Manufacturing articles and methods for procedures using adoptive cell therapy

Abstract

Methods of adoptive cell therapy for treating diseases and conditions, including certain B-cell malignancies, are provided, involving the administration of a dose of cells. The cells often express a recombinant receptor, e.g., a chimeric antigen receptor (CAR). In some embodiments, the methods are for treating a subject with non-Hodgkin's lymphoma (NHL). In some embodiments, the methods are for treating a subject with relapsed or refractory NHL. Also provided are articles of manufacture and prophylactic treatments related to the adoptive therapy methods.

Description

[Technical Field]

[0001] Cross-reference of related applications This application relates to U.S. Provisional Patent Application No. 62 / 514,774, filed on June 2, 2017, titled "ARTICLES OF MANUFACTURE AND METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY", U.S. Provisional Patent Application No. 62 / 515,530, filed on June 5, 2017, titled "ARTICLES OF MANUFACTURE AND METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY", and U.S. Provisional Patent Application No. 62 / 521,366, filed on June 16, 2017, titled "ARTICLES OF MANUFACTURE AND METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY". U.S. Provisional Patent Application No. 62 / 527,000, filed on June 29, 2017, with the title "THERAPY", U.S. Provisional Patent Application No. 62 / 549,938, filed on August 24, 2017, with the title "ARTICLES OF MANUFACTURE AND METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY", U.S. Provisional Patent Application No. 62 / 580,425, filed on November 1, 2017, with the title "ARTICLES OF MANUFACTURE AND METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY", U.S. Provisional Patent Application No. 62 / 593,871, filed on December 1, 2017, with the title "ARTICLES OF MANUFACTURE AND U.S. Provisional Patent Application No. 62 / 596, filed on December 8, 2017, with the title “METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY,”Claiming priority under U.S. Provisional Patent Application No. 62 / 614,957, filed on January 8, 2018, entitled "Articles of Manufacturing and Methods for Treatment Using Adoptive Cell Therapy," and incorporating by reference the entirety of the contents of each application.

[0002] Inclusion by referencing sequence listings This application is filed together with an electronic sequence listing. The sequence listing is provided as a file named 735042012140SeqList.txt, created on June 1, 2018, and is 35,306 bytes in size. The information in the electronic sequence listing is incorporated entirely by reference.

[0003] field This disclosure relates, in several aspects, to adoptive cell therapy involving the administration of a certain dose of cells for treating subjects having a disease and condition (e.g., certain B-cell malignancies), as well as related methods, compositions, uses, and manufactured articles. The cells generally express recombinant receptors (e.g., chimeric antigen receptors (CARs)). In some aspects, the disease or condition is non-Hodgkin lymphoma (NHL), e.g., relapsed or refractory NHL or certain NHL subtypes; in some aspects, the subjects are a specific group or subset of NHL subjects, e.g., subjects with multiple prior treatments or subjects with a poor prognosis. [Background technology]

[0004] background Various immunotherapies and / or cell therapies are available to treat diseases and conditions. For example, adoptive cell therapies (including those involving the administration of cells expressing chimeric receptors specific to the disease or disorder of interest, such as chimeric antigen receptors (CARs) and / or other recombinant antigen receptors, as well as other adoptive immunotherapy and adoptive T-cell therapies) may be beneficial in treating cancer or other diseases or disorders. Improved approaches are needed. This paper provides methods and uses to meet such needs. [Overview of the project]

[0005] overview Methods, uses, compositions, formulations, and manufactured articles for treating subjects having or suspected to have a disease or condition (e.g., cancer or tumor, optionally B-cell malignancies, e.g., NHL, ALL, or CLL or their subtypes). Such methods and other embodiments generally relate to administering T cells, generally modified T cells, e.g., those expressing or containing recombinant receptors, e.g., chimeric antigen receptors (CARs) or TCRs, to such subjects.

[0006] In some embodiments, the cells administered in the aforementioned dose or in connection with any aspect of the provided method, composition, manufactured article and use 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 their subtypes (e.g., modified or recombinant receptor-expressing CD4) + Includes cells. In some embodiments, CD8 + To present cells or subtypes or phenotypes in a specific dose, amount, or number; in some embodiments, CD4 + To provide cells, subtypes, or phenotypes in a specific dose, amount, or number. In some embodiments, CD8 +A cell or its subtype or phenotype and CD4 + A cell or its subtype or phenotype are present in the article or 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 dosage or administration comprises or is a particular quantity or number of a population of one such cell, and the ratio is a defined ratio or a naturally occurring ratio, e.g., the ratio in the blood of the subject from which the cell is derived, or a ratio that exists without selection or control for a particular ratio.

[0007] In some embodiments, CD4 + T cells (or a subset thereof) and CD8 + T cells (or a subset thereof) each contain a receptor that specifically binds to a target antigen expressed by the disease or condition or its cells or tissues and / or a target antigen associated with the disease or condition.

[0008] In some embodiments, CD4 + and CD8 + cells are administered and / or formulated together, e.g., in a single formulation and / or in a single container.

[0009] In some embodiments, separate administrations of the dosage of CD4 + cells and CD8 + cells are performed, and / or are separate formulations or containers, each of which individually contains CD4 + cells or CD4 + modified cells concentrated in a separate formulation or container (e.g., at least a particular percentage (%), e.g., at least 80%, 85%, 90%, or 95%, or more CD4 + cells, and / or a formulation containing more than 10% or more than 5% CD8 + T cells not included) and CD8 + cells or CD8 +A separate formulation or container in which the modified cells are concentrated (for example, at least a specific percentage (%), e.g., at least 80%, 85%, 90%, or 95%, or more CD8) + Cell-containing formulations and / or more than 10% or more than 5% CD4 + This includes preparations that do not contain T cells.

[0010] In some aspects, administration involves administering a plurality of separate compositions, the plurality of separate compositions being CD4 + T cells and CD8 + A first composition containing one of the T cells, and CD4 + T cells and CD8 + The method provided comprises a second composition containing the other of the T cells. In any particular embodiment of the method provided, CD4 + Receptors and / or CD8 contained in T cells + The receptors contained in T cells include recombinant receptor-expressing T cells and / or CD4 + T cells and / or CD8 + T cells have been genetically modified to express the receptor in question.

[0011] In some aspects of any of the embodiments provided, the administration of the first composition and the administration of the second composition are carried out on the same day, with an interval of about 0 to about 12 hours, about 0 to about 6 hours, or about 0 to 2 hours; and / or the initiation of the administration of the first composition and the initiation of the administration of the second composition are carried out with an interval of about 1 minute to about 1 hour, or about 5 minutes to about 30 minutes. In certain aspects of any of the methods provided, the first composition and the second composition are administered with an interval 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.

[0012] In any particular embodiment of the provided configuration, the first composition is CD4 + Contains T cells. In some embodiment of any of the methods provided, the first composition is CD8 +Contains T cells. In any particular embodiment of the method provided, administration of the first composition is initiated before administration of the second composition. In any particular embodiment of the method provided, the cells of the dose have recombinant receptor expression CD4 at a specified ratio. + Cells and recombinant receptor expression CD8 + Cells and / or CD4 in specified ratios + Cells and CD8 + The composition includes cells, the ratio of which is arbitrarily 1:1, approximately 1:1, or approximately 1:3 to approximately 3:1; and / or CD4 containing the receptor in one of the first and second compositions. + T cells and CD8 containing the receptor in the other of the first and second compositions. + CD4 cells containing the receptor are present in a specified ratio, which can be any ratio of 1:1, approximately 1:1, or approximately 1:3 to approximately 3:1; and / or CD4 cells containing the receptor are administered in the first and second compositions. + T cells and CD8 containing the receptor in question + T cells are present in a specified ratio, which is arbitrarily 1:1, approximately 1:1, or approximately 1:3 to approximately 3:1. In some aspects of any of the methods provided, the specified ratio is 1:1 or approximately 1:1. In certain aspects of any of the methods provided, the dose of T cells is administered to a subject as a single dose or only once within a period of 2 weeks, 1 month, 3 months, 6 months, 1 year, or longer. In certain aspects of any of the methods provided, the dose of T cells is administered as a dual dose comprising a first dose of T cells and a subsequent dose of T cells, where one or both of the first and second doses constitute the administration of the plurality of compositions of T cells. In some aspects of any of the methods provided, the subsequent dose is administered at a point at least approximately 7 days or at least approximately 14 days after the start of administration of the first dose of cells, and no later than approximately 28 days after the start of administration of the first dose of cells.

[0013] In a particular embodiment of any of the methods or aspects provided, the cells of such dose are 1 × 10 5 Or approximately 1 x 10 5 ~5×108 Or approximately 5 x 10 8 1 x 10¹ fully recombinant receptor-expressing T cells or whole T cells 5 Or approximately 1 x 10 5 ~1 × 10 8 Or approximately 1 x 10 8 5 × 10¹ fully recombinant receptor-expressing T cells or whole T cells 5 Or approximately 5 x 10 5 ~1 × 10 7 Or approximately 1 x 10 7 1 x 10¹ fully recombinant receptor-expressing T cells or whole T cells 6 Or approximately 1 x 10 6 ~1 × 10 7 Or approximately 1 x 10 7 The method comprises 1 × 10¹⁵ fully recombinant receptor-expressing T cells or whole T cells, each including values ​​at both ends. In any particular embodiment of the method provided, the T cells of the dose are 1 × 10¹⁵ 8 1 × 10¹ or fewer fully recombinant receptor-expressing T cells or whole T cells 7 0.5 × 10¹ or fewer fully recombinant receptor-expressing T cells or whole T cells 7 1 × 10¹ or fewer fully recombinant receptor-expressing T cells or whole T cells 6 0.5 × 10¹ or fewer fully recombinant receptor-expressing T cells or whole T cells 6 The method includes administration of 5 × 10⁶ or fewer fully recombinant receptor-expressing T cells or whole T cells. In some embodiment of any of the methods provided, the dose of T cells is 5 × 10⁶ 7 Or approximately 5 x 10 7 ~1 × 10 8 Or approximately 1 x 10 8 It contains recombinant receptor-expressing T cells, each containing values ​​at both ends.

[0014] In any particular embodiment of the method provided, the recombinant receptor specifically binds to an antigen associated with the disease or condition, or to an antigen expressed on cells in the environment of a lesion associated with the disease or condition. In any particular embodiment of the method provided, the disease or condition is cancer. In some embodiment of the method provided, the disease or condition is myeloma, leukemia, or lymphoma.In any particular embodiment of the method provided, 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, antifolate 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, and 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 preferential expression antigen (PRAME), Survivin, TAG72, B7-H6, IL-13 receptor alpha2 (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, dual antigen, cancer testicular antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, tumor embryonic 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 antigen. In any particular embodiment of the method provided, the antigen is CD19.

[0015] In some aspects of any of the methods provided, the disease or condition is a B-cell malignancy and / or acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL). In certain aspects of any of the methods provided, 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 (non-specific type) (de novo and indolent transformed types), primary mediastinal large B-cell lymphoma (PMBCL), T-cell / histiocyte-rich large B-cell lymphoma (TCHRBCL), Burkitt lymphoma, mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B).

[0016] In some embodiments of any of the methods provided, 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, which is optionally a single-chain fragment. In certain embodiments of any of the methods provided, the fragment comprises a variable region of the antibody linked by a flexible linker. In some embodiments, the fragment comprises an scFv. In some embodiments of any of the methods provided, the recombinant receptor also comprises a spacer and / or hinge region.

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

[0018] In any particular embodiment of the method provided, the recombinant receptor also includes a transmembrane domain positioned between the extracellular domain and the intracellular signaling region.

[0019] In some embodiments of the methods provided, the intracellular signaling region also includes a co-stimulatory signaling region. In some embodiments, the co-stimulatory signaling region includes the intracellular signaling domain or signaling moiety of a T cell co-stimulatory molecule. In certain embodiments of the methods provided, the co-stimulatory signaling region includes the intracellular signaling domain or signaling moiety of CD28, 4-1BB, or ICOS. In some embodiments, the co-stimulatory signaling region is located between the transmembrane domain and the intracellular signaling region.

[0020] In any particular embodiment of the method provided, 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, wherein optionally, the intracellular signaling domain comprises an intracellular domain of a CD3-zeta (CD3ζ) chain; and / or the CAR further comprises a co-stimulatory signaling region optionally comprising a signaling domain of CD28 or 4-1BB.

[0021] In some embodiments, the manufactured article expresses a recombinant receptor CD4 + A container (e.g., a vial) containing a composition containing T cells, and a subject having a disease or pathological condition, and the CD4 + The CD4 + The composition of T cells is CD8, which expresses recombinant receptors. + Administered as multiple compositions together with a composition containing T cells, or the multiple CD4 + All or part of T cells and CD8 expressing recombinant receptors + The composition containing T cells is administered as a unit dose of cells. In some embodiments, the manufactured article contains CD8 cells expressing recombinant receptors. + A container (e.g., a vial) containing a composition containing T cells, and a subject having a disease or pathological condition, and the CD8 + The CD8 + The T cell composition is CD4 expressing recombinant receptors. + Administered as multiple compositions together with a composition containing T cells, or the multiple CD4 + All or part of T cells and CD8 expressing recombinant receptors + It is administered as a unit dose of cells containing a composition that includes T cells.

[0022] In some 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 4-1BB or containing 4-1BB), and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule (optionally a CD3 zeta signaling domain or containing one), optionally further comprising a spacer between the transmembrane domain and the scFv.

[0023] In some 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 containing 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 the embodiments, the CAR comprises, 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 a CD3 zeta signaling domain or containing one).

[0025] In some aspects, the spacer is (a) containing or consisting of all or part of an immunoglobulin hinge or a modified version thereof, or containing about 15 or fewer amino acids and not including the CD28 extracellular domain or the CD8 extracellular domain; (b) containing or consisting of all or part of an immunoglobulin hinge (optionally an IgG4 hinge) or a modified version thereof, and / or containing about 15 or fewer amino acids and not including the CD28 extracellular domain or the CD8 extracellular domain; or (c) being 12 amino acid length or about 12 amino acid length and / or containing or consisting of all or part of an immunoglobulin (optionally IgG4) hinge or a modified version 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 A sequence encoded by NO:34, or having or consisting of any variant of the said having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher sequence identity; or (e) a polypeptide spacer comprising or consisting of formula X1PPX2P, where X1 is glycine, cysteine, or arginine, and X2 is cysteine ​​or threonine; and / or a co-stimulatory domain, 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; and / or the primary signaling domain includes SEQ ID NO:13, 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;And / or scFv is 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 YAMDYWG (SEQ ID NO:40) contains the CDRH3 sequence, or scFv contains the heavy chain variable region and light chain variable region of FMC63, and / or the CDRL1 sequence, CDRL2 sequence, CDRL3 sequence, CDRH1 sequence, CDRH2 sequence, and CDRH3 sequence of FMC63, or binds to the same epitope as any of the above, or competes with any of the above for binding, and optionally scFv is in order V; H , linker (optionally including SEQ ID NO:24), and V L The scFv includes a flexible linker and / or an amino acid sequence indicated as SEQ ID NO:24.

[0026] In some embodiments, the spacer includes or consists of SEQ ID NO:1, the co-stimulatory domain includes 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, the transmembrane domain is of CD28 or includes 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, and the scFv is the binding domain of FMC63 or CDR or V H and V LThe primary signaling domain includes SEQ ID NO: 13, 14, or 15 and / or variants thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher sequence identity.

[0027] In some embodiments, the spacer includes or consists of SEQ ID NO:30, the co-stimulatory domain includes 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, the transmembrane domain is of CD28 or includes 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, and the scFv is the binding domain of FMC63 or CDR or V H and V L The primary signaling domain includes SEQ ID NO: 13, 14, or 15 and / or variants thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher sequence identity.

[0028] In some embodiments, the spacer includes or consists of SEQ ID NO:31, the co-stimulatory domain includes 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, the transmembrane domain is of CD28 or includes 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, and the scFv is the binding domain of FMC63 or CDR or V H and V L The primary signaling domain includes SEQ ID NO: 13, 14, or 15 and / or variants thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher sequence identity.

[0029] In some embodiments, the spacer includes or consists of SEQ ID NO:33, the co-stimulatory domain includes 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, the transmembrane domain is of CD28 or includes 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, and the scFv is the binding domain of FMC63 or CDR or V H and V Lcomprising, the primary signaling domain comprises SEQ ID NO:13, 14 or 15 and / or variants thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto.

[0030] In some embodiments, the spacer comprises or consists of SEQ ID NO:34, the co-stimulatory domain comprises SEQ ID NO:12 or variants 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 variants 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 CDR or V H and V L comprising, the primary signaling domain comprises SEQ ID NO:13, 14 or 15 and / or variants thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity thereto.

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

[0032] In certain embodiments of any of the provided articles of manufacture, the vial contains cells at about 10 million cells / ml to about 70 million cells / ml, about 10 million cells / ml to about 50 million cells / ml, about 10 million cells / ml to about 25 million cells / ml, about 10 million cells / ml to about 15 million cells / ml, 15 million cells / ml to about 70 million cells / ml, about 15 million cells / ml to about 50 million cells / ml, about 15 million cells / ml to about 25 million cells / ml, about 25 million cells / ml to about 70 million cells / ml, about 25 million cells / ml to about 50 million cells / ml, and about 50 million cells / ml to about 70 million cells / ml. In some embodiments of any of the provided articles of manufacture, the composition further comprises a cryoprotective substance 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 2×10 7 or about 2×10 7 to 4×10 7 or about 4×10 7 CD8 + cells, such as about 2×10 7 , about 2.5×10 7 , about 3×10 7 , about 3.5×10 7 , or about 4×10 7 [[ID=3))2]]CD8 + cells, and 2×10 7 or about 2×10 7 to 4×10 7 or about 4×10 7 CD4 + cells, such as about 2×10 7 , about 2.5×10 7 , about 3×10 7 , about 3.5×10 7 , or about 4×10 7 CD4 +The composition contains a dose of cells, each containing values ​​at both ends. In some embodiments, the composition or multiple compositions are approximately 3 × 10 7 CD8 + Cells and approximately 3.5 × 10 7 CD4 + Contains cells in doses containing cells.

[0034] In any particular embodiment of the manufactured article provided, cells of multiple compositions express recombinant receptor CD4 in a specified ratio. + Cells and recombinant receptor expression CD8 + Cells and / or CD4 in specified ratios + Cells and CD8 + The cells are included, and the ratio is arbitrarily about 1:1 or about 1:3 to about 3:1. In any particular embodiment of the manufactured article provided, the specified ratio is 1:1 or about 1:1. In some embodiment of the manufactured article provided, the multiple compositions together amount to 1 × 10 5 Or approximately 1 x 10 5 ~5×10 8 Or approximately 5 x 10 8 1 x 10¹ fully recombinant receptor-expressing T cells or whole T cells 5 ~1 × 10 8 5 × 10¹ fully recombinant receptor-expressing T cells or whole T cells 5 Or approximately 5 x 10 5 ~1 × 10 7 Or approximately 1 x 10 7 1 x 10⁶ total recombinant receptor-expressing T cells or total T cells, or 1 x 10⁶ 6 Or approximately 1 x 10 6 ~1 × 10 7 Or approximately 1 x 10 7 The article contains a certain dose of cells, each containing either a total recombinant receptor-expressing T cell or a total T cell, with each containing values ​​at both ends. In any particular embodiment of the provided manufactured article, the multiple compositions together comprise 1 × 10⁶ 8 1 × 10¹ or fewer fully recombinant receptor-expressing T cells or whole T cells 7 0.5 × 10¹ or fewer fully recombinant receptor-expressing T cells or whole T cells 71 × 10¹ or fewer fully recombinant receptor-expressing T cells or whole T cells 6 0.5 × 10¹ or fewer fully recombinant receptor-expressing T cells or whole T cells 6 A certain dose of cells comprising 5 or fewer fully recombinant receptor-expressing T cells or whole T cells. In any particular embodiment of the provided manufactured article, the multiple compositions together comprise 5 × 10 7 Or approximately 5 x 10 7 pieces~1×10 8 Or approximately 1 x 10 8 A certain dose of cells, each containing recombinant receptor-expressing T cells, is included, with each containing values ​​at both ends.

[0035] In some embodiment of any of the manufactured articles provided, CD4 + Composition containing T cells and CD8 + The instructions specify that the composition containing T cells be administered at intervals of 0-12 hours, 0-6 hours, or 0-2 hours. In any particular embodiment of the manufactured article provided, CD4 + Composition containing T cells and CD8 + The composition containing T cells is specified to be 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. In any particular embodiment of the manufactured article provided, the instructions specify CD4 + A composition containing T cells, CD8 + It is specified to be administered before administering compositions containing cells. In some embodiments of any of the manufactured articles provided, the instructions specify CD8 + A composition containing T cells, CD4 + It is specified that this drug be administered before administering compositions containing cells.

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

[0037] In any particular embodiment of the manufactured article provided, 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, antifolate 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, and 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 preferential expression antigen (PRAME), Survivin, TAG72, B7-H6, IL-13 receptor alpha2 (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, dual antigen, cancer testicular antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, tumor embryonic 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 antigen. In any particular embodiment of the manufactured article provided, the antigen is CD19.

[0038] In some aspects of any of the manufactured articles provided, the disease or condition is a B-cell malignancy and / or acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL). In certain aspects of any of the manufactured articles provided, the disease or condition is NHL, and NHL is selected from the group consisting of aggressive NHL, diffuse large B-cell lymphoma (DLBCL), NOS (de novo and indolent transformed types), primary mediastinal large B-cell lymphoma (PMBCL), T-cell / histiocyte-rich large B-cell lymphoma (TCHRBCL), Burkitt lymphoma, mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B).

[0039] In any particular aspect of the manufactured product provided, the T cells are primary T cells derived from the subject. In some aspect of the manufactured product provided, the T cells are autologous cells of the subject. In any particular aspect of the manufactured product provided, the T cells are allogeneic to the subject.

[0040] In any particular embodiment of the manufactured article provided, the recombinant receptor is a functional non-TCR antigen receptor or a TCR or its antigen-binding fragment, or comprises the same. In some embodiments, the recombinant receptor is a chimeric antigen receptor (CAR).

[0041] In certain embodiments of the provided manufactured articles, 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 (optionally a single-chain fragment). In some embodiments, the fragment comprises a variable region of the antibody linked by a flexible linker. In some embodiments, the fragment comprises an scFv.

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

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

[0044] In any particular embodiment of the provided manufactured article or method, the recombinant receptor also includes a transmembrane domain positioned between the extracellular domain and the intracellular signaling region.

[0045] In some embodiments of any of the provided manufactured articles or methods, the intracellular signaling region also includes a co-stimulatory signaling region. In some embodiments, the co-stimulatory signaling region includes the intracellular signaling domain or signaling moiety of a T cell co-stimulatory molecule. In some embodiments of any of the provided manufactured articles, the co-stimulatory signaling region includes the intracellular signaling domain or signaling moiety of CD28, 4-1BB, or ICOS. In some embodiments, the co-stimulatory signaling region is located between the transmembrane domain and the intracellular signaling region.

[0046] In some embodiments, methods and articles are for or can treat subjects having non-Hodgkin lymphoma (NHL). In some aspects, a formulation that can be administered to a subject in a certain dose or number of T cells is accompanied by and / or designated or included by the product. In some aspects, the T cells are T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by NHL, e.g., CD8 + T cells and / or CD4 + Includes T cells.

[0047] In some embodiments, the T cells at that dose are 5 × 10 7 Or approximately 5 x 10 7 pieces~1×10 8 Or approximately 1 x 10 8 The study includes CAR-expressing T cells (including values ​​at both ends); 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 subjects are identified as having or possessing Performance Status (ECOG) status 0 or 1 of the US East Coast Cancer Clinical Trials Group.

