do not exhibit early-onset CRS or neurotoxicity, and / or exhibits no onset of CRS earlier than 3 days after initiation of said administration, and / or exhibits no onset of neurotoxicity earlier than 5 days after initiation of said administration, and / or the median onset of neurotoxicity in subjects treated according to said method is at or after the median peak of CRS in subjects treated according to said method, or is at or after the median time to resolution of CRS in subjects treated according to said method, and / or the median onset of neurotoxicity in subjects treated according to said method is greater than or about 8 days, greater than or about 9 days, greater than or about 10 days, or greater than or about 11 days.

[0102] In certain embodiments of any of the provided methods, prior to initiation of administration of the dose of cells, the subject has not been administered an agent or treatment that can treat, prevent, delay, reduce, or attenuate the onset of, or the risk of, toxicity. In certain embodiments of any of the provided methods, the subject is not administered an agent or treatment for treating or preventing, or reducing or attenuating, neurotoxicity and / or cytokine release syndrome, or the risk thereof, within a period of time after administration of the dose, which period of time is optionally 1 or about 1 day, 2 or about 2 days, 3 or about 3 days, 4 or about 4 days, 5 or about 5 days, or optionally 6 or about 6 days, 7 or about 7 days, 8 or about 8 days, 9 or about 9 days, 10 or about 10 days, 11 or about 11 days, or optionally 1 week, 2 weeks, 3 weeks, or 4 weeks. In certain embodiments of any of the provided methods, the subject is not administered an agent or treatment for treating or preventing or reducing or attenuating the risk of neurotoxicity and / or cytokine release syndrome, or the risk thereof, after administration of the dose, before the subject shows signs or symptoms of toxicity, or unless the subject shows signs or symptoms of toxicity, and / or before the subject shows signs or symptoms of toxicity other than fever, and optionally the fever is not persistent, or the fever is reduced or reduced, or reduced or reduced by more than 1° C. after treatment with an antipyretic. In certain embodiments of any of the provided methods, the administration and follow-up is optionally on an outpatient basis, and / or without admitting the subject to a hospital, and / or without involving an overnight stay in a hospital, and / or without requiring hospital admission or an overnight stay in a hospital, unless or until the subject shows a persistent fever, or a fever that is not reduced or reduced, or does not reduce or reduce by more than 1° C. after treatment with an antipyretic.

[0103] In some embodiments of any of the provided methods, the subject has not been administered an anti-IL-6 or anti-IL-6R antibody (optionally tocilizumab or siltuximab) and / or a steroid (optionally dexamethasone) prior to initiation of administration of the dose of cells. In particular embodiments of any of the provided methods, the subject has not been administered an anti-IL-6 or anti-IL-6R antibody (optionally tocilizumab or siltuximab) and / or a steroid (optionally dexamethasone) within a period of time after administration of the dose, which period of time is optionally 1 or about 1 day, 2 or about 2 days, 3 or about 3 days, 4 or about 4 days, 5 or about 5 days, or optionally 6 or about 6 days, 7 or about 7 days, 8 or about 8 days, 9 or about 9 days, 10 or about 10 days, 11 or about 11 days, or optionally 1 week, 2 weeks, 3 weeks, or 4 weeks. In certain embodiments of any of the provided methods, after administration of the cell dose, an anti-IL-6 or anti-IL-6R antibody (optionally tocilizumab or siltuximab) is not administered to the subject, and / or a steroid (optionally dexamethasone) is not administered, before or unless the subject shows signs or symptoms of toxicity (optionally neurotoxicity or CRS), and / or before or unless the subject shows signs or symptoms of toxicity (optionally neurotoxicity or CRS) other than fever, and / or unless the subject shows signs or symptoms of toxicity other than fever, and optionally, wherein the fever is not persistent or has decreased or decreased or has decreased by more than 1°C after treatment with an antipyretic. In certain embodiments of any of the provided methods, administration and optional follow-up occurs on an outpatient basis and / or without admitting the subject to a hospital and / or without involving an overnight stay in a hospital and / or without requiring hospital admission or an overnight stay in a hospital, optionally unless or until the subject exhibits a fever that does not or has not subsided or does not or has not subsided by more than 1° C. after treatment with the antipyretic.

[0104] In some embodiments of any of the provided methods, administration occurs on an outpatient basis and / or occurs without the need for hospital admission or an overnight stay in a hospital. In some embodiments of any of the provided methods, if a subject being treated on an outpatient basis or being treated on an outpatient basis exhibits a persistent fever or a fever that does not decrease or does not decrease after treatment with antipyretics or that does not decrease or does not decrease by more than 1°C, the subject is admitted to a hospital or an overnight stay in a hospital and / or an agent or treatment for treating or preventing or reducing or attenuating neurotoxicity and / or cytokine release syndrome or the risk thereof is administered.

[0105] In certain embodiments of any of the provided methods, the NHL is selected from the group consisting of aggressive NHL, diffuse large B-cell lymphoma (DLBCL), NOS (transformed from de novo and indolent lymphoma), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B). In certain embodiments of any of the provided methods, the NHL comprises diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), NOS (transformed from de novo or indolent lymphoma), or follicular lymphoma grade 3B. In some examples, the NHL comprises DLBCL. In some embodiments of any of the provided methods, the DLBCL is transformed from de novo or follicular lymphoma (FL) and / or does not include DLBCL transformed from MZL, and DLBCL transformed from CLL (Richter's transformation).

[0106] In certain embodiments of any of the provided methods, the subject is identified as having, or has been identified as having, an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. In certain embodiments of any of the provided methods, the subject is identified as having, or has been identified as having, an ECOG status of 0 or 1. In some embodiments of any of the provided methods, at or immediately prior to administration of the dose of cells, the subject has relapsed after remission following treatment with one or more prior therapies for NHL (optionally one, two, or three prior therapies other than another dose of cells expressing a CAR) or has become refractory to the prior therapies.

[0107] In some embodiments of any of the provided methods, the subject is identified as having or has been identified as having lymphoma associated with or involving central nervous system (CNS) infiltration at or before administration of the dose of cells. In some embodiments of any of the provided methods, at least 70%, at least 80%, at least 90%, or at least 95% of subjects treated according to the method who exhibited or were identified as exhibiting lymphoma with CNS infiltration at or before administration of the dose of cells achieved regression of the CNS disease.

[0108] In certain embodiments of any of the provided methods, the subject is identified as having or has been identified as having double / triple hit lymphoma (or aggressive B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements (double / triple hit) with DLBCL histology) at the time of or prior to administration of the dose of cells; the subject is identified as having or has been identified as having chemotherapy-resistant lymphoma (optionally chemotherapy-resistant DLBCL); the subject has not achieved a complete remission (CR) in response to prior therapy; and / or the subject has relapsed within or less than one year after receiving an autologous stem cell transplant (ASCT).

[0109] In some embodiments of any of the provided methods, the method includes, prior to administration of the dose of cells, identifying or selecting a subject for administration of the dose of cells who has double / triple hit lymphoma (or high-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements (double / triple hit) with DLBCL histology), chemotherapy-resistant lymphoma (optionally chemotherapy-resistant DLBCL), has not achieved complete remission (CR) in response to prior therapy for treating the malignancy (optionally NHL); and / or has relapsed within or less than one year after undergoing autologous stem cell transplant (ASCT); and / or has lymphoma associated with or involving central nervous system (CNS) infiltration.

[0110] In some embodiments of any of the provided methods, the method includes administering a therapeutic agent other than a cell therapy, optionally including a CAR +The method further comprises administering an additional therapeutic agent or therapy other than T cell therapy. In some embodiments, the additional therapeutic agent or therapy is for treating NHL or malignant tumors and / or enhances the persistence, activity, and / or efficacy of the dose of cells. In some embodiments, the additional therapeutic agent or therapy is administered if the subject does not respond to the cell therapy, optionally without CR or OR, within 1 month, 2 months, or 3 months after administration of the dose of cells. In some embodiments, the additional therapeutic agent or therapy is administered to a subject who has been identified or identified as having stable or progressive disease (SD / PD) after treatment with prior therapy (optionally prior treatment with a chemotherapeutic agent), a subject who has been identified or identified as having Eastern Cooperative Oncology Group (ECOG) performance status 2, a subject who has been identified or identified as having transformed follicular lymphoma (tFL), and / or a subject who has DLBCL transformed from MZL and CLL. In some embodiments, prior to administration of the dose of cells or additional therapeutic agent or therapy, the method comprises identifying or selecting a subject for administration of the dose of cells who has stable or progressive disease (SD / PD) after prior treatment, optionally with a prior chemotherapy agent, Eastern Cooperative Oncology Group performance status (ECOG) status of 2, transformed follicular lymphoma (tFL) and / or DLBCL transformed from MZL and CLL. In some of any such embodiments, the additional therapeutic agent or therapy is administered before, with, or simultaneously with, and / or after initiation of administration of the dose of cells.

[0111] In certain embodiments of any of the provided methods, the CAR comprises an scFv specific for an antigen, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule that is optionally 4-1BB, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule that is optionally CD3 zeta. In some embodiments of any of the provided methods, the antigen is a B cell antigen, optionally CD19.

[0112] In certain embodiments of any of the provided methods, prior to said administering, the subject is preconditioned with lymphocyte depletion therapy comprising administration of fludarabine and / or cyclophosphamide. Certain embodiments of any of the provided methods further comprise administering to the subject lymphocyte depletion therapy comprising administration of fludarabine and / or cyclophosphamide immediately prior to said administering. In some embodiments of any of the provided methods, the lymphocyte depletion therapy is administered at a dose of about 200 to 400 mg / m, inclusive. 2 (Optionally 300 or about 300 mg / m 2 ) cyclophosphamide, and / or approximately 20–40 mg / m 2 (Optionally 30 mg / m 2 ) fludarabine daily for 2-4 days (optionally 3 days). In certain embodiments of any of the provided methods, the lymphocyte depletion therapy comprises administering 300 mg / m 2 or approximately 300 mg / m 2 of cyclophosphamide and approximately 30 mg / m 2 of fludarabine administered daily for three days.

[0113] In certain embodiments of any of the provided methods, administration of the cell dose and / or lymphocyte depletion therapy is performed on an outpatient basis. In some embodiments of any of the provided methods, the dose of cells is administered parenterally, optionally intravenously.

[0114] In certain embodiments of any of the provided methods, at least 40% or at least 50% of subjects treated according to the method achieve a complete remission (CR) and exhibit a progression-free survival (PFS) and / or overall survival (OS) of greater than at or about 3 months, greater than at or about 6 months, or greater than at or about 12 months; on average, subjects treated according to the method exhibit a median PFS or OS of greater than at or about 6 months, greater than at or about 12 months, or greater than at or about 18 months; and / or subjects exhibit a PFS or OS of at least 6 or about 6 months, 12 or about 12 months, 18 or about 18 months, or longer, following treatment. In certain embodiments of any of the provided methods, CAR detectable in the blood of the subject, or detectable in a majority of subjects so treated by the method, is detected 14 or about 14 days or 28 or about 28 days after initiation of administration of the dose of cells. + T cells (optionally, CAR + CD8 + T cells and / or CAR + CD4 + T cells) is greater than 1 cell per μL, greater than 5 cells per μL, or greater than 10 cells per μL.

[0115] In some embodiments of any of the provided methods, the T cells are primary T cells obtained from the subject. In certain embodiments of any of the provided methods, the T cells are autologous to the subject. In certain embodiments of any of the provided methods, the T cells are allogeneic to the subject. In some embodiments of any of the provided methods, the T cells are CD4 T cells administered as multiple compositions. + T cells and CD8 + T cells, and the plurality of compositions + T cells or CD8 + administration of a first composition comprising T cells and + T cells or CD8 + The administration of a second composition comprising the other of the T cells.

[0116] In certain embodiments of any of the provided methods, the first composition and the second composition are administered 0 to 12 hours apart, 0 to 6 hours apart, or 0 to 2 hours apart. In certain embodiments of any of the provided methods, the first composition and the second composition are administered 2 hours or less, 1 hour or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less apart. In some embodiments of any of the provided methods, the first composition is CD4 + In certain embodiments of any of the provided methods, the first composition comprises CD8 T cells. + In certain embodiments of any of the provided methods, the first composition is administered before the second composition.

[0117] In some embodiments of any of the provided methods, the dose of T cells is administered to the subject as a single dose, or only once within a two-week, one-month, three-month, six-month, one-year, or longer period. In particular embodiments of any of the provided methods, the dose of T cells is administered as a double dose comprising a first dose of T cells and a subsequent dose of T cells, wherein one or both of the first and second doses constitute administration of the plurality of compositions of T cells. In particular embodiments of any of the provided methods, the subsequent dose is administered at least about 7 days or more, or at least about 14 days or more, after initiation of administration of the first dose of cells, but before about 28 days after initiation of administration of the first dose of cells.

[0118] 1. An article of manufacture comprising a cell therapy comprising a dose or composition of genetically modified cells expressing a chimeric antigen receptor (CAR) and instructions for administering the cell therapy, wherein the dose of cells is to be administered to a subject who has or has been identified as having non-Hodgkin's lymphoma (NHL), the NHL being selected from diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), NOS (transformed from de novo or indolent lymphoma), or follicular lymphoma grade 3B, and the subject is identified as having or will be identified as having an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and the dose of T cells administered is 5×10 7 or about 5 x 10 7 pieces~1×10 8 or about 1 x 10 8 Provided herein are articles of manufacture, wherein the instructions specify that the dose of T cells comprises CAR-expressing CD8 T cells (inclusive). In some embodiments of any of the provided articles of manufacture, the dose of T cells is comprised of CAR-expressing CD8 T cells. + CAR-expressing CD4 cells + Defined ratio of cells and / or CD8 + CD4 on cells + The instructions specify that the cells are administered at a defined ratio, optionally about 1:1, or about 1:3 to about 3:1.

[0119] An article of manufacture comprising a cell therapy comprising a dose or composition of genetically modified cells expressing a chimeric antigen receptor (CAR) and instructions for administering the cell therapy, wherein the dose of T cells is a CD4 T cell expressing the CAR. + Cells: CD8 expressing the CAR + Defined ratio of cells and / or CD4 + Cell: CD8 +Provided herein is an article of manufacture, wherein the instructions specify that a dose of cells should be administered at a defined ratio of cells, the ratio being about 1:1 or 1:1; and that the dose of cells should be administered to a subject who has or has been identified as having non-Hodgkin's lymphoma (NHL), wherein the NHL is selected from diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), NOS (transformed from de novo or indolent lymphoma), or follicular lymphoma grade 3B.

[0120] 1. An article of manufacture comprising a cell therapy comprising a dose or composition of genetically modified cells expressing a chimeric antigen receptor (CAR) and instructions for administering the cell therapy, wherein the dose of cells is to be administered to a subject having or identified as having non-Hodgkin's lymphoma (NHL), optionally wherein the NHL is selected from aggressive NHL, diffuse large B-cell lymphoma (DLBCL), NOS (de novo and indolent transformed), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B), and wherein the dose of administered T cells is 5×10 7 or about 5 x 10 7 pieces~1×10 8 or about 1 x 10 8 (inclusive) CAR-expressing T cells; and the dose of T cells comprises CD4 + Cells: CD8 expressing the CAR + Defined ratio of cells and / or CD4 + Cell: CD8 + Provided herein are articles of manufacture in which the instructions specify that cells should be administered in a defined ratio, said ratio being about 1:1 or 1:1.

[0121] In some embodiments of any of the provided articles of manufacture, the instructions further specify that the dose of cells should be administered to a subject who is or has been identified as having an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (optionally, an ECOG status of 0 or 1). In particular embodiments of any of the provided articles of manufacture, the instructions specify that administration is in a subject who, immediately prior to administration of the dose of cells or within one month or about one month of administration of the dose of cells, is not receiving an agent or treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of, or the risk of, toxicity. In some embodiments of any of the provided articles of manufacture, the agent is or includes an anti-IL-6 or anti-IL-6R antibody (optionally tocilizumab or siltuximab) and / or a steroid (optionally dexamethasone). In certain embodiments of any of the provided articles of manufacture, the instructions specify that the dose of cells is not for administration in subjects with DLBCL transformed from MZL and CLL (Richter's) and / or for subjects with DLBCL that is a disease transformed from de novo or indolent. In some embodiments of any of the provided articles of manufacture, the instructions specify that the subject does not have DLBCL transformed from MZL and CLL (Richter's).

[0122] In some embodiments of any of the provided articles of manufacture, the instructions specify that the cell therapy application is for subjects identified or identified as having double / triple-hit lymphoma (or high-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements (double / triple-hit) with DLBCL histology); subjects identified or identified as having chemotherapy-resistant lymphoma (optionally chemotherapy-resistant DLBCL); and / or subjects who have not achieved complete remission (CR) in response to prior therapy. In certain embodiments of any of the provided articles of manufacture, the CAR comprises an scFv specific for the antigen, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, optionally 4-1BB, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, optionally CD3 zeta. In certain embodiments of any of the provided articles of manufacture, the antigen is a B-cell antigen, optionally CD19.

[0123] Certain embodiments of any of the provided articles of manufacture further comprise instructions for use with, after, or in association with lymphocyte depletion therapy, the lymphocyte depletion therapy optionally including fludarabine and / or cyclophosphamide. In certain embodiments of any of the provided articles of manufacture, the lymphocyte depletion therapy is administered at a dose of about 200 to 400 mg / m, inclusive. 2 (Optionally 300 or about 300 mg / m 2 ) cyclophosphamide, and / or approximately 20–40 mg / m 2 (Optionally 30 mg / m 2 ) of fludarabine administered daily for 2-4 days (optionally 3 days). In certain embodiments of any of the provided articles of manufacture, the lymphocyte depletion therapy comprises administering 300 mg / m 2 or approximately 300 mg / m 2 of cyclophosphamide and approximately 30 mg / m 2 of fludarabine administered daily for three days.

[0124] In some embodiments of any of the provided articles of manufacture, the instructions further specify that the administration of the cell therapy should or can be performed on the subject in an outpatient setting, and / or without the subject being hospitalized overnight or for one or more consecutive days, and / or without the subject being hospitalized for one or more days. In certain embodiments of any of the provided articles of manufacture, the instructions further specify that the cell therapy is for parenteral administration, optionally for intravenous administration. In certain embodiments of any of the provided articles of manufacture, the cell therapy comprises primary T cells obtained from the subject. In some embodiments of any of the provided articles of manufacture, the T cells are autologous to the subject. In certain embodiments of any of the provided articles of manufacture, the T cells are allogeneic to the subject.

[0125] In certain embodiments of any of the provided articles of manufacture, the article of manufacture comprises a plurality of cell therapy compositions, the plurality of compositions comprising CD4 + T cells or CD8 + a first composition of genetically modified cells comprising T cells, wherein the first composition is a CD4 + T cells or CD8 + The instructions specify that the composition is for use with a second composition comprising another of the T cells, and optionally the cells of the first composition and the cells of the second composition are derived from the same subject.

[0126] In some embodiments of any of the provided articles of manufacture, the first composition and the second composition comprise a recombinant receptor-expressing CD4 + Cells: recombinant receptor-expressing CD8 + Defined ratio of cells and / or CD4 + Cell: CD8 +The instructions specify that the cells should be administered at a predetermined ratio, optionally about 1:1, or about 1:3 to about 3:1. In certain embodiments of any of the provided articles of manufacture, the predetermined ratio is 1:1 or about 1:1. In certain embodiments of any of the provided articles of manufacture, the composition further comprises a cryoprotectant and / or the article further comprises instructions for thawing the composition prior to administration to a subject.

[0127] In some embodiments of any of the provided articles of manufacture, CD4 + Compositions containing T cells and CD8 + The instructions specify that the compositions comprising T cells are administered 0-12 hours apart, 0-6 hours apart, or 0-2 hours apart. + Compositions containing T cells and CD8 + The instructions specify that the compositions comprising T cells be 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. + The composition comprising T cells is + In some embodiments of any of the provided articles of manufacture, the instructions specify administering the CD8 + The composition comprising T cells is + The instructions specify that the administration be performed before administering the composition containing the cells.

[0128] Provided herein is an article of manufacture comprising one or more reagents capable of detecting one or more analytes and, optionally, instructions for using the reagents to assay a biological sample from a subject who is a candidate for treatment with a cell therapy, wherein the cell therapy optionally comprises a dose or composition of genetically modified cells expressing a recombinant receptor, wherein the one or more analytes are selected from LDH, ferritin, CRP, IL-6, IL-7, IL-8, IL-10, IL-15, IL-16, TNF-alpha, IFN-gamma, MCP-1, MIP-1 beta, eotaxin, G-CSF, IL-1R alpha, IL-1R beta, IP-10, perforin, and D-dimer (a fibrin degradation product).

[0129] Certain embodiments of any of the provided articles of manufacture further comprise a cell therapy and / or instructions for use with, prior to, and / or in conjunction with the cell therapy treatment. Certain embodiments of any of the provided articles of manufacture further comprise one or more agents or treatments for treating, preventing, delaying, reducing, or attenuating the onset of, or the risk of, toxicity; and / or instructions for application of one or more agents or treatments for treating, preventing, delaying, reducing, or attenuating the onset of, or the risk of, toxicity in a subject.

[0130] In some embodiments of any of the provided articles of manufacture, if the level, amount, or concentration of the analyte in the sample is at or above a threshold level for the analyte, then administering to the subject an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of, or the risk of, toxicity (i) prior to initiation of administration of cell therapy to the subject, (ii) within 1, 2, or 3 days of initiation of administration of cell therapy to the subject, (iii) concurrently with initiation of administration of cell therapy to the subject, and / or (iv) at the first onset of fever after initiation of administration of cell therapy to the subject; and / or administering to the subject at a low dose or at a time that is consistent with the administration of cell therapy. The instructions further specify that, after administration of the law, the cell therapy is administered to the subject at a dose that does not involve the risk of causing toxicity or severe toxicity, or that does not involve the risk of causing toxicity or severe toxicity in a majority of subjects and / or in a majority of subjects having a disease or condition that the subject has or is suspected of having; and / or that the cell therapy is administered to the subject in an inpatient setting and / or with one or more days of hospitalization, where optionally the cell therapy is otherwise administered to the subject on an outpatient basis or without one or more days of hospitalization.

[0131] In certain embodiments of any of the provided articles of manufacture, the instructions further specify that if the level, amount, or concentration of the analyte is below a threshold level for the analyte, then the subject is administered a cell therapy, optionally at a non-low dose, optionally on an outpatient basis or without hospitalization for one or more days.

[0132] In certain embodiments of any of the provided articles of manufacture, the instructions further specify administering a cell therapy to the subject, and if the level, amount, or concentration of the analyte is below a threshold level, the administering of the cell therapy does not include administering an agent or treatment that can treat, prevent, delay, or attenuate the onset of toxicity prior to or concurrently with the administering of the cell therapy, and / or prior to the onset of signs of a symptom of toxicity other than fever; and / or the instructions further specify that the administering of the cell therapy should or can be administered to the subject in an outpatient setting, and / or without the subject being hospitalized overnight or for one or more consecutive days, and / or without the subject being hospitalized for one or more days.

[0133] In some embodiments of any of the provided articles of manufacture, the threshold level is within 25%, within 20%, within 15%, within 10%, or within 5% of the mean level, amount, or concentration of the analyte in biological samples obtained from a group of subjects prior to receiving the recombinant receptor-expressing therapeutic cell composition, and / or within a standard deviation of the mean level, amount, or concentration of the analyte in biological samples obtained from a group of subjects prior to receiving the recombinant receptor-expressing therapeutic cell composition, wherein each subject in the group is a subject that developed toxicity after receiving a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition. Provided herein is an article of manufacture comprising a cell therapy (which optionally comprises a dose or composition of genetically modified cells that express a recombinant receptor) and instructions for administering the cell therapy according to or based on the results of an assessment in a biological sample of the level or amount or concentration of one or more analytes in the biological sample, wherein the biological sample was obtained from a subject prior to administering the cell therapy and / or the biological sample does not comprise the recombinant receptor and / or the modified cells, and the one or more analytes are selected from LDH, ferritin, CRP, IL-6, IL-7, IL-8, IL-10, IL-15, IL-16, TNF-alpha, IFN-gamma, MCP-1, MIP-1 beta, eotaxin, G-CSF, IL-1R alpha, IL-1R beta, IP-10, perforin, and D-dimer (a fibrin degradation product).

[0134] In certain embodiments of any of the provided articles of manufacture, the evaluating comprises detecting, optionally comprising contacting a reagent capable of directly or indirectly detecting an analyte with the biological sample and determining the level, amount, or concentration of the analyte in the biological sample. Certain embodiments of any of the provided articles of manufacture further comprise the reagent and / or instructions for use with, prior to, and / or in association with the reagent for detecting the analyte. Some embodiments of any of the provided articles of manufacture further comprise one or more agents or treatments for treating, preventing, delaying, reducing, or attenuating the onset of, or the risk of, toxicity; and / or instructions for applying one or more agents or treatments for treating, preventing, delaying, reducing, or attenuating the onset of, or the risk of, toxicity in a subject.

[0135] In certain embodiments of any of the provided articles of manufacture, if the level, amount, or concentration of the analyte in the sample is at or above a threshold level, administering to the subject an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of, or the risk of, toxicity (i) prior to initiation of administration of the therapeutic cell composition or genetically modified cells, (ii) within 1, 2, or 3 days of initiation of administration of the therapeutic cell composition or genetically modified cells, (iii) concurrently with initiation of administration of the therapeutic cell composition or genetically modified cells, and / or (iv) at the first onset of fever after initiation of administration of the therapeutic cell composition or genetically modified cells; and / or applies the cell therapy to the subject at a low dose or at a dose that is not associated with the risk of developing toxicity or severe toxicity following administration of the cell therapy, or that is not associated with the risk of developing toxicity or severe toxicity in a majority of subjects and / or in a majority of subjects having a disease or condition that the subject has or is suspected of having; and / or applies the cell therapy to the subject in an inpatient setting and / or with one or more days of hospitalization, where optionally the instructions for applying the cell therapy specify that the cell therapy is otherwise applied to the subject on an outpatient basis or without one or more days of hospitalization.

[0136] In certain embodiments of any of the provided articles of manufacture, the instructions for administering cell therapy specify that if the level, amount, or concentration of the analyte in the sample is below a threshold level, then administer the cell therapy to the subject, optionally at a non-low dose, optionally on an outpatient basis, or without hospitalization for one or more days. In some embodiments of any of the provided articles of manufacture, the instructions further specify that if the level, amount, or concentration of the analyte is below a threshold level, then do not administer an agent or treatment that can treat, prevent, delay, or attenuate the onset of toxicity prior to or concurrently with the administration of the cell therapy and / or prior to the onset of signs or symptoms of toxicity other than fever; and / or that the administration of cell therapy should or can be administered to the subject in an outpatient setting, and / or without the subject being hospitalized overnight or for one or more consecutive days, and / or without the subject being hospitalized for one or more days.

[0137] In certain embodiments of any of the provided articles of manufacture, the threshold level is within 25%, within 20%, within 15%, within 10%, or within 5% of the mean level, amount, or concentration of the analyte in biological samples obtained from a group of subjects prior to receiving the recombinant receptor-expressing therapeutic cell composition, and / or within a standard deviation of the mean level, amount, or concentration of the analyte in biological samples obtained from a group of subjects prior to receiving the recombinant receptor-expressing therapeutic cell composition, wherein each subject in the group is a subject that developed toxicity after receiving a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0138] Provided herein is an article of manufacture, comprising: an agent that can treat, prevent, delay, reduce or attenuate the occurrence of toxicity or its risk; and instructions for administering the agent according to or based on the results of the evaluation of the level, amount or concentration of one or more analytes in a biological sample, wherein the one or more analytes are selected from LDH, ferritin, CRP, IL-6, IL-7, IL-8, IL-10, IL-15, IL-16, TNF-alpha, IFN-gamma, MCP-1, MIP-1 beta, eotaxin, G-CSF, IL-1R alpha, IL-1R beta, IP-10, perforin, and D-dimer (fibrin degradation product).In certain embodiments of any of the provided articles of manufacture, the evaluation comprises detection, optionally comprising contacting a reagent that can directly or indirectly detect analyte with the biological sample, and determining the level, amount, or concentration of the analyte in the biological sample.

[0139] In some embodiments of any of the provided articles of manufacture, the instructions specify that the agent should be administered i) prior to initiation of administration of the cell therapy to the subject, (ii) within 1, 2, or 3 days of initiation of administration of the cell therapy to the subject, (iii) concurrently with initiation of administration of the cell therapy to the subject, and / or (iv) at the first onset of fever after initiation of administration of the cell therapy to the subject, and / or further comprise instructions for use with, prior to, and / or in association with treatment with the cell therapy. In certain embodiments of any of the provided articles of manufacture, the biological sample is obtained from the subject prior to administration of the agent or cell therapy. In certain embodiments of any of the provided articles of manufacture, the reagent is a marker of a myeloid cell population or a binding molecule that specifically binds to the cells. In some embodiments of any of the provided articles of manufacture, the reagent is an antibody or antigen-binding fragment thereof. In certain embodiments of any of the provided articles of manufacture, the biological sample is a blood sample, plasma sample, or serum sample, or is obtained from a blood sample, plasma sample, or serum sample. In certain embodiments of any of the provided articles of manufacture, the article further comprises a reagent for detecting an analyte and / or further comprises instructions for use with, prior to, and / or in association with the reagent for detecting an analyte. Some embodiments of any of the provided articles of manufacture further comprise a cell therapy and / or further comprise instructions for use with, prior to, and / or in association with treatment with the cell therapy.

[0140] In certain embodiments of any of the provided articles of manufacture, the instructions for administering the agent specify administering the agent to the subject if the level, amount, or concentration of the analyte in the sample is at or above a threshold level. In certain embodiments of any of the provided articles of manufacture, the instructions further specify administering a cell therapy to the subject, wherein administration of the agent should occur (i) prior to initiation of administration of the cell therapy to the subject, (ii) within 1, 2, or 3 days of initiation of administration of the cell therapy to the subject, (iii) concurrently with initiation of administration of the cell therapy to the subject, and / or (iv) at the first onset of fever after initiation of administration of the cell therapy to the subject. In some embodiments of any of the provided articles of manufacture, the instructions for administering the agent specify that if the level, amount, or concentration is below a threshold level, then the cell therapy is administered to the subject, and optionally the instructions specify that the cell therapy should be administered to the subject in an outpatient setting and / or without the subject being hospitalized overnight or for one or more consecutive days, or that the cell therapy can be administered to the subject in an outpatient setting and / or without the subject being hospitalized overnight or for one or more consecutive days, and / or without the subject being hospitalized for one or more days.

[0141] In certain embodiments of any of the provided articles of manufacture, the threshold level is within 25%, within 20%, within 15%, within 10%, or within 5% of the mean level, amount, or concentration of the analyte in biological samples obtained from a group of subjects prior to receiving the recombinant receptor-expressing therapeutic cell composition, and / or within a standard deviation of the mean level, amount, or concentration of the analyte in biological samples obtained from a group of subjects prior to receiving the recombinant receptor-expressing therapeutic cell composition, wherein each subject in the group is a subject who developed toxicity after receiving a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition. In certain embodiments of any of the provided articles of manufacture, the assay or evaluation of the cells of the analyte is by immunoassay.

[0142] In some embodiments of any of the provided articles of manufacture, the toxicity comprises neurotoxicity or cytokine release syndrome (CRS), optionally neurotoxicity or CRS of Grade 1 or greater. In particular embodiments of any of the provided articles of manufacture, the toxicity comprises severe neurotoxicity, and / or comprises neurotoxicity of Grade 2 or greater, neurotoxicity of Grade 3 or greater, prolonged neurotoxicity of at least Grade 3, or neurotoxicity of Grade 4 or greater or Grade 5 or greater; and / or the toxicity comprises severe CRS, and / or comprises CRS of Grade 2 or greater, or CRS of Grade 3 or greater. In particular embodiments of any of the provided articles of manufacture, the toxicity is associated with cerebral edema.

[0143] In some embodiments of any of the provided articles of manufacture, the agent or other treatment is or includes one or more of: a steroid; an antagonist or inhibitor of a cytokine receptor or cytokine selected from among IL-10, IL-10R, IL-6, IL-6 receptor, IFNγ, IFNGR, IL-2, IL-2R / CD25, MCP-1, CCR2, CCR4, MIP1β, CCR5, TNFalpha, TNFR1, IL-1, and IL-1Ralpha / IL-1beta; or an agent capable of suppressing, blocking, or reducing the activity or function of microglial cells. In certain embodiments of any of the provided articles of manufacture, the antagonist or inhibitor is or includes an agent selected from among an antibody or antigen-binding fragment, a small molecule, a protein or peptide, and a nucleic acid. In certain embodiments of any of the provided articles of manufacture, the agent or other treatment is an anti-IL-6 antibody or an anti-IL6 receptor antibody.

[0144] In some embodiments of any of the provided articles of manufacture, the agent or other treatment is or includes an agent selected from among tocilizumab, siltuximab, clazakizumab, sarilumab, olokizumab (CDP6038), elcilimomab, ALD518 / BMS-945429, sirukumab (CNTO 136), CPSI-2634, ARGX-109, FE301, and FM101. In certain embodiments of any of the provided articles of manufacture, the agent or other treatment is or includes tocilizumab. In certain embodiments of any of the provided articles of manufacture, the agent or other treatment is or includes siltuximab. In some embodiments of any of the provided articles of manufacture, the steroid is or includes dexamethasone.

[0145] In certain embodiments of any of the provided articles of manufacture, the agent capable of suppressing, blocking, or reducing the activity or function of microglial cells is selected from an anti-inflammatory agent, an inhibitor of NADPH oxidase (NOX2), a calcium channel blocker, a sodium channel blocker, inhibits GM-CSF, inhibits CSF1R, specifically binds CSF-1, specifically binds IL-34, inhibits the activation of nuclear factor kappa B (NF-κB), activates the CB2 receptor and / or is a CB2 agonist, a phosphodiesterase inhibitor, inhibits microRNA-155 (miR-155), or upregulates microRNA-124 (miR-124). In certain embodiments of any of the provided articles of manufacture, the agent capable of suppressing, blocking, or reducing the activation or function of microglial cells is a small molecule, peptide, protein, antibody or antigen-binding fragment thereof, antibody mimic, aptamer, or nucleic acid molecule.

[0146] In some embodiments of any of the provided articles of manufacture, the agent is selected from the group consisting of minocycline, naloxone, nimodipine, riluzole, MOR103, lenalidomide, cannabinoids (optionally WIN55 or 212-2), intravenous immunoglobulin (IVIg), ibudilast, anti-miR-155 locked nucleic acid (LNA), MCS110, PLX-3397, PLX647, PLX108-D1, PLX7486, JNJ-40346 527, JNJ28312141, ARRY-382, AC-708, DCC-3014, 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580), AZD6495, Ki20227, BLZ945, emactuzumab, IMC-CS4, FPA008, LY-3022855, AMG-820, and TG-3003. In certain embodiments of any of the provided articles of manufacture, the agent is an inhibitor of colony-stimulating factor 1 receptor (CSF1R). In certain embodiments of any of the provided articles of manufacture, the inhibitor is selected from PLX-3397, PLX647, PLX108-D1, PLX7486, JNJ-40346527, JNJ28312141, ARRY-382, AC-708, DCC-3014, 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580), AZD6495, Ki20227, BLZ945, or a pharmaceutical salt or prodrug thereof; emactuzumab, IMC-CS4, FPA008, LY-3022855, AMG-820, and TG-3003, or an antigen-binding fragment thereof; or a combination of any of the foregoing. In some embodiments of any of the provided articles of manufacture, the inhibitor is PLX-3397.

[0147] In certain embodiments of any of the provided articles of manufacture, the disease or condition is cancer. In certain embodiments of any of the provided articles of manufacture, the disease or condition is myeloma, leukemia, or lymphoma. In some embodiments of any of the provided articles of manufacture, the disease or condition is a B-cell malignancy and / or is acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin's lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL).

[0148] In certain embodiments of any of the provided articles of manufacture, the antigen is selected from the group consisting of ROR1, B-cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), tEGFR, Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, anti-folate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, EGFR vIII, folate-binding protein (FBP), FCRL5, FCRH5, fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, kinase insert domain receptor (kdr), kappa light chain, Lewis Y, L1 cell adhesion molecule (L1-CAM), melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, melanoma preferentially expressed antigen (PRAME), survivin, TAG72, B7-H6, IL-13 receptor alpha 2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, bispecific antigen, cancer-testis antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, oncofetal antigen, ROR 1, TAG72, VEGF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms' tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, G protein-coupled receptor 5D (GPCR5D), or pathogen-specific antigens.

[0149] In certain embodiments of any of the provided articles of manufacture, the recombinant receptor is a T cell receptor or a functional non-T cell receptor. In some embodiments of any of the provided articles of manufacture, the recombinant receptor is a chimeric antigen receptor (CAR). In certain embodiments of any of the provided articles of manufacture, the CAR comprises an extracellular antigen recognition domain that specifically binds to an antigen and an intracellular signaling domain comprising an ITAM, optionally, the intracellular signaling domain comprises the intracellular domain of the CD3-zeta (CD3ζ) chain; and / or the CAR further comprises a costimulatory signaling region optionally comprising the signaling domain of CD28 or 4-1BB.

[0150] In certain embodiments of any of the provided articles of manufacture, the modified cells are T cells, optionally CD4 + and / or CD8 + In some embodiments of any of the provided articles of manufacture, the T cells are primary T cells obtained from a subject. In certain embodiments of any of the provided articles of manufacture, a dose without risk of toxicity or severe toxicity is 5×10 7 Less than or about 5 x 10 7 less than 10 whole recombinant receptor-expressing cells, optionally including CAR + cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), e.g., 2.5 x 10 7 Less than or about 2.5 x 10 7 Less than 1.0 x 10 7 Less than or about 1.0 x 10 7 Less than 5.0 x 10 6 Less than or about 5.0 x 10 6 Less than 1.0 x 10 6 Less than or about 1.0 x 10 6 Less than 5.0 x 10 5 Less than or about 5.0 x 10 5 Less than 1 x 10 5 Less than or about 1 x 10 5 less than 10 whole recombinant receptor-expressing cells, optionally including CAR +In certain embodiments of any of the provided articles of manufacture, the dose without risk of toxicity or severe toxicity is or comprises 1 x 10 cells, total T cells, or total peripheral blood mononuclear cells (PBMCs). 5 or about 1 x 10 5 ~5×10 7 or about 5 x 10 7 whole recombinant receptor-expressing cells, optionally CAR + cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), e.g., 1 x 10 5 ~2.5×10 7 , 1×10 5 ~1.0×10 7 , 1×10 5 ~5.0×10 6 , 1×10 5 ~1.0×10 6 , 1.0×10 5 ~5.0×10 5 , 5.0×10 5 ~5×10 7 , 5×10 5 ~2.5×10 7 , 5×10 5 ~1.0×10 7 , 5×10 5 ~5.0×10 6 , 5×10 5 ~1.0×10 6 , 1.0×10 6 ~5×10 7 , 1×10 6 ~2.5×10 7 , 1×10 6 ~1.0×10 7 , 1×10 6 ~5.0×10 6 , 5.0×10 6 ~5×10 7 , 5×10 6 ~2.5×10 7 , 5×10 6 ~1.0×10 7 , 1.0×10 7 ~5×10 7 , 1×10 7 ~2.5×10 7 , or 2.5 × 10 7 ~5×10 7whole recombinant receptor-expressing cells (optionally, CAR + cells, whole T cells, or whole peripheral blood mononuclear cells (PBMCs).

[0151] In certain embodiments of any of the provided articles of manufacture, the reagent is detectably labeled, and optionally fluorescently labeled. In some embodiments of any of the provided articles of manufacture, the one or more analytes are LDH, ferritin, CRP, IL-6, IL-8, IL-10, TNF-alpha, IFN-alpha2, MCP-1, and MCP-1 beta. In certain embodiments of any of the provided articles of manufacture, the one or more analytes is or includes LDH.

[0152] 1. A method of selecting a subject for treatment, comprising the steps of: (a) contacting a biological sample with one or more reagents capable of detecting or specific for one or more analytes, wherein the one or more analytes are selected from LDH, ferritin, CRP, IL-6, IL-7, IL-8, IL-10, IL-15, IL-16, TNF-alpha, IFN-gamma, MCP-1, MIP-1 beta, eotaxin, G-CSF, IL-1R alpha, IL-1R beta, IP-10, perforin, and D-dimer (a fibrin degradation product), wherein the biological sample is a candidate for treatment with a cell therapy. Provided herein are methods comprising the steps of: (a) administering a cell therapy to a subject that is a candidate for the cell therapy; the cell therapy optionally comprising a dose or composition of genetically modified cells that express a recombinant receptor; the biological sample being obtained from the subject prior to administering the cell therapy and / or the biological sample being free of the recombinant receptor and / or the modified cells; and (b) selecting either (i) a subject in which the level, amount, or concentration of the analyte in the sample is at or above a threshold level, thereby identifying the subject as being at risk of developing toxicity to the cell therapy; or (ii) a subject in which the level, amount, or concentration of the analyte is below a threshold level.

[0153] In certain embodiments of any of the provided methods, the subject of (a)(i) is selected for administration to the subject of (1) an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of, or the risk of, toxicity, and (2) a cell therapy, wherein administration of the agent is to occur (i) prior to initiation of administration of the cell therapy to the subject, (ii) within 1, 2, or 3 days of initiation of administration of the cell therapy to the subject, (iii) concurrently with initiation of administration of the cell therapy to the subject, and / or (iv) at the first onset of fever after initiation of administration of the cell therapy to the subject; and / or the subject of (c)(i) is selected for administration of a low dose of or (b)(i) is selected for administration of cell therapy to the subject at a dose that does not involve the risk of developing toxicity or severe toxicity following administration of the cell therapy, or that does not involve the risk of developing toxicity or severe toxicity in a majority of subjects and / or in a majority of subjects having a disease or condition that the subject has or is suspected of having; and / or (b)(i) is selected for administration of cell therapy to the subject in an inpatient setting and / or with one or more days of hospitalization, where optionally, the cell therapy is otherwise administered to the subject on an outpatient basis or without one or more days of hospitalization.

[0154] In some embodiments of any of the provided methods, (i) a subject is selected, and the method comprises: (a) administering to the subject (1) an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of, or risk of, toxicity, and (2) a cell therapy, wherein the administration of the agent occurs (i) before initiation of administration of cell therapy to the subject, (ii) within 1, 2, or 3 days of initiation of administration of cell therapy to the subject, (iii) concurrently with initiation of administration of cell therapy to the subject, and / or (iv) at the time of first fever after initiation of administration of cell therapy to the subject; and / or (b) at a low dose or after administration of cell therapy, without risk of developing toxicity or severe toxicity, or in a majority of subjects, and / or for a disease or condition (which the subject has or is suspected of having). and / or (c) administering to the subject a cell therapy or a dose of genetically modified cells of the cell therapy without the risk of developing toxicity or severe toxicity after administration of the cell therapy, or without the risk of developing toxicity or severe toxicity in a majority of subjects and / or in a majority of subjects with a disease or condition that the subject has or is suspected of having; and / or (d) administering to the subject a cell therapy in an inpatient setting and / or with one or more days of hospitalization, optionally otherwise administering to the subject on an outpatient basis or without one or more days of hospitalization.

[0155] In certain embodiments of any of the provided methods, (a)(ii) subjects are selected for administration of cell therapy to the subject, optionally at a non-low dose, optionally on an outpatient basis or without hospitalization for one or more days; (b)(ii) subjects are selected for administration of cell therapy to the subject, which does not include administration of an agent or treatment that can treat, prevent, delay, or attenuate the onset of toxicity prior to or concurrently with administration of the cell therapy and / or prior to the onset of signs or symptoms of toxicity other than fever; and / or (ii) subjects are selected for administration of cell therapy in an outpatient setting and / or without the subject being hospitalized overnight or for one or more consecutive days in a hospital, and / or without the subject being hospitalized for one or more days in a hospital.

[0156] In certain embodiments of any of the provided methods, a (ii) subject is selected, and the method further comprises administering a cell therapy to the subject, optionally at a non-low dose, optionally on an outpatient basis or without hospitalization for one or more days. In some embodiments of any of the provided methods, a (ii) subject is selected, and the method further comprises administering a cell therapy to the subject, wherein the administration of the cell therapy does not include administering an agent or treatment that can treat, prevent, delay, or attenuate the onset of toxicity prior to or concurrently with the administration of the cell therapy, and / or prior to the onset of signs or symptoms of toxicity other than fever; and / or the administration of the cell therapy should or can be administered to the subject in an outpatient setting, and / or without the subject being hospitalized overnight or for one or more consecutive days, and / or without the subject being hospitalized for one or more days.

[0157] Provided herein are methods of treatment comprising: (a) assaying a biological sample for the level, amount, or concentration of one or more analytes, wherein the biological sample is optionally derived from a subject who is a candidate for treatment with a cell therapy, and the cell therapy optionally comprises a dose or composition of genetically modified cells expressing a recombinant receptor for treating a disease or condition, and the one or more analytes are selected from LDH, ferritin, CRP, IL-6, IL-7, IL-8, IL-10, IL-15, IL-16, TNF-alpha, IFN-gamma, MCP-1, MIP-1 beta, eotaxin, G-CSF, IL-1R alpha, IL-1R beta, IP-10, perforin, and D-dimer (a fibrin degradation product); and (b) administering to the subject the cell therapy and, optionally, an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the development of, or the risk of, toxicity according to or based on the results of the assay.