[0048] In some embodiment of any of the embodiments provided, the method further includes a step of identifying a treatment for a subject having 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 an ECOG status of 0 or 1, or the manufactured article includes information specifying a treatment for a subject having 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 an ECOG status of 0 or 1. In some embodiment of any of the embodiments provided, the dose of T cells and / or cells administered have a specified ratio of CAR-expressing CD4 + Cells and CAR expression CD8 + Cells and / or CD4 in specified ratios + Cells and CD8 + It contains cells, and the ratio is arbitrarily about 1:1 or about 1:3 to about 3:1.

[0049] In some aspects, the embodiments are for treating subjects with non-Hodgkin lymphoma (NHL) and involve administering a certain dose of T cells to the subject, including T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by NHL. In some aspects, the dose of T cells expresses a specified ratio of CAR-expressing CD4 + Cells and CAR expression CD8 + Cells and / or CD4 in specified ratios + Cells and CD8 + The cells include, in some aspects, the ratio is approximately 1:1 or 1:1. In some aspects, NHL includes diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), NOS (non-specific type) (transformed from de novo or indolent lymphoma), or follicular lymphoma grade 3B.

[0050] In any particular aspect of the provided embodiments, the subject is identified, identified as having, or designated to have, an ECOG Performance Status (ECOG) status of 0, 1, or 2.

[0051] In some embodiments of any of the provided embodiments, the administration of cells by the method and / or use and / or manufactured article achieves some outcome and / or is associated with some reduction in toxicity risk in a target population treated, for example, according to the method or the information provided in the manufactured article. In some aspects, at least 35%, at least 40%, or at least 50% of subjects treated according to the method achieve complete response (CR) and / or sustained CR; and / or at least 50%, at least 60%, or at least 70% of subjects treated according to the method achieve objective response (OR) and / or sustained OR. In certain embodiments of any of the provided embodiments, the response is sustained for more than 3 months or more than 6 months. In some embodiments, at the time of or prior to administration of the dose of cells, at least 40%, at least 50%, at least 60%, and at least 70% of subjects who had or were identified as having double / triple-hit lymphoma or relapse (optionally within 12 months) after autologous stem cell transplantation (ASCT) achieved an OR, which optionally persisted for 3 months or more or 6 months or more. In certain embodiments of the provided method, more than 50% or about 50% of subjects treated according to the method did not exhibit grade 3 or higher cytokine release syndrome (CRS) or grade 3 or higher neurotoxicity. In some embodiments, such subjects did not exhibit early-onset CRS and / or neurotoxicity.

[0052] A method for evaluating the likelihood of response to cell therapy is provided herein, 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 that is a candidate for treatment with cell therapy, and the cell therapy comprises a certain dose of genetically modified cells expressing a recombinant receptor; the biological sample is obtained from the subject before the application of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and comparing the level, amount, or concentration of the analytes in the sample individually to a threshold level, thereby determining the likelihood that the subject will achieve a sustained response to the cell therapy. In some embodiments, the method also comprises the step of applying the cell therapy to the subject if the subject is likely to achieve a response.

[0053] A method for selecting subjects for treatment is provided herein, 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 that is a candidate for treatment in cell therapy, and the cell therapy comprises a certain dose of genetically modified cells expressing a recombinant receptor; the biological sample is obtained from the subject before the application of the cell therapy, and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and selecting subjects that are likely to respond to the treatment based on the results of determining the likelihood that the subjects will achieve response to the cell therapy by individually comparing the level, amount, or concentration of the analytes in the sample to a threshold level. In some embodiments, the method also comprises the step of applying the cell therapy to the subjects selected for treatment.

[0054] A treatment method is provided herein, comprising the steps of: selecting subjects likely to respond to cell therapy based on the likelihood of a subject achieving 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 ferritin, LDH, CXCL10, G-CSF, and IL-10, wherein the biological sample is derived from a subject that is a candidate for cell therapy, the cell therapy comprises a certain dose of genetically modified cells expressing a recombinant receptor; the biological sample is obtained from the subject before the application of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and applying the cell therapy to the subjects selected for treatment.

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

[0056] In some embodiments, the threshold level is within 25%, 20%, 15%, 10%, or 5% below the median or mean level, amount, or concentration of the analyte in the biological sample obtained from the group of subjects before receiving cell therapy, and / or within a standard deviation below the median or mean, or the median or mean, or approximately the median or mean, where each subject in the group is a subject who achieved a response after administration of a recombinant receptor-expressing therapeutic cell composition for treating 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 level, amount, or concentration of the analyte in the biological sample obtained from the group of subjects prior to cell therapy, and / or within a standard deviation above the median or mean, wherein each subject in the group is a subject that exhibited stable disease (SD) and / or progressive disease (PD) after administration of a recombinant receptor-expressing therapeutic cell composition for treating the same disease or condition.

[0058] In some embodiments, response includes objective response. In some embodiments, objective response includes complete response (CR) or partial response (PR).

[0059] A method for evaluating the likelihood of a sustained response to cell therapy is provided herein, 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 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 that is a candidate for treatment with cell therapy, the cell therapy comprises a certain dose of genetically modified cells expressing a recombinant receptor; the biological sample is obtained from the subject before the application of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and comparing the level, amount, or concentration of the analytes in the sample individually to a threshold level to determine the likelihood that the subject will achieve a sustained response to the cell therapy.

[0060] In some embodiments, the method also includes the step of applying the cell therapy to a subject if the subject is likely to achieve a response.

[0061] A method for selecting subjects for treatment is provided herein, 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 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 that is a candidate for treatment in cell therapy, the cell therapy comprises a certain dose of genetically modified cells expressing a recombinant receptor; the biological sample is obtained from the subject before the application of the cell therapy, and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and selecting subjects that are likely to respond to the treatment 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 the analytes in the sample to a threshold level. In some embodiments, the method also includes the step of applying the cell therapy to a subject selected for treatment.

[0062] A treatment method is provided herein, comprising the steps of: selecting subjects likely to respond to cell therapy based on the likelihood of the subjects achieving 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 that is a candidate for treatment with cell therapy, the cell therapy comprises a certain dose of genetically modified cells expressing a recombinant receptor; the biological sample is obtained from the subject before the application of the cell therapy and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and applying the cell therapy to the subjects selected for treatment.

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

[0064] In some embodiments, the threshold level is within 25%, 20%, 15%, 10%, or 5% below the median or mean level, amount, or concentration of the analyte in the biological sample obtained from the group of subjects before receiving cell therapy, and / or within a standard deviation below the median or mean, or the median or mean, or approximately the median or mean, where each subject in the group is a subject who achieved a sustained response after administration of a recombinant receptor-expressing therapeutic cell composition for treating 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 level, amount, or concentration of the analyte in the biological sample obtained from the group of subjects before receiving cell therapy, and / or within a standard deviation above the median or mean, wherein each subject in the group is a subject that did not achieve a sustained response after administration of a recombinant receptor-expressing therapeutic cell composition for treating the same disease or condition.

[0066] In some embodiments, a sustained response includes a sustained complete response (CR) or partial response (PR) lasting for three months or longer, four months or longer, five months or longer, or six months or longer.

[0067] In some embodiments, a sustained response includes a sustained complete response (CR) or partial response (PR) lasting at least three months.

[0068] A method for evaluating the risk of developing toxicity after the application of cell therapy, comprising the step of evaluating the level, amount, or concentration of one or more analytes in a biological sample of interest, or a volume measurement of tumor burden in the subject, wherein the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (fibrin degradation product), IL-6, IL-8, IL-10, IL-15, IL-16, TNF-α, IFN-α2, MCP-1, MIP-1α, and MIP-1β, where, A method is provided herein that includes the steps of: the subject being a candidate for treatment in cell therapy, the cell therapy optionally comprising genetically modified cells expressing a recombinant receptor in a certain dose or composition; the biological sample being obtained from the subject before the application of the cell therapy and / or the biological sample not containing the recombinant receptor and / or the modified cells; and individually comparing the level, amount, or concentration of the analyte in the sample, or the volume measurement of tumor load, to a threshold level, thereby determining the risk of developing toxicity after the application of the cell therapy.

[0069] A method for identifying a subject is provided herein, comprising the steps of: evaluating the level, amount, or concentration of one or more analytes in a biological sample of the subject, or a volume measurement of tumor load in the subject, wherein the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (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 in cell therapy, the cell therapy optionally includes genetically modified cells expressing a recombinant receptor in a certain dose or composition; the biological sample is obtained from the subject before the application of the cell therapy, and / or the biological sample does not contain the recombinant receptor and / or the modified cells; and identifying a subject at risk of developing toxicity after the application of cell therapy by individually comparing the level, amount, or concentration of the analytes in the sample, or the volume measurement of tumor load, to a threshold level.

[0070] A step of evaluating the level, amount, or concentration of one or more analytes in a biological sample of interest, or a volume measurement of the tumor burden of the subject, wherein the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (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 in cell therapy, the cell therapy optionally includes genetically modified cells expressing recombinant receptors in a certain dose or composition; and the biological sample is obtained from the subject before the application of the cell therapy. A treatment method is provided herein, comprising the steps of: ensuring that the biological sample does not contain the recombinant receptor and / or the modified cells; individually comparing the level, amount, or concentration of the analyte in the sample, or the volume measurement of the tumor load, to a threshold level, thereby determining the risk of developing toxicity after the application of the cell therapy; and applying the cell therapy to the subject in accordance with or based on the results of the assessment, and optionally applying an active agent or other treatment that can treat, prevent, delay, reduce, or attenuate the development or risk of toxicity.

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

[0072] In some embodiments, the volume measurement of the tumor load is a two-way sum of products (SPD) or a volume measurement based on CT and / or MRI imaging or other imaging studies of the body. In some embodiments, the volume measurement of the tumor load is performed before treatment, before apheresis, or before the production of cell products.

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

[0074] In some embodiments, if the level, amount, or concentration of one or more analytes or the volume measurement of tumor load 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 volume measurement of tumor load is below the threshold level, the subject is at low risk of developing toxicity.

[0075] In some embodiments, the threshold level is within 25%, 20%, 15%, 10%, or 5% above the level, amount, or concentration of the analyte in a biological sample obtained from a group of subjects before cell therapy, or within 25%, 20%, 15%, 10%, or 5% above the median or mean of the volume measurement of tumor load in the biological sample, and / or within a standard deviation above the median or mean, or the median or mean, or approximately the median or approximately the mean, where each subject in the group is a subject that has not shown any toxicity after receiving a recombinant receptor-expressing therapeutic cell composition for treating 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 analyte level, amount, or concentration in a biological sample obtained from a group of subjects prior to cell therapy, or within a standard deviation below the median or mean value of the volume measurement of tumor load in the biological sample, where each subject in the group is a subject that developed toxicity after receiving a recombinant receptor-expressing therapeutic cell composition for treating the same disease or condition.

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

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

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

[0080] In some embodiments, the toxicity is neurotoxicity, the volume measurement of tumor load 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 neurotoxic, and one or more analytes are evaluated, 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 neurotoxic, and one or more analytes are evaluated, selected from IL-8, IL-10, and CXCL10.

[0083] In some aspects, neurotoxicity is severe neurotoxicity or neurotoxicity of grade 3 or higher.

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

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

[0086] In some embodiments, if a subject is identified as being at risk of developing toxicity, (1) an active substance or other treatment that can treat, prevent, delay, reduce or attenuate the development or risk of toxicity, and (2) cell therapy should be applied to the subject, wherein the administration of the active substance should be (i) before the commencement of the application of the cell therapy to the subject, (ii) within one, two, or three days of the commencement of the application of the cell therapy to the subject, (iii) in parallel with the commencement of the application of the cell therapy to the subject, and / or (iv) at the time of the first fever after the commencement of the application of the cell therapy to the subject. ;and / or, administering cell therapy to subjects at a low dose or at a dose that does not carry a risk of developing toxicity or severe toxicity after the administration of cell therapy, or at a dose that does not carry a risk of developing toxicity or severe toxicity in the majority of subjects and / or in the majority of subjects having the disease or condition (which the subject has or is suspected to have);and / or, administering cell therapy to subjects in an inpatient setting and / or with one or more days of hospitalization, here optionally, otherwise administering cell therapy to subjects on an outpatient basis or without one or more days of hospitalization.

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

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

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

[0090] In some embodiments, a volume measurement is evaluated, the volume measurement is an SPD, and the threshold level is 30 or approximately 30 cm⁻¹. 2 40 or approximately 40 cm 2 50 or approximately 50 cm 2 , 60 or approximately 60 cm 2 , or 70 or approximately 70 cm 2 In some embodiments, the volume measurement is SPD, and the threshold level is 50 cm⁻¹. 2 or about 50 cm 2 That is the case.

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

[0092] In some embodiments, the recombinant receptor specifically binds to an antigen associated with the disease or condition, or to 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 acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL).

[0093] In some embodiments, recombinant receptors are chimeric antigen receptors (CARs). In some embodiments, modified cells are T cells, optionally CD4 + and / or CD8 +This includes, in some embodiments, primary T cells obtained from the subject or autologous cells of the subject.

[0094] A method for treating a subject with non-Hodgkin lymphoma (NHL), comprising the step of administering to the subject a certain dose of T cells, the T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by NHL, wherein the dose of T cells is 5 × 10⁻¹⁴ 7 Or approximately 5 x 10 7 pieces~1×10 8 Or approximately 1 x 10 8 The dose comprises (including the values ​​at both ends) recombinant receptor-expressing T cells, wherein the dose is a specified ratio of recombinant receptor-expressing CD4 + Cells and recombinant receptor expression CD8 + Cells and / or CD4 in specified ratios + Cells and CD8 + The present invention provides a method comprising cells in a ratio of approximately 1:1 or 1:1; wherein the method results in (1) a complete response (CR) in at least 35%, at least 40%, or at least 50% of the treated subjects and / or an objective response (OR) in at least 50%, at least 60%, or at least 70% of the treated subjects, and (2) no more than 50% of the subjects exhibiting cytokine release syndrome (CRS) of grade 2 or higher and / or neurotoxicity of grade 2 or higher.

[0095] In some embodiment of the method provided, at the time of or prior to administration of such dose of cells, at least 40%, at least 50%, at least 60%, and at least 70% of subjects who had or were identified as having double / triple-hit lymphoma (or high-grade B-cell lymphoma with DLBCL histology, MYC and BCL2 and / or BCL6 rearrangement (double / triple-hit)) or relapse after autologous stem cell transplantation (ASCT) achieve an OR, optionally sustained for three months or more or six months or more.

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

[0097] In some embodiments, CR or OR is persistent 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 persistent CR; at least 60%, 70%, 80%, 90%, or 95% of subjects treated with the method and achieving CR remain in CR, remain in response, or remain alive for more than 3 months, more than 6 months, or more than 9 months; and / or at least 60%, 70%, 80%, 90%, or 95% of subjects treated with the method and achieving CR within 1 month and / or 3 months remain in CR for more than 3 months and / or more than 6 months and / or remain in response, in complete response (CR), and / or survive for 9 months or longer; and / or at least 50%, at least 60%, or at least 70% of subjects treated in accordance with the said method achieve an objective response (OR), optionally sustained for 3 months or 6 months or longer, or sustained for 3 months or 6 months or longer in at least 60%, 70%, 80%, 90%, or 95% of subjects achieving an OR; and / or at least 60%, 70%, 80%, 90%, or 95% of subjects treated in the said method achieving an OR remain in response or survive for 3 months and / or 6 months or longer.

[0098] In some embodiments, subjects were identified as having, or having, lymphoma associated with or with central nervous system (CNS) infiltration at or before the administration of the dose of cells; and / or at least 70%, at least 80%, at least 90%, or at least 95% of subjects treated according to the method who showed, or were identified as showing, lymphoma with CNS infiltration at or before the administration of the dose of cells achieved resolution of the CNS disease.

[0099] This specification provides a method for treating a subject having lymphoma, comprising the step of administering a certain dose of T cells, comprising 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. In some aspects, at the time of or before administration of the dose of cells, the subject includes brain lesions, optionally temporal lobe brain lesions. In some examples, the lymphoma is a B-cell malignancy. In some aspects, the lymphoma is non-Hodgkin lymphoma (NHL).

[0100] In any of such embodiments, at least 35%, at least 40%, or at least 50% of subjects treated according to the method achieve complete response (CR) or remission of CNS disease and / or reduction or disappearance of CNS disease, optionally, the CR or remission or reduction or disappearance of CNS disease persists for three months or six months or longer, or persists for three months or six months or longer in at least 60%, 70%, 80%, 90%, or 95% of subjects achieving CR; and / or at least 60%, 70%, 80%, 90%, or 95% of subjects achieving CR or remission or other reduction of CNS disease by one month and / or three months remain in a state of response, remain in remission (e.g., CR), or still show signs of reduction or remission for three months or longer and / or six months or longer and / or nine months or longer. The subjects are and / or are alive or alive without progression; and / or at least 50%, at least 60%, or at least 70% of the subjects treated in accordance with the said method achieve an objective response (OR) or remission of the CNS disease, which optionally lasts for three months or six months or longer, or lasts for three months or six months or longer in at least 60%, 70%, 80%, 90%, or 95% of the subjects achieving the OR or remission of the CNS disease; and / or at least 60%, 70%, 80%, 90%, or 95% of the subjects achieving the OR or remission of the CNS disease remain in a state of response or remain alive for three months and / or six months or longer; and / or the size or volume of the brain lesions are optionally reduced by more than 25% or about 25%, more than 50% or about 50%, more than 75% or about 75%, or more.In some aspects, the reduction, remission, or disappearance of CNS disease is achieved without signs or symptoms of toxicity (e.g., neurotoxicity, e.g., severe neurotoxicity, e.g., grade 2 or higher or grade 3 or higher), and / or without toxicity caused by the activation or presence of cellular therapy cells in the subject's brain, and / or without higher toxicity levels compared to subjects with residual CNS disease and / or subjects treated with the therapy but not exhibiting CNS disease.

[0101] In some embodiment of any of the methods provided, more than 30% or about 30%, more than 35% or about 35%, more than 40% or about 40%, or more than 50% or about 50% of subjects treated according to the method do not exhibit cytokine release syndrome (CRS) or neurotoxicity of any grade. In some embodiment of any of the methods provided, 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 do not exhibit early-onset CRS or neurotoxicity, and / or The subject does not develop CRS earlier than 3 days after the start of administration, and / or does not develop neurotoxicity earlier than 5 days after the start of administration, and / or the median time to the onset of neurotoxicity in the subject treated according to the method is the median peak of CRS or thereafter, or the median time to the resolution of CRS in the subject treated according to the method or thereafter, and / or the median time to the onset of neurotoxicity in the subject treated according to the method is greater than 8 or about 8 days, greater than 9 or about 9 days, greater than 10 or about 10 days, or greater than 11 or about 11 days.

[0102] In any particular embodiment of the method provided, prior to the commencement of administration of such dose of cells, the subject has not been administered any agent or treatment that can treat, prevent, delay, reduce, or attenuate the occurrence of toxicity or the risk thereof. In any particular embodiment of the method provided, no agent or treatment for treating, preventing, reducing, or attenuating neurotoxicity and / or cytokine release syndrome or the risk thereof has been administered to the subject within a period after administration of such dose, which may be 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 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 1 week, 2 weeks, 3 weeks, or 4 weeks. In any particular embodiment of the method provided, an agent or treatment for the treatment, prevention, reduction, or attenuation of neurotoxicity and / or cytokine release syndrome or its risk thereof is not administered to the subject after the administration of such dose, unless 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, or unless the subject shows signs or symptoms of toxicity other than fever, and optionally, the fever is not sustained fever, or the fever has subsided or subsided, or has subsided or subsided by more than 1°C after treatment with an antipyretic. In any particular embodiment of the method provided, administration and follow-up are performed on an outpatient basis, and / or without hospitalization of the subject, and / or without hospitalization or an overnight stay in a hospital, and / or without requiring hospitalization or an overnight stay in a hospital, unless the subject shows sustained fever, or fever that has not subsided or subsided, or has not subsided or subsided by more than 1°C after treatment with an antipyretic, or until such fever appears.

[0103] In some aspects of the method provided, prior to the initiation of administration of the dose of cells, the subject has not received an anti-IL-6 or anti-IL-6R antibody (optionally tocilizumab or siltuximab) and / or a steroid (optionally dexamethasone). In certain aspects of the method provided, the subject has not received an anti-IL-6 or anti-IL-6R antibody (optionally tocilizumab or siltuximab) and / or a steroid (optionally dexamethasone) during a period following the administration of the dose, and such period 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 any particular embodiment of the method provided, after administration of the cell dose, before the subject shows signs or symptoms of toxicity (optionally neurotoxicity or CRS), unless the subject shows signs or symptoms of such toxicity, and / or before the subject shows signs or symptoms of toxicity other than fever (optionally neurotoxicity or CRS), or unless the subject shows signs or symptoms of such toxicity other than fever, no anti-IL-6 or anti-IL-6R antibody (optionally tocilizumab or siltuximab) is administered to the subject, and / or no steroid (optionally dexamethasone) is administered, where optionally, the fever is not sustained fever, or has subsided or subsided or subsided by more than 1°C after treatment with an antipyretic. In any particular embodiment of the method provided, administration and optional follow-up are performed on an outpatient basis, and / or without hospitalization of the subject, and / or without hospitalization or an overnight stay in a hospital, and / or without requiring hospitalization or an overnight stay in a hospital, unless the subject optionally exhibits a fever that does not subside or has not subsided or has not subsided or has not subsided or has not subsided by more than 1°C after treatment with an antipyretic, or until such fever develops.

[0104] In some embodiments of the methods provided, administration is carried out on an outpatient basis and / or without requiring hospitalization or an overnight stay in a hospital. In some embodiments of the methods provided, if a subject being treated on an outpatient basis exhibits sustained fever or fever that does not subside or has not subsided after treatment with an antipyretic, or fever that does not subside or has not subsided or has not subsided by more than 1°C, the subject may be admitted to a hospital or an overnight stay in a hospital and / or be administered an agent or treatment for the treatment, prevention, reduction or attenuation of neurotoxicity and / or cytokine release syndrome or its risk.

[0105] In any particular embodiment of the method provided, 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 any particular embodiment of the method provided, 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. In some examples, NHL includes DLBCL. In some embodiment of any of the methods provided, DLBCL is a de novo or follicular lymphoma (FL) transformed form and / or does not include DLBCL transformed from MZL and DLBCL transformed from CLL (Richter's transformation).

[0106] In certain embodiments of the methods provided, the subject is identified as having or having an ECOG status of 0, 1, or 2 in the US East Coast Cancer Clinical Trials Group. In certain embodiments of the methods provided, the subject is identified as having or having an ECOG status of 0 or 1. In some embodiments of the methods provided, at or immediately before the administration of the dose of cells, the subject is either relapsed after remission following treatment with one or more prior treatments for NHL (optionally, one, two, or three prior treatments other than another dose of cells expressing CAR) or refractory to such prior treatments.

[0107] In some embodiments of the methods provided, at the time of or prior to administration of the dose of cells, subjects are identified as having, or are identified as having, a lymphoma associated with or involving central nervous system (CNS) infiltration. In some embodiments of the methods provided, at least 70%, at least 80%, at least 90%, or at least 95% of subjects treated according to the methods who showed, or were identified as showing, a lymphoma with CNS infiltration at the time of or prior to administration of the dose of cells achieved resolution of the CNS disease.

[0108] In any particular embodiment of the method provided, the subject is identified as having, or has been identified as having, a double / triple-hit lymphoma (or high-grade B-cell lymphoma with DLBCL histology and BCL2 and / or BCL6 rearrangement (double / triple-hit)) at or before the administration of the dose of cells; the subject is identified as having, or has been identified as having, a chemotherapy-resistant lymphoma (optionally, chemotherapy-resistant DLBCL); the subject has not achieved complete remission (CR) in response to prior treatment; and / or the subject has relapsed within or less than one year after receiving autologous stem cell transplantation (ASCT).