[0158] Provided herein are methods of treatment that include administering to a subject (i) a cell therapy, optionally including a dose or composition of a genetically modified form that expresses a recombinant receptor for treating a disease or condition, and optionally (ii) an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of, or the risk of, toxicity, according to or based on the results of an assay for the level, amount, or concentration of one or more analytes in a biological sample from the subject, wherein a biological sample is obtained from the subject prior to administering the cell therapy; the one or more analytes are selected from LDH, ferritin, CRP, IL-6, IL-7, IL-8, IL-10, IL-15, IL-16, TNF-alpha, IFN-gamma, MCP-1, MIP-1 beta, eotaxin, G-CSF, IL-1R alpha, IL-1R beta, IP-10, perforin, and D-dimer (a fibrin degradation product).

[0159] In certain embodiments of any of the provided methods, the assaying comprises detecting, optionally comprising contacting a reagent capable of directly or indirectly detecting the analyte with the biological sample and determining the level, amount, or concentration of the analyte in the biological sample. In certain embodiments of any of the provided methods, if the level, amount, or concentration of the analyte in the sample is at or above a threshold level, an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of, or risk of, toxicity is administered to the subject (i) prior to initiation of administration of cell therapy to the subject, (ii) within 1, 2, or 3 days of initiation of administration of cell therapy to the subject, (iii) concurrently with initiation of administration of cell therapy to the subject, and / or (iv) at the first fever after initiation of administration of cell therapy to the subject; and / or at a low dose or administering cell therapy to a subject at a dose that does not involve the risk of developing toxicity or severe toxicity following administration of the cell therapy, or that does not involve the risk of developing toxicity or severe toxicity in a majority of subjects and / or in a majority of subjects having a disease or condition that the subject has or is suspected of having; and / or administering cell therapy to a subject in an inpatient setting and / or with one or more days of hospitalization, wherein optionally, otherwise administering cell therapy to a subject on an outpatient basis or without one or more days of hospitalization.

[0160] In some embodiments of any of the provided methods, if the level, amount, or concentration of the analyte is at or above the threshold level, the administration of cell therapy does not include administering an agent or treatment that can treat, prevent, delay, or attenuate the onset of toxicity prior to or concurrently with the administration of cell therapy, and / or prior to the onset of signs or symptoms of toxicity other than fever; and / or the administration of cell therapy should or can be administered to the subject in an outpatient setting and / or without the subject being hospitalized overnight or for one or more consecutive days, and / or without the subject being hospitalized for one or more days.

[0161] In certain embodiments of any of the provided methods, the subject is administered an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of, or risk of, toxicity, wherein the subject is optionally a candidate for treatment with a cell therapy, said cell therapy optionally comprising a dose or composition of genetically modified cells expressing a recombinant receptor for treating a disease or condition; and the subject is assessed for risk of developing toxicity according to or based on the results of an assay for the level, amount, or concentration of one or more analytes in a biological sample from the subject. wherein the biological sample was obtained from the subject prior to administration of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells, and wherein the one or more analytes are selected from LDH, ferritin, CRP, IL-6, IL-7, IL-8, IL-10, IL-15, IL-16, TNF-alpha, IFN-gamma, MCP-1, MIP-1 beta, eotaxin, G-CSF, IL-1R alpha, IL-1R beta, IP-10, perforin, and D-dimer (a fibrin degradation product).

[0162] In certain embodiments of any of the provided methods, the assay comprises detecting, optionally comprising contacting a biological sample with a reagent capable of directly or indirectly detecting an analyte, and determining the level, amount, or concentration of the analyte in the biological sample. In some embodiments of any of the provided methods, an agent is administered to the subject if the level, amount, or concentration of the analyte in the sample is at or above a threshold level.

[0163] In certain embodiments of any of the provided methods, the agent is administered (i) prior to initiation of administration of cell therapy to the subject, (ii) within 1, 2, or 3 days of initiation of administration of cell therapy to the subject, (iii) concurrently with initiation of administration of cell therapy to the subject, and / or (iv) at the first onset of fever after initiation of administration of cell therapy to the subject. In certain embodiments of any of the provided methods, the threshold level is within 25%, within 20%, within 15%, within 10%, or within 5% of the mean percent or number of cell surface positive for the myeloid marker in a biological sample obtained from a group of subjects prior to receiving a recombinant receptor-expressing therapeutic cell composition, and / or within a standard deviation of the mean percent or number of cell surface positive for the myeloid marker in a biological sample obtained from a group of subjects prior to receiving a recombinant receptor-expressing therapeutic cell composition, where each subject in the group developed toxicity after receiving a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0164] In certain embodiments of any of the provided methods, the threshold level is within 25%, 20%, 15%, 10%, or 5% of the mean level, amount, or concentration of the analyte in biological samples obtained from a group of subjects prior to receiving the recombinant receptor-expressing therapeutic cell composition, and / or within a standard deviation of the mean level, amount, or concentration of the analyte in biological samples obtained from a group of subjects prior to receiving the recombinant receptor-expressing therapeutic cell composition, wherein each subject in the group developed toxicity after receiving the recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition. In certain embodiments of any of the provided methods, the reagent is a marker of a myeloid cell population or a binding molecule that specifically binds to the cells. In some embodiments of any of the provided methods, the reagent is an antibody or antigen-binding fragment thereof. In certain embodiments of any of the provided methods, the biological sample is a blood, plasma, or serum sample, or is obtained from a blood, plasma, or serum sample. In certain embodiments of any of the provided methods, the assay or evaluation of the cellular analyte comprises an immunoassay.

[0165] In some embodiments of any of the provided methods, the toxicity comprises neurotoxicity or cytokine release syndrome (CRS), optionally neurotoxicity or CRS of Grade 1 or higher. In particular embodiments of any of the provided methods, the toxicity comprises severe neurotoxicity, and / or comprises neurotoxicity of Grade 2 or higher, neurotoxicity of Grade 3 or higher, prolonged neurotoxicity of at least Grade 3, or neurotoxicity of Grade 4 or higher or Grade 5 or higher; and / or the toxicity comprises severe CRS, and / or comprises CRS of Grade 2 or higher, or Grade 3 or higher. In particular embodiments of any of the provided methods, the toxicity is associated with cerebral edema.

[0166] In some embodiments of any of the provided methods, the agent or other treatment is or includes one or more of: a steroid; an antagonist or inhibitor of a cytokine receptor or cytokine selected from among IL-10, IL-10R, IL-6, IL-6 receptor, IFNγ, IFNGR, IL-2, IL-2R / CD25, MCP-1, CCR2, CCR4, MIP1β, CCR5, TNFalpha, TNFR1, IL-1, and IL-1Ralpha / IL-1beta; or an agent capable of suppressing, blocking, or reducing the activity or function of microglial cells. In certain embodiments of any of the provided methods, the antagonist or inhibitor is or includes an agent selected from among an antibody or antigen-binding fragment, a small molecule, a protein or peptide, and a nucleic acid.

[0167] In certain embodiments of any of the provided methods, the agent or other treatment is an anti-IL-6 antibody or an anti-IL6 receptor antibody. In some embodiments of any of the provided methods, the agent or other treatment is or comprises an agent selected from among tocilizumab, siltuximab, clazakizumab, sarilumab, olokizumab (CDP6038), elcilimomab, ALD518 / BMS-945429, sirukumab (CNTO 136), CPSI-2634, ARGX-109, FE301, and FM101. In certain embodiments of any of the provided methods, the agent or other treatment is or comprises tocilizumab. In certain embodiments of any of the provided methods, the agent or other treatment is or comprises siltuximab.

[0168] In some embodiments of any of the provided methods, the steroid is or includes dexamethasone. In certain embodiments of any of the provided methods, the agent that can suppress, block, or reduce the activity or function of microglial cells is selected from an anti-inflammatory agent, an inhibitor of NADPH oxidase (NOX2), a calcium channel blocker, a sodium channel blocker, inhibits GM-CSF, inhibits CSF1R, specifically binds to CSF-1, specifically binds to IL-34, inhibits activation of nuclear factor kappa B (NF-κB), activates the CB2 receptor, and / or is a CB2 agonist, a phosphodiesterase inhibitor, inhibits microRNA-155 (miR-155), or upregulates microRNA-124 (miR-124).

[0169] In certain embodiments of any of the provided methods, the agent capable of inhibiting, blocking, or reducing the activation or function of microglial cells is a small molecule, peptide, protein, antibody or antigen-binding fragment thereof, antibody mimetic, aptamer, or nucleic acid molecule. In some embodiments of any of the provided methods, the agent is selected from the group consisting of minocycline, naloxone, nimodipine, riluzole, MOR103, lenalidomide, cannabinoids (optionally WIN55 or 212-2), intravenous immunoglobulin (IVIg), ibudilast, anti-miR-155 locked nucleic acid (LNA), MCS110, PLX-3397, PLX647, PLX108-D1, PLX7486, JNJ- 40346527, JNJ28312141, ARRY-382, AC-708, DCC-3014, 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580), AZD6495, Ki20227, BLZ945, emactuzumab, IMC-CS4, FPA008, LY-3022855, AMG-820, and TG-3003.

[0170] In certain embodiments of any of the provided methods, the agent is an inhibitor of colony-stimulating factor 1 receptor (CSF1R). In certain embodiments of any of the provided methods, the inhibitor is selected from PLX-3397, PLX647, PLX108-D1, PLX7486, JNJ-40346527, JNJ28312141, ARRY-382, AC-708, DCC-3014, 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580), AZD6495, Ki20227, BLZ945 or a pharmaceutical salt or prodrug thereof; emactuzumab, IMC-CS4, FPA008, LY-3022855, AMG-820, and TG-3003, or an antigen-binding fragment thereof; or any combination of the foregoing.

[0171] In some embodiments of any of the provided methods, the inhibitor is PLX-3397. In particular embodiments of any of the provided methods, the recombinant receptor specifically binds to an antigen associated with the disease or condition, or to an antigen expressed in cells in the environment of a lesion associated with the disease or condition. In particular embodiments of any of the provided methods, the disease or condition is cancer. In some embodiments of any of the provided methods, the disease or condition is myeloma, leukemia, or lymphoma. In particular embodiments of any of the provided methods, the disease or condition is a B-cell malignancy and / or is acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin's lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL).

[0172] In certain embodiments of any of the provided methods, the antigen is selected from the group consisting of ROR1, B-cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), tEGFR, Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, anti-folate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, EGFR vIII, folate-binding protein (FBP), FCRL5, FCRH5, fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, kinase insert domain receptor (kdr), kappa light chain, Lewis Y, L1 cell adhesion molecule (L1-CAM), melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, melanoma preferentially expressed antigen (PRAME), survivin, TAG72, B7-H6, IL-13 receptor alpha 2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, bispecific antigen, cancer-testis antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, oncofetal antigen, ROR 1, TAG72, VEGF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms' tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, G protein-coupled receptor 5D (GPCR5D), or pathogen-specific antigens.

[0173] In some embodiments of any of the provided methods, the recombinant receptor is a T cell receptor or a functional non-T cell receptor. In particular embodiments of any of the provided methods, the recombinant receptor is a chimeric antigen receptor (CAR). In particular embodiments of any of the provided methods, the CAR comprises an extracellular antigen recognition domain that specifically binds to an antigen and an intracellular signaling domain comprising an ITAM, optionally, the intracellular signaling domain comprises the intracellular domain of the CD3-zeta (CD3ζ) chain; and / or the CAR further comprises a costimulatory signaling region that optionally comprises the signaling domain of CD28 or 4-1BB.

[0174] In some embodiments of any of the provided methods, the modified cells are T cells, optionally CD4 + and / or CD8 + In certain embodiments of any of the provided methods, the T cells are primary T cells obtained from the subject. In certain embodiments of any of the provided methods, the cell therapy comprises 1 x 10 5 Or about 1 x 10 5 ~1×10 8 Or about 1 x 10 8 5 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) 5 Or about 5 x 10 5 ~1×10 7 Or about 1 x 10 7 1 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) or 1 x 10 6 Or about 1 x 10 6 ~1×10 7 Or about 1 x 10 7 This includes administration of whole recombinant receptor-expressing cells, whole T cells, or whole peripheral blood mononuclear cells (PBMCs), each inclusive.

[0175] In some embodiments of any of the provided methods, the cell therapy comprises 1 x 10 8 ≤1 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) 7≤0.5 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) 7 ≤1 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) 6 ≤0.5 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) 6 This involves the administration of up to 100 whole recombinant receptor-expressing cells, whole T cells, or whole peripheral blood mononuclear cells (PBMCs).

[0176] In certain embodiments of any of the provided methods, a dose without risk of developing toxicity or severe toxicity is 5×10 7 Less than or about 5 x 10 7 less than 10 whole recombinant receptor-expressing cells, optionally including CAR + cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), e.g., 2.5 x 10 7 Less than or about 2.5 x 10 7 Less than 1.0 x 10 7 Less than or about 1.0 x 10 7 Less than 5.0 x 10 6 Less than or about 5.0 x 10 6 Less than 1.0 x 10 6 Less than or about 1.0 x 10 6 Less than 5.0 x 10 5 Less than or about 5.0 x 10 5 Less than 1 x 10 5 Less than or about 1 x 10 5 less than 10 whole recombinant receptor-expressing cells, optionally including CAR + The antibody may be or comprise whole T cells, whole T cells, or whole peripheral blood mononuclear cells (PBMCs).

[0177] In certain embodiments of any of the provided methods, a dose that is not associated with a risk of developing toxicity or severe toxicity is 1×10 5 or about 1 x 10 5 ~5×10 7 or about 5 x 10 7 whole recombinant receptor-expressing cells, optionally CAR +cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), e.g., 1 x 10 5 ~2.5×10 7 , 1×10 5 ~1.0×10 7 , 1×10 5 ~5.0×10 6 , 1×10 5 ~1.0×10 6 , 1.0×10 5 ~5.0×10 5 , 5.0×10 5 ~5×10 7 , 5×10 5 ~2.5×10 7 , 5×10 5 ~1.0×10 7 , 5×10 5 ~5.0×10 6 , 5×10 5 ~1.0×10 6 , 1.0×10 6 ~5×10 7 , 1×10 6 ~2.5×10 7 , 1×10 6 ~1.0×10 7 , 1×10 6 ~5.0×10 6 , 5.0×10 6 ~5×10 7 , 5×10 6 ~2.5×10 7 , 5×10 6 ~1.0×10 7 , 1.0×10 7 ~5×10 7 , 1×10 7 ~2.5×10 7 , or 2.5 × 10 7 ~5×10 7 whole recombinant receptor-expressing cells (optionally, CAR + In some embodiments of any of the provided methods, the modified cells are or comprise autologous cells for the subject. In certain embodiments of any of the provided methods, the modified cells are allogeneic to the subject. In certain embodiments of any of the provided methods, the reagent is detectably labeled, and optionally fluorescently labeled.

[0178] In some embodiments, the instructions provide, for each of the one or more analytes individually, information regarding a threshold level that indicates whether the subject is likely to respond to treatment with the cell therapy. In some embodiments, the instructions provide, for each of the one or more analytes individually, information regarding a threshold level that indicates whether the subject is likely to have a sustained response after administration of the cell therapy. In some embodiments, the instructions provide, for each of the one or more analytes individually, information regarding a threshold level that indicates whether the subject is likely to experience toxicity after administration of the cell therapy. [The present invention 1001] A method of treating a subject having or suspected of having a disease or condition, comprising administering a dose of CD4 + T cells and CD8 + administering to said subject CD4 T cells; + T cells and the CD8 + wherein each of the T cells individually comprises a receptor that specifically binds to a target antigen expressed by the disease or condition or a cell or tissue thereof and / or a target antigen associated with the disease or condition, and wherein the administering comprises administering a plurality of separate compositions, the plurality of separate compositions comprising the CD4 + T cells and the CD8 + a first composition comprising one of the CD4 T cells, + T cells and the CD8 + a second composition comprising the other of the T cells. [The present invention 1002] CD4 + Receptors contained in T cells and / or the CD8 + The receptors contained in the T cells contain the same recombinant receptor and / or the CD4 + T cells and / or the CD8 + 1001. The method of claim 1001, wherein the T cells are genetically modified to express the same recombinant receptor. [The present invention 1003] the administration of the first composition and the administration of the second composition are administered on the same day, about 0 to about 12 hours apart, about 0 to about 6 hours apart, or about 0 to 2 hours apart; or The administration of the first composition and the administration of the second composition are started about 1 minute to about 1 hour apart, or about 5 minutes to about 30 minutes apart. The method of the present invention 1001 or the method of the present invention 1002. [The present invention 1004] Any of the methods of 1001 to 1003, wherein the first composition and the second composition are administered at intervals of 2 hours or less, 1 hour or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less. [The present invention 1005] The first composition comprises the CD4 + The method of any one of claims 1001 to 1004, comprising a T cell. [The present invention 1006] The first composition is + The method of any one of claims 1001 to 1004, comprising a T cell. [The present invention 1007] The method of any of claims 1001 to 1006, wherein the administration of said first composition is initiated before the administration of said second composition. [The present invention 1008] The above dose of CD4 + and CD8 + T cells expressing a defined ratio of recombinant receptors + Cells and recombinant receptor-expressing CD8 + cells, and / or defined ratios of CD4 + Cells and CD8 + cells, the ratio being 1:1 or about 1:1, or about 1:3 to about 3:1; and / or the CD4 receptor-containing antibody in one of the first and second compositions. + T cells and CD8 T cells containing the receptor in the other of the first and second compositions. + and T cells are present in a defined ratio, the ratio being 1:1 or about 1:1, or about 1:3 to about 3:1; and / or The CD4 receptor-containing antibody administered in the first and second compositions + T cells and CD8 containing the receptor + T cells are present at a specified ratio, and the ratio is 1:1 or about 1:1, or about 1:3 to about 3:1. Any of the methods 1001 to 1007 of the present invention. [The present invention 1009] 1008. The method of claim 10, wherein said defined ratio is 1:1 or about 1:1. [The present invention 1010] The above dose of CD4 + and CD8 + T cells 5×10 7 Or about 5 x 10 7 ~1×10 8 Or about 1 x 10 8 (inclusive) total recombinant receptor-expressing T cells; 1×10 7 Or about 1 x 10 7 ~2×10 8 Or about 2 x 10 8 (inclusive) total recombinant receptor-expressing T cells; 5×10 7 Or about 5 x 10 7 ~1.5×10 8 Or about 1.5 x 10 8 total recombinant receptor-expressing T cells; 5×10 7 Or about 5 x 10 7 total recombinant receptor-expressing T cells; or 1×10 8 Or about 1 x 10 8 total recombinant receptor-expressing T cells; or 1.5×10 8 Or about 1.5 x 10 8 Total recombinant receptor-expressing T cells Any of the methods 1001 to 1014 of the present invention, comprising: [The present invention 1011] The above dose of CD4 + and CD8 + T cells 5×10 6Or about 5 x 10 6 ~1×10 8 Or about 1 x 10 8 (inclusive) recombinant receptor-expressing CD8 + T cells; 1×10 7 Or about 1 x 10 7 ~0.75×10 8 Or about 0.75 x 10 8 (inclusive) recombinant receptor-expressing CD8 + T cells; 2.5×10 7 Or about 2.5 x 10 7 Recombinant receptor-expressing CD8 + T cells; 5×10 7 Or about 5 x 10 7 Recombinant receptor-expressing CD8 + T cells; or 0.75×10 8 Or about 0.75 x 10 8 Recombinant receptor-expressing CD8 + T cells Any of the methods 1001 to 1010 of the present invention, comprising: [The present invention 1012] 1012. The method of any of claims 1001 to 1011, wherein said recombinant receptor specifically binds to an antigen associated with said disease or pathology, or to an antigen expressed in cells in the environment of a lesion associated with said disease or pathology. [The present invention 1013] The method of any one of claims 1001 to 1012, wherein the disease or condition is cancer. [The present invention 1014] The method of any one of claims 1001 to 1013, wherein said disease or condition is myeloma, leukemia, or lymphoma. [The present invention 1015] The method of any one of claims 1001 to 1014, wherein the antigen is CD19. [The present invention 1016] Any of the methods of claims 1001 to 1015, wherein the disease or condition is a B-cell malignancy and / or is acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin's lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL). [The present invention 1017] 1017. The method of any one of claims 1001 to 1016, wherein said recombinant receptor is a chimeric antigen receptor (CAR). [The present invention 1018] The method of claim 1017, wherein the CAR comprises an extracellular antigen recognition domain that specifically binds to the antigen, an intracellular signaling domain comprising the CD3-zeta (CD3ζ) chain, and a costimulatory signaling region that is the signaling domain of CD28 or 4-1BB. [The present invention 1019] The method of any of claims 1001 to 1018, wherein said T cells are primary T cells obtained from the subject. [The present invention 1020] The method of any of claims 1001 to 1019, wherein said T cells are autologous cells of said subject. [The present invention 1021] (1) Multiple CD4 receptors expressing recombinant receptors + a vial containing a composition comprising T cells; and (2) the plurality of CD4 + A unit dose of the composition containing all or a portion of the T cells and a recombinant CD8 receptor-expressing T cell that is not contained in the vial. + and instructions for administering the composition to a subject having a disease or condition. 1. An article of manufacture comprising: [The present invention 1022] (1) Multiple CD8 receptors expressing recombinant receptors + a vial containing a composition comprising T cells; and (2) the plurality of CD8 + The composition contains a unit dose of the composition containing all or a portion of the T cells and a recombinant receptor-expressing CD4 +and instructions for administering the composition to a subject having a disease or condition. 1. An article of manufacture comprising: [The present invention 1023] CD4 + Recombinant receptors expressed by CD8 cells + whether the recombinant receptors expressed by the T cells are the same; The CD4 + Recombinant receptors expressed by cells and the CD8 + The recombinant receptors expressed by the T cells are different; or The CD4 + Recombinant receptors expressed by cells and the CD8 + the recombinant receptors expressed by the T cells bind to the same antigen, which antigen is expressed by or associated with the disease or condition or a cell or tissue thereof; An article of manufacture of the present invention 1021 or the present invention 1022. [The present invention 1024] The vial is 10 x 10 6 Or about 10 x 10 6 >15 x 10 T cells or recombinant receptor-expressing T cells 6 Or about 15 x 10 6 >25 x 10 T cells or recombinant receptor-expressing T cells 6 Or about 25 x 10 6 1024. The article of manufacture of any of claims 1021 to 1023, comprising more than 10 T cells or recombinant receptor-expressing T cells. [The present invention 1025] The article of manufacture of any of claims 1021 to 1024, wherein the vial contains cells at about 10 million / mL to about 70 million / mL, about 10 million / mL to about 50 million / mL, about 10 million / mL to about 25 million / mL, about 10 million / mL to about 15 million / mL, 15 million / mL to about 70 million / mL, about 15 million / mL to about 50 million / mL, about 15 million / mL to about 25 million / mL, about 25 million / mL to about 70 million / mL, about 25 million / mL to about 50 million / mL, and about 50 million / mL to about 70 million / mL. [The present invention 1026] The article of manufacture of any of claims 1021 to 1025, wherein the composition further comprises a cryoprotectant and / or the article further comprises instructions for thawing the composition prior to administration to the subject. [The present invention 1027] The article of manufacture of any one of claims 1021 to 1026, wherein the recombinant receptor is a chimeric antigen receptor. [The present invention 1028] 1. A method of treating a subject having or suspected of having non-Hodgkin's lymphoma (NHL), comprising administering to the subject a dose of T cells, the T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by the NHL; The dose of T cells was 2.5 x 10 7 or approximately 2.5 x 10 7 pieces~2×10 8 or about 2 x 10 8 (inclusive) CAR-expressing T cells; and The method, wherein the NHL comprises diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), NOS (transformed from de novo or indolent lymphoma), or follicular lymphoma grade 3B, and the subject is identified as having or is identified as having an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. [The present invention 1029] The dose of T cells comprises a defined ratio of CD4 T cells expressing the CAR. + cells and CD8 expressing the CAR + cells, and / or defined ratios of CD4 + Cells and CD8 + 1028. The method of claim 1028, wherein the ratio is about 1:1, or about 1:3 to about 3:1. [The present invention 1030] A method of treating a subject with non-Hodgkin's lymphoma (NHL) comprising administering to the subject a dose of T cells, the T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by the NHL, wherein the dose of T cells binds to a defined ratio of CD4 T cells expressing the CAR. + Cells and CD8 expressing the CAR + cells, and / or defined ratios of CD4 + Cells and CD8 + cells, wherein the ratio is about 1:1 or 1:1, and the NHL comprises diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), NOS (transformed from de novo or indolent lymphoma), or follicular lymphoma grade 3B. [The present invention 1031] The method of claim 1030, wherein said subject is identified as having or is identified as having ECOG status 0 or 1. [The present invention 1032] at least 35%, at least 40%, or at least 50% of subjects treated according to the method achieve a complete response (CR); At least 60%, 70%, 80%, 90%, or 95% of subjects who achieve a CR demonstrate a sustained CR for 3 months or more or 6 months or more; and / or At least 60%, 70%, 80%, 90%, or 95% of subjects who achieve a CR by 1 month and / or by 3 months remain in response, remain in CR, and / or are alive or alive without progression for 3 or more months and / or 6 or more months and / or 9 or more months after achieving CR; and / or at least 50%, at least 60%, or at least 70% of subjects treated according to the method achieve an objective response (OR); At least 60%, 70%, 80%, 90%, or 95% of subjects achieving an OR demonstrate a sustained OR for 3 months or more or 6 months or more; and / or At least 35%, at least 40%, or at least 50% of subjects who achieve OR remain in response or alive for 3 or more months and / or 6 or more months after achieving OR; and / or At least 40%, at least 50%, at least 60%, at least 70% of subjects who had or were identified as having double / triple hit lymphoma or relapse at or before administration of said dose of cells achieved OR or durable OR for 3 months or more or 6 months or more after administration of autologous stem cell transplant (ASCT), Any of the methods of 1028 to 1031 of the present invention. [The present invention 1033] the cells are autologous to the subject, and No minimum absolute lymphocyte count (ALC) for apheresis is required and / or specified for production of the Therapy; and / or the cells are produced by a process capable of generating a cell product for administration by the method for at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of a subject or a selected population of subjects with a disease or condition; Any of the methods of 1028 to 1032 of the present invention. [The present invention 1034] greater than or about 50%, greater than or about 60%, greater than or about 70%, or greater than or about 70%, or greater than or about 80% of subjects treated according to the method do not experience Grade 3 or higher cytokine release syndrome (CRS) and / or do not experience Grade 3 or higher neurotoxicity, and / or greater than 40%, or greater than 50%, or greater than 55% do not experience any neurotoxicity or CRS. Any of methods 1028 to 1033 of the present invention. [This invention 1035] 1. A method of treating a subject having non-Hodgkin's lymphoma (NHL), comprising administering to the subject a dose of T cells, the T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by the NHL; The dose of T cells is 5×10 7 Or about 5 x 10 7 pieces~1×10 8 Or about 1 x 10 8 (inclusive) recombinant receptor-expressing T cells, wherein the dose is a defined ratio of CD4 + Cells and CD8 expressing the recombinant receptor + cells, and / or defined ratios of CD4 + Cells and CD8 + cells, the ratio being about 1:1 or 1:1; and The method (1) results in a complete response (CR) in at least 35%, at least 40%, or at least 50% of treated subjects, and / or results in an objective response (OR) in at least 50%, at least 60%, or at least 70% of treated subjects, and (2) results in no more than 50% of subjects experiencing cytokine release syndrome (CRS) greater than Grade 2 and / or neurotoxicity greater than Grade 2. method. [The present invention 1036] The method of the present invention 1035, wherein at least 40%, at least 50%, at least 60%, at least 70% of subjects who had or were identified as having double / triple hit lymphoma or relapse after autologous stem cell transplant (ASCT) at the time of or prior to administration of said dose of cells achieved OR or sustained OR for 3 months or more or 6 months or more. [This invention 1037] the CR or OR is sustained for more than 3 months or more than 6 months; and / or at least 20%, at least 25%, at least 35%, at least 40%, or at least 50% of subjects treated according to the method achieve a sustained CR for more than 3 months or more than 6 months; and / or at least 60%, 70%, 80%, 90%, or 95% of subjects treated with the method who achieve a CR remain in CR, remain in response, or remain alive for 3 months or more, or 6 months or more, or 9 months or more; and / or at least 60%, 70%, 80%, 90%, or 95% of subjects treated with the method who achieve a CR by 1 month and / or by 3 months remain in response, remain in CR, and / or are alive or alive without progression for 3 or more months and / or 6 or more months and / or 9 or more months; and / or at least 50%, at least 60%, or at least 70% of subjects treated according to the method achieve an objective response (OR); At least 60%, 70%, 80%, 90%, or 95% of the subjects achieve a sustained OR for 3 months or more or 6 months or more; and / or At least 35%, at least 40%, or at least 50% of subjects treated with the method who achieve an OR remain in response or are alive for 3 months or more and / or 6 months or more. The method of the present invention 1035 or the method of the present invention 1036. [The present invention 1038] At the time of or prior to administration of said dose of cells, said subject is identified as having or has been identified as having a lymphoma associated with or involving central nervous system (CNS) involvement; and / or Any of the methods of claims 1028 to 1037, wherein at least 70%, at least 80%, at least 90%, or at least 95% of subjects treated according to said method and exhibiting or identified as exhibiting lymphoma with CNS infiltration at or before administration of said dose of cells achieve regression of said CNS disease. [This invention 1039] 1. A method of treating a subject, comprising administering to a subject having a lymphoma a dose of T cells, the T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by the lymphoma, wherein the subject's lymphoma is associated with or involves central nervous system (CNS) infiltration. [The present invention 1040] The method of claim 1038 or claim 1039, wherein said subject comprises a brain lesion, optionally a temporal lobe brain lesion, at the time of or prior to administration of said dose of cells. [The present invention 1041] The method of claim 1039 or claim 1040, wherein said lymphoma is a B-cell malignancy. [The present invention 1042] The method of any of claims 1039 to 1041, wherein said lymphoma is non-Hodgkin's lymphoma (NHL). [This invention 1043] at least 35%, at least 40%, or at least 50% of subjects treated according to the method achieve a complete response (CR) or remission of the CNS disease; At least 60%, 70%, 80%, 90%, or 95% of subjects who achieve a CR remain in CR for 3 months or more or 6 months or more; and / or At least 60%, 70%, 80%, 90%, or 95% of subjects who achieve a CR or remission of CNS disease by 1 month and / or by 3 months remain in response, remain in CR, and / or are alive or alive without progression for 3 months or more and / or 6 months or more and / or 9 months or more; and / or at least 50%, at least 60%, or at least 70% of subjects treated according to the method achieve an objective response (OR) or remission of the CNS disease; At least 60%, 70%, 80%, 90%, or 95% of subjects achieving OR for ≥3 months or ≥6 months; and / or At least 60%, 70%, 80%, 90%, or 95% of subjects who achieve OR or remission of their CNS disease remain in response or are alive for 3 months or more and / or 6 months or more; and / or a reduction in the size or volume of brain lesions by more than 25% or about 25%, more than 50% or about 50%, more than 75% or about 75%, or more; and / or Reduction or remission or elimination of the CNS disease is achieved in at least 35%, at least 40%, or at least 50% of subjects treated according to the method. Any of methods 1038 to 1042 of the present invention. [This invention 1044] greater than or about 30%, greater than or about 30%, greater than or about 35%, greater than or about 40%, or greater than or about 50% of subjects treated according to the method do not exhibit cytokine release syndrome (CRS) or neurotoxicity of any grade; and / or at least 45 or about 45%, at least 50 or about 50%, at least 60 or about 60%, at least 65 or about 65%, at least 70 or about 70%, at least 75 or about 75%, at least 80 or about 80%, at least 85 or about 85%, at least 90 or about 90%, or at least 95 or about 95% of subjects treated according to the method show no onset of CRS earlier than day 3 after initiation of said administration and / or no onset of neurotoxicity earlier than day 5 after initiation of said administration; and / or the median onset of neurotoxicity in subjects treated according to the method is at or after the median peak of CRS in subjects treated according to the method, or is at or after the median time to resolution of CRS in subjects treated according to the method, and / or the median onset of neurotoxicity in subjects treated according to the method is after 8 or about 8 days, after 9 or about 9 days, after 10 or about 10 days, or after 11 or about 11 days. Any of methods 1028 to 1043 of the present invention. [This invention 1045] Prior to the start of administration of said dose of cells, said subject has not been administered an agent or treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of, or risk of, toxicity following administration of said dose of cells; Any of methods 1028 to 1044 of the present invention. [The present invention 1046] 1045. The method of claim 1045, wherein said agent is or comprises an anti-IL-6 antibody, an anti-IL-6R antibody, or a steroid. [This invention 1047] The method of claim 1045 or claim 1046, wherein said agent is or comprises tocilizumab, siltuximab, or dexamethasone. [This invention 1048] said administration and any follow-up is performed on an outpatient basis and / or without the need for hospital admission or overnight stay in a hospital; and If the subject exhibits persistent fever, or a fever that does not subside or does not subside after treatment with antipyretics or does not subside or does not subside by more than 1°C, the subject is admitted to a hospital or an overnight stay in a hospital and / or is administered an agent or treatment for the treatment or prevention or reduction or attenuation of neurotoxicity and / or cytokine release syndrome or the risk thereof. Any of methods 1028 to 1047 of the present invention. [This invention 1049] Any of the methods of claims 1028 to 1038 and 1042 to 1048, wherein the NHL is selected from the group consisting of aggressive NHL, diffuse large B-cell lymphoma (DLBCL), NOS (de novo and indolent transformed), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B). [The present invention 1050] Any of the methods of claims 1028 to 1038 and 1042 to 1049, wherein the NHL comprises diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), NOS (de novo or transformed from indolent lymphoma), or follicular lymphoma grade 3B. [This invention 1051] Any of the methods of claims 1028 to 1038 and 1042 to 1050, wherein the NHL comprises DLBCL. [This invention 1052] The method of claim 1051, wherein said DLBCL does not include DLBCL transformed from MZL and CLL (Richter's), and / or wherein the subject to whom said dose of cells is administered has DLBCL characterized by transformation from de novo or indolent and / or does not include DLBCL transformed from MZL and CLL. [This invention 1053] Any of the methods of claims 1028 to 1038 and 1042 to 1052, wherein said NHL does not comprise PMBCL and / or the subject administered said dose of cells does not comprise PMBCL. [This invention 1054] Any of the methods of claims 1035 to 1053, wherein the subject is identified as having or is identified as having an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. [This invention 1055] 1054. The method of any of claims 1028 to 1054, wherein the subject is identified as having or is identified as having ECOG status 0 or 1. [This invention 1056] Any of the methods of claims 1028 to 1055, wherein at or immediately prior to the administration of said dose of cells, said subject has relapsed after remission following treatment with one or more prior therapies for NHL, optionally one, two, or three prior therapies other than another dose of cells expressing the CAR, or has become refractory to said prior therapies. [This invention 1057] At or before administration of the dose of cells, the subject is identified as having or has been identified as having double / triple hit lymphoma; and / or the subject is identified as having or has been identified as having chemotherapy-resistant lymphoma, optionally chemotherapy-resistant DLBCL; and / or the subject has not achieved a complete remission (CR) in response to prior therapy; and / or the subject has relapsed within or less than one year after undergoing autologous stem cell transplantation (ASCT); Any of methods 1028 to 1056 of the present invention. [This invention 1058] The method includes, prior to administering the dose of cells, identifying or selecting a subject for administration of the dose of cells, the subject comprising: have double / triple hit lymphoma; chemotherapy-resistant lymphoma, optionally with chemotherapy-resistant DLBCL; have not achieved complete remission (CR) in response to prior therapy to treat a malignant tumor, optionally NHL; and / or Relapsed within or less than one year after autologous stem cell transplantation (ASCT); and / or have lymphoma associated with or involving central nervous system (CNS) involvement, Any of methods 1028 to 1057 of the present invention. [This invention 1059] Additional therapeutic agents or therapies, optionally other than cell therapies, optionally CAR + The method of any one of claims 1028 to 1058, further comprising the step of administering to said subject a therapy other than T cell therapy. [The present invention 1060] the CAR comprises an scFv specific for an antigen, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, which optionally is or comprises 4-1BB, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which optionally is or comprises a CD3 zeta signaling domain, and optionally further comprises a spacer between the transmembrane domain and the scFv; the CAR comprises, in order, an scFv specific for an antigen, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule that optionally is or includes a 4-1BB signaling domain, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule that optionally is a CD3 zeta signaling domain; or the CAR comprises, in order, an scFv specific for an antigen, a spacer, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, which optionally is a 4-1BB signaling domain, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which optionally is or includes a CD3 zeta signaling domain; The spacer (a) comprises or consists of all or a portion of an immunoglobulin hinge, or a modified form thereof, or comprises about 15 amino acids or less and does not comprise the CD28 or CD8 extracellular region; (b) comprises or consists of all or a portion of an immunoglobulin hinge, optionally an IgG4 hinge, or a modified form thereof, and / or comprises about 15 amino acids or less and does not comprise the CD28 or CD8 extracellular region; or (c) is 12 amino acids or about 12 amino acids in length and / or comprises or consists of all or a portion of an immunoglobulin hinge, optionally an IgG4 hinge, or a modified form thereof; or (d) has the sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID (e) a polypeptide spacer comprising or consisting of the formula X1PPX2P, where X1 is glycine, cysteine, or arginine and X2 is cysteine ​​or threonine; and / or the costimulatory domain comprises SEQ ID NO:12, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto; and / or the primary signaling domain comprises SEQ ID NO: 13 or 14 or 15, which has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto; and / or The scFv has a CDRL1 sequence of RASQDISKYLN (SEQ ID NO:35), a CDRL2 sequence of SRLHSGV (SEQ ID NO:36), and / or a CDRL3 sequence of GNTLPYTFG (SEQ ID NO:37), and / or a CDRH1 sequence of DYGVS (SEQ ID NO:38), a CDRH2 sequence of VIWGSETTYYNSALKS (SEQ ID NO:39), and / or a CDRH3 sequence of YAMDYWG (SEQ ID NO:39). or the scFv comprises the heavy chain variable region of FMC63 and the light chain variable region of FMC63, and / or the CDRL1 sequence of FMC63, the CDRL2 sequence of FMC63, the CDRL3 sequence of FMC63, the CDRH1 sequence of FMC63, the CDRH2 sequence of FMC63, and the CDRH3 sequence of FMC63, or binds to the same epitope as any of the foregoing or competes for binding with any of the foregoing, and optionally the scFv comprises, in order, H and optionally a linker comprising SEQ ID NO: 24; and V L and / or the scFv comprises a flexible linker and / or comprises the amino acid sequence shown as SEQ ID NO:24, Any of methods 1028 to 1059 of the present invention. [This invention 1061] The method of any of claims 1028 to 1060, wherein said antigen is a B cell antigen, optionally CD19. [This invention 1062] The method of any of claims 1001 to 1020 and 1028 to 1061, wherein prior to said administration, said subject has been pretreated with lymphocyte depletion therapy comprising administration of fludarabine and / or cyclophosphamide. [This invention 1063] The method of any of inventions 1001 to 1020 and 1028 to 1062, further comprising the step of administering to the subject lymphocyte depletion therapy comprising administration of fludarabine and / or cyclophosphamide immediately before the administration. [This invention 1064] The administration of the cell dose and / or lymphocyte depletion therapy is performed on an outpatient basis; and If the subject exhibits persistent fever, or a fever that does not subside or does not subside after treatment with antipyretics or does not subside or does not subside by more than 1°C, the subject is admitted to a hospital or an overnight stay in a hospital and / or is administered an agent or treatment for the treatment or prevention or reduction or attenuation of neurotoxicity and / or cytokine release syndrome or the risk thereof. The method of the present invention 1063. [This invention 1065] The method of any of claims 1028 to 1064, wherein said dose of cells is administered parenterally, optionally intravenously. [The present invention 1066] The method of any of claims 1028 to 1065, wherein the T cells are primary T cells obtained from the subject. [This invention 1067] The method of any one of claims 1028 to 1066, wherein said T cells are autologous cells of said subject. [The present invention 1068] said dose of T cells comprising a CD4 + T cells and CD8 expressing the CAR + T cells, and said administering + T cells and the CD8 + a first composition comprising one of the CD4 T cells and the + T cells or the CD8 + separately administering a second composition comprising the other of the T cells; Any of methods 1028 to 1067 of the present invention. [The present invention 1069] the first composition and the second composition are administered 0 to 12 hours apart, 0 to 6 hours apart, or 0 to 2 hours apart, or the administration of the first composition and the administration of the second composition are administered on the same day and are administered about 0 to about 12 hours apart, about 0 to about 6 hours apart, or about 0 to about 2 hours apart; and / or The administration of the first composition and the administration of the second composition are started about 1 minute to about 1 hour apart, or about 5 minutes to about 30 minutes apart. The method of the present invention 1068. [The present invention 1070] The method of claim 1067 or claim 1068, wherein the first composition and the second composition are administered less than 2 hours, less than 1 hour, less than 30 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes apart. [This invention 1071] The first composition comprises the CD4 + The method of any one of claims 1067 to 1070, comprising T cells. [This invention 1072] The first composition is + The method of any one of claims 1067 to 1071, comprising a T cell. [This invention 1073] 13. The method of any of claims 1067 to 1072, wherein said first composition is administered before said second composition. [This invention 1074] 1. A method for assessing likelihood of response to cell therapy, comprising: (a) assessing the level, amount, or concentration of one or more analytes in a biological sample, wherein the one or more analytes are selected from ferritin, LDH, CXCL10, G-CSF, and IL-10, wherein: the biological sample is from a subject who is a candidate for treatment with the cell therapy, the cell therapy comprising a dose of genetically modified cells that express a recombinant receptor; and the biological sample is obtained from the subject prior to administration of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and (b) individually comparing the level, amount, or concentration of the analyte in the sample to a threshold level, thereby determining the likelihood that the subject will achieve a response to the cell therapy. A method comprising: [This invention 1075] 1075. The method of claim 1074, further comprising administering said cell therapy to said subject if said subject is likely to achieve a response. [This invention 1076] 1. A method of selecting a subject for treatment, comprising: (a) assessing the level, amount, or concentration of one or more analytes in a biological sample, wherein the one or more analytes are selected from ferritin, LDH, CXCL10, G-CSF, and IL-10, wherein: the biological sample is derived from a subject who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of genetically modified cells that express a recombinant receptor; and the biological sample is obtained from the subject prior to administration of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and (b) selecting subjects likely to respond to treatment based on the results of determining the likelihood of a subject achieving a response to the cell therapy by individually comparing the level, amount, or concentration of the analyte in the sample to a threshold level. A method comprising: [This invention 1077] The method of claim 1076, further comprising administering said cell therapy to a subject selected for treatment. [This invention 1078] (a) selecting a subject likely to respond to treatment with a cell therapy based on determining the likelihood of the subject achieving a response to the cell therapy by individually comparing the level, amount, or concentration of one or more analytes in the biological sample to a threshold level, wherein the one or more analytes are selected from ferritin, LDH, CXCL10, G-CSF, and IL-10; the biological sample is from a subject who is a candidate for treatment with the cell therapy, the cell therapy comprising a dose of genetically modified cells that express a recombinant receptor; and the biological sample is obtained from the subject prior to administration of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and (b) administering the cell therapy to a subject selected for treatment. A method of treatment comprising: [This invention 1079] Any of the methods of claims 1074 to 1078, wherein the subject is more likely to achieve a response if the level, amount, or concentration of one or more of said analytes is below a threshold level, and the subject is less likely to achieve a response if the level, amount, or concentration of one or more of said analytes is above a threshold level. [The present invention 1080] Any of the methods of inventions 1074 to 1079, wherein the threshold level is within 25%, 20%, 15%, 10%, or 5% below the median or mean value of the level, amount, or concentration of the analyte in biological samples obtained from a group of subjects prior to receiving cell therapy, and / or is within a standard deviation below the