[0109] In some embodiment of the method provided, the method includes identifying or selecting subjects for administration of the dose of cells who, prior to administration of the dose, have not achieved complete remission (CR) in response to prior treatment for double / triple-hit lymphoma (or high-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 reorganization (double / triple-hit) having DLBCL histology), chemotherapy-resistant lymphoma (optionally chemotherapy-resistant DLBCL), malignancy (optionally NHL); and / or have 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) infiltration.

[0110] In some embodiments of the method provided, the method optionally uses CAR, which is otherwise cell therapy. +The process further includes the application of additional therapeutic agents or treatments other than T-cell therapy. In some embodiments, the additional therapeutic agent or treatment 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 treatment is administered if the subject does not respond to the cell therapy within one month, two months, or three months after administration of the dose of cells, and optionally does not show a complete response (CR) or an alternative response (OR). In some embodiments, the additional therapeutic agent or treatment is administered to subjects identified or specified as having stable or progressive disease (SD / PD) after prior treatment (optionally prior treatment with chemotherapeutic agents), subjects identified or specified as having Performance Status 2 of the US East Coast Clinical Oncology Group (ECOG), subjects identified or specified as having transformed follicular lymphoma (tFL), and / or subjects identified or specified as having DLBCL transformed from MZL and CLL. In some embodiments, prior to the application of the dose of cells or additional therapeutic agents or treatments, the method includes identifying or selecting subjects having prior treatment, optionally prior treatment with chemotherapeutic agents, stable or progressive disease (SD / PD), performance status (ECOG) status 2 of the US East Coast Clinical Oncology Group, transformed follicular lymphoma (tFL), and / or DLBCL transformed from MZL and CLL, for administration of the dose of cells. In any one of such embodiments, the additional therapeutic agent or treatment is applied before the commencement of administration of the dose of cells, at the same time as the commencement of administration of the dose of cells, or concurrently with the commencement of administration of the dose of cells, and / or after the commencement of administration of the dose of cells.

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

[0112] In certain embodiments of any of the methods provided, prior to such administration, the subject is preconditioned with lymphocyte apheresis including the administration of fludarabine and / or cyclophosphamide. In certain embodiments of any of the methods provided, the step of applying lymphocyte apheresis including the administration of fludarabine and / or cyclophosphamide to the subject immediately before such administration is further included. In some embodiments of any of the methods provided, the lymphocyte apheresis is administered at approximately 200-400 mg / m², including both extreme values. 2 (Optionally 300 or approximately 300 mg / m²) 2 ) Cyclophosphamide, and / or about 20-40 mg / m² 2 (Optional: 30 mg / m²) 2 The treatment involves administering fludarabine at a dose of 300 mg / m² daily for 2 to 4 days (optionally 3 days). In any particular embodiment of the method provided, the lymphocyte apheresis therapy is 300 mg / m². 2 Or approximately 300 mg / m² 2 Cyclophosphamide and approximately 30 mg / m² 2 This includes administering fludarabine daily for three days.

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

[0114] In any particular embodiment of the method provided, at least 40% or at least 50% of subjects treated according to the method achieve complete remission (CR) and exhibit progression-free survival (PFS) and / or overall survival (OS) longer than 3 or about 3 months, 6 or about 6 months, or 12 or about 12 months; on average, subjects treated according to the method exhibit a median PFS or OS longer than 6 or about 6 months, 12 or about 12 months, or 18 or about 18 months; and / or subjects exhibit at least 6 or about 6 months, 12 or about 12 months, 18 or about 18 months, or longer PFS or OS after treatment. In any particular embodiment of the method provided, CARs detectable in the blood of subjects, or detectable in the majority of subjects thus treated by the method, are detected 14 or about 14 days or 28 or about 28 days after the start of administration of the dose of cells. + T cells (optionally, CAR + CD8 + T cells and / or CARs + CD4 + The number of 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 aspects of the methods provided, the T cells are primary T cells obtained from the subject. In certain aspects of the methods provided, the T cells are autologous cells of the subject. In certain aspects of the methods provided, the T cells are allogeneic to the subject. In some aspects of the methods provided, the T cells are CD4 cells administered as multiple compositions. + T cells and CD8 + The plurality of compositions include T cells, and CD4 + T cells or CD8 + Administration of a first composition containing T cells and CD4 + T cells or CD8 + The method includes administration of a second composition containing the other of the T cells.

[0116] In certain embodiments of the method provided, the first composition and the second composition are administered with an interval of 0 to 12 hours, 0 to 6 hours, or 0 to 2 hours. In certain embodiments of the method provided, the first composition and the second composition are administered with an interval 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. In some embodiments of the method provided, the first composition is CD4 + Contains T cells. In any particular embodiment of the method provided, the first composition is CD8 + Contains T cells. In any particular embodiment of the method provided, the first composition is administered before the second composition.

[0117] In some aspects of any of the methods provided, the dose of T cells is administered to a subject as a single dose or only once within a period of 2 weeks, 1 month, 3 months, 6 months, 1 year, or longer. In certain aspects of any of the methods provided, the dose of T cells is administered as a dual dose comprising a first dose of T cells and a subsequent dose of T cells, where one or both of the first and second doses constitute the administration of the plurality of compositions of T cells. In certain aspects of any of the methods provided, the subsequent dose is administered at least about 7 days or more after the commencement of administration of the first dose of cells, or at least about 14 days or more after the commencement of administration of the first dose of cells, but at least 28 days before the commencement of administration of the first dose of cells.

[0118] A manufactured article comprising a cell therapy comprising genetically modified cells expressing a chimeric antigen receptor (CAR) in a certain dose or composition, and instructions for administering the cell therapy, wherein the dose of cells is to be administered to subjects who have or have been identified as having non-Hodgkin 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 subjects being identified or identified as having a Performance Status (ECOG) status of 0 or 1 of the US East Coast Cancer Clinical Trials Group; and the dose of T cells to be administered is 5 × 10⁶ 7 Or approximately 5 x 10 7 pieces~1×10 8 Or approximately 1 x 10 8 A manufactured article is provided herein, which is specified in the description to contain (including the values ​​at both ends) CAR-expressing T cells. In some embodiment of any of the manufactured articles provided, the T cells of such dose are CAR-expressing CD8 + CAR expression CD4 in cells + The prescribed ratio of cells, and / or CD8 + CD4 in cells + The cells are administered in a specified ratio, which is arbitrarily approximately 1:1 or approximately 1:3 to 3:1, as specified in the instructions.

[0119] A manufactured article comprising a cell therapy comprising genetically modified cells expressing a chimeric antigen receptor (CAR) in a certain dose or composition, and instructions for administering the cell therapy, wherein the T cells in the dose express the CAR and are CD4 + Cells: CD8 cells expressing the CAR + The specified ratio of cells, and / or CD4 + Cell: CD8 +A manufactured product is provided herein, which is to be administered in a specified ratio of cells, such ratio being approximately 1:1 or 1:1; the dose of cells to be administered to subjects having or identified as having non-Hodgkin 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, as specified in the description.

[0120] A manufactured article comprising a cell therapy comprising genetically modified cells expressing a chimeric antigen receptor (CAR) in a certain dose or composition, 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 lymphoma (NHL), optionally 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 the dose of T cells administered is 5 × 10⁶ 7 Or approximately 5 x 10 7 pieces~1×10 8 Or approximately 1 x 10 8 The dose comprises (including the values ​​at both ends) CAR-expressing T cells; and the T cells of the dose express the CAR on CD4 + Cells: CD8 cells expressing the CAR + The specified ratio of cells, and / or CD4 + Cell: CD8 + A manufactured article is provided herein, which should be administered in a specified ratio of cells, the ratio of which is approximately 1:1 or 1:1, as specified in the instructions.

[0121] In some aspects of any of the manufactured articles offered, the description further specifies that the dose of cells should be administered to subjects identified as having, or having, a Performance Status (ECOG) status 0, 1, or 2 (optionally ECOG status 0 or 1) of the U.S. East Coast Clinical Trials Group. In certain aspects of any of the manufactured articles offered, the description further specifies that the administration should be in subjects who have not received any active agent or treatment that can treat, prevent, delay, reduce, or attenuate the occurrence or risk of toxicity immediately before or within one month or approximately one month before the administration of the dose of cells. In some aspects of any of the manufactured articles offered, the active 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 manufactured articles offered, the description specifies that the dose of cells is not for administration to subjects having DLBCL transformed from MZL and CLL (Richter), and / or for subjects having disease-associated DLBCL transformed from de novo or indolent. In some embodiments of any of the manufactured articles offered, the description specifies that the subjects do not have DLBCL transformed from MZL and CLL (Richter).

[0122] In some embodiments of any of the manufactured articles provided, the indications for cell therapy are specified in the description to be for subjects identified or identified as having double / triple-hit lymphoma (or high-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangement (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 treatment. In certain embodiments of any of the manufactured articles provided, the CAR comprises an antigen-specific scFv, a transmembrane domain, an intracellular signaling domain derived from a costimulatory molecule which is optionally 4-1BB, and an intracellular signaling domain derived from a primary signaling ITAM-containing molecule which is optionally CD3 zeta. In certain embodiments of any of the manufactured articles provided, the antigen is a B-cell antigen, optionally CD19.

[0123] Certain embodiments of the manufactured articles provided further include instructions for use with, after, or in conjunction with lymphocyte apheresis, and the lymphocyte apheresis optionally comprises fludarabine and / or cyclophosphamide. In certain embodiments of the manufactured articles provided, the lymphocyte apheresis is administered at approximately 200-400 mg / m², including both end values. 2 (Optionally 300 or approximately 300 mg / m²) 2 ) Cyclophosphamide, and / or about 20-40 mg / m² 2 (Optional: 30 mg / m²) 2 The treatment involves administering fludarabine at a dose of 300 mg / m² daily for 2 to 4 days (optionally 3 days). In any particular embodiment of the manufactured article provided, the lymphocyte apheresis therapy is 300 mg / m². 2 Or approximately 300 mg / m² 2 Cyclophosphamide and approximately 30 mg / m² 2 This includes administering fludarabine daily for three days.

[0124] In some aspects of any of the manufactured articles provided, the instructions further specify that the application of cell therapy should or may be performed on the subject in an outpatient setting and / or without the subject being hospitalized overnight, for one day or more consecutive days and / or without the subject being hospitalized for one day or more consecutive days. In certain aspects of any of the manufactured articles provided, the instructions further specify that the cell therapy is for parenteral administration, optionally for intravenous administration. In certain aspects of any of the manufactured articles provided, the cell therapy comprises primary T cells obtained from the subject. In some aspects of any of the manufactured articles provided, the T cells are the subject's own cells. In certain aspects of any of the manufactured articles provided, the T cells are allogeneic to the subject.

[0125] In any particular embodiment of the manufactured article provided, the manufactured article comprises a plurality of compositions of cell therapy, wherein the plurality of compositions are CD4 + T cells or CD8 + The first composition comprises genetically modified cells including T cells, wherein the first composition is CD4 + T cells or CD8 + The instructions specify that it is intended for use in conjunction with a second composition containing the other 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 embodiment of any of the manufactured articles provided, the first composition and the second composition are recombinant receptor-expressing CD4 + Cells: Recombinant receptor-expressing CD8 + The specified ratio of cells, and / or CD4 + Cell: CD8 +The cell is to be administered in a specified ratio, which is arbitrarily about 1:1 or about 1:3 to about 3:1 as specified in the instructions. In any particular embodiment of the manufactured article provided, the specified ratio is 1:1 or about 1:1. In any particular embodiment of the manufactured article provided, the composition further comprises a cryoprotective substance and / or the article further comprises instructions for thawing the composition before administration to the subject.

[0127] In some embodiment of any of the manufactured articles provided, CD4 + Composition containing T cells and CD8 + The instructions specify that the composition containing T cells be administered at intervals of 0-12 hours, 0-6 hours, or 0-2 hours. In any particular embodiment of the manufactured article provided, CD4 + Composition containing T cells and CD8 + The instructions specify that the composition containing T cells should be 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. In any particular embodiment of the manufactured article provided, CD4 + A composition containing T cells, CD8 + The instructions specify that it should be administered before administering compositions containing cells. In some embodiments of any of the manufactured articles provided, CD8 + A composition containing T cells, CD4 + The instructions specify that it should be administered before administering any compositions containing cells.

[0128] A manufactured article is provided herein, 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 that is a candidate for treatment in cell therapy, wherein the cell therapy optionally comprises genetically modified cells expressing a recombinant receptor in a certain dose or composition, 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).

[0129] Any particular aspect of the manufactured article provided further comprises a cell therapy and / or instructions for use before and / or in connection with the cell therapy, in conjunction with the cell therapy. Any particular aspect of the manufactured article provided further comprises one or more active substances or treatments for treating, preventing, delaying, reducing or attenuating the occurrence of toxicity or the risk thereof; and / or instructions for the application of one or more active substances or treatments for treating, preventing, delaying, reducing or attenuating the occurrence of toxicity or the risk thereof in a subject.

[0130] In any embodiment of the manufactured article provided, if the level, amount, or concentration of an analyte in a sample is above the threshold level of the analyte, an active substance or other treatment that can treat, prevent, delay, reduce, or attenuate the occurrence or risk of toxicity is applied to the subject (i) before the commencement of cell therapy application to the subject, (ii) within one, two, or three days of the commencement of cell therapy application to the subject, (iii) in parallel with the commencement of cell therapy application to the subject, and / or (iv) at the time of the first fever after the commencement of cell therapy application to the subject; and / or in low doses or cell therapy The instructions further specify that cell therapy should be administered to subjects at doses that do not pose a risk of toxicity or severe toxicity after the application of the Act, or that do not pose a risk of toxicity or severe toxicity in the majority of subjects and / or in the majority of subjects having the disease or condition (which the subject has or is suspected to have); and / or administered to subjects in an inpatient setting and / or with one or more days of hospitalization, where optionally, otherwise administered to subjects on an outpatient basis or without one or more days of hospitalization, as specified in the instructions.

[0131] In any particular embodiment of the manufactured article provided, if the level, quantity, or concentration of the analyte is below the threshold level of the analyte, the instructions further specify that cell therapy may be applied to the subject optionally at a non-low dose, optionally on an outpatient basis, or without a one-day or multi-day hospital stay.

[0132] In any particular embodiment of the manufactured article provided, it is further specified that cell therapy be applied to a subject, and if the level, amount, or concentration of the analyte is below a threshold level, the application of cell therapy does not include the application of any active substance or treatment that can treat, prevent, delay, or reduce the manifestation of toxicity before or concurrently with the application of such cell therapy and / or before the manifestation of any sign of toxic symptoms other than thermal symptoms; and / or the description further specifies that the application of cell therapy should or may be performed on the subject in an outpatient setting and / or without the subject being hospitalized overnight, for one day or more consecutive days and / or without the subject being hospitalized for one day or more days.

[0133] In some embodiment of any of the manufactured articles provided, the threshold level is within 25%, 20%, 15%, 10%, or 5% of the mean level, amount, or concentration of the analyte in the biological sample obtained from a group of subjects before receiving the recombinant receptor-expressing therapeutic cell composition, and / or within the standard deviation of the mean level, amount, or concentration of the analyte in the biological sample obtained from a group of subjects before receiving the recombinant receptor-expressing therapeutic cell composition, where each subject in the group is a subject that developed toxicity after receiving the recombinant receptor-expressing therapeutic cell composition for treating the same disease or condition. A manufactured article is provided herein, comprising a cell therapy (which optionally includes genetically modified cells expressing a recombinant receptor in a certain dose or composition) and instructions for applying the cell therapy according to or based on the results of an evaluation of the level, amount or concentration of one or more analytes in the biological sample, wherein the biological sample is obtained from a subject prior to the application of 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, 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).

[0134] In any particular embodiment of the manufactured article provided, the evaluation includes detection, optionally comprising contacting a biological sample with a reagent capable of directly or indirectly detecting an analyte, and examining the level, amount, or concentration of the analyte in the biological sample. Any particular embodiment of the manufactured article provided further comprises such reagent and / or instructions for use before and / or in conjunction with such reagent, together with the reagent for detecting an analyte. Any particular embodiment of the manufactured article provided further comprises one or more active substances or treatments for treating, preventing, delaying, reducing, or attenuating the manifestation of toxicity or the risk thereof; and / or instructions for the application of one or more active substances or treatments for treating, preventing, delaying, reducing, or attenuating the manifestation of toxicity or the risk thereof in a subject.

[0135] In any particular embodiment of the manufactured article provided, if the level, amount, or concentration of the analyte in the sample is above a threshold level, an active substance or other treatment that can treat, prevent, delay, reduce, or attenuate the occurrence or risk of toxicity is applied to the subject (i) before the commencement of administration of the therapeutic cell composition or genetically modified cells, (ii) within one, two, or three days after the commencement of administration of the therapeutic cell composition or genetically modified cells, (iii) concurrently with the commencement of administration of the therapeutic cell composition or genetically modified cells, and / or (iv) at the time of the first fever after the commencement of administration of the therapeutic cell composition or genetically modified cells; and / or The instructions for administering cell therapy specify that the cell therapy should be administered at a low dose, or at a dose that does not carry a risk of causing toxicity or severe toxicity in the majority of subjects and / or in the majority of subjects having the disease or condition (which the subject has or is suspected to have); and / or administered in an inpatient setting and / or with one or more days of hospitalization, where optionally, otherwise administered on an outpatient basis or without one or more days of hospitalization, as specified in the instructions for administering cell therapy.

[0136] In certain embodiments of any of the manufactured articles provided, if the level, amount, or concentration of the analyte in the sample is below a threshold level, the instructions for applying cell therapy specify that the cell therapy may be applied 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 manufactured articles provided, the instructions further specify that the cell therapy may be applied to the subject, and if the level, amount, or concentration of the analyte is below a threshold level, no active agent or treatment that can treat, prevent, delay, or reduce the manifestation of toxicity should be applied before or concurrently with the application of such cell therapy, and / or before the manifestation of any sign or symptom of toxicity other than thermal; and / or the application of cell therapy should or may be performed on the subject in an outpatient setting, and / or without hospitalization for one or more consecutive days, and / or without hospitalization for one or more days.

[0137] In any particular embodiment of the manufactured article provided, the threshold level is within 25%, 20%, 15%, 10%, or 5% of the mean level, amount, or concentration of the analyte in the biological sample obtained from a group of subjects prior to receiving the recombinant receptor-expressing therapeutic cell composition, and / or within the standard deviation of the mean level, amount, or concentration of the analyte in the biological sample 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 the recombinant receptor-expressing therapeutic cell composition for treating the same disease or condition.

[0138] Provided herein are manufactured articles comprising an active substance capable of treating, preventing, delaying, reducing, or attenuating the manifestation or risk of toxicity, and instructions for administering the active substance according to, or based on, the results of an assessment 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 products). In any particular embodiment of the manufactured articles provided, the assessment optionally includes detection, which involves contacting a biological sample with a reagent capable of directly or indirectly detecting the analyte, and examining the level, amount, or concentration of the analyte in the biological sample.

[0139] In some aspects of the manufactured articles provided, the instructions specify that the active agent should be administered i) before the commencement of the application of the cell therapy to the subject, (ii) within one, two, or three days of the commencement of the application of the cell therapy to the subject, (iii) in parallel with the commencement of the application of the cell therapy to the subject, and / or (iv) at the time of the first fever after the commencement of the application of the cell therapy to the subject, and / or further instructions for use before and / or in connection with the cell therapy procedure. In certain aspects of the manufactured articles provided, the biological sample is obtained from the subject before the application of the active agent or cell therapy. In certain aspects of the manufactured articles provided, the reagent is a marker of a bone marrow cell population or a binding molecule that specifically binds to cells. In some aspects of the manufactured articles provided, the reagent is an antibody or its antigen-binding fragment. In certain aspects of the manufactured articles provided, the biological sample is a blood sample, plasma sample or serum sample, or obtained from a blood sample, plasma sample or serum sample. In certain embodiments of any of the manufactured articles provided, the article comprises a reagent for detecting an analyte and / or further provides instructions for use before and / or in conjunction with the reagent, together with the reagent for detecting an analyte. Some embodiments of any of the manufactured articles provided further comprise a cell therapy and / or further provides instructions for use before and / or in conjunction with the cell therapy, together with the treatment.

[0140] In any particular embodiment of the manufactured article provided, the instructions for administering an active substance specify that the subject should be administered the active substance if the level, amount, or concentration of the analyte in the sample is above a threshold level. In any particular embodiment of the manufactured article provided, the instructions further specify that the subject should be administered cell therapy, where the administration of the active substance should be (i) before the commencement of the administration of cell therapy to the subject, (ii) within one, two, or three days of the commencement of the administration of cell therapy to the subject, (iii) concurrently with the commencement of the administration of cell therapy to the subject, and / or (iv) at the time of the first fever after the commencement of the administration of cell therapy to the subject. In some embodiment of any of the manufactured articles provided, instructions for administering an active substance specify that cell therapy should be administered to a subject if the level, amount, or concentration is below a threshold level, and optionally the instructions specify that cell therapy should be administered to the subject in an outpatient setting and / or without the subject being hospitalized overnight, for one day or more consecutive days, or that cell therapy may be administered to the subject in an outpatient setting and / or without the subject being hospitalized overnight, for one day or more consecutive days, and / or without the subject being hospitalized for one day or more consecutive days.

[0141] In any particular embodiment of the manufactured article provided, the threshold level is within 25%, 20%, 15%, 10%, or 5% of the mean level, amount, or concentration of the analyte in the biological sample obtained from a group of subjects before receiving the recombinant receptor-expressing therapeutic cell composition, and / or within the standard deviation of the mean level, amount, or concentration of the analyte in the biological sample obtained from a group of subjects before receiving the recombinant receptor-expressing therapeutic cell composition, where each subject in the group is a subject that developed toxicity after receiving the recombinant receptor-expressing therapeutic cell composition for treating the same disease or condition. In any particular embodiment of the manufactured article provided, the cellular assay or evaluation of the analyte is performed by immunoassay.

[0142] In some aspect of any of the manufactured articles provided, toxicity includes neurotoxicity or cytokine release syndrome (CRS), optionally including neurotoxicity or CRS of grade 1 or higher. In certain aspect of any of the manufactured articles provided, toxicity includes severe neurotoxicity and / or 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 toxicity includes severe CRS and / or CRS of grade 2 or higher or grade 3 or higher. In certain aspect of any of the manufactured articles provided, toxicity is associated with cerebral edema.

[0143] In some aspects of any of the provided manufactured articles, the active agent or treatment is one or more of the following: steroids; cytokine receptors or cytokine antagonists or inhibitors selected from IL-10, IL-10R, IL-6, IL-6 receptor, IFNγ, IFNGR, IL-2, IL-2R / CD25, MCP-1, CCR2, CCR4, MIP1β, CCR5, TNF-alpha, TNFR1, IL-1 and IL-1R-alpha / IL-1-beta; or one or more active agents capable of suppressing, blocking, or reducing the activity or function of microglial cells. In certain aspects of any of the provided manufactured articles, the antagonist or inhibitor is an active agent selected from antibodies or antigen-binding fragments, small molecules, proteins or peptides and nucleic acids, or includes an active agent selected from antibodies or antigen-binding fragments, small molecules, proteins or peptides and nucleic acids. In certain aspects of any of the provided manufactured articles, the active agent or treatment is an anti-IL-6 antibody or an anti-IL-6 receptor antibody.

[0144] In some aspects of any of the manufactured articles provided, the active substance or other treatment is or includes an active substance selected from tocilizumab, siltuximab, crazakizumab, sarilumab, olokizumab (CDP6038), elcilimomab, ALD518 / BMS-945429, silkumab (CNTO 136), CPSI-2634, ARGX-109, FE301, and FM101. In certain aspects of any of the manufactured articles provided, the active substance or other treatment is or includes tocilizumab. In certain aspects of any of the manufactured articles provided, the active substance or other treatment is or includes siltuximab. In some aspects of any of the manufactured articles provided, the steroid is or includes dexamethasone.

[0145] In any particular embodiment of the provided manufactured article, the active agents that can suppress, block, or reduce the activity or function of microglial cells are selected from anti-inflammatory agents, NADPH oxidase (NOX2) inhibitors, calcium channel blockers, sodium channel blockers, GM-CSF inhibitors, CSF1R inhibitors, substances that specifically bind to CSF-1, substances that specifically bind to IL-34, substances that inhibit the activation of nuclear factor kappa B (NF-κB), substances that activate CB2 receptors and / or CB2 agonists, phosphodiesterase inhibitors, substances that inhibit microRNA-155 (miR-155), or substances that upmodulate microRNA-124 (miR-124). In any particular embodiment of the provided manufactured article, the active agents that can suppress, block, or reduce the activation or function of microglial cells are small molecules, peptides, proteins, antibodies or their antigen-binding fragments, antibody mimes, aptamers, or nucleic acid molecules.

[0146] In some aspects of the manufactured articles provided, the active ingredients are 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, and JNJ-40346. Selected from 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 any particular embodiment of the manufactured article provided, the active ingredient is an inhibitor of the colony-stimulating factor 1 receptor (CSF1R). In certain embodiments of any of the manufactured articles provided, the inhibitor is 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 their pharmaceutically active salts or prodrugs; emactuzumab, IMC-CS4, FPA008, LY-3022855, AMG-820 and TG-3003, or their antigen-binding fragments; or any combination thereof. In some embodiments of any of the manufactured articles provided, the inhibitor is PLX-3397.

[0147] In any particular aspect of the manufactured articles offered, the disease or condition is cancer. In any particular aspect of the manufactured articles offered, the disease or condition is myeloma, leukemia, or lymphoma. In some aspects of the manufactured articles offered, the disease or condition is a B-cell malignancy and / or acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL).

[0148] In any particular embodiment of the manufactured article provided, 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, antifolate 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, and 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 preferential expression antigen (PRAME), Survivin, TAG72, B7-H6, IL-13 receptor alpha2 (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, dual antigen, cancer testicular antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, tumor embryonic 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 antigen.

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

[0150] In any particular aspect of the manufactured article provided, the modified cells are T cells, optionally CD4 + and / or CD8 + , including. In some aspects of any of the manufactured articles provided, the T cells are primary T cells obtained from the subject. In certain aspects of any of the manufactured articles provided, the dose that does not carry a risk of causing toxicity or severe toxicity is 5 × 10⁶ 7 Less than one or approximately 5 x 10 7 Fewer than 1 total recombinant receptor-expressing cells, optionally CAR + Cells, all T cells, or all peripheral blood mononuclear cells (PBMCs), e.g., 2.5 × 10⁶ 7 Less than one or approximately 2.5 × 10 7 Less than 1.0 × 10 7 Less than one or approximately 1.0 × 10 7 Less than 5.0 × 10 6 Less than one or approximately 5.0 × 10 6 Less than 1.0 × 10 6 Less than one or approximately 1.0 × 10 6 Less than 5.0 × 10 5 Less than one or approximately 5.0 × 10 5 Less than one, or 1 x 10⁻⁶ 5 Less than one or approximately 1 x 10 5 Fewer than 1 total recombinant receptor-expressing cells, optionally CAR +Cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), or containing them. In any particular embodiment of the manufactured article provided, the dose that does not carry a risk of developing toxicity or severe toxicity is 1 × 10⁻⁶ 5 Or approximately 1 x 10 5 ~5×10 7 Or approximately 5 x 10 7 Individual fully recombinant receptor-expressing cells, optionally CAR + Cells, all T cells, or all peripheral blood mononuclear cells (PBMCs), e.g., 1 × 10⁶ 5 ~2.5×10 7 , 1 x 10 5 ~1.0×10 7 , 1 x 10 5 ~5.0×10 6 , 1 x 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 x 10 6 ~2.5×10 7 , 1 x 10 6 ~1.0×10 7 , 1 x 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 x 10 7 ~2.5×10 7 , or 2.5 × 10 7 ~5×10 7individual fully recombinant receptor-expressing cells (optional, CAR + Cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), or containing them.

[0151] In certain embodiments of any of the manufactured articles provided, the reagents are detectably labeled and optionally fluorescently labeled. In some embodiments of any of the manufactured articles provided, the one or more analytes are LDH, ferritin, CRP, IL-6, IL-8, IL-10, TNF-alpha, IFN-alpha 2, MCP-1, and MCP-1 beta. In certain embodiments of any of the manufactured articles provided, the one or more analytes are LDH or contain LDH.

[0152] A method for selecting a target for treatment, comprising the steps of (a) contacting a biological sample with one or more reagents that can detect one or more analytes or are specific to 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 (fibrin degradation product), wherein the biological sample is a candidate for treatment in cell therapy. A method is provided herein that comprises the steps of: (b) (i) identifying subjects in which the level, amount, or concentration of the analyte in the sample is above a threshold level, thereby posing a risk of toxicity to the cell therapy; or (ii) identifying subjects in which the level, amount, or concentration of the analyte in the sample is below a threshold level.

[0153] In any particular aspect of the method provided, (a)(i) the subject is selected to be subjected to (1) an active substance or other treatment that can treat, prevent, delay, reduce or attenuate the occurrence or risk of toxicity, and (2) cell therapy, wherein the administration of the active substance should be done (i) before the commencement of the application of cell therapy to the subject, (ii) within one, two, or three days of the commencement of the application of cell therapy to the subject, (iii) in parallel with the commencement of the application of cell therapy to the subject, and / or (iv) at the time of the first fever after the commencement of the application of cell therapy to the subject; and / or (c)(i) the subject is subjected to a low dose, or (b)(i) subjects are selected for the application of cell therapy at doses that do not carry a risk of developing toxicity or severe toxicity after the application of cell therapy, or in the majority of subjects and / or in the majority of subjects having the disease or condition (which the subject has or is suspected to have); and / or subjects under (b)(i) are selected for the application of cell therapy in an inpatient setting and / or with one or more days of hospitalization, here optionally, otherwise, cell therapy is applied to subjects on an outpatient basis or without one or more days of hospitalization.

[0154] In any part of the provided method, (i) a subject is selected, and the method is a step of (a) applying to the subject an active substance or other treatment that can (1) treat, prevent, delay, reduce or attenuate the occurrence or risk of toxicity, and (2) cell therapy, wherein the administration of the active substance is performed (i) before the commencement of the application of cell therapy to the subject, (ii) within one, two or three days of the commencement of the application of cell therapy to the subject, (iii) in parallel with the commencement of the application of cell therapy to the subject, and / or (iv) at the time of the first fever after the commencement of the application of cell therapy to the subject; and / or (b) at a low dose or after the application of cell therapy, without the risk of developing toxicity or severe toxicity in the majority of the subject and / or disease or condition (that the subject has or is suspected to have) (c) a step of applying cell therapy to a subject at a dose that does not carry a risk of causing toxicity or severe toxicity in the majority of subjects having (a) a disease or condition (that the subject has or is suspected of having); and / or (c) a step of applying cell therapy, or genetically modified cells of a certain dose of cell therapy, to the subject, after the application of cell therapy, at a rate that does not carry a risk of causing toxicity or severe toxicity in the majority of the subject and / or in the majority of the subject having (a) a disease or condition (that the subject has or is suspected of having); and / or (d) a step of applying cell therapy to a subject in an inpatient setting and / or involving a day or more of hospitalization, and optionally, otherwise, an outpatient setting or without a day or more of hospitalization, to the subject.

[0155] In any particular embodiment of the method provided, the subject in (a)(ii) is selected to receive cell therapy optionally at a non-low dose, optionally on an outpatient basis, or without hospitalization for one or more days; the subject in (b)(ii) is selected to receive cell therapy, the cell therapy not including the application of any active substance or treatment that can treat, prevent, delay, or reduce the occurrence of toxicity before or concurrently with the cell therapy, and / or before the occurrence of any sign or symptom of toxicity other than fever; and / or the subject in (ii) is selected to receive cell therapy in an outpatient setting and / or without hospitalization for one or more consecutive days and / or without hospitalization for one or more days.

[0156] In any particular embodiment of the Method Provided, a subject (ii) is selected, and the Method further includes the step of applying the cell therapy to the subject, optionally in a non-low dose, optionally on an outpatient basis, or without hospitalization for one or more days. In any particular embodiment of the Method Provided, a subject (ii) is selected, and the Method further includes the step of applying the cell therapy to the subject, wherein the application of the cell therapy does not include the step of applying any active substance or treatment that can treat, prevent, delay or reduce the manifestation of toxicity before or in conjunction with the application of the cell therapy and / or before the manifestation of any sign or symptom of toxicity other than fever; and / or the application of the cell therapy should or may be performed on the subject in an outpatient setting and / or without hospitalization for one or more consecutive days and / or without hospitalization for one or more days.

[0157] (a) Assaying a biological sample for the level, amount, or concentration of one or more analytes, wherein the biological sample optionally originates from a subject that is a candidate for treatment in cell therapy, and the cell therapy optionally comprises genetically modified cells in a certain dose or composition that express recombinant receptors 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 (fibrin degradation products); and (b) applying the cell therapy and optionally an active agent or other treatment that can treat, prevent, delay, reduce, or attenuate the manifestation or risk of toxicity to the subject, according to or based on the results of the assay.

[0158] A treatment method is provided herein, comprising the steps of applying to a subject (i) a cell therapy optionally comprising a genetically modified form at a certain dose or composition expressing a recombinant receptor for treating a disease or condition, and optionally (ii) an active substance or other treatment that can treat, prevent, delay, reduce or attenuate the manifestation or risk of toxicity, wherein the biological sample is obtained from the subject before the application of the cell therapy; and the one or more analytes 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), according to or based on the results of an assay for the level, amount, or concentration of one or more analytes of a biological sample derived from the subject.

[0159] In any particular embodiment of the method provided, the assay includes detection, optionally comprising contacting a biological sample with a reagent capable of directly or indirectly detecting the analyte, and examining the level, amount, or concentration of the analyte in the biological sample. In any particular embodiment of the method provided, if the level, amount, or concentration of the analyte in the sample is above a threshold level, an active substance or other treatment capable of treating, preventing, delaying, reducing, or attenuating the manifestation or risk of toxicity is applied to the subject (i) before the commencement of cell therapy application to the subject, (ii) within one, two, or three days of the commencement of cell therapy application to the subject, (iii) in parallel with the commencement of cell therapy application to the subject, and / or (iv) at the time of the first fever after the commencement of cell therapy application to the subject; and / or in a low dose or fine dose. Administering cell therapy to subjects at doses that do not carry a risk of toxicity or severe toxicity after the application of cell therapy, or that do not carry a risk of toxicity or severe toxicity in the majority of subjects and / or in the majority of subjects having the disease or condition (which the subject has or is suspected to have); and / or administering cell therapy to subjects in an inpatient setting and / or with one or more days of hospitalization, herein optionally, otherwise on an outpatient basis or without one or more days of hospitalization.

[0160] In any embodiment of the method provided, if the level, amount, or concentration of the analyte is above a threshold level, the application of cell therapy shall not include the application of any active substance or treatment that can treat, prevent, delay, or reduce the manifestation of toxicity before or in conjunction with the application of cell therapy and / or before the manifestation of any sign or symptom of toxicity other than thermal; and / or the application of cell therapy shall be or may be performed on the subject in an outpatient setting and / or without the subject being hospitalized overnight, for one day or more consecutive days and / or without the subject being hospitalized for one day or more days.

[0161] In any particular embodiment of the method provided, an active substance or other treatment is applied to a subject that can treat, prevent, delay, reduce or attenuate the occurrence or risk of toxicity, wherein the subject is optionally a candidate treatment in cell therapy, which optionally comprises genetically modified cells in a certain dose or composition that express recombinant receptors for treating a disease or condition; the subject is treated according to, or based on, the results of an assay for the level, amount, or concentration of one or more analytes of a biological sample derived from the subject, which reduces the risk of toxicity. It is specified that the biological sample is obtained from a subject prior to the application of the cell therapy, and / or the biological sample does not contain the recombinant receptor and / or the modified cells, wherein 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).

[0162] In any particular embodiment of the method provided, the assay includes detection, optionally comprising contacting a biological sample with a reagent capable of directly or indirectly detecting the analyte, and examining the level, amount, or concentration of the analyte in the biological sample. In some embodiment of the method provided, the active agent is administered to a subject if the level, amount, or concentration of the analyte in the sample is above a threshold level.

[0163] In any particular aspect of the method provided, the active ingredient is administered (i) before the initiation of cell therapy to the subject, (ii) within one, two, or three days of the initiation of cell therapy to the subject, (iii) in parallel with the initiation of cell therapy to the subject, and / or (iv) at the time of the first fever after the initiation of cell therapy to the subject. In any particular aspect of the method provided, the threshold level is within 25%, 20%, 15%, 10%, or 5% of the mean percentage or number of cell surfaces positive for bone marrow markers in biological samples obtained from a group of subjects before receiving the recombinant receptor-expressing therapeutic cell composition, and / or within the standard deviation of the mean percentage or number of cell surfaces positive for bone marrow markers in biological samples obtained from a group of subjects before receiving the recombinant receptor-expressing therapeutic cell composition, where each subject in the group is a subject that developed toxicity after receiving the recombinant receptor-expressing therapeutic cell composition for the treatment of the same disease or condition.

[0164] In any particular aspect of the method provided, the threshold level is within 25%, 20%, 15%, 10%, or 5% of the mean level, amount, or concentration of the analyte in the biological sample obtained from a group of subjects before receiving the recombinant receptor-expressing therapeutic cell composition, and / or within the standard deviation of the mean level, amount, or concentration of the analyte in the biological sample obtained from a group of subjects before receiving the recombinant receptor-expressing therapeutic cell composition, where each subject in the group is a subject that developed toxicity after receiving the recombinant receptor-expressing therapeutic cell composition for treating the same disease or condition. In any particular aspect of the method provided, the reagent is a marker of a bone marrow cell population or a binding molecule that specifically binds to cells. In some aspects of the method provided, the reagent is an antibody or its antigen-binding fragment. In any particular aspect of the method provided, 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 any particular aspect of the method provided, the analyte comprises an immunoassay or an assay or evaluation of cells.

[0165] In some aspects of the methods provided, toxicity includes neurotoxicity or cytokine release syndrome (CRS), optionally including neurotoxicity or CRS of grade 1 or higher. In certain aspects of the methods provided, toxicity includes severe neurotoxicity and / or 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 toxicity includes severe CRS and / or CRS of grade 2 or higher or grade 3 or higher. In certain aspects of the methods provided, toxicity is associated with cerebral edema.

[0166] In some aspect of any of the methods provided, the active agent or other treatment is one or more of the following: steroids; cytokine receptors or cytokine antagonists or inhibitors selected from IL-10, IL-10R, IL-6, IL-6 receptor, IFNγ, IFNGR, IL-2, IL-2R / CD25, MCP-1, CCR2, CCR4, MIP1β, CCR5, TNF-alpha, TNFR1, IL-1 and IL-1R-alpha / IL-1-beta; or one or more of the following active agents that can suppress, block, or reduce the activity or function of microglial cells. In a particular aspect of any of the methods provided, the antagonist or inhibitor is an active agent selected from antibodies or antigen-binding fragments, small molecules, proteins or peptides and nucleic acids, or includes an active agent selected from antibodies or antigen-binding fragments, small molecules, proteins or peptides and nucleic acids.

[0167] In any particular aspect of the method provided, the active agent or other treatment is an anti-IL-6 antibody or an anti-IL-6 receptor antibody. In some aspects of the method provided, the active agent or other treatment is an active agent selected from tocilizumab, siltuximab, crazakizumab, sarilumab, olokizumab (CDP6038), elcilimomab, ALD518 / BMS-945429, silkumab (CNTO 136), CPSI-2634, ARGX-109, FE301, and FM101, or includes the same. In any particular aspect of the method provided, the active agent or other treatment is tocilizumab or includes tocilizumab. In any particular aspect of the method provided, the active agent or other treatment is siltuximab or includes siltuximab.

[0168] In some aspects of the methods provided, the steroid is or contains dexamethasone. In certain aspects of the methods provided, the active ingredient that can suppress, block, or reduce the activity or function of microglial cells is selected from anti-inflammatory agents, NADPH oxidase (NOX2) inhibitors, calcium channel blockers, sodium channel blockers, GM-CSF inhibitors, CSF1R inhibitors, CSF-1 specific binding agents, IL-34 specific binding agents, CB2 receptor activators, and / or CB2 agonists, phosphodiesterase inhibitors, microRNA-155 (miR-155), or microRNA-124 (miR-124).

[0169] In certain aspects of the methods provided, the active agents that can suppress, block, or reduce the activation or function of microglial cells are small molecules, peptides, proteins, antibodies or their antigen-binding fragments, antibody mimes, aptamers, or nucleic acid molecules. In some aspects of the methods provided, the active agents are 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- Selected from 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 any particular embodiment of the method provided, the active ingredient is an inhibitor of the colony-stimulating factor 1 receptor (CSF1R). In any particular embodiment of the method provided, the inhibitor is 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 their pharmaceutically salts or prodrugs; emactuzumab, IMC-CS4, FPA008, LY-3022855, AMG-820 and TG-3003 or their antigen-binding fragments; or any combination of the above.

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

[0172] In any particular embodiment of the method provided, 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, antifolate 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, and 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 preferential expression antigen (PRAME), Survivin, TAG72, B7-H6, IL-13 receptor alpha2 (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, dual antigen, cancer testicular antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, tumor embryonic 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 antigen.

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

[0174] In some aspect of the provided method, the modified cells are T cells, optionally CD4 + and / or CD8 + This includes. In any particular aspect of the method provided, the T cells are primary T cells obtained from the subject. In any particular aspect of the method provided, the cell therapy is 1 × 10⁶ 5 Or approximately 1 x 10 5 ~1 × 10 8 Or approximately 1 x 10 8 5 × 10¹ fully recombinant receptor-expressing cells, all T cells, or all peripheral blood mononuclear cells (PBMCs), 5 Or approximately 5 x 10 5 ~1 × 10 7 Or approximately 1 x 10 7 10¹ whole recombinant receptor-expressing cells, whole T cells, or whole peripheral blood mononuclear cells (PBMCs) or 1 × 10¹⁶ 6 Or approximately 1 x 10 6 ~1 × 10 7 Or approximately 1 x 10 7 This includes administration of 100 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), each including values ​​at both ends.

[0175] In some embodiment of any of the methods provided, cell therapy is 1 × 10 8 1 × 10¹ or fewer fully recombinant receptor-expressing cells, all T cells, or all peripheral blood mononuclear cells (PBMCs), 1 × 10¹⁶ 70.5 × 10¹ or fewer fully recombinant receptor-expressing cells, all T cells, or all peripheral blood mononuclear cells (PBMCs), 7 1 × 10¹ or fewer fully recombinant receptor-expressing cells, all T cells, or all peripheral blood mononuclear cells (PBMCs), 1 × 10¹⁶ 6 0.5 × 10¹ or fewer fully recombinant receptor-expressing cells, all T cells, or all peripheral blood mononuclear cells (PBMCs), 6 This includes administration of one or fewer fully recombinant receptor-expressing cells, fully T cells, or fully peripheral blood mononuclear cells (PBMCs).

[0176] In any particular embodiment of the method provided, a dose that does not carry a risk of causing toxicity or severe toxicity is 5 × 10 7 Less than one or approximately 5 x 10 7 Fewer than 1 total recombinant receptor-expressing cells, optionally CAR + Cells, all T cells, or all peripheral blood mononuclear cells (PBMCs), e.g., 2.5 × 10⁶ 7 Less than one or approximately 2.5 × 10 7 Less than 1.0 × 10 7 Less than one or approximately 1.0 × 10 7 Less than 5.0 × 10 6 Less than one or approximately 5.0 × 10 6 Less than 1.0 × 10 6 Less than one or approximately 1.0 × 10 6 Less than 5.0 × 10 5 Less than one or approximately 5.0 × 10 5 Less than one, or 1 x 10⁻⁶ 5 Less than one or approximately 1 x 10 5 Fewer than 1 total recombinant receptor-expressing cells, optionally CAR + Cells, all T cells, or all peripheral blood mononuclear cells (PBMCs), or containing them.

[0177] In any particular embodiment of the method provided, a dose that does not carry a risk of causing toxicity or severe toxicity is 1 × 10⁻⁶ 5 Or approximately 1 x 10 5 ~5×10 7 Or approximately 5 x 10 7 Individual fully recombinant receptor-expressing cells, optionally CAR +Cells, all T cells, or all peripheral blood mononuclear cells (PBMCs), e.g., 1 × 10⁶ 5 ~2.5×10 7 , 1 x 10 5 ~1.0×10 7 , 1 x 10 5 ~5.0×10 6 , 1 x 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 x 10 6 ~2.5×10 7 , 1 x 10 6 ~1.0×10 7 , 1 x 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 x 10 7 ~2.5×10 7 , or 2.5 × 10 7 ~5×10 7 individual fully recombinant receptor-expressing cells (optional, CAR + The modified cells are, or include, cells, all T cells, or all peripheral blood mononuclear cells (PBMCs). In some aspects of the methods provided, the modified cells are the autologous cells of the subject. In certain aspects of the methods provided, the modified cells are allogeneic to the subject. In certain aspects of the methods provided, the reagents are detectably labeled and optionally fluorescently labeled.