median or mean value, or is the median or mean value, or is about the median or about the mean value, wherein each subject in the group is a subject who has achieved a response following administration of a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition. [This invention 1081] Any of the methods of claims 1074 to 1079, wherein the threshold level is within 25%, 20%, 15%, 10%, or 5% above the median or mean value of the level, amount, or concentration of the analyte in a biological sample obtained from a group of subjects prior to receiving cell therapy, and / or is within a standard deviation above the median or mean value, wherein each subject in the group is a subject that has demonstrated stable disease (SD) and / or progressive disease (PD) following administration of a recombinant receptor-expressing therapeutic cell composition for treating the same disease or condition. [This invention 1082] 1082. Any of the methods of claims 1074 to 1081, wherein the response comprises an objective response. [This invention 1083] The method of claim 1082, wherein said objective response comprises a complete response (CR) or a partial response (PR). [This invention 1084] 1. A method for assessing likelihood of a durable response to a cell therapy, comprising: (a) assessing the level, amount, or concentration of one or more analytes in a biological sample, wherein the one or more analytes are selected from LDH, ferritin, CRP, D-dimer, SAA-1, IL-6, IL-10, IL-15, IL-16, TNF-α, IFN-γ, MIP-1α, CXCL-10, IL-8, MCP-1, and MIP-1β, the biological sample is derived from a subject who is a candidate for treatment with the cell therapy, the cell therapy comprising a dose of genetically modified cells that express a recombinant receptor; and the biological sample is obtained from the subject prior to administration of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and (b) individually comparing the level, amount, or concentration of the analyte in the sample to a threshold level, thereby determining the likelihood that the subject will achieve a sustained response to the cell therapy. A method comprising: [This invention 1085] The method of claim 1084, further comprising administering said cell therapy to said subject if said subject is likely to achieve a response. [The present invention 1086] 1. A method of selecting a subject for treatment, comprising: (a) assessing the level, amount, or concentration of one or more analytes in a biological sample, wherein the one or more analytes are selected from LDH, ferritin, CRP, D-dimer, SAA-1, IL-6, IL-10, IL-15, IL-16, TNF-α, IFN-γ, MIP-1α, CXCL-10, IL-8, MCP-1, and MIP-1β, the biological sample is derived from a subject who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of genetically modified cells that express a recombinant receptor; and the biological sample is obtained from the subject prior to administration of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and (b) selecting subjects likely to respond to treatment based on the results of determining the likelihood that a subject will achieve a sustained response to the cell therapy by individually comparing the level, amount, or concentration of the analyte in the sample to a threshold level. A method comprising: [This invention 1087] The method of claim 1086, further comprising administering said cell therapy to a subject selected for treatment. [This invention 1088] (a) selecting subjects who are likely to benefit from treatment with a cell therapy based on the results of determining the likelihood of the subject achieving a sustained response to the cell therapy by individually comparing the level, amount, or concentration of one or more analytes in the biological sample to a threshold level, wherein the one or more analytes are selected from LDH, ferritin, CRP, D-dimer, SAA-1, IL-6, IL-10, IL-15, IL-16, TNF-α, IFN-γ, MIP-1α, CXCL-10, IL-8, MCP-1, and MIP-1β, wherein: the biological sample is from a subject who is a candidate for treatment with the cell therapy, the cell therapy comprising a dose of genetically modified cells that express a recombinant receptor; and the biological sample is obtained from the subject prior to administration of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and (b) administering the cell therapy to a subject selected for treatment. A method of treatment comprising: [This invention 1089] Any of the methods of claims 1085 to 1088, wherein the subject is more likely to achieve a sustained response if the level, amount, or concentration of the one or more analytes is below a threshold level, and wherein the subject is less likely to achieve a sustained response if the level, amount, or concentration of the one or more analytes is above a threshold level. [The present invention 1090] Any of the methods of inventions 1085 to 1088, wherein the threshold level is within 25%, 20%, 15%, 10%, or 5% below the median or mean value of the level, amount, or concentration of the analyte in a biological sample obtained from a group of subjects prior to receiving cell therapy, and / or is within a standard deviation below the median or mean value, or is the median or mean value, or is at or about the median or mean value, and wherein each subject in the group is a subject who has achieved a sustained response following administration of a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition. [This invention 1091] Any of the methods of inventions 1085 to 1088, wherein the threshold level is within 25%, 20%, 15%, 11%, or 5% above the median or mean value of the level, amount, or concentration of the analyte in a biological sample obtained from a group of subjects prior to receiving cell therapy, and / or within a standard deviation above the median or mean value, wherein each subject in the group is a subject who has not achieved a sustained response following administration of a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition. [This invention 1092] 1092. The method of any of claims 1085 to 1091, wherein said sustained response comprises a complete response (CR) or partial response (PR) sustained for 3 months or more, 4 months or more, 5 months or more, or 6 months or more. [This invention 1093] 13. The method of any of claims 1085 to 1092, wherein said sustained response comprises a CR or PR that is sustained for at least 3 months. [This invention 1094] 1. A method for assessing the risk of developing toxicity after administration of a cell therapy, comprising: (a) assessing the level, amount, or concentration of one or more analytes in a biological sample from the subject, or a volumetric measure of tumor burden in the subject, wherein the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (a fibrin degradation product), IL-6, IL-8, IL-10, IL-15, IL-16, TNF-α, IFN-α2, MCP-1, MIP-1α, and MIP-1β, wherein: the subject is a candidate for treatment with the cell therapy, which optionally comprises a dose or composition of genetically modified cells that express a recombinant receptor; and the biological sample is obtained from the subject prior to administration of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and (b) individually comparing the level, amount, or concentration of the analyte in the sample, or the volumetric measurement of the tumor burden, to a threshold level, thereby determining the risk of developing toxicity following administration of the cell therapy. A method comprising: [This invention 1095] A method for identifying a target, comprising: (a) assessing the level, amount, or concentration of one or more analytes in a biological sample from the subject, or a volumetric measure of tumor burden in the subject, wherein the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (a fibrin degradation product), IL-6, IL-8, IL-10, IL-15, IL-16, TNF-α, IFN-α2, MCP-1, MIP-1α, and MIP-1β, wherein: the subject is a candidate for treatment with the cell therapy, which optionally comprises a dose or composition of genetically modified cells that express a recombinant receptor; and the biological sample is obtained from the subject prior to administration of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and (b) identifying subjects at risk of developing toxicity following administration of the cell therapy by individually comparing the level, amount, or concentration of the analyte in the sample, or the volumetric measurement of the tumor burden, to a threshold level. A method comprising: [This invention 1096] (a) assessing the level, amount, or concentration of one or more analytes in a biological sample of a subject, or a volumetric measure of tumor burden in said subject, wherein said one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (a fibrin degradation product), IL-6, IL-8, IL-10, IL-15, IL-16, TNF-α, IFN-α2, MCP-1, MIP-1α, and MIP-1β, wherein: the subject is a candidate for treatment with a cell therapy, which optionally includes a dose or composition of genetically modified cells that express a recombinant receptor; and the biological sample is obtained from the subject prior to administration of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and (b) individually comparing the level, amount, or concentration of the analyte in the sample, or the volumetric measurement of the tumor burden, to a threshold level, thereby determining the risk of developing toxicity following administration of the cell therapy; and (c) administering the cell therapy to the subject according to or based on the results of the assessment, optionally administering an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the occurrence of, or the risk of, toxicity. A method of treatment comprising: [This invention 1097] 1097. The method of any one of claims 1094 to 1096, wherein said biological sample is a blood sample or a plasma sample. [This invention 1098] 8. The method of any of claims 1094 to 1097, wherein the volumetric measure of tumor burden is a sum of two-way products (SPD) or a volumetric measure based on CT and / or MRI imaging of the body or other imaging modality. [This invention 1099] 1098. The method of claim 1098, wherein said volumetric measurement of tumor burden is performed prior to treatment, prior to apheresis, or prior to cell product manufacturing. [The present invention 1100] Any of the methods of claims 1094 to 1099, further comprising the step of monitoring the subject for symptoms of toxicity if the subject is administered the cell therapy and is identified as being at risk of developing toxicity. [The present invention 1101] Any of the methods of claims 1094 to 1100, wherein if the level, amount, or concentration of said one or more analytes or the volume measurement of tumor burden is above a threshold level, said subject is at risk of developing toxicity, and if the level, amount, or concentration of said one or more analytes or the volume measurement of tumor burden is below a threshold level, said subject is at low risk of developing toxicity. [The present invention 1102] Any of the methods of inventions 1094 to 1101, wherein the threshold level is within 25%, 20%, 15%, 10%, or 5% above the median or mean value of the level, amount, or concentration of an analyte in biological samples, or volumetric measurement of tumor burden in said biological samples, obtained from a group of subjects prior to receiving cell therapy, and / or is within a standard deviation above said median or mean value, or is said median or mean value, or is about said median or about said mean value, wherein each subject in the group is a subject that has not experienced any toxicity after receiving a recombinant receptor-expressing therapeutic cell composition for treating the same disease or condition. [The present invention 1103] Any of the methods of inventions 1094 to 1102, wherein the threshold level is within 25%, 20%, 15%, 10%, or 5% below the median or mean value of the level, amount, or concentration of an analyte in biological samples, or a volume measurement of tumor burden in said biological samples, obtained from a group of subjects prior to receiving cell therapy, and / or is within a standard deviation below said median or mean value, wherein each subject in the group is a subject who developed toxicity after receiving a recombinant receptor-expressing therapeutic cell composition for treating the same disease or condition. [The present invention 1104] The method of any one of claims 1094 to 1103, wherein the toxicity is neurotoxicity or CRS. [This invention 1105] The method of any of claims 1094 to 1104, wherein the toxicity is grade 1 or higher neurotoxicity or CRS. [The present invention 1106] the toxicity is severe neurotoxicity, or is Grade 2 or greater neurotoxicity, Grade 3 or greater neurotoxicity, prolonged neurotoxicity of at least Grade 3, or Grade 4 or greater or Grade 5 or greater neurotoxicity; or the toxicity is severe CRS or includes Grade 2 or higher or Grade 3 or higher CRS; Any of the methods of 1094 to 1105 of the present invention. [This invention 1107] Any of the methods of claims 1094 to 1106, wherein said toxicity is neurotoxicity, said volumetric measurement of tumor burden is SPD, and said one or more analytes are selected from LDH, IL-10, IL-15, IL-16, TNF-α, and MIP-1β. [This invention 1108] 1106. The method of any of claims 1094 to 1106, wherein said toxicity is neurotoxicity, one or more analytes are assessed, and said analytes are selected from LDH, ferritin, CRP, IL-6, IL-8, IL-10, TNF-α, IFN-α2, MCP-1, and MIP-1β. [This invention 1109] 1106. The method of any of claims 1094 to 1106, wherein said toxicity is neurotoxicity, and one or more analytes are assessed, and said analytes are selected from IL-8, IL-10, and CXCL10. [The present invention 1110] 1109. The method of claim 1109, wherein said neurotoxicity is severe neurotoxicity or grade 3 or higher neurotoxicity. [The present invention 1111] 1094-1106. Any of the methods of claims 1094-1106, wherein said toxicity is CRS and said one or more analytes or volume measurements of tumor burden are selected from LDH, SPD, CRP, d-dimer, IL-6, IL-15, TNF-α and MIP-1α. [The present invention 1112] The method of claim 1111, wherein the CRS is severe CRS or CRS of grade 3 or higher. [The present invention 1113] If a subject is identified as being at risk for developing toxicity, (a) (1) administering to the subject an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of, or the risk of, toxicity, and (2) said cell therapy, wherein the administration of the agent occurs (i) prior to initiation of administration of the cell therapy to the subject, (ii) within 1, 2, or 3 days of initiation of administration of the cell therapy to the subject, (iii) concurrently with initiation of administration of the cell therapy to the subject, and / or (iv) at the time of the first fever after initiation of administration of the cell therapy to the subject; and / or (b) administering the cell therapy to the subject at a low dose or doses that are not associated with a risk of developing toxicity or severe toxicity following administration of the cell therapy, or that are not associated with a risk of developing toxicity or severe toxicity in a majority of subjects and / or in a majority of subjects with a disease or condition that the subject has or is suspected of having; and / or (c) administering the cell therapy to the subject in an inpatient setting and / or with one or more days of hospitalization, and optionally, otherwise administering the cell therapy to the subject on an outpatient basis or without one or more days of hospitalization; Any of methods 1094 to 1112 of the present invention. [This invention 1114] 1113. The method of claim 1113, wherein said agent or other treatment is an anti-IL-6 antibody or an anti-IL6 receptor antibody. [This invention 1115] The method of claim 1114, wherein said agent or other treatment is or comprises an agent selected from among tocilizumab, siltuximab, clazakizumab, sarilumab, olokizumab (CDP6038), elsilimomab, ALD518 / BMS-945429, sirukumab (CNTO 136), CPSI-2634, ARGX-109, FE301, and FM101. [The present invention 1116] 1113. The method of claim 1113, wherein said agent or other treatment is or comprises a steroid, optionally dexamethasone. [This invention 1117] A volume measurement is evaluated, the volume measurement is an SPD, and the threshold level is 30 cm 2 Or about 30 cm 2 , 40 cm 2 Or about 40 cm 2 , 50 cm 2 Or about 50 cm 2 , 60 cm 2 Or about 60 cm 2 , or 70 cm 2 Or about 70 cm 2 Any of the methods of the present inventions 1094 to 1107 and 1113 to 1116, [This invention 1118] The volume measurement is an SPD and the threshold level is 50 cm 2 or about 50 cm 2 The method of the present invention 1117. [This invention 1119] 17. The method of any of claims 1094 to 1116, wherein said one or more analytes is or comprises LDH and said threshold level is at or about 300 units / liter, 400 units / liter or about 400 units / liter, 500 units / liter or about 500 units / liter, or 600 units / liter or about 600 units / liter. [The present invention 1120] 1119. The method of any of claims 1119, wherein said analyte is LDH and said threshold level is at or about 500 units / liter. [This invention 1121] 1120. The method of any of claims 1074 to 1120, wherein said recombinant receptor specifically binds to an antigen associated with a disease or pathological condition, or an antigen expressed in cells in the environment of a lesion associated with said disease or pathological condition. [This invention 1122] The method of any one of claims 1074 to 1121, wherein the disease or condition is cancer. [This invention 1123] The method of any one of claims 1074 to 1122, wherein said disease or condition is myeloma, leukemia, or lymphoma. [This invention 1124] The method of any of claims 1074 to 1123, wherein the disease or condition is a B-cell malignancy and / or is acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin's lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL). [Invention 1125] The method of any of claims 1074 to 1124, wherein said recombinant receptor is a chimeric antigen receptor (CAR). [The present invention 1126] The modified cells are T cells, optionally CD4 + and / or CD8 + Any of the methods of claims 1074 to 1125, comprising: [This invention 1127] 1127. The method of claim 1126, wherein said T cells are primary T cells obtained from the subject or are autologous cells of said subject. [This invention 1128] An article of manufacture comprising one or more doses of a cell therapy and instructions for administering the cell therapy, wherein each dose comprises cells expressing a chimeric antigen receptor (CAR); the instructions state that the dose of cells is to be administered to a subject who has or has been identified as having non-Hodgkin's lymphoma (NHL), the NHL being selected from diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), NOS (de novo or transformed from indolent lymphoma), or follicular lymphoma grade 3B, and the subject is identified as having or has been identified as having Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Specify; and The instructions specify the number of T cells to be administered or specify the administration of an amount or volume of one or more formulations corresponding to or containing the specified number of cells, wherein the specified number of cells is greater than or equal to 5×10 7 Or about 5 x 10 7 pieces~1×10 8 Or about 1 x 10 8 (inclusive) CAR-expressing T cells, 5 x 10 7 Or about 5 x 10 7 pieces~1.5×10 8 Or about 1.5 x 10 8 (inclusive) CAR-expressing T cells, 5 x 10 7 Or about 5 x 10 7 CAR-expressing T cells, 1 x 10 8 Or about 1 x 10 8 CAR-expressing T cells, or 1.5 x 10 8 Or about 1.5 x 10 8 2.5 x 10 CAR-expressing T cells, inclusive 7 Or about 2.5 x 10 7 pieces~5×10 7 Or about 5 x 107 (inclusive) CD8 + CAR-expressing T cells, 2.5 × 10 7 Or about 2.5 x 10 7 pieces~0.75×10 8 Or about 0.75 x 10 8 (inclusive) CD8 + CAR-expressing T cells, or 2.5 × 10 7 Or about 2.5 x 10 7 CD8 + CAR-expressing T cells, 5 × 10 7 Or about 5 x 10 7 CAR-expressing T cells, or 0.75 x 10 8 Or about 0.75 x 10 8 CD8 + comprising CAR-expressing T cells, or specifying the administration of a viable population of any of the foregoing; Manufactured articles. [This invention 1129] The instructions include instructions for administering to a subject a CD4 + Cell: CD8 + 1128. The article of manufacture of claim 1128, wherein said cell therapy is administered at a defined ratio of cells. [The present invention 1130] 1. An article of manufacture comprising a cell therapy, or one of a plurality of compositions of a cell therapy, comprising a dose or composition of genetically modified cells that express a chimeric antigen receptor (CAR), and instructions for administering the cell therapy, the instructions comprising: The dose of T cells comprises a CD4 + Cells: CD8 expressing the CAR + Defined ratio of cells and / or CD4 + Cell: CD8 + the cells should be administered at a defined ratio, which is about 1:1 or 1:1; and The dose of cells is to be administered to a subject who has or has been identified as having non-Hodgkin's lymphoma (NHL), the NHL being selected from diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), NOS (transformed from de novo or indolent lymphoma), or follicular lymphoma grade 3B. Specifying an article of manufacture. [This invention 1131] 1. An article of manufacture comprising a cell therapy, or one of a plurality of compositions of a cell therapy, comprising a dose or composition of genetically modified cells that express a chimeric antigen receptor (CAR), and instructions for administering the cell therapy, the instructions comprising: said dose of cells is to be administered to a subject who has or has been identified as having non-Hodgkin's lymphoma (NHL), optionally wherein the NHL is selected from aggressive NHL, diffuse large B-cell lymphoma (DLBCL), NOS (de novo and indolent transformed), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B); The dose of T cells administered is 5 x 10 7 Or about 5 x 10 7 pieces~1×10 8 Or about 1 x 10 8 (inclusive) CAR-expressing T cells; and The dose of T cells comprises a CD4 + Cells: CD8 expressing the CAR + Defined ratio of cells and / or CD4 + Cell: CD8 + The cells should be administered at a defined ratio, which is about 1:1 or 1:1. Specifying an article of manufacture. [This invention 1132] The article of manufacture of invention 1130 or invention 1131, wherein the instructions further specify that the cell therapy should be administered to subjects identified as having or identified as having Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2, and / or subjects identified as having or identified as having ECOG status of 0 or 1. [This invention 1133] The article of manufacture of any of claims 1128 to 1132, wherein the instructions specify that administration of the cell dose may be performed on an outpatient basis and / or without the need for hospital admission or overnight stay in a hospital. [This invention 1134] The article of manufacture of invention 1133, wherein said instructions further specify that if, after administering said cell dose on an outpatient basis without the need for hospital admission or overnight hospital stay, said subject develops a persistent fever or a fever that does not subside or does not subside after treatment with antipyretics or that does not subside or does not subside by more than 1° C., said subject should be admitted to hospital or an overnight hospital stay and / or should be administered an agent or treatment for the treatment or prevention or reduction or attenuation of neurotoxicity and / or cytokine release syndrome or the risk thereof. [This invention 1135] 1133 or 1134, an article of manufacture of claim 1134, wherein said agent is or comprises an anti-IL-6 or anti-IL-6R antibody, optionally tocilizumab or siltuximab, and / or a steroid, optionally dexamethasone. [This invention 1136] Any of the articles of manufacture of claims 1128 to 1135, wherein the article of manufacture further comprises instructions for use with, after, or in association with lymphocyte depletion therapy, the lymphocyte depletion therapy optionally comprising fludarabine and / or cyclophosphamide. [This invention 1137] The article of manufacture comprises CD4 +T cells or CD8 + and one of a plurality of compositions of cell therapy comprising a first composition of genetically modified cells comprising T cells, wherein the first composition is a CD4 + T cells or the CD8 + Any of the articles of manufacture of claims 1128 to 1136, which are specified for use in conjunction with a second composition comprising another of the T cells, and optionally the cells of the first composition and the cells of the second composition are derived from the same subject. [This invention 1138] The instructions further comprise: the first composition and the second composition comprising a recombinant CD4 receptor-expressing + Cell: CD8 expressing the recombinant receptor + Defined ratio of cells and / or CD4 + Cell: CD8 + 1137. The article of manufacture of claim 1137, which specifies that the cells are to be administered at a specified ratio, said ratio being about 1:1, or about 1:3 to about 3:1. [This invention 1139] An article of manufacture comprising one or more reagents capable of detecting one or more analytes and instructions for using the reagents to assay a biological sample derived from a subject who is a candidate for treatment with a cell therapy, wherein the cell therapy comprises a dose or composition of genetically modified cells expressing a recombinant receptor, and the one or more analytes are selected from ferritin, LDH, CXCL10, G-CSF, and IL-10. [This invention 1140] A cell therapy comprising a dose of genetically modified cells expressing a recombinant receptor; and 10. Instructions for administering the cell therapy according to or based on the results of an assessment in a biological sample of the level or amount or concentration of one or more analytes in the biological sample, wherein the biological sample was obtained from the subject prior to administering the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells, and wherein the one or more analytes are selected from ferritin, LDH, CXCL10, G-CSF, and IL-10. 1. An article of manufacture comprising: [This invention 1141] The article of manufacture of claim 1139 or claim 1140, wherein the instructions provide information regarding a threshold level for each of the one or more analytes individually that indicates whether the subject is likely to respond to treatment with a cell therapy. [This invention 1142] 1. An article of manufacture comprising one or more reagents capable of detecting one or more analytes and instructions for using the reagents to assay a biological sample from a subject who is a candidate for treatment with a cell therapy, wherein the cell therapy comprises a dose or composition of genetically modified cells expressing a recombinant receptor, and the one or more analytes are selected from LDH, ferritin, CRP, D-dimer, SAA-1, IL-6, IL-10, IL-15, IL-16, TNF-α, IFN-γ, MIP-1α, CXCL-10, IL-8, MCP-1, and MIP-1β. [This invention 1143] A cell therapy comprising a dose of genetically modified cells expressing a recombinant receptor; and 10. Instructions for administering a cell therapy according to or based on the results of an assessment in a biological sample of the level or amount or concentration of one or more analytes in the biological sample, wherein the biological sample was obtained from the subject prior to administering the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cell, and the one or more analytes are selected from LDH, ferritin, CRP, D-dimer, SAA-1, IL-6, IL-10, IL-15, IL-16, TNF-α, IFN-γ, MIP-1α, CXCL-10, IL-8, MCP-1, and MIP-1β. 1. An article of manufacture comprising: [This invention 1144] The article of manufacture of claim 1142 or claim 1143, wherein the instructions provide information regarding a threshold level for each of the one or more analytes individually, which indicates whether the subject is likely to show a sustained response after administration of the cell therapy. [Invention 1145] 1. An article of manufacture comprising one or more reagents capable of detecting one or more analytes and instructions for using the reagents to assay a biological sample from a subject who is a candidate for treatment with a cell therapy, wherein the cell therapy comprises a dose or composition of genetically modified cells expressing a recombinant receptor, and the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (a fibrin degradation product), IL-6, IL-8, IL-10, IL-15, IL-16, TNF-α, IFN-α2, MCP-1, MIP-1α, and MIP-1β. [Invention 1146] A cell therapy comprising a dose of genetically modified cells expressing a recombinant receptor; and 10. Instructions for administering a cell therapy according to or based on the results of an assessment in a biological sample of the level or amount or concentration of one or more analytes in the biological sample, wherein the biological sample was obtained from the subject prior to administering the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells, and the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (a fibrin degradation product), IL-6, IL-8, IL-10, IL-15, IL-16, TNF-α, IFN-α2, MCP-1, MIP-1α, and MIP-1β. 1. An article of manufacture comprising: [This invention 1147] The article of manufacture of claim 1145 or claim 1146, wherein the instructions provide, for each of the one or more analytes individually, information regarding a threshold level that indicates whether a subject is likely to exhibit toxicity following administration of the cell therapy. [Invention 1148] 8. The article of manufacture of any of claims 1139 to 1147, wherein the recombinant receptor specifically binds to an antigen associated with a disease or pathological condition, or an antigen expressed in cells in the environment of a lesion associated with the disease or pathological condition. [This invention 1149] The article of manufacture according to any one of claims 1139 to 1148, wherein the disease or condition is cancer. [This invention 1150] The article of manufacture of any one of claims 1139 to 1149, wherein the disease or condition is myeloma, leukemia, or lymphoma. [This invention 1151] The article of manufacture of any of claims 1139 to 1150, wherein the disease or condition is a B-cell malignancy and / or is acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin's lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL). [This invention 1152] The antigens include ROR1, B-cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), tEGFR, Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, anti-folate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, EGFR vIII, folate-binding protein (FBP), FCRL5, FCRH5, fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, kinase insert domain receptor (kdr), kappa light chain, Lewis Y, L1 cell adhesion molecule (L1-CAM), melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, melanoma preferentially expressed antigen (PRAME), survivin, TAG72, B7-H6, IL-13 receptor alpha 2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, bispecific antigen, cancer-testis antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, oncofetal antigen, ROR1, TAG72, VEG The article of manufacture of any of claims 1148 to 1151, which is F-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms' tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, G protein-coupled receptor 5D (GPCR5D), or a pathogen-specific antigen. [This invention 1153] The article of manufacture of any one of claims 1138 to 1152, wherein the recombinant receptor is a T cell receptor or a functional non-T cell receptor. [This invention 1154] The article of manufacture of any one of claims 1138 to 1153, wherein the recombinant receptor is a chimeric antigen receptor (CAR). [This invention 1155] the CAR comprises an scFv specific for an antigen, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, optionally being or comprising 4-1BB, and optionally being a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, optionally being or comprising a CD3 zeta signaling domain, and optionally further comprising a spacer between the transmembrane domain and the scFv; the CAR comprises, in order, an scFv specific for an antigen, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule that optionally is or includes a 4-1BB signaling domain, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule that optionally is a CD3 zeta signaling domain; or the CAR comprises, in order, an scFv specific for an antigen, a spacer, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, which optionally is a 4-1BB signaling domain, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which optionally is or includes a CD3 zeta signaling domain; The spacer (a) comprises or consists of all or a portion of an immunoglobulin hinge, or a modified form thereof, or comprises about 15 amino acids or less and does not comprise the CD28 or CD8 extracellular region; (b) comprises or consists of all or a portion of an immunoglobulin hinge, optionally an IgG4 hinge, or a modified form thereof, and / or comprises about 15 amino acids or less and does not comprise the CD28 or CD8 extracellular region; or (c) is 12 amino acids or about 12 amino acids in length and / or comprises or consists of all or a portion of an immunoglobulin hinge, optionally an IgG4 hinge, or a modified form thereof; or (d) has the sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID (e) a polypeptide spacer comprising or consisting of the formula X1PPX2P, where X1 is glycine, cysteine, or arginine and X2 is cysteine ​​or threonine; and / or the costimulatory domain comprises SEQ ID NO:12, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto; and / or the primary signaling domain comprises SEQ ID NO: 13 or 14 or 15, which has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto; and / or The scFv has a CDRL1 sequence of RASQDISKYLN (SEQ ID NO:35), a CDRL2 sequence of SRLHSGV (SEQ ID NO:36), and / or a CDRL3 sequence of GNTLPYTFG (SEQ ID NO:37), and / or a CDRH1 sequence of DYGVS (SEQ ID NO:38), a CDRH2 sequence of VIWGSETTYYNSALKS (SEQ ID NO:39), and / or a CDRH3 sequence of YAMDYWG (SEQ ID NO:39). or the scFv comprises the heavy chain variable region of FMC63 and the light chain variable region of FMC63, and / or the CDRL1 sequence of FMC63, the CDRL2 sequence of FMC63, the CDRL3 sequence of FMC63, the CDRH1 sequence of FMC63, the CDRH2 sequence of FMC63, and the CDRH3 sequence of FMC63, or binds to the same epitope as any of the foregoing or competes for binding with any of the foregoing, and optionally the scFv comprises, in order, H and optionally a linker comprising SEQ ID NO: 24; and V L and / or the scFv comprises a flexible linker and / or comprises the amino acid sequence shown as SEQ ID NO:24, An article of manufacture according to any one of claims 1128 to 1154. [Invention 1156] 1156. The article of manufacture of claim 1156, wherein the antigen is a B cell antigen, optionally CD19. [This invention 1157] The modified cells are T cells, optionally CD4 + and / or CD8 + Any one of the manufactured articles of the present inventions 1128 to 1156, comprising: [This invention 1158] 1157. The article of manufacture of claim 1157, wherein the T cells are primary T cells obtained from a subject. [Brief explanation of the drawings]