[0178] In some embodiments, the description provides, individually for each of the one or more analytes, information regarding a threshold level indicating whether the subject is likely to respond to treatment with cell therapy. In some embodiments, the description provides, individually for each of the one or more analytes, information regarding a threshold level indicating whether the subject is likely to show a sustained response after the application of cell therapy. In some embodiments, the description provides, individually for each of the one or more analytes, information regarding a threshold level indicating whether the subject is likely to show toxicity after the application of cell therapy. [Invention 1001] A method for treating a subject who has a disease or condition, or is suspected to have a disease or condition, comprising a certain dose of CD4 + T cells and CD8 + The process includes administering T cells to the subject; the CD4 + T cells and the CD8 + Each T cell individually contains a receptor that specifically binds to a target antigen expressed by the disease or condition or its cells or tissues and / or a target antigen associated with the disease or condition, and the administration comprises the administration of a plurality of separate compositions, the plurality of separate compositions of the CD4 + T cells and the CD8 + A first composition comprising one of the T cells, and the CD4 + T cells and the CD8 + A method comprising a second composition containing the other of the T cells. [Invention 1002] The aforementioned CD4 + Receptors and / or CD8 contained in T cells + The receptor contained in the T cell includes the same recombinant receptor and / or the CD4 + T cells and / or the CD8 + The method of the present invention 1001, wherein T cells are genetically modified to express the same recombinant receptor. [Invention 1003] The administration of the first composition and the administration of the second composition are carried out on the same day, with an interval of approximately 0 to 12 hours, approximately 0 to 6 hours, or approximately 0 to 2 hours; or The administration of the first composition and the administration of the second composition are performed with an interval of approximately 1 minute to 1 hour, or approximately 5 minutes to 30 minutes. The method of the present invention 1001 or the present invention 1002. [Invention 1004] A method according to any one of the present invention 1001 to 1003, wherein the first composition and the second composition are administered with an interval 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. [Invention 1005] The first composition is the CD4 + A method of the present invention, comprising T cells, any of the methods described in items 1001 to 1004. [Invention 1006] The first composition is the CD8 + A method of the present invention, comprising T cells, any of the methods described in items 1001 to 1004. [Invention 1007] A method according to any one of the present invention 1001 to 1006, wherein the administration of the first composition is initiated before the administration of the second composition. [Invention 1008] CD4 of the aforementioned dose + and CD8 + T cells express recombinant CD4 at a specified ratio. + Cells and recombinant receptor expression CD8 + Cells and / or CD4 in specified ratios + Cells and CD8 + It contains cells, and the ratio is 1:1 or approximately 1:1, or approximately 1:3 to approximately 3:1; and / or CD4 comprising the receptor in one of the first and second compositions + T cells and CD8 containing the receptor in the other of the first and second compositions. + T cells and other cells are present in a predetermined ratio, such that the ratio is 1:1 or approximately 1:1, or approximately 1:3 to approximately 3:1; and / or CD4 containing the receptor administered in the first and second compositions + T cells and CD8 containing the receptor + T cells and other cells are present in a specified ratio, which is 1:1, approximately 1:1, or approximately 1:3 to approximately 3:1. Any method of the present invention 1001 to 1007. [Invention 1009] The method of the present invention 1008, wherein the ratio of the aforementioned provisions is 1:1 or approximately 1:1. [Invention 1010] CD4 of the aforementioned dose + and CD8 + T cells 5×10 7 Or approximately 5 x 10 7 ~1×10 8 Or approximately 1 x 10 8 Individual (including values ​​at both ends) fully recombinant receptor-expressing T cells; 1×10 7 Or approximately 1 x 10 7 ~2×10 8 Or approximately 2 x 10 8 Individual (including values ​​at both ends) fully recombinant receptor-expressing T cells; 5×10 7 Or approximately 5 x 10 7 ~1.5×10 8 Or approximately 1.5 x 108 Individual fully recombinant receptor-expressing T cells; 5×10 7 Or approximately 5 x 10 7 individual fully recombinant receptor-expressing T cells; or 1×10 8 Or approximately 1 x 10 8 individual fully recombinant receptor-expressing T cells; or 1.5×10 8 Or approximately 1.5 x 10 8 individual fully recombinant receptor-expressing T cells A method of the present invention, including any of the methods described in items 1001 to 1014. [Invention 1011] CD4 of the aforementioned dose + and CD8 + T cells 5×10 6 Or approximately 5 x 10 6 ~1×10 8 Or approximately 1 x 10 8 Recombinant receptor expression CD8 (including values ​​at both ends) + T cells; 1×10 7 Or approximately 1 x 10 7 ~0.75×10 8 Alternatively, approximately 0.75 × 10 8 Recombinant receptor expression CD8 (including values ​​at both ends) + T cells; 2.5×10 7 Or approximately 2.5 x 10 7 Individual recombinant receptor expression CD8 + T cells; 5×10 7 Or approximately 5 x 10 7 Individual recombinant receptor expression CD8 + T cell; or 0.75×10 8 Alternatively, approximately 0.75 × 10 8 Individual recombinant receptor expression CD8 + T cells A method of the present invention, including any of the methods described in items 1001 to 1010. [Invention 1012] The method according to any of the 1001 to 1011 of the present invention, wherein the recombinant receptor specifically binds to an antigen associated with the disease or pathological condition, or to an antigen expressed in cells in the environment of a lesion associated with the disease or pathological condition. [Invention 1013] Any method 1001 to 1012 of the present invention, wherein the disease or condition is cancer. [Invention 1014] A method according to any one of items 1001 to 1013 of the present invention, wherein the disease or condition is myeloma, leukemia, or lymphoma. [Invention 1015] The method of any of the present invention 1001 to 1014, wherein the antigen is CD19. [Invention 1016] The method according to any one of items 1001 to 1015 of the present invention, wherein the disease or condition is a B-cell malignancy and / or acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL). [Invention 1017] The method according to any of the present invention 1001 to 1016, wherein the recombinant receptor is a chimeric antigen receptor (CAR). [Invention 1018] The method of the present invention 1017, wherein the CAR comprises an extracellular antigen recognition domain that specifically binds to the antigen, an intracellular signaling domain containing a CD3-zeta (CD3ζ) chain, and a co-stimulatory signaling region which is a CD28 or 4-1BB signaling domain. [Invention 1019] The method according to any one of the present invention 1001 to 1018, wherein the T cells are primary T cells obtained from the subject. [Invention 1020] The method according to any one of the present invention 1001 to 1019, wherein the T cells are the autologous cells of the subject. [Invention 1021] (1) Multiple CD4 expressing recombinant receptors + vial containing a composition comprising T cells; and (2) The plurality of CD4 + A unit dose of the composition containing all or part of T cells, and a CD8 cell expressing a recombinant receptor, which is not included in the vial. + Instructions for administering a unit dose composition containing T cells to a subject with a disease or condition. A manufactured article that is equipped with the following features. [Invention 1022] (1) Multiple CD8 expressing recombinant receptors + Vials containing compositions containing T cells; and (2) The multiple CD8 + A unit dose of the composition containing all or part of T cells, and a CD4 cell expressing a recombinant receptor, which is not included in the vial. + Instructions for administering a unit dose composition containing T cells to a subject with a disease or condition. A manufactured article that is equipped with the following features. [Invention 1023] The aforementioned CD4 + Recombinant receptors expressed by cells and the CD8 + Are the recombinant receptors expressed by T cells the same? CD4+ Recombinant receptors expressed by cells and the CD8 + The recombinant receptors expressed by T cells are different; or CD4 + Recombinant receptors expressed by cells and the CD8 + Recombinant receptors expressed by T cells bind to the same antigen, and the antigen is expressed by the disease or pathological condition or its cells or tissues, or is associated with the disease or pathological condition or its cells or tissues. A manufactured article of the present invention 1021 or the present invention 1022. [Invention 1024] The vial is 10 × 10 6 Or approximately 10 x 10 6 More than 15 T cells or recombinant receptor-expressing T cells, 15 × 10 6 Or approximately 15 x 10 6 More than 10 T cells or recombinant receptor-expressing T cells, 25 × 10 6 Or approximately 25 x 10 6 A manufactured article according to any of the inventions 1021 to 1023, comprising more than 1 T cells or recombinant receptor-expressing T cells. [Invention 1025] A manufactured article according to any of the inventions 1021 to 1024, wherein the vial contains cells in a quantity of approximately 10 million cells / mL to approximately 70 million cells / mL, approximately 10 million cells / mL to approximately 50 million cells / mL, approximately 10 million cells / mL to approximately 25 million cells / mL, approximately 10 million cells / mL to approximately 15 million cells / mL, 15 million cells / mL to approximately 70 million cells / mL, approximately 15 million cells / mL to approximately 50 million cells / mL, approximately 15 million cells / mL to approximately 25 million cells / mL, approximately 25 million cells / mL to approximately 70 million cells / mL, approximately 25 million cells / mL to approximately 50 million cells / mL, and approximately 50 million cells / mL to approximately 70 million cells / mL. [Invention 1026] A manufactured article of any of the inventions 1021 to 1025, wherein the composition further comprises a cryoprotective substance and / or the article further comprises instructions for thawing the composition before administration to the subject. [Invention 1027] A manufactured article according to any of the present invention 1021 to 1026, wherein the recombinant receptor is a chimeric antigen receptor. [Invention 1028] A method for treating a subject having or suspected of having non-Hodgkin lymphoma (NHL), comprising the step of administering to the subject a certain dose of T cells, which include T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by the NHL, The T cells produced by this dose are 2.5 × 10⁶ 7 Or approximately 2.5 × 10 7 pieces~2×10 8 Or approximately 2 × 10 8 It contains (including the values ​​at both ends) CAR-expressing T cells; and A method wherein 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 having a Performance Status (ECOG) of 0 or 1 on the East Coast Cancer Group. [Invention 1029] The aforementioned dose of T cells expresses the CAR in a specified ratio of CD4 + Cells and CD8 expressing the aforementioned CAR + Cells and / or CD4 in specified ratios + Cells and CD8 + The method of the present invention 1028, comprising cells, wherein the ratio is approximately 1:1 or approximately 1:3 to approximately 3:1. [Invention 1030] A method for treating a subject having non-Hodgkin lymphoma (NHL), comprising the step of administering a certain dose of T cells to the subject, 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 expresses the CAR in a specified ratio of CD4 + Cells and CD8 expressing the CAR + Cells and / or CD4 in specified ratios + Cells and CD8 + A method comprising cells in a ratio of approximately 1:1 or 1:1, 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. [Invention 1031] The method of the present invention 1030, wherein the subject is identified as having an ECOG status of 0 or 1, or is identified as having such a status. [Invention 1032] At least 35%, at least 40%, or at least 50% of subjects treated according to the above method achieved a complete response (CR); At least 60%, 70%, 80%, 90%, or 95% of those achieving CR exhibit sustained CR for three months or more, or six months or more; and / or At least 60%, 70%, 80%, 90%, or 95% of subjects achieving CR within 1 month and / or 3 months remain in response, still 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 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 those achieving OR demonstrate sustained OR over a period of 3 months or more, or 6 months or more; and / or At least 35%, at least 40%, or at least 50% of those who achieve OR remain in response or are alive for at least 3 months and / or 6 months after achieving OR; and / or At the time of or prior to administration of the aforementioned dose of cells, at least 40%, at least 50%, at least 60%, and at least 70% of subjects who had or were identified as having double / triple-hit lymphoma or relapsed lymphoma achieved an OR, or a sustained OR for 3 months or more or 6 months or more, after autologous stem cell transplantation (ASCT). Any method according to invention 1028 to 1031. [Invention 1033] The cells are the autologous cells of the subject, and The minimum absolute number of lymphocytes (ALC) required for apheresis is not required and / or specified for the production of such treatment; and / or The cells are produced by a process capable of generating cell products for administration by the method for subjects with a disease or condition or for at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of a selected target population. Any method according to invention 1028 to 1032. [Invention 1034] More than 50% or approximately 50%, more than 60% or approximately 60%, more than 70% or approximately 70%, or more than 80% or approximately 80% of subjects treated according to the above method did not show grade 3 or higher cytokine release syndrome (CRS) and / or grade 3 or higher neurotoxicity, and / or more than 40% or more 50% or more 55% showed neither neurotoxicity nor CRS. Any method according to invention 1028 to 1033. [Invention 1035] A method for treating a subject having non-Hodgkin lymphoma (NHL), comprising the step of administering to the subject a certain dose of T cells, which include T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a target antigen expressed by the NHL, The T cells produced by this dose were 5 × 10 7 Or approximately 5 x 10 7 pieces~1×10 8 Or approximately 1 x 10 8 A dose comprising (including the values ​​at both ends) recombinant receptor-expressing T cells, wherein the dose is a specified ratio of CD4 cells expressing the recombinant receptor. + Cells and CD8 expressing the recombinant receptor + Cells and / or CD4 in specified ratios + Cells and CD8 + It contains cells, and the ratio is approximately 1:1 or 1:1; and The method results in (1) complete response (CR) in at least 35%, at least 40%, or at least 50% of the treated subjects, and / or objective response (OR) in at least 50%, at least 60%, or at least 70% of the treated subjects, and (2) less than 50% of the subjects exhibiting cytokine release syndrome (CRS) of grade 2 or higher and / or neurotoxicity of grade 2 or higher. method. [Invention 1036] The method of the present invention 1035, wherein at least 40%, at least 50%, at least 60%, and at least 70% of subjects who had or were identified as having double / triple-hit lymphoma or relapse after autologous stem cell transplantation (ASCT) at the time of or prior to administration of the aforementioned dose of cells achieved OR, or sustained OR for three months or more or six months or more. [Invention 1037] The aforementioned CR or OR persists 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 described above achieve sustained complete response (CR) for more than 3 months or more than 6 months; and / or At least 60%, 70%, 80%, 90%, or 95% of subjects treated by this method who achieve complete response (CR) remain in complete response (CR), remain in response (response), or remain alive for three months or more, six months or more, or nine months or more; and / or At least 60%, 70%, 80%, 90%, or 95% of subjects treated with the said method who achieve complete response (CR) within one month and / or three months remain in response, remain in complete response, and / or are alive or alive without progression for three months or more and / or six months or more and / or nine 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); At least 60%, 70%, 80%, 90%, or 95% of the subjects achieve sustained OR for three months or more, or six months or more; and / or At least 35%, at least 40%, or at least 50% of subjects treated by this method who achieve OR remain in response or are alive for at least 3 months and / or 6 months. The method of Invention 1035 or Invention 1036. [Invention 1038] At the time of or prior to the administration of the aforementioned dose of cells, the subject is identified as having, or is identified as having, a lymphoma associated with or involving central nervous system (CNS) infiltration; and / or A method according to any one of the invention 1028-1037, wherein at least 70%, at least 80%, at least 90%, or at least 95% of subjects treated according to the method described above who showed or were identified as showing lymphoma with CNS infiltration at the time of or before administration of the dose of cells achieved resolution of the CNS disease. [Invention 1039] A method for treating a subject, comprising the step of administering to a subject having lymphoma a certain 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 lymphoma of the subject is associated with or involves central nervous system (CNS) infiltration. [Invention 1040] The method of Invention 1038 or Invention 1039, wherein the subject includes a brain lesion, optionally a temporal lobe brain lesion, at or before the administration of the aforementioned dose of cells. [Invention 1041] The method of the present invention 1039 or 1040, wherein the lymphoma is a B-cell malignant tumor. [Invention 1042] The method according to any one of the present invention 1039 to 1041, wherein the lymphoma is non-Hodgkin lymphoma (NHL). [Invention 1043] At least 35%, at least 40%, or at least 50% of subjects treated according to the method described above achieved complete response (CR) or remission of CNS disease; At least 60%, 70%, 80%, 90%, or 95% of those achieving CR remain in CR status for three months or more, or six months or more; and / or At least 60%, 70%, 80%, 90%, or 95% of subjects who achieve complete response (CR) or remission of CNS disease by 1 month and / or 3 months remain in response, remain in CR, and / or survive or survive 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 achieved an objective response (OR) or remission of the CNS disease; At least 60%, 70%, 80%, 90%, or 95% of those who achieve OR have been doing so for 3 months or more or 6 months or more; and / or At least 60%, 70%, 80%, 90%, or 95% of patients achieving OR or remission for CNS disease remain in response or are alive for at least 3 months and / or 6 months; and / or The size or volume of the brain lesion is reduced by more than 25 or about 25%, more than 50 or about 50%, more than 75 or about 75%, or more than that; and / or Reduction, remission, or elimination of CNS disease is achieved in at least 35%, at least 40%, or at least 50% of subjects treated according to the method. Any method described in invention 1038 to 1042. [Invention 1044] More than 30 or about 30%, more than 35 or about 35%, more than 40 or about 40%, or more than 50 or about 50% of subjects treated according to the above method did not show 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 will not develop CRS earlier than 3 days after the start of the administration, and / or will not develop neurotoxicity earlier than 5 days after the start of the 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 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 8 or about 8 days later, 9 or about 9 days later, 10 or about 10 days later, or 11 or about 11 days later. Any method described in invention 1028 to 1043. [Invention 1045] Prior to the commencement of administration of the aforementioned dose of cells, the subject has not been subjected to any substance or treatment that can treat, prevent, delay, reduce, or attenuate the occurrence or risk of toxicity after administration of the aforementioned dose of cells. Any method of the present invention described in items 1028 to 1044. [Invention 1046] The method of the present invention 1045, wherein the active substance is an anti-IL-6 antibody, an anti-IL-6R antibody, or a steroid, or comprises the same. [Invention 1047] The method of the present invention 1045 or 1046, wherein the active substance is tocilizumab, siltuximab, or dexamethasone, or comprises the same. [Invention 1048] The aforementioned administration and any follow-up are performed on an outpatient basis and / or without requiring hospitalization or an overnight stay in a hospital; and If the subject exhibits sustained fever, or a fever that does not subside or has not subsided after treatment with antipyretics, or a fever that does not subside or has not subsided by more than 1°C, the subject may be admitted to a hospital or admitted for one night, and / or may be treated with a substance or treatment for the treatment, prevention, reduction, or attenuation of neurotoxicity and / or cytokine release syndrome or its risk. Any method described in invention 1028 to 1047. [Invention 1049] The method according to any one of items 1028-1038 and 1042-1048 of the present invention, wherein the NHL is selected from the group consisting of aggressive NHL, diffuse large B-cell lymphoma (DLBCL), NOS (transformed from de novo and indolent), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B). [Invention 1050] The method according to any one of items 1028-1038 and 1042-1049 of the present invention, wherein 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. [Invention 1051] The method according to any of the present invention 1028-1038 and 1042-1050, wherein the NHL includes DLBCL. [Invention 1052] The method of the present invention 1051, wherein the DLBCL does not include DLBCL transformed from MZL and CLL (Richter), and / or the subjects administered the aforementioned dose of cells have DLBCL characterized by transformation from de novo or indolent, and / or do not include DLBCL transformed from MZL and CLL. [Invention 1053] Any method of the present invention 1028-1038 and 1042-1052, wherein the NHL does not contain PMBCL and / or the subject to whom the cells are administered the dose does not contain PMBCL. [Invention 1054] The method according to any one of items 1035 to 1053 of the present invention, wherein the subject is identified as having or having a Performance Status (ECOG) status of 0, 1, or 2 of the East Coast Cancer Clinical Trials Group. [Invention 1055] The method according to any one of the present invention 1028 to 1054, wherein the subject is identified as having an ECOG status of 0 or 1, or is identified as having such a status. [Invention 1056] The method according to any of items 1028 to 1055 of the present invention, wherein, at or immediately before the administration of the aforementioned dose of cells, the subject has relapsed after remission following treatment with one or more prior treatments for NHL, or optionally one, two, or three prior treatments other than one, two, or three prior treatments of another dose of cells expressing the CAR, or has become refractory to said prior treatment. [Invention 1057] At or before administering the aforementioned dose of cells, The subject is identified as having or having double / triple-hit lymphoma; and / or The subject is identified as having chemotherapy-resistant lymphoma, optionally chemotherapy-resistant DLBCL, or has been identified as having such cancer; and / or The subject has not achieved complete remission (CR) in response to prior treatment; and / or The subject has experienced a relapse within one year or less of one year after receiving autologous stem cell transplantation (ASCT). Any method described in 1028 to 1056 of this invention. [Invention 1058] The method includes a step of identifying or selecting a target to whom the dose of cells is administered, before administering the dose of cells, Having double / triple-hit lymphoma; Chemotherapy-resistant lymphoma, optionally with chemotherapy-resistant DLBCL; Malignant tumor, optionally NHL, has not achieved complete remission (CR) in response to prior treatment; and / or Relapse within one year or less of one year after autologous stem cell transplantation (ASCT); and / or Lymphoma associated with or with central nervous system (CNS) infiltration, Any method described in invention 1028 to 1057. [Invention 1059] Additional therapeutic agents or treatments, optionally non-cell therapies, optionally CAR + Any method of the present invention 1028 to 1058 further comprising the step of applying something other than T-cell therapy to the subject. [Invention 1060] The CAR comprises an antigen-specific scFv, a transmembrane domain, an intraplasmic signaling domain derived from a costimulatory molecule, optionally being or containing 4-1BB, and an intraplasmic signaling domain derived from a primary signaling ITAM-containing molecule, optionally being or containing a CD3 zeta signaling domain, and optionally further comprising a spacer between the transmembrane domain and the scFv; The CAR comprises, in order, an antigen-specific scFv, a transmembrane domain, an intracellular signaling domain derived from a co-stimulatory molecule which is or contains a 4-1BB signaling domain, and an intracellular signaling domain derived from a primary signaling ITAM-containing molecule which is optionally a CD3 zeta signaling domain; or The CAR comprises, in order, an antigen-specific scFv, a spacer, a transmembrane domain, an intracellular signaling domain derived from a co-stimulatory molecule which is optionally a 4-1BB signaling domain, and an intracellular signaling domain derived from a primary signaling ITAM-containing molecule which is optionally a CD3 zeta signaling domain or contains one; where, The spacer (a) contains or consists of all or part of an immunoglobulin hinge or a modified version thereof, or contains about 15 or fewer amino acids and does not contain the CD28 extracellular region or the CD8 extracellular region; (b) contains or consists of all or part of an immunoglobulin hinge, optionally an IgG4 hinge, or a modified version thereof, and / or contains about 15 or fewer amino acids and does not contain the CD28 extracellular region or the CD8 extracellular region; or (c) is 12 amino acid long or about 12 amino acid long and / or contains or consists of all or part of an immunoglobulin, optionally IgG4, hinge or a modified version 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 A sequence encoded by NO:34, or having, or consisting of, any variant of the aforementioned having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher sequence identity with them; or (e) Formula X 1 PPX 2 A formula containing or consisting of P, where X 1 is glycine, cysteine, or arginine, X 2 is a polypeptide spacer which is cysteine ​​or threonine; and / or The co-stimulatory domain includes 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; and / or The primary signaling domain includes SEQ ID NO: 13, 14, or 15, and has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher sequence identity; and / or The scFv is 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 YAMDYWG (SEQ ID NO:40) contains the CDRH3 sequence, or the scFv contains the heavy chain variable region and the light chain variable region of FMC63, and / or the CDRL1 sequence, CDRL2 sequence, CDRL3 sequence, CDRH1 sequence, CDRH2 sequence, and CDRH3 sequence of FMC63, or binds to the same epitope as any of the above, or competes with any of the above for binding, and optionally the scFv is in order V H And optionally, a linker including SEQ ID NO:24, and V L and / or the scFv comprises a flexible linker and / or comprises an amino acid sequence indicated as SEQ ID NO:24, Any method described in 1028 to 1059 of this invention. [Invention 1061] The method according to any one of the present invention 1028 to 1060, wherein the antigen is a B cell antigen, optionally CD19. [Invention 1062] The method according to any one of items 1001-1020 and 1028-1061 of the present invention, wherein, prior to the administration, the subject is pretreated with lymphocyte apheresis including the administration of fludarabine and / or cyclophosphamide. [Invention 1063] The method according to any one of the present invention 1001-1020 and 1028-1062, further comprising the step of applying a lymphocyte apheresis therapy, including the administration of fludarabine and / or cyclophosphamide, to the subject immediately before the administration. [Invention 1064] The application of the aforementioned cell dose and / or lymphocyte apheresis therapy is performed on an outpatient basis; and If the subject exhibits sustained fever, or a fever that does not subside or has not subsided after treatment with antipyretics, or a fever that does not subside or has not subsided by more than 1°C, the subject may be admitted to a hospital or admitted for one night, and / or may be treated with a substance or treatment for the treatment, prevention, reduction, or attenuation of neurotoxicity and / or cytokine release syndrome or its risk. The method of the present invention 1063. [Invention 1065] The method according to any of items 1028 to 1064 of the present invention, wherein the aforementioned dose of cells is administered parenterally, or optionally intravenously. [Invention 1066] The method according to any of items 1028 to 1065 of the present invention, wherein the T cells are primary T cells obtained from the subject. [Invention 1067] The method according to any one of the present invention 1028 to 1066, wherein the T cells are the autologous cells of the subject. [Invention 1068] The T cells at the aforementioned dose express the CAR CD4 + T cells and CD8 expressing the CAR + The administration includes T cells, and the CD4 + T cells and the CD8 + A first composition comprising one of the T cells and the CD4 + T cell or CD8 + The procedure involves separately administering a second composition containing the other of the T cells. Any method of the present invention 1028 to 1067. [Invention 1069] The first composition and the second composition are administered with an interval of 0 to 12 hours, 0 to 6 hours, or 0 to 2 hours between them, or the administration of the first composition and the administration of the second composition are performed on the same day, with an interval of approximately 0 to approximately 12 hours, approximately 0 to approximately 6 hours, or approximately 0 to 2 hours; and / or The administration of the first composition and the administration of the second composition are performed with an interval of approximately 1 minute to 1 hour, or approximately 5 minutes to 30 minutes. The method of the present invention 1068. [Invention 1070] The method of the present invention 1067 or 1068, wherein the first composition and the second composition are administered with an interval 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. [Invention 1071] The first composition is the CD4 + A method according to any of the present invention 1067 to 1070, comprising T cells. [Invention 1072] The first composition is the CD8 + A method comprising T cells, any of the methods described in items 1067 to 1071 of the present invention. [Invention 1073] A method according to any of items 1067 to 1072 of the present invention, wherein the first composition is administered before the second composition. [Invention 1074] A method for evaluating the potential for response to cell therapy, (a) A step 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, The biological sample is derived from a subject that is a candidate for treatment in the cell therapy, and the cell therapy comprises a certain dose of genetically modified cells that express recombinant receptors; and The process involves the biological sample being obtained from the subject before the application of the cell therapy, and / or the biological sample not containing the recombinant receptor and / or the modified cells; and (b) A step of individually comparing the level, quantity, or concentration of the analyte in the sample to a threshold level, thereby determining the likelihood that the subject will achieve efficacy to the cell therapy. Methods that include... [Invention 1075] The method of the present invention 1074, further comprising the step of applying the cell therapy to the subject if the subject is likely to achieve a response. [Invention 1076] A method for selecting the target for treatment, (a) A step 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, The biological sample is derived from a subject that is a candidate for treatment in cell therapy, and the cell therapy comprises a certain dose of genetically modified cells that express recombinant receptors; and The process involves the biological sample being obtained from the subject before the application of the cell therapy, and / or the biological sample not containing the recombinant receptor and / or the modified cells; and (b) A step of selecting subjects who are likely to respond to the treatment, based on the results of determining the likelihood that a subject will achieve a response to the cell therapy by individually comparing the level, amount, or concentration of the analyte in the sample with a threshold level. Methods that include... [Invention 1077] The method of the present invention 1076, further comprising the step of applying the cell therapy to a target selected for treatment. [Invention 1078] (a) A step of selecting subjects likely to respond to cell therapy treatment, based on the results of determining the likelihood of a subject achieving a response to 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, The biological sample is derived from a subject that is a candidate for treatment in the cell therapy, and the cell therapy comprises a certain dose of genetically modified cells that express recombinant receptors; and The process involves the biological sample being obtained from the subject before the application of the cell therapy, and / or the biological sample not containing the recombinant receptor and / or the modified cells; and (b) The step of applying the cell therapy to the target selected for the treatment. Treatment methods, including those mentioned above. [Invention 1079] A method according to any of the present invention 1074 to 1078, wherein if the level, amount, or concentration of one or more of the analytes is below a threshold level, the target is likely to achieve efficacy, and if the level, amount, or concentration of one or more of the analytes is above a threshold level, the target is unlikely to achieve efficacy. [Invention 1080] The method according to any one of the present invention 1074 to 1079, wherein the threshold level is within 25%, 20%, 15%, 10%, or 5% below the median or mean level, amount, or concentration of the analyte in the biological sample obtained from the group of subjects before receiving cell therapy, and / or within a standard deviation below the median or mean, or the median or mean, or approximately the median or approximately the mean, wherein each subject in the group is a subject that achieved a response after administration of a recombinant receptor expression therapeutic cell composition for treating the same disease or condition. [Invention 1081] The method according to any one of the invention 1074 to 1079, wherein the threshold level is within 25%, 20%, 15%, 10%, or 5% above the median or mean level, amount, or concentration of the analyte in the biological sample obtained from a group of subjects before receiving cell therapy, and / or within a standard deviation above the median or mean, wherein each subject in the group is a subject that showed stable (SD) and / or progressive disease (PD) after administration of a recombinant receptor-expressing therapeutic cell composition for treating the same disease or condition. [Invention 1082] Any method 1074 to 1081 of the present invention, wherein the aforementioned response includes an objective response. [Invention 1083] The method of the present invention 1082, wherein the objective response includes complete response (CR) or partial response (PR). [Invention 1084] A method for evaluating the potential for sustained response to cell therapy, (a) A step 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 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, where, The biological sample is derived from a subject that is a candidate for treatment in the cell therapy, and the cell therapy comprises a certain dose of genetically modified cells that express recombinant receptors, and The process involves the biological sample being obtained from the subject before the application of the cell therapy, and / or the biological sample not containing the recombinant receptor and / or the modified cells; and (b) A step of individually comparing the level, quantity, 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. Methods that include... [Invention 1085] The method of the present invention 1084, further comprising the step of applying the cell therapy to the subject if the subject is likely to achieve a response. [Invention 1086] A method for selecting the target for treatment, (a) A step 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 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, where, The biological sample is derived from a subject that is a candidate for treatment in cell therapy, and the cell therapy comprises a certain dose of genetically modified cells that express recombinant receptors; and The process involves the biological sample being obtained from the subject before the application of the cell therapy, and / or the biological sample not containing the recombinant receptor and / or the modified cells; and (b) A step of selecting subjects who are likely to respond to the 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. Methods that include... [Invention 1087] The method of the present invention 1086, further comprising the step of applying the cell therapy to a target selected for treatment. [Invention 1088] (a) A step of selecting subjects who are likely to respond to cell therapy, based on the results of determining the likelihood of a subject achieving a sustained response to 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, where, The biological sample is derived from a subject that is a candidate for treatment in the cell therapy, and the cell therapy comprises a certain dose of genetically modified cells that express recombinant receptors; and The process involves the biological sample being obtained from the subject before the application of the cell therapy, and / or the biological sample not containing the recombinant receptor and / or the modified cells; and (b) The step of applying the cell therapy to the target selected for the treatment. Treatment methods, including those mentioned above. [Invention 1089] A method according to any one of the present invention 1085 to 1088, wherein the subject is likely to achieve a sustained response if the level, amount, or concentration of one or more analytes is below a threshold level, and the subject is unlikely to achieve a sustained response if the level, amount, or concentration of one or more analytes is above a threshold level. [Invention 1090] The method according to any one of the present invention 1085 to 1088, wherein the threshold level is within 25%, 20%, 15%, 10%, or 5% below the median or mean level, amount, or concentration of the analyte in the biological sample obtained from the group of subjects before receiving cell therapy, and / or within a standard deviation below the median or mean, or the median or mean, or approximately the median or approximately the mean, wherein each subject in the group is a subject that achieved a sustained response after administration of a recombinant receptor expression therapeutic cell composition for treating the same disease or condition. [Invention 1091] The method according to any one of the present invention 1085 to 1088, wherein the threshold level is within 25%, 20%, 15%, 11%, or 5% above the median or mean level, amount, or concentration of the analyte in the biological sample obtained from the group of subjects before receiving cell therapy, and / or within a standard deviation above the median or mean, wherein each subject in the group is a subject that did not achieve a sustained response after administration of a recombinant receptor expression therapeutic cell composition for treating the same disease or condition. [Invention 1092] The method according to any one of the invention 1085 to 1091, wherein the sustained response includes a sustained complete response (CR) or partial response (PR) lasting for 3 months or more, 4 months or more, 5 months or more, or 6 months or more. [Invention 1093] The method according to any one of the invention 1085 to 1092, wherein the sustained response includes a sustained complete response (CR) or partial response (PR) lasting for at least three months. [Invention 1094] A method for evaluating the risk of developing toxicity after the application of cell therapy, (a) A step of evaluating the level, amount, or concentration of one or more analytes in a biological sample of interest, or a volume measurement of tumor load in the subject, wherein the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (fibrin degradation product), IL-6, IL-8, IL-10, IL-15, IL-16, TNF-α, IFN-α2, MCP-1, MIP-1α, and MIP-1β, where, The subject is a candidate for treatment in the cell therapy, and the cell therapy is optional and includes genetically modified cells expressing recombinant receptors in a certain dose or composition, and The process involves the biological sample being obtained from the subject before the application of the cell therapy, and / or the biological sample not containing the recombinant receptor and / or the modified cells; and (b) A step of individually comparing the level, quantity, or concentration of the analyte in the sample, or the volume measurement of the tumor load, to a threshold level, thereby determining the risk of developing toxicity after the application of the cell therapy. Methods that include... [Invention 1095] A method for identifying the target, (a) A step of evaluating the level, amount, or concentration of one or more analytes in a biological sample of interest, or a volume measurement of tumor load in the subject, wherein the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (fibrin degradation product), IL-6, IL-8, IL-10, IL-15, IL-16, TNF-α, IFN-α2, MCP-1, MIP-1α, and MIP-1β, where, The subject is a candidate for treatment in the cell therapy, and the cell therapy optionally includes genetically modified cells expressing recombinant receptors in a certain dose or composition; and The process involves the biological sample being obtained from the subject before the application of the cell therapy, and / or the biological sample not containing the recombinant receptor and / or the modified cells; and (b) The process of identifying subjects at risk of developing toxicity after the application of the cell therapy by individually comparing the level, amount, or concentration of the analyte in the sample, or the volume measurement of the tumor load, to a threshold level. Methods that include... [Invention 1096] (a) A step of evaluating the level, amount, or concentration of one or more analytes in a biological sample of interest, or a volume measurement of the tumor burden of the subject, wherein the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (fibrin degradation product), IL-6, IL-8, IL-10, IL-15, IL-16, TNF-α, IFN-α2, MCP-1, MIP-1α, and MIP-1β, where, The subject is a candidate for treatment in cell therapy, and the cell therapy is optional and includes genetically modified cells expressing recombinant receptors in a certain dose or composition, and The process involves the biological sample being obtained from the subject before the application of the cell therapy, and / or the biological sample not containing the recombinant receptor and / or the modified cells; and (b) a step of individually comparing the level, amount, or concentration of the analyte in the sample, or a volume measurement of the tumor load, to a threshold level, thereby determining the risk of developing toxicity after the application of the cell therapy; and (c) A step of applying the cell therapy to the subject in accordance with or based on the results of the evaluation, wherein optionally, an active substance or other treatment that can treat, prevent, delay, reduce or attenuate the occurrence or risk of toxicity. Treatment methods, including those mentioned above. [Invention 1097] The method according to any one of the present invention 1094 to 1096, wherein the biological sample is a blood sample or a plasma sample. [Invention 1098] Any method 1094 to 1097 of the present invention, wherein the volume measurement of the tumor load is a bidirectional sum of products (SPD), or a volume measurement based on CT and / or MRI imaging of the body or other imaging diagnostics. [Invention 1099] The method of the present invention 1098, wherein the volume measurement of the tumor load is performed before treatment, before apheresis, or before the production of the cell product. [Invention 1100] Any method of the present invention 1094 to 1099, further comprising the step of monitoring the subject for symptoms of toxicity if the subject is identified as being subject to the cell therapy and at risk of developing toxicity. [Invention 1101] Any method of the present invention 1094 to 1100, wherein if the level, amount, or concentration of one or more analytes or the volume measurement of the tumor load is above a threshold level, the subject is at risk of exhibiting toxicity, and if the level, amount, or concentration of one or more analytes or the volume measurement of the tumor load is below a threshold level, the subject has a low risk of exhibiting toxicity. [Invention 1102] The method according to any of the Invention 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 a biological sample obtained from a group of subjects before receiving cell therapy, or within 25%, 20%, 15%, 10%, or 5% above the median or mean value, and / or within a standard deviation above the median or mean value, or the median or mean value, wherein each subject in the group is a subject that did not exhibit any toxicity after receiving a recombinant receptor-expressing therapeutic cell composition for treating the same disease or condition. [Invention 1103] The method according to any of the 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 a biological sample obtained from a group of subjects before receiving cell therapy, or within a standard deviation below the median or mean value of the volume measurement of tumor load in the biological sample, wherein each subject in the group is a subject that developed toxicity after receiving a recombinant receptor-expressing therapeutic cell composition for treating the same disease or condition. [Invention 1104] A method according to any one of the present invention 1094 to 1103, wherein the toxicity is neurotoxicity or CRS. [Invention 1105] The method according to any one of the present invention 1094 to 1104, wherein the toxicity is grade 1 or higher neurotoxicity or CRS. [Invention 1106] The toxicity is severe neurotoxicity, or grade 2 or higher neurotoxicity, grade 3 or higher neurotoxicity, at least grade 3 prolonged neurotoxicity, or grade 4 or higher or grade 5 or higher neurotoxicity; or The aforementioned toxicity is severe CRS, or includes Grade 2 or higher CRS or Grade 3 or higher. Any method according to invention 1094 to 1105. [Invention 1107] A method according to any one of the present invention 1094 to 1106, wherein the toxicity is neurotoxic, the volume measurement of the tumor load is SPD, and the one or more analytes are selected from LDH, IL-10, IL-15, IL-16, TNF-α, and MIP-1β. [Invention 1108] A method according to any of the present invention 1094 to 1106, wherein the toxicity is neurotoxic, one or more analytes are evaluated, and the analyte is selected from LDH, ferritin, CRP, IL-6, IL-8, IL-10, TNF-α, IFN-α2, MCP-1, and MIP-1β. [Invention 1109] A method according to any of the present invention 1094 to 1106, wherein the toxicity is neurotoxic, one or more analytes are evaluated, and the analytes are selected from IL-8, IL-10, and CXCL10. [Invention 1110] The method of the present invention 1109, wherein the neurotoxicity is severe neurotoxicity or neurotoxicity of grade 3 or higher. [Invention 1111] A method according to any of the present invention 1094 to 1106, wherein the toxicity is CRS, and the volume measurement of one or more analytes or tumor load is selected from LDH, SPD, CRP, d-dimer, IL-6, IL-15, TNF-α, and MIP-1α. [Invention 1112] The method of the present invention 1111, wherein the CRS is a severe CRS or a CRS of grade 3 or higher. [Invention 1113] If the subject is identified as having a risk of exhibiting toxicity, (a) (1) an active substance or other treatment that can treat, prevent, delay, reduce or attenuate the occurrence or risk of toxicity, and (2) the cell therapy applied to the subject, wherein the application of the active substance is performed (i) before the commencement of the application of the cell therapy to the subject, (ii) within one, two or three days of the commencement of the application of the cell therapy to the subject, (iii) in parallel with the commencement of the application of the cell therapy to the subject, and / or (iv) at the time of the first fever after the commencement of the application of the cell therapy to the subject; and / or (b) Applying cell therapy to the subject at a low dose or at a dose that does not carry a risk of developing toxicity or severe toxicity after the application of cell therapy, or in the majority of the subject and / or in the majority of the subject having or suspected to have a disease or condition; and / or (c) Applying cell therapy to the subject in the context of hospitalization and / or involving one or more days of hospitalization, optionally, otherwise applying cell therapy to the subject on an outpatient basis or without one or more days of hospitalization. Any method described in Invention 1094 to 1112. [Invention 1114] The method of the present invention 1113, wherein the active substance or other treatment is an anti-IL-6 antibody or an anti-IL-6 receptor antibody. [Invention 1115] The method of the present invention 1114, wherein the active substance or other treatment is an active substance selected from or comprising tocilizumab, siltuximab, crazakizumab, sarilumab, olokizumab (CDP6038), elcilimomab, ALD518 / BMS-945429, silkumab (CNTO 136), CPSI-2634, ARGX-109, FE301, and FM101. [Invention 1116] The method of the present invention 1113, wherein the active substance or other treatment is a steroid, optionally dexamethasone, or includes the same. [Invention 1117] A volume measurement is evaluated, and if the volume measurement is 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 The present invention relates to any of the methods described in 1094-1107 and 1113-1116. [Invention 1118] The volume measurement value is SPD, and the threshold level is 50 cm 2 or about 50 cm 2 The method of the present invention 1117. [Invention 1119] A method according to any one of the invention 1094 to 1116, wherein the one or more analytes is or contains LDH, and the threshold level is 300 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. [Invention 1120] The method according to any of the invention 1119, wherein the analyte is LDH and the threshold level is 500 units / liter or about 500 units / liter. [Invention 1121] The method according to any of the present invention 1074 to 1120, wherein the recombinant receptor specifically binds to an antigen associated with a disease or pathological condition, or to an antigen expressed in cells in the environment of a lesion associated with the disease or pathological condition. [Invention 1122] A method according to any of the present invention 1074 to 1121, wherein the disease or condition is cancer. [Invention 1123] A method according to any one of the present invention 1074 to 1122, wherein the disease or condition is myeloma, leukemia, or lymphoma. [Invention 1124] The method according to any one of items 1074 to 1123 of the present invention, wherein the disease or condition is a B-cell malignancy and / or acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL). [Invention 1125] The method according to any of the present invention 1074 to 1124, wherein the recombinant receptor is a chimeric antigen receptor (CAR). [Invention 1126] The modified cells are T cells, optionally CD4 + and / or CD8 + A method of the present invention, including any of the methods described in items 1074 to 1125. [Invention 1127] The method of the present invention 1126, wherein the T cells are primary T cells obtained from the subject or are the autologous cells of the subject. [Invention 1128] A manufactured article comprising one or more doses of cell therapy and instructions for administering the cell therapy, wherein each dose comprises cells expressing a chimeric antigen receptor (CAR), This instruction states that the dose of cells should be administered to subjects who have or have been identified as having non-Hodgkin lymphoma (NHL), and that 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, and that the subject has or has been identified as having a Performance Status (ECOG) status of 0 or 1 in the US East Coast Clinical Oncology Group. Specify; and The instructions specify a number of T cells to be administered, or an administration of one or more preparations in an amount or volume equivalent to or containing the specified number of cells, wherein the specified number of cells is 5 × 10 7 Or approximately 5 x 10 7 pieces~1×10 8 Or approximately 1 x 108 5 × 10¹ CAR-expressing T cells (including values ​​at both ends), 7 Or approximately 5 x 10 7 pieces~1.5×10 8 Or approximately 1.5 x 10 8 5 × 10¹ CAR-expressing T cells (including values ​​at both ends), 7 Or approximately 5 x 10 7 1 x 10⁶ CAR-expressing T cells 8 Or approximately 1 x 10 8 1.5 × 10⁶ CAR-expressing T cells, or 1.5 × 10⁶ 8 Or approximately 1.5 x 10 8 CAR-expressing T cells, 2.5 × 10⁶ values ​​including both ends. 7 Or approximately 2.5 x 10 7 pieces~5×10 7 Or approximately 5 x 10 7 CD8 (including the values ​​at both ends) + CAR-expressing T cells, 2.5 × 10⁶ 7 Or approximately 2.5 x 10 7 pieces~0.75×10 8 Alternatively, approximately 0.75 × 10 8 CD8 (including the values ​​at both ends) + CAR-expressing T cells, or 2.5 × 10⁶ 7 Or approximately 2.5 x 10 7 CD8 + CAR-expressing T cells, 5 × 10 7 Or approximately 5 x 10 7 A single CAR-expressing T cell, or 0.75 × 10⁶ 8 Alternatively, approximately 0.75 × 10 8 CD8 + Specifying administration of a surviving population containing CAR-expressing T cells, or any of the aforementioned populations, Manufactured articles. [Invention 1129] The above-mentioned instruction manual describes the CD4 that exhibits the CAR. + Cell: CD8 + A manufactured article of the present invention 1128, specifying that the cell therapy is applied in a specified ratio of cells. [Invention 1130] A manufactured article comprising a cell therapy, or one of several compositions of a cell therapy, comprising genetically modified cells expressing a chimeric antigen receptor (CAR) in a certain dose or composition, and instructions for administering the cell therapy, wherein the instructions are T cells at this dose express the CAR CD4 + Cells: CD8 cells expressing the CAR + The specified ratio of cells, and / or CD4 + Cell: CD8 + The cells should be administered in a prescribed ratio, which is approximately 1:1 or 1:1; and The cells in this dose should be administered to subjects who have or have been identified as having non-Hodgkin lymphoma (NHL), and the NHL should be 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. A manufactured product that specifies a particular item. [Invention 1131] A manufactured article comprising a cell therapy, or one of several compositions of a cell therapy, comprising genetically modified cells expressing a chimeric antigen receptor (CAR) in a certain dose or composition, and instructions for administering the cell therapy, wherein the instructions are The dose of cells should be administered to subjects having or identified as having non-Hodgkin lymphoma (NHL), and optionally, the NHL should be selected from aggressive NHL, diffuse large B-cell lymphoma (DLBCL), NOS (transformed from de novo and indolent), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B); The T cells administered in this dose are 5 × 10⁶ 7 Or approximately 5 x 10 7 pieces~1×10 8 Or approximately 1 x 10 8 It includes (including the values ​​at both ends) CAR-expressing T cells; and T cells at this dose express the CAR CD4 + Cells: CD8 cells expressing the CAR + The specified ratio of cells, and / or CD4 + Cell: CD8 + The cells should be administered in a prescribed ratio, which is approximately 1:1 or 1:1. A manufactured product that specifies a particular item. [Invention 1132] A manufactured article of Invention 1130 or Invention 1131, wherein the description further specifies that cell therapy should be applied to subjects identified as having or having a Performance Status (ECOG) status of 0, 1, or 2 of the U.S. East Coast Cancer Clinical Trials Group, and / or subjects identified as having or having an ECOG status of 0 or 1. [Invention 1133] A manufactured article of any of the inventions 1128 to 1132, wherein the description specifies that the administration of the cell dose may be carried out on an outpatient basis and / or without requiring hospitalization or an overnight stay in a hospital. [Invention 1134] A manufactured article of the present invention 1133, wherein the instruction manual further specifies that if, after administering the cell dose on an outpatient basis without requiring hospitalization or an overnight stay in a hospital, the subject exhibits sustained fever or a fever that does not subside or has not subsided after treatment with an antipyretic, or a fever that does not subside or has not subsided or has not subsided by more than 1°C, the subject should be admitted to a hospital or an overnight stay in a hospital, and / or an active agent or treatment for the treatment, prevention, reduction, or attenuation of neurotoxicity and / or cytokine release syndrome or the risk thereof should be applied. [Invention 1135] A manufactured article of the present invention 1133 or 1134, wherein the active substance is an anti-IL-6 or anti-IL-6R antibody, optionally tocilizumab or siltuximab, and / or a steroid, optionally dexamethasone, or contains the same. [Invention 1136] The manufactured article further comprises instructions for use in conjunction with, after, or in association with lymphocyte apheresis, wherein the lymphocyte apheresis optionally comprises fludarabine and / or cyclophosphamide, any manufactured article of the present invention 1128 to 1135. [Invention 1137] The aforementioned manufactured article is CD4 + T cells or CD8 + The description comprises one of a plurality of compositions of a cell therapy comprising a first composition of genetically modified cells including T cells, wherein the first composition is the CD4 + T cell or CD8 + A manufactured article of any of the inventions 1128 to 1136, specified to be for use in conjunction with a second composition comprising the other of T cells, wherein optionally the cells of the first composition and the cells of the second composition are derived from the same subject. [Invention 1138] The above description states that the first composition and the second composition express the recombinant receptor CD4 + Cells: CD8 cells expressing the recombinant receptor + The specified ratio of cells, and / or CD4+ Cell: CD8 + A manufactured article of the present invention 1137, which is to be administered in a specified ratio of cells, specifying that the ratio is about 1:1 or about 1:3 to about 3:1. [Invention 1139] A manufactured article 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 that is a candidate for treatment in cell therapy, wherein the cell therapy comprises genetically modified cells expressing a recombinant receptor in a certain dose or composition, and the one or more analytes are selected from ferritin, LDH, CXCL10, G-CSF, and IL-10. [Invention 1140] Cell therapy comprising a certain dose of genetically modified cells expressing recombinant receptors; and Instructions for applying the cell therapy according to or based on the results of an evaluation of the level, amount, or concentration of one or more analytes in the biological sample, wherein the biological sample is obtained from a subject prior to the application of 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 ferritin, LDH, CXCL10, G-CSF, and IL-10. A manufactured article that is equipped with the following features. [Invention 1141] A manufactured article of the present invention 1139 or 1140, wherein the description provides, individually for each of the one or more analytes, information regarding a threshold level indicating whether the subject is likely to respond to treatment in cell therapy. [Invention 1142] A manufactured article 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 that is a candidate for treatment in cell therapy, wherein the cell therapy comprises genetically modified cells expressing a recombinant receptor in a certain dose or composition, 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. [Invention 1143] Cell therapy comprising a certain dose of genetically modified cells expressing recombinant receptors; and Instructions for applying the cell therapy according to or based on the results of an evaluation of the level, amount, or concentration of one or more analytes in the biological sample, wherein the biological sample is obtained from a subject prior to the application of 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, 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. A manufactured article that is equipped with the following features. [Invention 1144] A manufactured article of the present invention 1142 or 1143, wherein the description provides, individually for each of the one or more analytes, information regarding a threshold level indicating whether the subject is likely to show a sustained response after the application of the cell therapy. [Invention 1145] A manufactured article 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 that is a candidate for treatment in cell therapy, wherein the cell therapy comprises genetically modified cells expressing a recombinant receptor in a certain dose or composition, and the one or more analytes are selected from LDH, ferritin, C-reactive protein (CRP), D-dimer (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] Cell therapy comprising a certain dose of genetically modified cells expressing recombinant receptors; and Instructions for applying the cell therapy according to or based on the results of an evaluation of the level, amount, or concentration of one or more analytes in the biological sample, wherein the biological sample is obtained from a subject prior to the application of 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 (fibrin degradation product), IL-6, IL-8, IL-10, IL-15, IL-16, TNF-α, IFN-α2, MCP-1, MIP-1α, and MIP-1β. A manufactured article that is equipped with the following features. [Invention 1147] A manufactured article of the present invention 1145 or 1146, wherein the description provides, individually for each of the one or more analytes, information regarding a threshold level indicating whether the subject is likely to exhibit toxicity after the application of the cell therapy. [Invention 1148] A manufactured article according to any of the present invention 1139 to 1147, wherein the recombinant receptor specifically binds to an antigen associated with a disease or pathological condition, or to an antigen expressed in cells in the environment of a lesion associated with the disease or pathological condition. [Invention 1149] A manufactured article according to any of the inventions 1139 to 1148, wherein the disease or condition is cancer. [Invention 1150] A manufactured article according to any of the inventions 1139 to 1149, wherein the disease or condition is myeloma, leukemia, or lymphoma. [Invention 1151] A manufactured article of any of the present inventions 1139 to 1150, wherein the disease or condition is a B-cell malignancy and / or acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL). [Invention 1152] The aforementioned 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, antifolate 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, and 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 preferential expression antigen (PRAME), Survivin, TAG72, B7-H6, IL-13 receptor alpha2 (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, dual antigen, cancer testicular antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, tumor embryonic antigen, ROR1, TAG72, VEG A manufactured article according to any of the inventions 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. [Invention 1153] A manufactured article according to any of the inventions 1138 to 1152, wherein the recombinant receptor is a T cell receptor or a functional non-T cell receptor. [Invention 1154] A manufactured article according to any of the present invention 1138 to 1153, wherein the recombinant receptor is a chimeric antigen receptor (CAR). [Invention 1155] The CAR comprises an antigen-specific scFv, a transmembrane domain, an intraplasmic signaling domain derived from a costimulatory molecule, optionally being 4-1BB or containing 4-1BB, and an intraplasmic signaling domain derived from a primary signaling ITAM-containing molecule, optionally being a CD3 zeta signaling domain or containing the same, and optionally further comprising a spacer between the transmembrane domain and the scFv; The CAR comprises, in order, an antigen-specific scFv, a transmembrane domain, an intracellular signaling domain derived from a co-stimulatory molecule which is or contains a 4-1BB signaling domain, and an intracellular signaling domain derived from a primary signaling ITAM-containing molecule which is optionally a CD3 zeta signaling domain; or The CAR comprises, in order, an antigen-specific scFv, a spacer, a transmembrane domain, an intracellular signaling domain derived from a co-stimulatory molecule which is optionally a 4-1BB signaling domain, and an intracellular signaling domain derived from a primary signaling ITAM-containing molecule which is optionally a CD3 zeta signaling domain or contains one; where, The spacer (a) contains or consists of all or part of an immunoglobulin hinge or a modified version thereof, or contains about 15 or fewer amino acids and does not contain the CD28 extracellular region or the CD8 extracellular region; (b) contains or consists of all or part of an immunoglobulin hinge, optionally an IgG4 hinge, or a modified version thereof, and / or contains about 15 or fewer amino acids and does not contain the CD28 extracellular region or the CD8 extracellular region; or (c) is 12 amino acid long or about 12 amino acid long and / or contains or consists of all or part of an immunoglobulin, optionally IgG4, hinge or a modified version 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 A sequence encoded by NO:34, or having, or consisting of, any variant of the aforementioned having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher sequence identity with them; or (e) Formula X 1 PPX 2 A formula containing or consisting of P, where X 1 is glycine, cysteine, or arginine, X 2 is a polypeptide spacer which is cysteine ​​or threonine; and / or The co-stimulatory domain includes 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; and / or The primary signaling domain includes SEQ ID NO: 13, 14, or 15, and has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher sequence identity; and / or The scFv is 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 YAMDYWG (SEQ ID NO:40) contains the CDRH3 sequence, or the scFv contains the heavy chain variable region and the light chain variable region of FMC63, and / or the CDRL1 sequence, CDRL2 sequence, CDRL3 sequence, CDRH1 sequence, CDRH2 sequence, and CDRH3 sequence of FMC63, or binds to the same epitope as any of the above, or competes with any of the above for binding, and optionally the scFv is in order V H And optionally, a linker including SEQ ID NO:24, and V L and / or the scFv comprises a flexible linker and / or comprises an amino acid sequence indicated as SEQ ID NO:24, A manufactured article according to any of the inventions 1128 to 1154. [Invention 1156] The manufactured article of the present invention 1156, wherein the antigen is a B cell antigen, optionally CD19. [Invention 1157] The modified cells are T cells, optionally CD4 + and / or CD8 + A manufactured article containing any of the inventions 1128 to 1156. [Invention 1158] The manufactured article of the present invention 1157, wherein the T cells are primary T cells obtained from the subject. [Brief explanation of the drawing]