[0179] [Figure 1]The percentages of subjects with laboratory abnormalities occurring in ≥20% of subjects and treatment-emergent adverse events (TEAEs) are shown. *: One Grade 5 AE of multi-organ failure due to lymphoma progression unrelated to study treatment; †: One Grade 5 AE of diffuse alveolar damage assessed by the investigator as related to fludarabine, cyclophosphamide, and CAR T-cell therapy, occurring on Day 23 in a subject who was receiving growth factors and broad-spectrum antibiotics and antifungals and was neutropenic but refused mechanical ventilation for progressive respiratory failure.

[0180] [Figure 2] Kaplan-Meier curves showing observed time to onset of CRS and neurotoxicity.

[0181] [Figure 3A] The 3-month objective response rate (ORR) in treated subgroups is shown. [Figure 3B] The 3-month objective response rate (ORR) in treated subgroups is shown.

[0182] [Figure 4A] Duration of response (CR / PR, CR, or PR) and overall survival in the full cohort of subjects will be shown. [Figure 4B] Duration of response (CR / PR, CR, or PR) and overall survival in the core cohort of subjects will be shown.

[0183] [Figure 5A] Pharmacokinetics of CAR+ T cells in peripheral blood at various time points after treatment at different dose levels. [Figure 5B] 1 shows the pharmacokinetics of CAR+ T cells in peripheral blood at different time points after treatment between responders and non-responders. [Figure 5C] 1 shows the pharmacokinetics of CAR+ T cells in peripheral blood at various time points after treatment in subjects who developed any neurotoxicity or did not develop any neurotoxicity.

[0184] [Figure 6A] Figure 1 shows the number of CD3+ / CAR+, CD4+ / CAR+, and CD8+ / CAR+ T cells in the peripheral blood of subjects with chemotherapy-resistant transformed DLBCL measured at specific time points. [Figure 6B] Pre-treatment axial PET-CT images are shown showing intracranial abnormalities in the right middle cranial foss and extensive abnormalities in the subcutaneous tissue in the right postauricular region. [Figure 6C] Post-treatment PET-CT images showing resolution of the abnormality in Figure 2B after treatment with anti-CD19 CAR+ T cells. [Figure 6D] Pre-treatment brain MRI (high-resolution T1-weighted image with enhancement material; axial view) showing a homogeneously growing mass in the right middle cranial fossa. [Figure 6E] Post-treatment MRI image showing near complete regression of the growing mass. [Figure 6F] Axial PET-CT image at the time of recurrence showing a right postauricular tumor recurrence (arrow) associated with strong 18F-flurodeoxyglycose uptake. [Figure 6G] PET-CT imaging showing regression of postauricular tumor after incisional biopsy and re-expansion of CAR+ T cells.

[0185] [Figure 7] 1 shows the correlation between the levels of analytes measured in the serum of subjects prior to administration of CAR+ T cells and the onset of neurotoxicity.

[0186] [Figure 8]Figure 1 shows graphs plotting time to progression (months) and illustrating best overall response and durability of response observed over time and individual clinical outcomes for individual subjects within the full and core cohorts of NHL subjects treated with anti-CD19 cell therapy including CAR-T-expressing CD4+ and CD8+ T cells. a: Patients achieved BOR at 1 month unless otherwise noted; b: Complete resolution of CNS infiltration by lymphoma observed in two patients; c: One patient had re-expansion growth after biopsy at disease progression.

[0187] [Figure 9A] Shown are the median (± quartiles) number of CAR-expressing CD3+ cells / μL blood assessed by flow cytometry using an antibody specific for the truncated receptor (CD3, circles; N=87); or the median (± quartiles) number of integrated CAR transgene copies / μg genomic DNA assessed by quantitative polymerase chain reaction (qPCR) using primers specific for the woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) present in the CAR-encoding vector (qPCR, squares; N=85) in blood samples from 87 subjects receiving anti-CD19 CAR-expressing cells. The cutoff for detection of CAR+ cells by flow cytometry was set at ≥25 events in the CAR+ gate, and the detection limit for qPCR was ≥12.5 copies of CAR transgene / μg genomic DNA.

[0188] [Figure 9B] Shown are the relative numbers of CD4+ and CD8+ CAR-expressing cells / μL in blood and bone marrow samples from 67 subjects receiving anti-CD19 CAR-expressing cells on day 11±3. The lines represent lines of unity, not regression lines.

[0189] [Figure 10]Figures 10A and 10B show the median (±quartiles) area under the curve from day 0 to day 28 (AUC; Figure 10A) and maximum serum concentration (Cmax; CAR+ cells / µL blood; Figure 10B) of CD4+ and CD8+ CAR+ cells in the subgroup of subjects with diffuse large B-cell lymphoma transformed from de novo or indolent lymphoma (DLBCL, NOS; N=27), transformed follicular lymphoma (tFL; N=10), DLBCL transformed from marginal zone lymphoma or chronic lymphocytic leukemia (tMZL / tCLL; N=4), or mantle cell lymphoma (MCL; N-5) who received CAR-expressing T cells at DL1.

[0190] [Figure 11A] Figures 11A and 11B show the median (±quartiles) area under the curve (AUC; Figure 11A) and maximum serum concentration (Cmax; CAR+ cells / μL blood; Figure 11B) of CD3+, CD4+, and CD8+ CAR+ cells from day 0 to day 28 in subjects who received CAR+ cells on DL1 or DL2. [Figure 11B] See legend to Figure 11A.

[0191] [Figure 12A] Figures 12A-12D show the median (±quartiles) number of CAR-expressing CD4+ and CD8+ CAR+ cells / μL blood over time in subjects who developed cytokine release syndrome (any CRS) compared with subjects who did not develop CRS (no CRS) (CD4+: Figure 12A; CD8+: Figure 12B) or in subjects who developed neurotoxicity (any NT) compared with subjects who did not develop NT (no NT) (CD4+: Figure 12C; CD8+: Figure 12D). [Figure 12B] See legend to Figure 12A. [Figure 12C] See legend to Figure 12A. [Figure 12D] See legend to Figure 12A.

[0192] [Figure 13A]Figures 13A and 13B show peak CD3+CAR+ cell counts / μL (CD3+Cmax) in subjects grouped by subjects who had a best overall response (BOR) of CR, PR, or PD or a 3-month (M3) durable response of CR, PR, or PD. [Figure 13B] See legend to Figure 13A.

[0193] [Figure 14A] Pre-lymphocyte depletion blood analyte levels are shown in serum samples from subjects with high CAR+ cell expansion (CD3+Cmax>500) and low CAR+ cell expansion (CD3+Cmax<500).

[0194] [Figure 14B] Peak blood analyte levels are shown in serum samples from subjects who showed high CAR+ cell expansion (CD3+Cmax>500) and low CAR+ cell expansion (CD3+Cmax<500).

[0195] [Figure 15] A plot showing pre-lymphocyte depletion SPD (cm2) versus AUC0-28 (cells*day / μL) of CD3+CAR+ cells for individual subjects receiving CAR+ cells on DL1 or DL2 is shown.

[0196] [Figure 16A] Figures 16A and 16B show pre-lymphocyte depletion blood analyte levels in serum samples from subjects who developed cytokine release syndrome (CRS grades 1-4) compared with subjects who did not develop CRS (CRS grade 0) (Figure 16A) or subjects who developed neurotoxicity (NT grade 0) compared with subjects who did not develop NT (NT grades 1-4) (Figure 16B). Units were ferritin and D-dimer (μg / L); CRP (mg / L) and cytokines (pg / mL). [Figure 16B] See legend to Figure 16A.

[0197] [Figure 17] Pre-lymphocyte depletion patient parameters include assessment of tumor burden as sum of two-way products (SPD; cm2) and lactate dehydrogenase (LDH; U / L) levels in subjects who developed cytokine release syndrome (any CRS) compared with subjects who did not develop CRS (no CRS) or subjects who developed neurotoxicity (any NT) compared with subjects who did not develop NT (no NT).

[0198] [Figure 18A] Plots showing pre-lymphocyte-depleted SPD (cm²) versus pre-lymphocyte-depleted LDH (U / L) levels for individuals with neurotoxicity (grades 1-4 NT) or no NT (grade 0 NT) (left panel) and for individuals with CRS (grades 1-4 CRS) or no CRS (grade 0 CRS) (right panel). Dotted lines represent SPD levels (≥50 cm²) or LDH levels (≥500 U / L) associated with high rates of CRS or NT. [Figure 18B] Estimates of odds ratios for the development of CRS or NT based on SPD levels (≥50 cm2) or LDH levels (≥500 U / L) with 95% confidence intervals (CI) are shown. [Figure 18C] Shown are estimates of odds ratios for the development of CRS or NT based on SPD or LDH levels, including estimates of odds ratios at values ​​below the threshold with 95% confidence intervals (CI).

[0199] [Figure 19] Pre-lymphocyte depletion tumor burden parameters (SPD) and blood analyte levels are shown for subjects with a sustained response at 3 months versus subjects without a response at 3 months. Units were ferritin and D-dimer (μg / L); CRP and SAA-1 (mg / L), and cytokines (pg / mL).

[0200] [Figure 20A]Figures 20A and 20B show peak blood analyte levels in serum samples from subjects who developed cytokine release syndrome (any CRS) compared with subjects who did not develop CRS (no CRS) (Figure 20A) or subjects who developed neurotoxicity (any NT) compared with subjects who did not develop NT (no NT) (Figure 20B). Units are CRP (mg / L), SAA-1 (mg / L), and cytokines (pg / mL). [Figure 20B] See legend to Figure 20A.

[0201] [Figure 21A] Peak blood analyte levels in serum samples from subjects (N=57) who had a best overall response (BOR) of complete response (CR) or partial response (PR) are shown compared to levels in subjects (N=17) who had stable disease (SD) or progressive disease (PD). [Figure 21B] Peak blood analyte levels in serum samples from subjects with a 3-month response of SD / PD (N=31) compared with subjects with a 3-month response of CR / PR (N=35) are shown. Units are CRP (mg / L), SAA-1 (mg / L), and cytokines (pg / mL).

[0202] [Figure 22] The 3-month objective response rate (ORR) in treated subgroups with 95% confidence intervals is shown.

[0203] [Figure 23A] For subjects who achieved CR, PR, all subjects who responded, non-responders, and all treated subjects, Figures 23A and 23B show the duration of response (DOR) for the full cohort (Figure 23A) and core cohort (Figure 23B), and Figures 23C and 23D show the overall survival for the full cohort (Figure 23C) and core cohort (Figure 23D). The median F / U was 6.3 months for duration of response. [Figure 23B] See legend to Figure 23A. [Figure 23C] See legend to Figure 23A. [Figure 23D] See legend to Figure 23A.

[0204] [Figure 24] The percentage of subjects who experienced a treatment-emergent adverse event (TEAE) that occurred in ≥20% of patients in the full DLBCL cohort is shown. Data from five patients with MCL who were treated with the matching product in DL1 and had at least 28 days of follow-up were not included. b: One grade 5 AE was septic shock unrelated to CAR+ T cell administration. c: One grade 5 AE was diffuse alveolar damage that occurred on day 23 in a patient who was receiving fludarabine, cyclophosphamide, and CAR+ T cells and who was neutropenic but refused mechanical ventilation for progressive respiratory failure, and who was receiving growth factors and broad-spectrum antibiotics and antifungals, as assessed by the investigator. d: Abnormal laboratory values.

[0205] [Figure 25] The percentage of subjects who developed CRS or neurotoxicity over time in the full cohort is shown.

[0206] [Figure 26] 1 shows a box plot illustrating the T cell purity of T cell compositions enriched for CD4+ and CD8+ cells at different stages of the method for generating an engineered cell composition comprising CAR T cells described in Example 8. The frequency of CD4+ and CD8+ cells (% of total white blood cells) in the composition is shown.

[0207] [Figure 27-1] Figures 27A-27C show box plots illustrating the concentration (Figure 27A), viability (Figure 27B), and frequency of caspase-3 negativity (Figure 27C) of CD4+ and CD8+ CAR+ T cells in high or low formulation volume therapeutic cell compositions. [Figure 27-2] See description of Figure 27-1.

[0208] [Figure 28A]The number of CD3+ CAR+ T cells present in the CAR T cell composition for administration at DL1 and DL2 is shown. [Figure 28B] The numbers of CD4+CAR+ and CD8+CAR+ cells and CD4+CAR+TNF-α+ cells and CD8+CAR+TNF-α+ cells present in the CAR T cell compositions for administration in DL1 and DL2 are shown.

[0209] [Figure 29] The percentage of subjects who experienced a treatment-emergent adverse event (TEAE) that occurred in ≥20% of subjects in the full DLBCL cohort at the time of study described in Example 6 is shown. Data were not included for 6 subjects with MCL who were treated with the matching product at DL1 and had at least 28 days of follow-up. b: One Grade 5 AE of septic shock unrelated to CAR+ T cell administration that occurred in the setting of disease progression. c: One Grade 5 AE of diffuse alveolar damage assessed by the investigator as related to fludarabine, cyclophosphamide, and CAR+ T cells that occurred on Day 23 in a patient who was receiving growth factors and broad-spectrum antibiotics and antifungals and was neutropenic but refused mechanical ventilation for progressive respiratory failure. d: Abnormal laboratory values.

[0210] [Figure 30] Six-month objective response rates (ORR) in subgroups of treated subjects with 95% confidence intervals are shown. a Includes all DLBCL subjects treated at all dose levels in the core cohort.

[0211] [Figure 31A] For subjects who achieved CR, PR, all subjects who responded, non-responders, and all treated subjects, Figures 31A and 31B show the duration of response (DOR) for the full cohort (Figure 31A) and core cohort (Figure 31B), and Figures 31C and 31D show the overall survival for the full cohort (Figure 31C) and core cohort (Figure 31D). NE: Not estimable. [Figure 31B] See legend to Figure 31A. [Figure 31C]See legend to Figure 31A. [Figure 31D] See legend to Figure 31A. DETAILED DESCRIPTION OF THE INVENTION

[0212] Detailed Description I. Cell Therapy Methods and Uses Using Genetically Modified Cells Methods and uses of modified cells (e.g., T cells) and / or compositions thereof for treating subjects having a disease or condition, generally being or including a cancer or tumor (e.g., leukemia or lymphoma, most particularly non-Hodgkin's lymphoma (NHL)), are provided. In some aspects, the methods and uses result in or provide improved response and / or more durable response or efficacy and / or a lower risk of toxicity or other side effects, e.g., in a particular group of treated subjects, compared to certain alternative methods. In some embodiments, the methods are advantageous by virtue of administering specified or relative numbers of modified cells, administering defined ratios of particular types of cells, treating particular patient populations, e.g., patient populations with particular risk profiles, disease stages and / or treatment histories, and / or combinations thereof. Also provided are methods that include evaluating particular parameters, e.g., expression of specific biomarkers or analytes, that may correlate with the development of toxicity, as well as methods for treatment, e.g., interventional therapy, to prevent and / or ameliorate toxicity. Also provided are methods involving assessing outcomes after the administration of immunotherapy and / or cell therapy, for example, treatment outcomes, for example, response, for example, complete response (CR) or partial response (PR), optionally a durable response, for example, a durable response for at least 3 months, 6 months, or longer; or safety outcomes, for example, toxicity manifestations, for example, neurotoxicity or CRS, which may be correlated with specific parameters, for example, the expression or analytes of specific biomarkers. Also provided are methods for assessing the likelihood of response and / or the likelihood of toxicity risk based on the evaluation of parameters, for example, the expression or analytes of biomarkers. Also provided are compositions for use in cell therapy. Also provided are articles of manufacture and kits, for example, for use in the methods provided herein. In some embodiments, the articles of manufacture and kits optionally include instructions for use according to the methods provided herein.

[0213] In some embodiments, the methods and uses involve administering to a subject cells that express a genetically modified (recombinant) cell surface receptor, typically a chimeric receptor, e.g., a chimeric antigen receptor (CAR), that recognizes an antigen expressed by, associated with, and / or specific for a leukemia or lymphoma and / or the cell type from which it is derived, in an adoptive cell therapy setting. The cells are typically administered in a composition formulated for administration; the methods generally involve administering one or more doses of cells to a subject, which doses may include specific or relative numbers of cells or modified cells and / or two or more subtypes (e.g., CD4 T cells and CD8 T cells) in a defined ratio or composition in the composition.

[0214] In some embodiments, the cells, populations, and compositions are administered to a subject with a particular disease or condition to be treated, for example, by adoptive cell therapy, e.g., adoptive T cell therapy. In some embodiments, the method involves treating a subject with lymphoma or leukemia, e.g., non-Hodgkin's lymphoma (NHL), with a dose of antigen receptor-expressing cells (e.g., CAR-expressing cells).

[0215] In some embodiments, provided methods involve treating the subjects of a specific group or subset, for example, the subjects who are identified as having high-risk disease, for example, high-risk NHL.In some aspects, the method treats the subjects with aggressive and / or poor prognosis form of B-cell non-Hodgkin's lymphoma (NHL), for example, the NHL that is relapsed or refractory (R / R) to standard treatment and has poor prognosis.In some cases, the overall response rate (ORR; also known as objective response rate in some cases) of available treatment, standard treatment, or the reference treatment indicated for this disease and / or patient population is less than 40%, and / or the complete response (CR; also known as complete remission in some cases) is less than 20%. In some embodiments, in chemotherapy-resistant DLBCL, treatment with reference therapy or available treatment or standard of care has an ORR of about 26% and a CR rate of about 8% (Crump et al. Outcomes in refractory aggressive diffuse large B-cell lymphoma (DLBCL): Results from the international SCHOLAR study. ASCO 2016 [Abstract 7516]). In some aspects, the provided methods, compositions, uses, and articles of manufacture result in improved and superior responses to available therapies.