[0179] [Figure 1] This shows the percentage of subjects who experienced abnormal laboratory values ​​or adverse events (TEAEs) during the investigational treatment (20% or more). *: One Grade 5 AE in a patient with multiple organ failure due to lymphoma progression, unrelated to the study treatment; †: One Grade 5 AE in a patient who was assessed by the investigator as being related to fludarabine, cyclophosphamide, and CAR T-cell therapy, was receiving growth factors, broad-spectrum antibiotics and antifungal agents, was neutropenic, but refused mechanical ventilation for progressive respiratory failure, and developed diffuse alveolar damage on day 23.

[0180] [Figure 2]This is a Kaplan-Meier curve showing the observed time to the onset of CRS and neurotoxicity.

[0181] [Figure 3A] This shows the 3-month objective response rate (ORR) in the subgroup treated. [Figure 3B] This shows the 3-month objective response rate (ORR) in the subgroup treated.

[0182] [Figure 4A] This shows the duration of response (CR / PR, CR, or PR) and overall survival rates in the full cohort. [Figure 4B] This shows the duration of response (CR / PR, CR, or PR) and overall survival rates in the core cohort.

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

[0184] [Figure 6A] This indicates 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 a specific point in time. [Figure 6B] The image shows a pre-treatment axial PET-CT image revealing intracranial abnormalities in the right middle cranial fossa and extensive abnormalities in the subcutaneous tissue of the right posterior auricle region. [Figure 6C] This is a post-treatment PET-CT image showing the resolution of the abnormality shown in Figure 2B after treatment with anti-CD19 CAR+ T cells. [Figure 6D]This is a pre-treatment MRI of the brain (high-resolution T1-weighted image with enhancement; axial view) showing a homogeneously enlarged aneurysm in the right middle cranial fossa. [Figure 6E] This is a post-treatment MRI image showing the almost complete disappearance of the enlarged tumor. [Figure 6F] This is a PET-CT image taken in the axial direction at the time of recurrence, showing recurrence (arrow) of a right posterior auricular tumor associated with strong uptake of 18F-flurodeoxyglycose. [Figure 6G] This is a PET-CT imaging diagnosis showing the regression of a posterior auricular tumor after incisional biopsy and relentless proliferation of CAR+ T cells.

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

[0186] [Figure 8] The graph plots progression-free survival (months) and shows the best overall response and duration of response observed over time in individual subjects within the full cohort and core cohort of NHL subjects treated with anti-CD19 cell therapy including CAR-T-expressing CD4+ and CD8+ T cells, as well as individual clinical outcomes. a: Patients achieved BOR at 1 month unless otherwise noted; b: Complete resolution of CNS infiltration due to lymphoma observed in 2 patients; c: One patient experienced regrowth after biopsy at disease progression.

[0187] [Figure 9A]The median (± quartiles) of CAR-expressing CD3+ cell count / μL blood (CD3, circles; N=87), evaluated by flow cytometry using antibodies specific to the truncated receptor in blood samples from 87 subjects administered anti-CD19 CAR-expressing cells, or the median (± quartiles) of the copy number of integrated CAR-transformed genes / μg genomic DNA (qPCR, squares; N=85), evaluated by quantitative polymerase chain reaction (qPCR) using primers specific to the woodchuck virus post-transcriptional regulatory element (WPRE) present in the CAR coding vector, are shown. The cutoff for detecting CAR+ cells by flow cytometry was set to ≥25 events at the CAR+ gate, and the detection limit of qPCR was ≥12.5 copies of CAR-transformed genes / μg genomic DNA.

[0188] [Figure 9B] This shows the relative number of CD4+ and CD8+ CAR-expressing cells / μL in blood and bone marrow samples from 67 subjects who received anti-CD19 CAR-expressing cells on day 11±3. The straight line represents the unity line and is not the regression line.

[0189] [Figure 10] Figures 10A and 10B show the area under the curve (AUC0-28; Figure 10A) and median (± quartiles) of maximum serum concentration (Cmax; CAR+ cells / μL blood; Figure 10B) of CD4+ and CD8+ CAR+ cells from day 0 to day 28 in a control subgroup with diffuse large B-cell lymphoma (DLBCL, NOS; N=27), transformed follicular lymphoma (tFL; N=10), or DLBCL (tMZL / tCLL; N=4) or mantle cell lymphoma (MCL; N-5) transformed from de novo or indolent lymphoma, who received CAR-expressing T cells via DL1.

[0190] [Figure 11A]Figures 11A and 11B show the area under the curve (AUC0-28; Figure 11A) and the median (± interquartiles) of the 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+ cell administration at DL1 or DL2. [Figure 11B] Refer to the explanation in Figure 11A.

[0191] [Figure 12A] Figures 12A-12D show the median (± interquartiles) of CAR-expressing CD4+ and CD8+CAR+ cell counts / μL blood over time in comparisons between subjects exhibiting cytokine release syndrome (either CRS) and subjects not exhibiting CRS (no CRS) (CD4+: Figure 12A; CD8+: Figure 12B) or between subjects exhibiting neurotoxicity (either NT) and subjects not exhibiting NT (no NT) (CD4+: Figure 12C; CD8+: Figure 12D). [Figure 12B] Refer to the explanation in Figure 12A. [Figure 12C] Refer to the explanation in Figure 12A. [Figure 12D] Refer to the explanation in Figure 12A.

[0192] [Figure 13A] Figures 13A and 13B show the peak CD3+CAR+cell count / μL (CD3+Cmax) for subjects grouped by those who achieved the best overall response (BOR) of complete response (CR), partial response (PR), or PD, or a sustained response of CR, PR, or PD for 3 months (M3). [Figure 13B] Refer to the explanation in Figure 13A.

[0193] [Figure 14A] This shows the levels of blood analytes before lymphocyte removal in serum samples from subjects exhibiting high CAR+ cell proliferation (CD3+Cmax > 500) and subjects exhibiting low CAR+ cell proliferation (CD3+Cmax < 500).

[0194] [Figure 14B]This shows the peak blood analyte levels in serum samples from subjects exhibiting high CAR+ cell proliferation (CD3+Cmax > 500) and subjects exhibiting low CAR+ cell proliferation (CD3+Cmax < 500).

[0195] [Figure 15] This plot shows the pre-lymphocyte depletion SPD (cm2) relative to the AUC0-28 (cells * days / μL) of CD3+ CAR+ cells in individual subjects who were administered CAR+ cells at DL1 or DL2.

[0196] [Figure 16A] Figures 16A and 16B show the levels of serum analytes before lymphocyte removal in serum samples derived from subjects that exhibited cytokine release syndrome (CRS grade 1-4) compared with subjects that did not exhibit CRS (CRS grade 0) (Figure 16A), or subjects that exhibited neurotoxicity (NT grade 0) compared with subjects that did not exhibit NT (NT grade 1-4) (Figure 16B). The units were ferritin and D-dimer (μg / L); CRP (mg / L); and cytokines (pg / mL). [Figure 16B] Refer to the explanation in Figure 16A.

[0197] [Figure 17] This report presents the evaluation of the two-way sum of product (SPD; cm2) and lactate dehydrogenase (LDH; U / L) levels, which indicate tumor burden, as pre-lymphocyte apheresis patient parameters, comparing subjects who exhibited cytokine release syndrome (either CRS) with subjects who did not exhibit CRS (no CRS), or subjects who exhibited neurotoxicity (either NT) with subjects who did not exhibit NT (no NT).

[0198] [Figure 18A]This plot shows pre-lymphocyte depletion SPD (cm2) against pre-lymphocyte depletion LDH (U / L) levels for individuals exhibiting neurotoxicity (grade 1-4 NT) or subjects without NT (grade 0 NT) (left panel) and individuals exhibiting CRS (grade 1-4 CRS) or subjects without CRS (grade 0 CRS) (right panel). The dotted lines represent SPD levels (≥50 cm2) or LDH levels (≥500 U / L) associated with high rates of CRS or NT. [Figure 18B] This shows an estimate of the odds ratio for CRS or NT expression based on SPD levels (≥50 cm2) or LDH levels (≥500 U / L) within a 95% confidence interval (CI). [Figure 18C] This shows estimates of the odds ratios for CRS or NT expression based on SPD or LDH levels, including estimates of the odds ratios below the threshold in the 95% confidence interval (CI).

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

[0200] [Figure 20A] Figures 20A and 20B show the peak blood analyte levels in serum samples derived from subjects that exhibited cytokine release syndrome (either CRS) and subjects that did not exhibit CRS (no CRS) (Figure 20A), or subjects that exhibited neurotoxicity (either NT) and subjects that did not exhibit NT (no NT) (Figure 20B). The units were CRP (mg / L), SAA-1 (mg / L), and cytokine (pg / mL). [Figure 20B] Refer to the explanation in Figure 20A.

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

[0202] [Figure 22] This shows the 3-month objective response rate (ORR) in the treatment subgroup within a 95% confidence interval.

[0203] [Figure 23A] Figures 23A and 23B show the duration of response (DOR) for the full cohort (Figure 23A) and core cohort (Figure 23B) for subjects who achieved CR or PR, all subjects who showed a response, non-responders, and all treated subjects, while Figures 23C and 23D show the overall survival rates for the full cohort (Figure 23C) and core cohort (Figure 23D). The median F / U for duration of response was 6.3 months. [Figure 23B] Refer to the explanation in Figure 23A. [Figure 23C] Refer to the explanation in Figure 23A. [Figure 23D] Refer to the explanation in Figure 23A.

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

[0205] [Figure 25] This shows the percentage of subjects (%) who developed CRS or neurotoxicity over time in the full cohort.

[0206] [Figure 26] The box plots show the T cell purity of the T cell composition enriched with CD4+ and CD8+ cells at different stages of the method for producing the modified cell composition containing CAR T cells described in Example 8. The frequency of CD4+ and CD8+ cells in the composition (percentage relative to total white blood cells) is shown.

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

[0208] [Figure 28A] This indicates the number of CD3+CAR+ T cells present in the CAR T cell composition for administration at DL1 and DL2. [Figure 28B]This shows the number of CD4+CAR+ and CD8+CAR+ cells, as well as CD4+CAR+TNF-α+ cells and CD8+CAR+TNF-α+ cells present in the CAR T cell composition for administration at DL1 and DL2.

[0209] [Figure 29] This shows the percentage of subjects (%) who experienced a study-induced adverse event (TEAE) in the full DLBCL cohort at the time of the study described in Example 6, which occurred in ≥20% of subjects. Data from 6 subjects with MCL treated with the compliant product at DL1 and followed for at least 28 days were not included. b: One Grade 5 AE, septic shock unrelated to CAR+T cell administration, occurring in the context of disease progression. c: One Grade 5 AE, diffuse alveolar damage, occurring on day 23 in a patient who was neutropenic, receiving growth factors and broad-spectrum antibiotics and antifungals, and was assessed by the investigator as being related to fludarabine, cyclophosphamide, and CAR+T cells, and who refused mechanical ventilation due to progressive respiratory failure. d: Abnormal laboratory values.

[0210] [Figure 30] This shows the 6-month objective response rate (ORR) in the treatment subgroup within the 95% confidence interval. a. Includes all DLBCL patients treated at all dose levels in the core cohort.

[0211] [Figure 31A] Figures 31A and 31B show the duration of response (DOR) for the full cohort (Figure 31A) and core cohort (Figure 31B) for subjects who achieved CR or PR, all subjects who showed a response, non-responders, and all treated subjects, while Figures 31C and 31D show the overall survival rates for the full cohort (Figure 31C) and core cohort (Figure 31D). NE: Not estimable. [Figure 31B] Refer to the explanation in Figure 31A. [Figure 31C] Refer to the explanation in Figure 31A. [Figure 31D] Refer to the explanation in Figure 31A. [Modes for carrying out the invention]

[0212] Detailed explanation I. Methods and Uses of Cell Therapy 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, cancer or tumor (e.g., leukemia or lymphoma, most particularly non-Hodgkin lymphoma (NHL)) or including thereof). In some aspects, the methods and uses result in improved response and / or more sustained response or efficacy and / or a lower risk of toxicity or other side effects compared to certain alternative methods, for example, in a particular group of treated subjects. In some embodiments, the methods are advantageous by the benefits of administering a specified number or relative number of modified cells, administering a specific type of cell in a predetermined ratio, or treating a particular patient population, for example, a patient population having a particular risk profile, disease stage and / or treatment history and / or combination thereof. Methods are also provided that include evaluating certain parameters that may correlate with the manifestation of toxicity, for example, the expression or analysis of specific biomarkers, as well as methods for treatments to prevent and / or mitigate toxicity, for example, interventional therapies. Furthermore, methods are provided for evaluating outcomes after the application of immunotherapy and / or cell therapy, such as therapeutic outcomes, such as response, such as complete response (CR) or partial response (PR), optionally sustained response, such as sustained response for at least 3 months, 6 months, or longer; or safety outcomes, such as the occurrence of toxicity, such as neurotoxicity or CRS, and specific parameters, such as the expression of specific biomarkers or analytes that may correlate with these outcomes. Methods are also provided for evaluating the likelihood of response and / or the likelihood of toxicity risk based on parameters, such as the expression of biomarkers or evaluation of analytes. Compositions for use in cell therapy are also provided. Furthermore, manufactured articles and kits for use in methods provided herein are also provided, for example. In some embodiments, manufactured articles and kits optionally include instructions for use in accordance with methods provided herein.

[0213] In some embodiments, methods and uses involve administering cells expressing genetically modified (recombinant) cell surface receptors in adoptive cell therapy, which are generally chimeric receptors, e.g., chimeric antigen receptors (CARs), that recognize antigens expressed by leukemia or lymphoma and / or cell types from which they originate, antigens associated with them, and / or antigens specific to them. The cells are generally administered in compositions formulated for administration; the methods generally involve administering one or more doses of cells to a target, which may include a specific number or relative number of cells or modified cells and / or two or more subtypes (e.g., CD4 T cells and CD8 T cells) in a specified ratio or composition in the composition.

[0214] In some embodiments, cells, populations, and compositions are administered to subjects having a specific disease or condition to be treated, for example, by adoptive cell therapy, for example, adoptive T cell therapy. In some embodiments, the method involves treating a subject having lymphoma or leukemia, for example, non-Hodgkin lymphoma (NHL), with a certain dose of antigen receptor-expressing cells (for example, CAR-expressing cells).

[0215] In some embodiments, the methods provided involve treating a specific group or subset of subjects, e.g., subjects identified as having a high-risk disease, e.g., high-risk NHL. In some aspects, the methods treat subjects with aggressive and / or poor-prognosis forms of B-cell non-Hodgkin lymphoma (NHL), e.g., relapsed or refractory to standard treatment (R / R) and having a poor prognosis. In some cases, the overall response rate (ORR; also known in some cases as objective response rate) to available treatments, standard treatments, or reference treatments directed to the disease and / or patient population is less than 40%, and / or the complete response rate (CR; also known in some cases as complete remission) is less than 20%. In some aspects, in chemotherapy-resistant DLBCL, the ORR with reference therapy, available treatment, or standard therapy is approximately 26%, and the CR rate is approximately 8% (Crump et al. Outomes in refractory aggressive diffuse large B-cell lymphoma (DLBCL): Results from the international SCHOLAR study. ASCO 2016 [Abstract 7516]). In some aspects, the methods, compositions, uses, and manufactured articles provided yield improved and superior responses compared to available therapies.

[0216] In some embodiments, the methods, uses, and manufactured articles involve or are used for the treatment of subjects, which involves selecting or identifying a particular group or subset of subjects (e.g., based on a specific disease type, diagnostic criteria, prior treatment, and / or response to prior treatment). In some embodiments, the methods involve treating subjects who have relapsed after remission following treatment with one or more prior treatments, or who are refractory to such prior treatments; or subjects who have relapsed or are refractory (R / R) to one or more prior treatments (e.g., first-line or subsequent standard treatment). In some embodiments, the methods involve treating subjects having diffuse large B-cell lymphoma (DLBCL), unspecified type (NOS; de novo and indolent transformed types), primary mediastinal B-cell lymphoma (PMBCL), or follicular lymphoma, e.g., follicular lymphoma grade 3B (FL3B). In some embodiments, the methods involve treating subjects having a Performance Status (ECOG) of 0-1 or 0-2 in the US East Coast Cancer Clinical Trials Group. In some embodiments, the method treats poor-prognosis populations or DLBCL patients or subjects who generally have an insufficient response to treatment or a specific reference treatment, for example, poor-prognosis populations or DLBCL patients or subjects with one or more, for example, two or three chromosomal translocations (e.g., poor-prognosis populations or DLBCL patients or subjects with so-called “double-hit” or “triple-hit” lymphoma; MYC / 8q24 locus 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), and / or poor-prognosis populations or DLBCL patients or subjects who have relapsed (optionally within 12 months) after autologous stem cell transplantation (ASCT), and / or poor-prognosis populations or DLBCL patients or subjects who are considered chemotherapy-resistant.

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

[0218] In some embodiments, an antigen receptor (e.g., CAR) specifically binds to a target antigen associated with the disease or condition, such as 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 the step of administering cells or a composition containing cells to a subject, tissue, or cell (e.g., one that has, is at risk of, or is suspected of having, a disease, condition, or disorder). In some embodiments, the subject is an adult subject. In some embodiments, the subject is 30 years or about 30 years old, 40 years or about 40 years old, 50 years or about 50 years old, 60 years or about 60 years old, or 70 years or about 70 years old or older.

[0220] In some embodiments, the method involves administering cells to subjects selected or identified as having a specific prognosis or risk of NHL. Non-Hodgkin lymphoma (NHL) can be a diverse disease. Some subjects with NHL may survive without treatment, while others may require immediate intervention. In some cases, subjects with NHL may be classified into groups from which information on disease prognosis and / or recommended treatment strategies can be obtained. In some cases, such groups may be “low-risk,” “intermediate-risk,” “high-risk,” and / or “very high-risk,” and patients may be classified into such groups based on several factors, for example, but not limited to, genetic abnormalities and / or morphological or physical characteristics. In some embodiments, subjects treated according to the method and / or by the manufactured article or composition are classified or identified based on their risk of NHL. In some embodiments, the subjects are those with high-risk NHL.