[0216] In some embodiments, the methods, uses, and articles of manufacture involve or are used to treat subjects, involving selecting or identifying a particular group or subset of subjects (e.g., based on a particular disease type, diagnostic criteria, previous treatment, and / or response to previous treatment). In some embodiments, the methods involve treating subjects who have relapsed after remission from one or more prior therapies or who have become refractory to the prior therapies; or who have relapsed or are refractory (R / R) to one or more prior therapies (e.g., first-line or subsequent standard of care). In some embodiments, the methods involve treating subjects with diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS; de novo and indolent transformed), primary mediastinal B-cell lymphoma (PMBCL), or follicular lymphoma, e.g., follicular lymphoma grade 3B (FL3B). In some embodiments, the methods involve treating subjects with Eastern Cooperative Oncology Group (ECOG) performance status (ECOG) of 0-1 or 0-2. In some embodiments, the method treats poor prognosis populations or DLBCL patients or subjects thereof who have generally responded poorly to therapy or a particular reference therapy, e.g., poor prognosis populations or DLBCL patients or subjects thereof with one or more, e.g., two or three, chromosomal translocations (e.g., so-called "double hit" or "triple hit" lymphomas; poor prognosis populations or DLBCL patients or subjects thereof with a translocation of the MYC / 8q24 locus, usually in combination with the t(14;18)(q32;q21) bcl-2 gene, or / and a BCL6 / 3q27 chromosomal translocation; see, e.g., Xu et al. (2013) Int J Clin Exp Pathol. 6(4):788-794), and / or poor prognosis populations or DLBCL patients or subjects thereof who have relapsed (optionally within 12 months) after autologous stem cell transplantation (ASCT), and / or poor prognosis populations or DLBCL patients or subjects thereof who are considered to be chemotherapy resistant.

[0217] In some aspects, the provided embodiments are based on the observation that the provided methods can be used to obtain high response rates with high durability compared to certain available cell therapy methods without high toxicity risks. In some embodiments, the provided methods allow for long-term persistence and / or low toxicity rates in subjects of adoptively transferred cells for cell therapy. In some embodiments, the methods can be used to select subjects who are likely to respond to treatment with cell therapy and / or to determine appropriate doses or dosing regimes for high response rates and / or more durable responses with minimal toxicity risks. Such methods can inform rational strategies to facilitate the safe and effective clinical application of adoptive cell therapy, such as CAR-T cell therapy.

[0218] In some embodiments, the antigen receptor (e.g., CAR) specifically binds to a target antigen associated with the disease or condition, e.g., a target antigen associated with NHL. In some embodiments, the antigen associated with the disease or disorder is selected from CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30.

[0219] In some embodiments, the method includes administering a cell or a composition comprising the cell to a subject, tissue, or cell (e.g., having, at risk for, or suspected of having a disease, condition, or disorder). In some embodiments, the subject is an adult subject. In some embodiments, the subject is over 30 years old, 40 years old, 50 years old, 60 years old, or 70 years old.

[0220] In some embodiments, the method involves administering cells to a subject selected or identified as having a particular prognosis or risk of NHL. Non-Hodgkin's lymphoma (NHL) can be a heterogeneous disease. Some subjects with NHL can survive without treatment, while others may require immediate intervention. In some cases, subjects with NHL can be classified into groups that can inform disease prognosis and / or recommended treatment strategies. In some cases, such groups can be "low risk," "intermediate risk," "high risk," and / or "very high risk," and patients can be classified into such groups depending on several factors, such as, but not limited to, genetic abnormalities and / or morphological or physical characteristics. In some embodiments, subjects treated according to the method and / or with the article of manufacture or composition are classified or identified based on the risk of NHL. In some embodiments, the subject is a subject with high-risk NHL.

[0221] In some embodiments, the subject has previously been treated with a therapy or therapeutic agent targeting the disease or condition, e.g., NHL, prior to administration of the cells expressing the recombinant receptor. In some embodiments, the subject has previously been treated with hematopoietic stem cell transplantation (HSCT), e.g., allogeneic HSCT or autogeneic HSCT. In some embodiments, the subject has had a poor prognosis after treatment with standard therapy and / or failed the first or subsequent previous therapy. In some embodiments, the subject has been treated with or previously received at least one or at least about one, at least two, at least about two, at least three, or at least about three, or at least four, or at least about four, or about four other therapies for treating NHL other than lymphocyte depletion therapy, and / or administration of the dose of cells expressing the antigen receptor. In some embodiments, the subject has previously been treated with chemotherapy or radiation therapy. In some aspects, the subject is refractory or non-responsive to other treatments or therapeutic agents, hi some embodiments, the subject has persistent or recurrent disease, e.g., after treatment with another treatment or intervention, e.g., chemotherapy or radiation.

[0222] In some embodiments, the subject is a transplant-eligible subject, e.g., a subject eligible for hematopoietic stem cell transplantation (HSCT), e.g., allogeneic HSCT. In some such embodiments, the subject, despite being eligible, has not previously undergone a transplant prior to administration of the modified cells (e.g., CAR-T cells) or compositions comprising the cells to the subject as described herein.

[0223] In some embodiments, the subject is a transplant-ineligible subject, e.g., a subject who is ineligible for hematopoietic stem cell transplantation (HSCT), e.g., allogeneic HSCT. In some embodiments, such a subject is administered modified cells (e.g., CAR-T cells) or compositions comprising the cells according to the embodiments provided herein.

[0224] In some embodiments, the method includes administering cells to a subject selected or identified as having high-risk NHL. In some embodiments, the subject exhibits one or more cytogenetic abnormalities associated with, for example, high-risk NHL. In some embodiments, the subject is selected or identified based on having a disease or condition characterized or determined to be aggressive NHL, diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), T-cell / histiocytocyte-rich large B-cell lymphoma (TCHRBCL), Burkitt's lymphoma, mantle cell lymphoma (MCL), and / or follicular lymphoma (FL). In certain embodiments, subjects treated using the methods provided herein include those with aggressive NHL, particularly those with diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS; transformed from de novo and indolent), primary mediastinal B-cell lymphoma (PMBCL), or follicular lymphoma grade 3B (FL3B). In some embodiments, the subjects have poor performance status. In some aspects, the treated population includes subjects with an Eastern Cooperative Oncology Group performance status (ECOG) of 0 to 2. In other aspects of any of the embodiments, the treated subjects include subjects with ECOG 0 to 1 or do not include subjects with ECOG 2. In some aspects of any of the embodiments, the treated subjects have failed two or more prior therapies. In some embodiments, the subjects do not have marginal zone lymphoma (MZL) or DLBCL transformed from chronic lymphocytic leukemia (CLL; Richter's). In some embodiments, subjects with CLL may exhibit Richter's syndrome (RS), which is defined as the transformation of CLL into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL) (see, for example, Parikh et al. Blood 2014 123:1647-1657). In some embodiments, the subject has mantle cell lymphoma (MCL). In some embodiments, the subject has a characteristic that correlates with poor overall survival.In some embodiments, the subject has never achieved a complete response (CR), has never undergone autologous stem cell transplantation (ASCT), is refractory to one or more second-line therapies, has primary refractory disease, and / or has an ECOG performance score of 2.

[0225] In some embodiments, the subjects to be treated include those with diffuse large B-cell lymphoma (DLBCL), de novo or transformed from indolent lymphoma (NOS), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3b (FL3B), and an ECOG score of 0-2, after failure of two lines of therapy, and the subjects may optionally have previously been treated with allogeneic stem cell transplant (SCT). In some embodiments, such a subject group may be referred to as a "full cohort." In some embodiments, subjects are selected for treatment with adoptive cell therapy if they meet the above criteria. In some embodiments, within the group ("full cohort"), a subject is not selected for or excluded from treatment if the subject has a poor performance status (e.g., ECOG 2) and / or has DLBCL transformed from marginal zone lymphoma (MZL) and chronic lymphocytic leukemia (CLL, Richter). Thus, in some embodiments, a subject is selected for treatment if the subject has diffuse large B-cell lymphoma (DLBCL), de novo or transformed from indolent lymphoma (NOS), primary mediastinal large B-cell lymphoma (PMBCL) and follicular lymphoma grade 3b (FL3B), and a subject with an ECOG score of 0 or 1 after failure of two lines of therapy, and the subject may optionally have been previously treated with allogeneic stem cell transplant (SCT), but does not have DLBCL transformed from marginal zone lymphoma (MZL) and chronic lymphocytic leukemia (CLL, Richter). In some embodiments, such a group of subjects may be referred to as a "core cohort." In some embodiments, the subjects to be treated are subjects of the "core cohort."

[0226] In some aspects, the provided embodiments are based on the observation that a particular subject population, e.g., a "core cohort" of subjects, receiving a particular dose of cell therapy, exhibits a complete response (CR) rate of greater than 55% and an overall response rate (ORR) of greater than 80% with high durability, e.g., responses that are maintained over an extended period of time, e.g., greater than 3 months, with a 3-month ORR of greater than 65% and a 3-month CR rate of about 50%. In particular, the provided observations showed that the 3-month ORR was higher in subjects with two or three chromosomal translocations ("double-hit" or "triple-hit" lymphomas; MYC / 8q24 translocation, usually in combination with the t(14;18)(q32;q21) bcl-2 gene, or / and BCL6 / 3q27 chromosomal translocation; see, e.g., Xu et al. (2013) Int J Clin Exp Pathol. 6(4):788-794), primary refractory lymphoma, chemotherapy-resistant DLBCL, as well as subjects who had not previously achieved a CR.

[0227] In some aspects, compositions, methods and uses are provided for the administration of cell therapy of a defined composition at a specific dose associated with a high response rate and / or high durability of response and a low toxicity level and / or incidence rate. In some embodiments, the administered composition or dose is a flat and / or fixed dose of cells and / or one or more cells having a specific phenotype, e.g., a strictly flat dose, e.g., a specific number or number of such cells that is within a specific range and / or degree of variability or dispersion compared to a target number. In some embodiments, the administered composition or dose is a specific ratio of CD4 + Cells and CD8 + cells (e.g., CD4 + CAR + T cells: CD8 + CAR + In some embodiments, the ratio of CD4 T cells is 1:1, and / or the ratio varies within a certain degree (e.g., within ±10%, e.g., within ±8%) from the ratio, e.g., the degree of variation or variance is ±10% or less, e.g., ±8% or less. +cells and CD8 + The cells are individually formulated and administered. In some embodiments, the administered cells exhibit consistent activity and / or function, such as cytokine production, apoptosis, and / or expansion. In some embodiments, the provided compositions exhibit highly consistent, defined activity and, for example, low variability in terms of cell number, cell function, and / or cell activity among cells in the composition, or low variability among preparations. In some embodiments, consistency in activity and / or function, such as low variability among preparations of the composition, allows for improved efficacy and / or safety. In some embodiments, administration of a defined composition has resulted in lower product variability and lower toxicity, such as CRS or neurotoxicity, compared to administration of a cell composition with high heterogeneity. In some embodiments, a defined, consistent composition also exhibits consistent cell expansion. Such consistency can facilitate dose specification, therapeutic window, dose-response assessment, and identification of target factors that may correlate with safety or toxicity outcomes.

[0228] In some embodiments, subjects in a particular cohort receiving a single infusion at a particular dose level may achieve a durable response rate of greater than 60% after 6 months. In some embodiments, subjects in some cohorts may achieve an overall response rate (ORR, in some cases also known as objective response rate) of greater than 80%, a complete response (CR) rate of greater than 60%, and / or a high durable CR rate at 6 months. In some embodiments, subjects receiving a prescribed dose exhibit improved safety outcomes, e.g., more than two-thirds of subjects do not experience any CRS or NT. In some aspects, the rate of severe CRS or severe NT is low. In some embodiments, the high exposure (e.g., C) observed at a particular prescribed dose is max and AUC 0-28) is not associated with toxicity, such as increased CRS or NT. In some embodiments, specific target factors, such as specific biomarkers, can be used to predict toxicity risk. In some embodiments, using the provided embodiments, high response rates can be achieved with low toxicity risk.

[0229] In some embodiments, of the subjects treated with the provided compositions, articles of manufacture, kits, methods, and uses, no more than 25%, no more than 20%, no more than 15%, no more than 10%, or no more than 5% are administered an agent to ameliorate, treat, or prevent toxicity (e.g., tocilizumab and / or dexamethasone) either before or after administration of the cell therapy. In some embodiments, the subjects are not administered any prophylactic treatment before receiving the modified cells (e.g., CAR-T cells).

[0230] In some embodiments, the provided embodiments provide advantages, e.g., enable the application of cell therapy on an outpatient basis. In some embodiments, the administration of cell therapy, e.g., a dose of T cells according to the provided embodiments, can be performed on an outpatient basis or does not require the subject to be admitted to a hospital, e.g., a hospital stay requiring an overnight stay. In some embodiments, such outpatient administration can allow for increased accessibility and reduced costs while maintaining low toxicity and high durable response rates. In some aspects, outpatient treatment can be advantageous for patients who are already immunocompromised in some other way, e.g., due to previous treatment after lymphodepletion, and who are at increased risk of exposure in a hospital stay or in an inpatient setting. Also, in some aspects, outpatient treatment increases treatment options for subjects who may not have access to an inpatient, hospital setting, or transplant center, thereby expanding the availability of treatment. In some embodiments, subjects treated on an outpatient basis using the provided compositions, articles of manufacture, kits, methods, and uses remain outpatients for at least 3 days, or a certain percentage (%) of subjects so treated, e.g., at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95% of subjects, remain outpatients for at least 3 days. In some aspects, subjects remain outpatients for at least 4 days, 5 days, 6 days, 7 days, 8 days, or longer. In some embodiments, subjects treated using the provided compositions, articles of manufacture, kits, methods, and uses exhibit a reduction in the duration of their hospital stay, e.g., by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40%, compared to subjects treated with other compositions, articles of manufacture, kits, methods, and uses.

[0231] In some embodiments, the methods, cells, and compositions may result in high and durable response rates across a range of patient characteristics and / or tumor burdens. In some embodiments, the methods, cells, and compositions may result in high and durable response rates with a low risk of adverse effects or toxicity for high-risk patients with poor prognosis. In some embodiments, the methods and uses result in or provide high response rates and / or more durable response or efficacy and / or a low risk of toxicity or other side effects that may be associated with cell therapy, such as neurotoxicity (NT) or cytokine release syndrome (CRS). In some aspects, the provided observations show a low rate of severe NT (sNT) or severe CRS (sCRS) and a high rate of patients free of any toxicity, such as NT or CRS.

[0232] In some embodiments, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%, or more, of subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions achieve a complete response (CR). In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions achieve an objective response (OR). In some embodiments, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or more, of subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions achieve a CR or OR by 1 month, by 2 months, or by 3 months.

[0233] In some embodiments, by 3 months, 4 months, 5 months, 6 months, or longer after initiation of cell therapy administration, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or more of the subjects treated according to the provided methods and / or subjects treated with the provided articles of manufacture or compositions are still in a response state, e.g., still in CR or OR. In some embodiments, such response, e.g., CR or OR, is sustained for at least 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, or 9 months in at least or at least about 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least about 95% of subjects treated according to the provided methods, or in such subjects achieving a CR by 1 month, or by 3 months. In some embodiments, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or more of the subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions, or such subjects achieving CR by 1 month, or by 3 months, survive or survive progression-free for 3 or longer than about 3 months, 4 or longer than about 4 months, 5 or longer than about 5 months, 6 or longer than about 6 months, 7 or longer than about 7 months, 8 or longer than about 8 months, or 9 or longer than about 9 months.

[0234] In some embodiments, the resulting response observed in such subjects by treatment according to the provided methods and / or with the provided articles of manufacture or compositions is associated with or results in a low risk of any toxicity or a low risk of severe toxicity in the majority of treated subjects. In some embodiments, more than or about 30%, more than or about 35%, more than or about 40%, more than or about 50%, more than or about 55%, more than or about 60%, or more than about 60%, of subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions do not exhibit any grade of CRS or any grade of neurotoxicity (NT). In some embodiments, greater than or about 50%, greater than or about 60%, greater than or about 60%, greater than or about 70%, greater than or about 80%, or more than or about 80% of subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions do not exhibit severe CRS or CRS at grade 3 or above. In some embodiments, greater than or about 50%, greater than or about 60%, greater than or about 60%, greater than or about 70%, greater than or about 80%, or more than or about 80% of subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions do not exhibit severe neurotoxicity or neurotoxicity at grade 3 or above, e.g., grade 4 or 5 neurotoxicity.

[0235] In some embodiments, at least 45 or about 45%, at least 50 or about 50%, at least 60 or about 60%, at least 65 or about 65%, at least 70 or about 70%, at least 75 or about 75%, at least 80 or about 80%, at least 85 or about 85%, at least 90 or about 90%, or at least 95 or about 95% of subjects treated according to the methods and / or with the provided articles of manufacture or compositions do not exhibit early onset CRS or neurotoxicity and / or do not exhibit onset of CRS earlier than 1, 2, 3, or 4 days after initiation of the administration. In some embodiments, at least 45 or about 45%, at least 50 or about 50%, at least 60 or about 60%, at least 65 or about 65%, at least 70 or about 70%, at least 75 or about 75%, at least 80 or about 80%, at least 85 or about 85%, at least 90 or about 90%, or at least 95 or about 95% of subjects treated according to the methods and / or with the provided articles of manufacture or compositions exhibit no onset of neurotoxicity earlier than day 3, 4, 5, 6, or 7 after initiation of the administration. In some aspects, the median onset of neurotoxicity in subjects treated according to the methods and / or with the provided articles of manufacture or compositions is at or after the median peak of CRS in subjects treated according to the methods or is at or after the median time to resolution of CRS in subjects treated according to the methods. In some cases, the median onset of neurotoxicity in subjects treated according to the method is after more than 8 or about 8 days, more than 9 or about 9 days, more than 10 or about 10 days, or more than 11 or about 11 days.

[0236] In some embodiments, such results are greater than 5×10 7 Or about 5 x 10 7 ~1.5×10 8 Or about 1.5 x 10 8 pieces, e.g. 5 x 10 7 ~1×10 8total recombinant receptor-expressing T cells, e.g., as described herein, in a defined ratio (e.g., a 1:1 or about 1:1 ratio), and / or in a precise or uniform or fixed number of CAR + T cells or certain types of CAR + T cells, e.g., CD4 + CAR + T cells and / or CD8 + CAR + T cells, and / or CD4 T cells administered in a number that is within a specified variance of any of such cells, e.g., + or - (plus or minus, in some cases indicated as ±) 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% relative to such exact or uniform or fixed number. + and CD8 + In some embodiments, such a uniform cell number or fixed cell number is observed after administration of a dose of T cells, including T cells. + T cells or CD8 + and / or CD4 + CAR + T cells, 2.5 × 10 7 Or about 2.5 x 10 7 , 5×10 7 Or about 5 x 10 7 , 10×10 7 Or about 10 x 10 7 , 15×10 7 Or about 15 x 10 7 , or 20 × 10 7 Or about 20 x 10 7 In some embodiments, the number of cells in the dose is 5 x 10 7 CD4 + CAR + T cells (optional 2.5 x 10 7 CD4 + CAR + T cells and 2.5 × 10 7 CD8 + CAR +In some embodiments, this comprises, consists of, or consists essentially of 10×10 T cells; 7 Cars + T cells (optional 5 x 10 7 CD4 + CAR + T cells and 5 × 10 7 CD8 + CAR + T cells). In some aspects, the number of cells administered is within a certain range of dispersion of such numbers in the aforementioned embodiments, e.g., within plus or minus (±) 5, 6, 7, 8, 9, or 10% of such cell numbers, e.g., within plus or minus 8%. In some aspects, the dose is administered within a certain range of dispersion of such cells (e.g., whole CAR T cells). + T cells or CD8 + and / or CD4 + CAR + Within this range, a correlation (optionally a linear relationship) is observed between the number of cells (e.g., T cells) and one or more outcomes indicative of a therapeutic response or its duration (e.g., likelihood of achieving remission, complete remission, and / or a particular duration of remission) and / or the duration of any of the foregoing. In some aspects, it has been observed that higher doses of cells administered can result in a greater response without affecting, or substantially affecting, or without affecting, or substantially affecting, the incidence or risk of toxicity (e.g., CRS or neurotoxicity) or the degree of incidence or risk of toxicity, e.g., severe CRS or severe neurotoxicity, in the subject.

[0237] In some aspects, the provided methods provide for high or specific response rates (e.g., response rates in a population evaluated after a specific period of time after administration (e.g., 3 months or 6 months)), e.g., 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 81%, 82%, 83%, 84%, or 85% or higher ORR (e.g., 6-month ORR or 3-month ORR), and 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 81%, 82%, 83%, 84%, or 85% or higher ORR (e.g., 6-month ORR or 3-month ORR). %, or about 75% or higher CR rates (e.g., 6-month CR rates or 3-month CR rates), which may also be sustained, for example, for a particular period or at least a particular period, for example, more than 1 month, more than 3 months, or more than 6 months, or longer, or 9 months or longer, after initiation of therapy. In some embodiments, such response rates and durability are achieved after only a single application or dose of such therapy. Also, treatment of such subjects with the provided methods and / or provided articles of manufacture or compositions will, in some embodiments, result in high response rates in subjects without a high incidence of toxicity, e.g., neurotoxicity or the development of CRS, even at high cell doses. In some embodiments, about or greater than 50%, about or greater than 55%, or about or greater than 60% of subjects who achieve such a response do not experience any grade of toxicity, e.g., do not experience any grade of CRS and / or neurotoxicity.

[0238] Thus, in some embodiments, the provided methods, articles of manufacture, and / or compositions may offer advantages over other available methods or solutions or approaches for treatment, e.g., adoptive cell therapy. In particular, some provided embodiments offer advantages for subjects with high-risk NHL by providing a high rate of durable responses with a low incidence of toxicity or side effects.

[0239] A. Treatment Method Provided herein are treatment methods involving administering modified cells, such as modified T cells, or compositions comprising the modified cells. Also provided are methods involving the administration of modified cells and / or compositions thereof, and uses of modified cells (e.g., T cells) and / or compositions thereof, for example, methods for treating subjects with a disease or condition, such as subjects with leukemia or lymphoma, e.g., non-Hodgkin's lymphoma (NHL). In some embodiments, the provided methods and uses may result in improved response and / or more durable response or efficacy and / or a lower risk of toxicity or other side effects, for example, in certain groups of treated subjects, compared to certain alternative methods. Also provided in some aspects are methods of administering modified cells, such as modified T cells, or compositions comprising the modified cells to a subject, for example, a subject with a disease or disorder. Also provided in some aspects are uses of modified cells, such as modified T cells, or compositions comprising the modified cells for the treatment of a disease or disorder. Also provided in some aspects are uses of modified cells, such as modified T cells, or compositions comprising the modified cells for the manufacture of a medicament for the treatment of a disease or disorder. Also provided in some aspects are methods of administering modified cells, such as modified T cells, or compositions comprising the modified cells, for use in treating a disease or disorder, or for administration to a subject having a disease or disorder. In some aspects, the use of the modified cells, such as modified T cells, or compositions comprising the modified cells, is according to any of the methods described herein.

[0240] The general method for administering cells for adoptive cell therapy is known and can be used in connection with the provided methods and compositions.For example, adoptive T cell therapy methods are described in, for example, U.S. Patent Application Publication No. 2003 / 0170238 to Gruenberg et al.; U.S. Patent No. 4,690,915 to Rosenberg; Rosenberg (2011) Nat Rev Clin Oncol.8(10):577-85).See, for example, Themeli et al.(2013) Nat Biotechnol.31(10):928-933; Tsukahara et al.(2013) Biochem Biophys Res Commun 438(1):84-9; Davila et al.(2013) PLoS ONE 8(4):e61338.

[0241] The disease or condition to be treated can be any in which the expression of an antigen is associated with and / or involved in the pathogenesis of the disease, condition, or disorder, e.g., causes, exacerbates, or otherwise contributes to the pathogenesis of the disease, condition, or disorder. Exemplary diseases and conditions can include diseases or conditions associated with malignant tumors or cellular transformation (e.g., cancer), autoimmune or inflammatory diseases, or infectious diseases caused by, for example, bacterial, viral, or other pathogens. Exemplary antigens, including antigens associated with various diseases and conditions that can be treated, are described above. In certain embodiments, the chimeric antigen receptor or transgenic TCR specifically binds to an antigen associated with the disease or condition.

[0242] Among such diseases, conditions, and disorders are tumors, e.g., solid tumors, hematopoietic malignancies, and melanoma, as well as, e.g., localized and metastatic tumors, infectious diseases, e.g., infections with viruses or other pathogens, e.g., HIV, HCV, HBV, CMV, HPV, and parasitic diseases, and autoimmune and inflammatory diseases. In some embodiments, the disease, disorder, or condition is a tumor, cancer, malignancy, neoplasm, or other proliferative disease or disorder. Such diseases include, but are not limited to, leukemias, lymphomas, such as acute myeloid (or myelogenous) leukemia (AML), chronic myeloid (or myelogenous) leukemia (CML), acute lymphocytic (or lymphoblastic) leukemia (ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), anaplastic large cell lymphoma (ALCL), follicular lymphoma, refractory follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM). In some embodiments, the disease or condition is a B-cell malignancy selected from among acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin's lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL). In some embodiments, the disease or condition is NHL, and the NHL is selected from the group consisting of aggressive NHL, diffuse large B-cell lymphoma (DLBCL), NOS (de novo and indolent transformed), primary mediastinal large B-cell lymphoma (PMBCL), T-cell / histiocytocyte-rich large B-cell lymphoma (TCHRBCL), Burkitt's lymphoma, mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B).

[0243] In some embodiments, NHL can be staged according to the Lugano classification (see, for example, Cheson et al., (2014) JCO 32(27):3059-3067; Cheson, BD (2015) Chin Clin Oncol 4(1):5). In some cases, the stage is described by Roman numerals I to IV (1-4), with localized stage (I or II) lymphoma affecting organs other than the lymphatic system (extranodal organs) being designated E. Stage I represents involvement of one lymph node or adjacent lymph node group or single extranodal involvement (IE) without lymph node involvement. Stage 2 represents stage I or II depending on the extent of lymph nodes with involvement of two or more lymph node groups on the same side of the diaphragm or localized contiguous extranodal involvement (IIE). Stage III represents intranodal involvement in lymph nodes on both sides of the diaphragm or above the diaphragm with splenic involvement. Stage IV represents non-contiguous extralymphatic involvement. In addition, the term "bulky mass lesion" can be used to describe large tumors in the chest, especially in stage II. The extent of disease is determined by positron emission tomography (PET)-computed tomography (CT) for avid lymphomas and by CT for non-avid lymphomas.

[0244] In some embodiments, the Eastern Cooperative Oncology Group (ECOG) performance status index can be used to evaluate subjects, such as subjects with poor performance in previous treatments, or to select subjects, such as subjects with poor performance in previous treatments, for treatment (see, for example, Oken et al. (1982) Am J Clin Oncol. 5:649-655). The ECOG Scale of performance status indicates a patient's functional level in terms of their ability to care for themselves, daily activities, and physical abilities (e.g., walking, working, etc.). In some embodiments, an ECOG performance status of 0 indicates that a subject can perform normal activities. In some aspects, a subject with an ECOG performance status of 1 shows some limitations in physical activity, but the subject's walking is complete. In some aspects, a patient with an ECOG performance status of 2 walks more than 50%. Also, in some cases, subjects with an ECOG performance status of 2 may be able to care for themselves; see, e.g., Sorensen et al., (1993) Br J Cancer 67(4)773-775. Criteria reflecting ECOG performance status are shown in Table 1 below: Table 1: ECOG Performance Status Criteria TIFF2025031805000002.tif82164

[0245] In some embodiments, the subject has or is identified as having double / triple-hit lymphoma or double / triple-hit molecular subtype lymphoma. In some embodiments, the lymphoma is a double-hit lymphoma characterized by the presence of gene rearrangements (e.g., translocations) of MYC (myelocytomatosis oncogene), BCL2 (B-cell lymphoma 2), and / or BCL6 (B-cell lymphoma 6). In some embodiments, the gene rearrangement affects the MYC / 8q24 locus in combination with another gene rearrangement. For example, the other gene rearrangement includes t(14;18)(q32;q21) involving BCL2. In some embodiments, the gene rearrangement affects the MYC / 8q24 locus in combination with BCL6 / 3q27. In some embodiments, the lymphoma is a triple-hit lymphoma characterized by the presence of MYC, BCL2, and BCL6 gene rearrangements; see, e.g., Aukema et al., (2011) Blood 117:2319-2331. In some aspects of such embodiments, the subject is ECOG 0-1, or does not have or is not suspected of having DLBCL transformed from MZL or CLL, or is not characterized as having DLBCL transformed from MZL or CLL. In aspects, the treatment is indicated for such subjects, and / or the instructions indicate administration to subjects within such populations. In some embodiments, based on the 2016 WHO criteria (Swerdlow et al., (2016) Blood 127(20):2375-2390), double / triple hit lymphoma can be considered a high-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements (double / triple hit) with DLBCL histology.

[0246] In some embodiments, the disease or condition is an infectious disease or condition, including, but not limited to, viral infection, retroviral infection, bacterial infection, and protozoal infection, immunodeficiency, cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, BK polyomavirus, hi some embodiments, the disease or condition is an autoimmune or inflammatory disease or condition, such as arthritis, e.g., rheumatoid arthritis (RA), type 1 diabetes, systemic lupus erythematosus (SLE), inflammatory bowel disease, psoriasis, scleroderma, autoimmune thyroid disease, Graves' disease, Crohn's disease, multiple sclerosis, asthma, and / or a disease or condition associated with transplantation.

[0247] In some embodiments, the antigen associated with the disease or disorder is αvβ6 integrin (avb6 integrin), B-cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (also known as CA9, CAIX, or G250), cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), cyclin, cyclin A2, CC motif chemokine ligand 1 (CCL-1), 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), epidermal growth factor receptor type III mutant (EGFR), or EGFR mutated type III (EGFR mutated type III).vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrin B2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor-like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), folate-binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3 , glycoprotein 100 (gp100), glypican-3 (GPC3), G protein-coupled receptor 5D (GPCR5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimer, human high molecular weight melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, human leukocyte antigen A1 (HLA-A1), human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha (IL-22R) α), IL-13 receptor alpha 2 (IL-13Rα2), kinase insert domain receptor (kdr), kappa light chain, L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, leucine-rich repeat-containing 8 family member A (LRRC8A), Lewis Y, melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV) ), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligand, melan-A (MART-1), neural cell adhesion molecule (NCAM), oncofetal antigen, preferentially expressed antigen in melanoma (PRAME), progesterone receptor, 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)The antigen targeted by the receptor is selected from among: 5T4, tumor-associated glycoprotein 72 (TAG72), tyrosinase-related protein 1 (also known as TRP1, 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-1), a pathogen-specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and / or a biotinylated molecule, and / or a molecule expressed by HIV, HCV, HBV, or other pathogens. Antigens targeted by the receptor in some embodiments include antigens associated with B-cell malignancies, such as any of several known B-cell markers. In some embodiments, the antigen is or comprises CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30.

[0248] In some embodiments, the antigen is or comprises a pathogen-specific or pathogen-expressed antigen, hi some embodiments, the antigen is a viral antigen (e.g., a viral antigen from HIV, HCV, HBV, etc.), a bacterial antigen, and / or a parasitic antigen.

[0249] In some embodiments, cell therapy, e.g., adoptive T cell therapy, is performed by autologous transfer, in which cells are isolated and / or otherwise prepared from the subject to be treated or from a sample derived from such a subject. Thus, in some aspects, cells are derived from a subject, e.g., a patient, in need of treatment, and the cells are administered to the same subject after isolation and processing.

[0250] In some embodiments, cell therapy, e.g., adoptive T cell therapy, is performed by allogeneic transfer, in which cells are isolated and / or otherwise prepared from a subject other than the subject who will receive cell therapy or who will ultimately receive cell therapy, e.g., a first subject. In such embodiments, the cells are then administered to a different subject of the same species, e.g., a second subject. In some embodiments, the first and second subjects are genetically identical. In some embodiments, the first and second subjects are genetically similar. In some embodiments, the second subject expresses the same HLA class or supertype as the first subject.

[0251] The cells can be administered by any suitable means, for example, by bolus infusion, injection, for example, intravenous or subcutaneous injection, intraocular injection, peribulbar injection, subretinal injection, intravitreal injection, transseptal injection, subscleral injection, intrachoroidal injection, intracapsular injection, subconjectval injection, subconjuntival injection, subtenon injection, retrobulbar injection, peribulbar injection, or posterior juxtascleral delivery. In some embodiments, the cells are administered parenterally, intrapulmonary, intranasally, and, if localized treatment is desired, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, a given dose is administered by a single bolus administration of the cells. In some embodiments, the dose is administered by repeated bolus administration of the cells over a period of, for example, 3 days or less, or by continuous infusion administration of the cells. In some embodiments, administration of the cell dose or any additional therapy, eg, lymphocyte depletion therapy, interventional therapy, and / or combination therapy, is performed on an outpatient basis.

[0252] For the prevention or treatment of disease, the appropriate dosage will depend on the type of disease being treated, the type of cells or recombinant receptor, whether the cells are administered for prophylactic or therapeutic purposes, the severity and course of the disease, previous treatments, the subject's medical history and response to the cells, and the discretion of the attending physician. The compositions and cells are in some embodiments suitably administered to a subject at one time or over a series of treatments.

[0253] In some embodiments, the cells are administered as part of a combination treatment, e.g., simultaneously with another or additional therapeutic intervention (e.g., an antibody or modified cells or receptor or agent, e.g., a cytotoxic or therapeutic agent), or sequentially in any order. The cells in some embodiments are co-administered with one or more additional therapeutic agents or in conjunction with another therapeutic intervention, either simultaneously or sequentially in any order. In some embodiments, the additional therapeutic agent is any intervention or agent described herein, e.g., any intervention or agent described herein that can ameliorate toxic symptoms, e.g., as described in Section II herein. In some situations, the cells are co-administered with another therapy sufficiently closely in time such that the cell population enhances the effect of one or more additional therapeutic agents, or vice versa. In some embodiments, the cells are administered before the one or more additional therapeutic agents. In some embodiments, the cells are administered after the one or more additional therapeutic agents. In some embodiments, the one or more additional agents include, e.g., a cytokine, e.g., IL-2, to enhance persistence. In some embodiments, the method includes administration of a chemotherapeutic agent.

[0254] In some embodiments, the method includes administering a chemotherapeutic agent, eg, a conditioning chemotherapeutic agent, eg, to reduce tumor burden prior to said administration.

[0255] Pre-treatment of a subject with immunoablative (eg, lymphocyte-depleting) therapy can improve the efficacy of adoptive cellular therapy (ACT) in some aspects.

[0256] Therefore, in some embodiments, the method comprises administering a pretreatment agent, such as lymphocyte depleting agent or chemotherapeutic agent, such as cyclophosphamide, fludarabine, or a combination thereof, to the subject before the start of cell therapy.For example, the pretreatment agent can be administered to the subject at least 2 days before the start of cell therapy, for example, at least 3 days before, at least 4 days before, at least 5 days before, at least 6 days before, or at least 7 days before.In some embodiments, the pretreatment agent is administered to the subject within 7 days, for example, within 6 days, within 5 days, within 4 days, within 3 days, within 2 days before the start of cell therapy.

[0257] In some embodiments, the subject is pretreated with cyclophosphamide at a dose of 20 mg / kg or about 20 mg / kg to 100 mg / kg, e.g., 40 mg / kg or about 40 mg / kg to 80 mg / kg or about 80 mg / kg. In some aspects, the subject is pretreated with 60 mg / kg or about 60 mg / kg cyclophosphamide. In some embodiments, cyclophosphamide can be administered in a single dose or in multiple doses, e.g., daily, every other day, or every three days. In some embodiments, cyclophosphamide is administered once daily for one or two days. In some embodiments, when the lymphocyte depleting agent includes cyclophosphamide, the cyclophosphamide is administered at a dose of 100 or about 100 mg / m 2 ~500 or approximately 500 mg / m 2 , e.g., 200 or about 200 mg / m 2 ~400 or approximately 400 mg / m 2 , or 250 or about 250 mg / m 2 ~350 or approximately 350 mg / m 2 In some cases, the subject is administered a dose of about 300 mg / m 2In some embodiments, cyclophosphamide is administered at a dose of about 300 mg / m prior to the initiation of cell therapy. In some embodiments, cyclophosphamide can be administered in a single dose or in multiple doses, e.g., daily, every other day, or every three days. In some embodiments, cyclophosphamide is administered daily, e.g., for 1-5 days, e.g., for 3-5 days. In some cases, cyclophosphamide is administered at a dose of about 300 mg / m prior to the initiation of cell therapy. 2 of cyclophosphamide is administered to the subject daily for three days.

[0258] In some embodiments, when the lymphocyte depleting agent comprises fludarabine, the fludarabine is administered at or about 1 mg / m 2 ~100 or about 100 mg / m 2 , e.g., 10 or about 10 mg / m 2 ~75 or approximately 75 mg / m 2 , 15 or about 15 mg / m 2 ~50 or approximately 50 mg / m 2 , 20 or about 20 mg / m 2 ~40 or approximately 40 mg / m 2 , or 24 or about 24 mg / m 2 ~35 or approximately 35 mg / m 2 In some cases, the subject is administered a dose of about 30 mg / m 2 of fludarabine is administered to the subject. In some embodiments, fludarabine can be administered in a single dose or in multiple doses, for example, daily, every other day, or every three days. In some embodiments, fludarabine is administered daily, for example, for 1 to 5 days, for example, for 3 to 5 days. In some cases, about 30 mg / m is administered prior to the initiation of cell therapy. 2 of fludarabine is administered to the subject daily for three days.

[0259] In some embodiments, the lymphocyte depleting agent comprises a combination of agents, e.g., a combination of cyclophosphamide and fludarabine. Thus, the combination of agents can include any dose or administration schedule, e.g., cyclophosphamide, of those described above, and any dose or administration schedule, e.g., fludarabine, of those described above. For example, in some aspects, a 60 mg / kg (about 2 g / m) dose is administered prior to the first or subsequent dose. 2 ) cyclophosphamide and 3 to 5 doses of 25 mg / m 2 of fludarabine is administered to the subject.

[0260] After administration of the cells, the biological activity of the engineered cell population in some embodiments is measured, for example, by any of several known methods. Parameters evaluated include specific binding of engineered T cells or natural T cells or other immune cells to an antigen in vivo, for example, by diagnostic imaging, or ex vivo, for example, by ELISA or flow cytometry. In certain embodiments, the ability of the engineered cells to destroy target cells can be measured using any suitable known method, such as, for example, the cytotoxicity assay described in Kochenderfer et al., J. Immunotherapy, 32(7):689-702 (2009) and Herman et al. J. Immunological Methods, 285(1):25-40 (2004). In certain embodiments, the biological activity of the cells is measured by assaying the expression and / or secretion of one or more cytokines (e.g., CD107a, IFNγ, IL-2, and TNF). In some aspects, biological activity is measured by assessing clinical outcomes, for example, reduction in tumor burden or tumor cell burden.

[0261] In certain embodiments, the engineered cells are further modified in any number of ways to enhance their therapeutic or prophylactic efficacy. For example, the engineered CAR or TCR expressed by the population can be conjugated to a targeting moiety either directly or indirectly via a linker. The practice of conjugating a compound, such as a CAR or TCR, to a targeting moiety is known. See, for example, Wadwa et al., J. Drug Targeting 3:1 1 1 (1995) and U.S. Patent 5,087,616. In some embodiments, the cells are administered as part of a combination treatment, for example, simultaneously with another therapeutic intervention (e.g., an antibody or engineered cell or receptor or agent, such as a cytotoxic or therapeutic agent), or sequentially in any order. In some embodiments, the cells are co-administered with one or more additional therapeutic agents or in conjunction with another therapeutic intervention, either simultaneously or sequentially in any order. In some situations, the cells are co-administered with another therapy sufficiently closely in time so that the cell population enhances the effect of one or more additional therapeutic agents, or vice versa. In some embodiments, the cells are administered before the one or more additional therapeutic agents. In some embodiments, the cells are administered after the one or more additional therapeutic agents. In some embodiments, the one or more additional agents include a cytokine, e.g., IL-2, for enhancing persistence.

[0262] B. Administration In some embodiments, a certain amount of cells is administered to a subject according to the provided method and / or in the provided article of manufacture or composition.In some embodiments, the size or timing of the dose is determined as a function of the specific disease or pathological condition of the subject.In some cases, the size or timing of the dose for a specific disease can be empirically determined in light of the provided explanation.

[0263] In some embodiments, the dose of cells is 2×10 5 or about 2 x 105 pieces / kg~2×10 6 or about 2 x 10 6 pieces / kg, e.g., 4 x 10 5 Or about 4 x 10 5 pieces / kg~1×10 6 Or about 1 x 10 6 pieces / kg, or 6 x 10 5 Or about 6 x 10 5 pieces / kg~8×10 5 Or about 8 x 10 5 In some embodiments, the dose comprises 2 x 10 cells per kilogram of subject body weight. 5 cells (e.g., antigen-presenting cells, e.g., CAR-expressing cells), e.g., 3 x 10 5 Or about 3 x 10 5 cells / kg or less, 4 x 10 5 Or about 4 x 10 5 Cells / kg or less, 5 x 10 5 Or about 5 x 10 5 Cells / kg or less, 6 x 10 5 Or about 6 x 10 5 cells / kg or less, 7 x 10 5 Or about 7 x 10 5 cells / kg or less, 8 x 10 5 Or about 8 x 10 5 Cells / kg or less, 9 x 10 5 Or about 9 x 10 5 Cells / kg or less, 1 x 10 6 Or about 1 x 10 6 cells / kg or less, or 2 x 10 6 Or about 2 x 10 6 In some embodiments, the dose comprises at least 2 x 10 cells per kilogram of subject body weight or less. 5 or at least about 2 × 10 5 or 2×10 5 or about 2 x 10 5 cells (e.g., antigen-presenting cells, e.g., CAR-expressing cells), for example at least 3 x 10 5 Or at least about 3 x 10 5Or 3 x 10 5 Or about 3 x 10 5 At least 4 x 10 cells / kg 5 Or at least about 4×10 5 Or 4 x 10 5 Or about 4 x 10 5 At least 5 x 10 cells / kg 5 Or at least about 5 x 10 5 Or 5 x 10 5 Or about 5 x 10 5 At least 6 x 10 cells / kg 5 Or at least about 6 x 10 5 Or 6 x 10 5 Or about 6 x 10 5 At least 7 x 10 cells / kg 5 Or at least about 7 x 10 5 Or 7 x 10 5 Or about 7 x 10 5 At least 8 x 10 cells / kg 5 Or at least about 8 x 10 5 Or 8 x 10 5 Or about 8 x 10 5 At least 9 x 10 cells / kg 5 Or at least about 9 x 10 5 Or 9 x 10 5 Or about 9 x 10 5 At least 1 x 10 cells / kg 6 Or at least about 1 × 10 6 Or 1 x 10 6 Or about 1 x 10 6 cells / kg, or at least 2 x 10 6 Or at least about 2 × 10 6 Or 2 x 10 6 Or about 2 x 10 6 Contains cells / kg.

[0264] In certain embodiments, the cells or cell populations of individual subtypes are in the range of about 1 million to about 100 billion cells and / or an amount of cells per kilogram of body weight, e.g., 1 million to about 50 billion cells (e.g., about 5 million, about 25 million, about 500 million, about 1 billion, about 5 billion, about 20 billion, about 30 billion, about 40 billion, or a range defined by any two of the foregoing values), e.g., about 10 million to about 100 billion cells (e.g., about 20 million, about 30 million, about 40 million, about 60 million, about 70 million, about 80 million, or The subject may be administered about 100 million, about 90 million, about 10 billion, about 25 billion, about 50 billion, about 75 billion, about 90 billion, or a range defined by any two of the foregoing values), and in some cases, about 100 million to about 50 billion (e.g., about 120 million, about 250 million, about 350 million, about 450 million, about 650 million, about 800 million, about 900 million, about 3 billion, about 30 billion, about 45 billion) cells, or any value between these ranges, and / or the aforementioned number of cells per kilogram of body weight. Dosages may vary depending on the disease or disorder and / or patient and / or other treatment-specific attributes.

[0265] In some embodiments, the dose of cells is a flat dose of cells or a fixed dose of cells, such that the cell dose is not related to or based on the subject's body surface area or weight.

[0266] In some embodiments, the dose of genetically modified cells is 1 x 10 5 Or about 1 x 10 5 ~5×10 8 Or about 5 x 10 8 1 x 10 total CAR-expressing T cells 5 ~2.5×10 8 1 x 10 total CAR-expressing T cells 5 ~1×10 8 1 x 10 total CAR-expressing T cells 5 ~5×10 7 1 x 10 total CAR-expressing T cells 5 ~2.5×107 1 x 10 total CAR-expressing T cells 5 ~1×10 7 1 x 10 total CAR-expressing T cells 5 ~5×10 6 1 x 10 total CAR-expressing T cells 5 ~2.5×10 6 1 x 10 total CAR-expressing T cells 5 ~1×10 6 1 x 10 total CAR-expressing T cells 6 ~5×10 8 1 x 10 total CAR-expressing T cells 6 ~2.5×10 8 1 x 10 total CAR-expressing T cells 6 ~1×10 8 1 x 10 total CAR-expressing T cells 6 ~5×10 7 1 x 10 total CAR-expressing T cells 6 ~2.5×10 7 1 x 10 total CAR-expressing T cells 6 ~1×10 7 1 x 10 total CAR-expressing T cells 6 ~5×10 6 1 x 10 total CAR-expressing T cells 6 ~2.5×10 6 total CAR-expressing T cells, 2.5 x 10 6 ~5×10 8 total CAR-expressing T cells, 2.5 x 10 6 ~2.5×10 8 total CAR-expressing T cells, 2.5 x 10 6 ~1×10 8 total CAR-expressing T cells, 2.5 x 10 6 ~5×10 7 total CAR-expressing T ...

Claims

[Claim 1] The invention described herein.

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