[0221] In some embodiments, the subject has been previously treated with a treatment or therapeutic agent targeting the disease or condition, e.g., NHL, prior to the administration of cells expressing the recombinant receptor. In some embodiments, the subject has been previously treated with hematopoietic stem cell transplantation (HSCT), e.g., allogeneic HSCT or autogeneic HSCT. In some embodiments, the subject had a poor prognosis after treatment with standard therapy and / or had no response to first-line or subsequent prior treatment. In some embodiments, the subject has been treated with, or has previously received, at least one or about one, at least two or at least two or about two, at least three or at least three or about three, or at least four or at least four or about four other treatments for treating NHL other than lymphocyte apheresis, and / or administration of cells expressing the antigen receptor in the dose thereof. In some embodiments, the subject has been previously treated with chemotherapy or radiotherapy. In some aspects, the subjects are refractory or unresponsive to other treatments or therapeutic agents. In some embodiments, the subjects have persistent or recurrent disease after, for example, another treatment or therapeutic intervention, such as chemotherapy or radiation therapy.

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

[0223] In some embodiments, the subjects are unsuitable for transplantation, for example, unsuitable for hematopoietic stem cell transplantation (HSCT), for example, allogeneic HSCT. In some embodiments, such subjects are administered modified cells (e.g., CAR-T cells) or compositions containing such cells according to the embodiments provided herein.

[0224] In some embodiments, the method involves administering cells to subjects selected or identified as having high-risk NHL. In some embodiments, the subjects exhibit one or more cytogenetic abnormalities associated with high-risk NHL, for example. In some embodiments, the subjects are selected or identified on the basis of 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 / histiocyte-rich large B-cell lymphoma (TCHRBCL), Burkitt lymphoma, mantle cell lymphoma (MCL), and / or follicular lymphoma (FL). In certain embodiments, subjects treated using the methods provided herein include subjects with aggressive NHL, particularly those with diffuse large B-cell lymphoma (DLBCL), unspecified type (NOS; de novo and indolent-transformed types), primary mediastinal B-cell lymphoma (PMBCL), or follicular lymphoma grade 3B (FL3B). In some embodiments, subjects have a poor performance status. In some aspects, the treated population includes subjects with an East Coast Cancer Clinical Trials 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 treatments. In some embodiments, the subjects do not have marginal zone lymphoma (MZL) or DLBCL transformed from chronic lymphocytic leukemia (CLL; Richter). In some embodiments, subjects with CLL may exhibit Richter syndrome (RS), defined as the transformation of CLL to aggressive lymphoma, most commonly to diffuse large B-cell lymphoma (DLBCL) (see, e.g., Parikh et al. Blood 2014 123:1647-1657). In some embodiments, subjects have mantle cell lymphoma (MCL). In some embodiments, subjects are characterized by a poor overall survival rate.In some embodiments, subjects have never achieved a complete response (CR), have never undergone autologous stem cell transplantation (ASCT), are refractory to one or more second-line therapies, have a primary refractory disease, and / or have an ECOG performance score of 2.

[0225] In some embodiments, subjects to be treated include those with diffuse large B-cell lymphoma (DLBCL), de novo or indolent lymphoma-transformed (NOS), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3b (FL3B) after failure of two lines of treatment, and who have an ECOG score of 0-2, and who may optionally have previously been treated with allogeneic stem cell transplantation (SCT). In some embodiments, such subjects may be referred to as a “full cohort.” In some embodiments, subjects are selected for treatment with adoptive cell therapy if they meet the aforementioned criteria. In some embodiments, within the group ("full cohort"), subjects are not selected for treatment or are excluded from treatment if they have a poor performance status (e.g., ECOG 2) and / or have DLBCL transformed from marginal zone lymphoma (MZL) and chronic lymphocytic leukemia (CLL, Richter). Therefore, in some embodiments, subjects are selected for treatment if they have diffuse large B-cell lymphoma (DLBCL), de novo or indolent lymphoma-transformed (NOS), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3b (FL3B) after failure of two lines of treatment, and have an ECOG score of 0 or 1, and subjects may optionally have been previously treated with allogeneic stem cell transplantation (SCT), but do not have marginal zone lymphoma (MZL) or DLBCL transformed from 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 observations that a specific target population, e.g., a “core cohort,” to which a particular dose of cell therapy is applied exhibits a complete response (CR) rate of over 55%, an overall response rate (ORR) of over 80% with high persistence, e.g., maintained over a long period, e.g., longer than 3 months, with a 3-month ORR of over 65% and a 3-month CR rate of approximately 50%. In particular, the observations provided indicate that the 3-month ORR is higher in patients with two or three chromosomal translocations ("double-hit" or "triple-hit" lymphomas; typically a translocation of the MYC / 8q24 locus, usually in combination with the t(14;18)(q32;q21)bcl-2 gene, or / or a BCL6 / 3q27 chromosomal translocation; see, e.g., Xu et al. (2013) Int J Clin Exp Pathol. 6(4):788-794), primary refractory lymphoma, patients with chemotherapy-resistant DLBCL, and patients who have never previously achieved a complete response (CR).

[0227] In some aspects, compositions, methods, and uses are provided for the administration of cell therapies of a prescribed composition at specific doses associated with high response rates and / or high duration of response, as well as low toxicity levels and / or incidence of toxicity. In some embodiments, the composition or dose administered is a uniform dose and / or fixed dose of cells and / or one or more cells having a particular phenotype, e.g., a strictly uniform dose, e.g., a numerical value in which the variability or dispersion is within a specific range and / or degree compared to a specific number or target value of such cells. In some embodiments, the composition or dose administered is a CD4 of a prescribed ratio. + Cells and CD8 + Cells (e.g., CD4) + CAR + T cells: CD8 + CAR + Includes ratios in which the T cell ratio is 1:1) and / or ratios in which the variability from said ratio is within a certain degree (e.g., within ±10%, e.g., within ±8%), e.g., ratios in which the degree of variability or dispersion is ±10% or less, e.g., ±8% or less. In some embodiments, CD4 +Cells and CD8 + Cells are individually formulated and administered. In some embodiments, the administered cells exhibit consistent activity and / or function, e.g., cytokine production, apoptosis, and / or proliferation. In some embodiments, the provided composition exhibits highly consistent prescribed activity, as well as low variability in terms of cell number, cellular function, and / or cellular activity between cells in the composition, or low variability between preparations. In some embodiments, consistency in activity and / or function, e.g., low variability between preparations of the composition, allows for improved efficacy and / or safety. In some embodiments, administration of a prescribed composition resulted in lower product variability and lower toxicity, e.g., CRS or neurotoxicity, compared to administration of cell compositions with high heterogeneity. Also in some embodiments, consistent prescribed composition demonstrates consistent cell proliferation. Such consistency can facilitate dose determination, therapeutic range, dose-response evaluation, and identification of target factors that may correlate with safety or toxicity outcomes.

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

[0229] In some embodiments, of subjects treated with the provided compositions, manufactured articles, kits, methods, and uses, the amount of active agents (e.g., tocilizumab and / or dexamethasone) administered either before or after the application of cell therapy is less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%. In some embodiments, no prophylactic measures are administered to subjects prior to the administration of modified cells (e.g., CAR-T cells).

[0230] In some embodiments, the embodiments provided offer advantages, for example, enabling the application of cell therapy on an outpatient basis. In some embodiments, cell therapy, for example, administration of T cells in doses according to the embodiments (embodimnents), can be performed on an outpatient basis or without requiring hospitalization to a target hospital, for example, a hospital stay requiring an overnight stay. In some embodiments, such outpatient administration may enable increased accessibility and cost reduction while maintaining low toxicity and high sustained response rates. In some cases, outpatient treatment may be advantageous for patients who are already immunocompromised in some other way due to previous treatment, for example, after lymphodepletion, and who are at higher risk of exposure during hospital stays or in an inpatient setting. Also in some cases, outpatient treatment increases the treatment options for subjects who may not have access to hospitalization, hospital settings, or transplant centers, thereby broadening the availability of treatment. In some embodiments, subjects treated on an outpatient basis with the provided compositions, manufactured articles, kits, methods and uses remain in an outpatient state for at least three days, or a certain percentage (%) of subjects treated in this manner, e.g., at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95%, remain in an outpatient state for at least three days. In some aspects, subjects remain in an outpatient state for at least four, five, six, seven, eight days, or longer. In some embodiments, subjects treated with the provided compositions, manufactured articles, kits, methods and uses exhibit a reduction in the duration of hospital stay by, for example, 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, manufactured articles, kits, methods and uses.

[0231] In some embodiments, methods, cells, and compositions may result in high sustained response rates for a range of patient characteristics and / or tumor burden targets. In some embodiments, methods, cells, and compositions may result in high sustained response rates with a low risk of adverse effects or toxicity in high-risk patients with poor prognosis. In some embodiments, methods and uses may result in or yield high response rates and / or more sustained responses 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 have shown a low proportion of severe NT (sNT) or severe CRS (sCRS) and a high proportion of patients without either 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 method and / or the provided manufactured article or composition achieve 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 method and / or the provided manufactured article or composition achieve 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 method and / or the provided manufactured article or composition achieve CR or OR within one month, two months, or three months.

[0233] In some embodiments, within three, four, five, six months, seven, eight, or nine months, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or more of subjects treated according to the provided method and / or subjects treated with the provided manufactured article or composition, after three, four, five, six months, or longer, following the initiation of cell therapy. In some embodiments, such responses, e.g., CR or OR, persist for at least three, four, five, six, seven, eight, or nine months, in, for example, at least 60% or about 60%, at least 70% or about 70%, at least 80% or about 80%, at least 90% or at least about 90%, at least 95%, or more of subjects treated according to the provided method, or in such subjects that have achieved CR by one month or three months. 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 method and / or subjects treated with the provided manufactured article or composition, or such subjects that achieve CR by one month or three months, survive or survive without progression for three or about three months, four or about four months, five or about five months, six or about six months, seven or about seven months, eight or about eight months, or nine or about nine months.

[0234] In some embodiments, the resulting response observed in such subjects by treatment according to the provided method and / or with the provided manufactured article or composition is associated with any low-risk toxicity or low-risk severe toxicity in the majority of the treated subjects, or results in any low-risk toxicity or low-risk severe toxicity in the majority of the treated subjects. In some embodiments, more than 30% or about 30%, more than 35% or about 35%, more than 40% or about 40%, more than 50% or about 50%, more than 55% or about 55%, more than 60% or about 60%, or more of the subjects treated according to the provided method and / or with the provided manufactured article or composition do not exhibit any grade of CRS or any grade of neurotoxicity (NT). In some embodiments, more than 50% or about 50%, more than 60% or about 60%, more than 70% or about 70%, more than 80% or about 80%, or more subjects treated according to the provided method and / or the provided manufactured article or composition, do not exhibit severe CRS or Grade 3 or higher CRS. In some embodiments, more than 50% or about 50%, more than 60% or about 60%, more than 70% or about 70%, more than 80% or about 80%, or more subjects treated according to the provided method and / or the provided manufactured article or composition, do not exhibit severe neurotoxicity or Grade 3 or higher neurotoxicity, 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 method and / or with the provided manufactured articles or compositions do not exhibit early-onset CRS or neurotoxicity, and / or do not exhibit the onset of CRS earlier than day 1, day 2, day 3, or day 4 after the start 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 method and / or with the provided manufactured article or composition do not exhibit the onset of neurotoxicity earlier than day 3, 4, 5, 6, or 7 after the start of such administration. In some aspects, the median onset of neurotoxicity in subjects treated according to the method and / or with the provided manufactured article or composition is the median peak of CRS in subjects treated according to the method or thereafter, or the median time to the resolution of CRS in subjects treated according to the method or thereafter. In some cases, the median onset of neurotoxicity in subjects treated according to the method is 8 or approximately 8 days later, 9 or approximately 9 days later, 10 or approximately 10 days later, or 11 or approximately 11 days later.

[0236] In some aspects, such results are 5 × 10 7 Or approximately 5 x 10 7 ~1.5×10 8 Or approximately 1.5 x 10 8 pieces, for example, 5 x 10 7 ~1 × 10 81001 + T cells or specific types of CARs + T cells, for example, CD4 + CAR + T cells and / or CD8 + CAR + CD4 cells administered in numbers that are + or - (plus or minus, sometimes expressed as ±) 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% of a specified degree of dispersion of any of such cells, for example, compared to such a precise number or uniform number or fixed number. + and CD8 + This is observed after administration of a certain dose of T cells, including T cells. In some embodiments, such a uniform or fixed number of cells is, for example, total CAR + T cell or CD8 + and / or CD4 + CAR + T cells, 2.5 × 10 7 Or approximately 2.5 x 10 7 , 5×10 7 Or approximately 5 x 10 7 , 10×10 7 Or approximately 10 x 10 7 , 15×10 7 Or approximately 15 x 10 7 , or 20×10 7 Or approximately 20 x 10 7 The number of cells in a dose is 5 × 10⁶. In some embodiments, the number of cells in a dose is 5 × 10⁶. 7 CD4 + CAR + T cells (optional 2.5 x 10 7 CD4 + CAR + T cells and 2.5 × 10 7 CD8 + CAR +It contains, or consists of, or is essentially composed of (T cells); in some embodiments, this is 10 × 10 7 individual CAR + T cells (optional 5 x 10 7 CD4 + CAR + T cells and 5 × 10 7 CD8 + CAR + It contains, consists of, or essentially consists of T cells. In some aspects, the number of cells administered is within a certain degree of dispersion of such number in the aforementioned aspects, for example, within plus or minus (±) 5, 6, 7, 8, 9, or 10% compared to such number of cells, for example, within plus or minus 8%. In some aspects, the dose is such that the number of cells (e.g., total CAR cells) is within plus or minus 8%. + T cell or CD8 + and / or CD4 + CAR + Within a range where a correlation (optionally linear) is observed between the number of T cells and one or more outcomes indicating the effectiveness or duration of treatment (e.g., the likelihood of achieving remission, complete remission, and / or a specific duration of remission) and / or the duration of any of the aforementioned. In some aspects, it has been observed that higher doses of administered cells may lead to greater effectiveness without affecting, or substantially affecting, the incidence or risk of toxicity (e.g., CRS or neurotoxicity) or the degree of toxicity in the subject, such as the incidence or risk of severe CRS or severe neurotoxicity.

[0237] In some aspects, the methods provided are based on high or specific response rates (e.g., response rates in a population evaluated after a specific period following application (e.g., 3 months or 6 months)), e.g., ≥40%, ≥45%, ≥50%, ≥55%, ≥60%, ≥65%, ≥70%, ≥75%, ≥80%, ≥81%, ≥82%, ≥83%, ≥84%, or ≥85%, or higher ORR (e.g., 6-month ORR or 3-month ORR), and ≥30%, ≥35%, ≥40%. It is possible to achieve a complete response rate (CR) of 45% or higher, 50% or higher, 55% or higher, 60% or higher, 65% or higher, 70% or higher, 71%, 72%, 73%, or higher, or approximately 75% or higher (e.g., a 6-month CR rate or a 3-month CR rate), which is also sustained, for example, over a specific period or at least over a specific period, for example, for more than 1 month, more than 3 months, or more than 6 months or longer, or for 9 months or longer, after the start of treatment. In some embodiments, such response rates and persistence are obtained after only a single application or dose of such treatment. Furthermore, treatment of such a subject by the method provided and / or with the provided manufactured articles or compositions will, in some embodiments, result in a high response rate in the subject without exhibiting toxicity, such as neurotoxicity or a high incidence of CRS, even at high cellular doses. In some embodiments, about 50% or more than 50%, about 55% or more than 55%, or about 60% or more than 60% of subjects achieving such response do not develop any grade of toxicity, for example, no grade of CRS and / or neurotoxicity.

[0238] Therefore, in some embodiments, the methods, manufactured articles and / or compositions provided may offer advantages over other available methods, solutions or approaches for treatment, such as adoptive cell therapy. In particular, some embodiments provided offer advantages for subjects with high-risk NHL by achieving a high rate of sustained response with a low incidence of toxicity or side effects.

[0239] A. Treatment method This specification provides methods for treatment involving the administration of modified cells, such as modified T cells, or compositions containing modified cells. Also provided are methods involving the administration of modified cells and / or compositions thereof, as well as the use of modified cells (e.g., T cells) and / or compositions thereof, for example, for the treatment of subjects with a disease or condition, such as leukemia or lymphoma, such as non-Hodgkin lymphoma (NHL). In some embodiments, the methods and uses provided may yield improved response and / or more sustained response or efficacy and / or a lower risk of toxicity or other side effects compared to certain alternative methods, for example, in a particular group of treated subjects. Furthermore, in some aspects, methods are provided for administering modified cells, such as modified T cells, or compositions containing modified cells, to subjects, such as subjects with a disease or disorder. Also, in some aspects, the use of modified cells, such as modified T cells, or compositions containing modified cells for the treatment of a disease or disorder is provided. Furthermore, in some aspects, the use of modified cells, such as modified T cells, or compositions containing modified cells for the manufacture of pharmaceuticals for the treatment of a disease or disorder is provided. Furthermore, in some aspects, methods are provided for administering modified cells, such as modified T cells, or compositions containing modified cells, for use in the treatment of a disease or disorder, or for administration to a subject having a disease or disorder. In some aspects, the use of modified cells, such as modified T cells, or compositions containing modified cells is carried out according to any of the methods described herein.

[0240] General methods for administering cells for adoptive cell therapy are known and can be used in conjunction with the methods and compositions provided. For example, methods for adoptive T cell therapy are described, for example, in U.S. Patent 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; and Davila et al. (2013) PLoS ONE 8(4):e61338.

[0241] The disease or condition being treated may be any in which the expression of an antigen is associated with the pathogenesis of the disease, condition or disorder, and / or is involved in the pathogenesis of the disease, condition or disorder, for example, causing, exacerbating, or otherwise being involved in such disease, condition or disorder. Examples of diseases and conditions may include diseases or conditions associated with malignant tumors or cell transformations (e.g., cancer), autoimmune or inflammatory diseases, or infectious diseases caused by, for example, bacterial pathogens, viral pathogens or other pathogens. Example antigens, including those 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 the antigen associated with the disease or condition.

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

[0243] In some aspects, NHL can be staging based on the Lugano classification (see, e.g., Cheson et al., (2014) JCO 32(27):3059-3067; Cheson, BD (2015) Chin Clin Oncol 4(1):5). In some cases, the stage is indicated by Roman numerals I-IV (1-4), with E indicating localized stage (I or II) lymphoma affecting non-lymphatic organs (extranodal organs). Stage I represents infiltration into one lymph node or adjacent lymph node groups, or a single extranodal lesion (IE) without lymph node infiltration. Stage II represents stage I or II depending on the extent of lymph node involvement, with infiltration into two or more lymph node groups on the same diaphragmatic side, or localized contiguous extranodal infiltration (IIE). Stage III represents intranodal infiltration in lymph nodes bilateral to or above the diaphragm, with splenic infiltration. Stage IV represents discontinuous further extralymphatic infiltration. In addition, the term "giant mass lesion" may be used to describe large tumors in the chest, particularly in Stage II. The severity of the disease is determined by positron emission tomography (PET)-computed tomography (CT) for avid lymphomas and by CT for non-avid histology.

[0244] In some embodiments, the East Coast Clinical Oncology Group (ECOG) Performance Status Scale can be used to evaluate subjects, for example, those with poor outcomes in prior treatments, or to select subjects, for example, those with poor outcomes in prior treatments, for treatment (see, e.g., Oken et al. (1982) Am J Clin Oncol. 5:649-655). The ECOG Performance Status Scale indicates a patient's level of functionality in terms of their ability to care for themselves, daily activities, and physical abilities (e.g., walking, working). In some embodiments, an ECOG Performance Status of 0 indicates that the subject is able to perform normal activities. In some cases, a subject with an ECOG Performance Status of 1 shows some limitations in physical activity, but their walking is complete. In some cases, a patient with an ECOG Performance Status of 2 walks more than 50%. Furthermore, in some cases, individuals with an ECOG performance status of 2 may be able to perform basic self-care tasks; see, for example, Sorensen et al., (1993) Br J Cancer 67(4)773-775. The criteria reflecting ECOG performance status are shown in Table 1 below: (Table 1) ECOG Performance Status Criteria TIFF0007871011000001.tif82164

[0245] In some embodiments, the subjects are identified as having or possessing double / triple-hit lymphoma or lymphoma of a double / triple-hit molecular subtype. In some embodiments, the lymphoma is a double-hit lymphoma characterized by the presence of gene rearrangements (e.g., translocations) in MYC (myelocyte neoplasm), 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, other gene rearrangements include t(14;18)(q32;q21) involved in 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 gene rearrangements in MYC, BCL2, and BCL6; see, e.g., Aukema et al., (2011) Blood 117:2319-2331. In some aspects of such embodiments, the subjects are ECOG 0-1 or do not have or are not suspected of having transformed DLBCL from MZL or CLL, or are not characterized as having transformed DLBCL from MZL or CLL. In some aspects, the treatment is directed to such subjects, and / or the instructions indicate administration to subjects within such populations. In some aspects, based on the 2016 WHO criteria (Swerdlow et al., (2016) Blood 127(20):2375-2390), double / triple-hit lymphoma may be considered a high-grade B-cell lymphoma with DLBCL histology, MYC, and BCL2 and / or BCL6 rearrangement (double / triple-hit).

[0246] In some embodiments, the disease or condition is an infectious disease or condition, such as, but not limited to, viral infections, retroviral infections, bacterial and protozoan infections, immunodeficiency, cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, or BK polyomavirus. In some embodiments, the disease or condition is an autoimmune or inflammatory disease or condition, such as arthritis, such as 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 diseases or conditions associated with transplantation.

[0247] In some embodiments, the antigens associated with the disease or disorder include 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 (also known as CTAG, 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), and type III epidermal growth factor receptor mutation (EGFR).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, mouse cytomegalovirus (CMV) ), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligand, melan A (MART-1), neuronal cell adhesion molecule (NCAM), tumor embryo antigen, melanoma preferential expression antigen (PRAME), progesterone receptor, prostate-specific antigen, prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), survivor, trophoblast glycoprotein (TPBG)The target is selected from among tumor-associated glycoprotein 72 (TAG72), tyrosinase-associated protein 1 (TRP1, TYRP1, or gp75), tyrosinase-associated protein 2 (TRP2, 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), pathogen-specific antigens or pathogen-expressed antigens, or antigens associated with a universal tag, and / or biotinylated molecules, and / or molecules 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 a pathogen-specific antigen or a pathogen-expressing antigen, or includes such an antigen. In some embodiments, the antigen is a viral antigen (e.g., a viral antigen derived from HIV, HCV, HBV, etc.), a bacterial antigen, and / or a parasitic antigen.

[0249] In some embodiments, cell therapy, such as adoptive T-cell therapy, is carried out by autotransfer, in which cells are isolated from or derived from a subject to be treated with cell therapy, and / or prepared in other ways. Thus, in some aspects, the cells originate from a subject requiring treatment, such as a patient, and these cells are administered to the same subject after isolation and processing.

[0250] In some embodiments, cell therapy, such as adoptive T-cell therapy, is carried out by allogeneic transfer, in which cells are isolated from a subject other than the subject intended to receive cell therapy or a subject other than the subject ultimately receiving cell therapy, e.g., a first subject, and / or prepared in another manner. 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] Cells may be administered by any suitable means, for example, by bolus infusion, injection, such as intravenous or subcutaneous injection, intraocular injection, periocular injection, subretinal injection, intravitreous injection, transseptal injection, subscleral injection, intrachoroidal injection, intracapsular injection, subconjectval injection, subconjuntival injection, subtenon's capsule injection, retrobulbar injection, peribulbar injection, or posterior juxtascleral delivery. In some embodiments, cells are administered parenterally, intrapulmonaryly and intranasally, and intrafocally if local treatment is desired. Parenteral infusions include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. In some embodiments, a given dose is administered by a single bolus of the cells. In some embodiments, the dose is administered by repeated bolus administrations of the cells over a period of, for example, three days or less, or by continuous infusions of the cells. In some embodiments, the administration of the cell dose or any additional treatment, such as lymphocyte apheresis, interventional therapy, and / or combination therapy, is performed on an outpatient basis.

[0252] For the prevention or treatment of disease, the appropriate dosage may depend on the type of disease being treated, the type of cells or recombinant receptor, the severity and course of the disease (whether the cell administration is for preventive or therapeutic purposes), previous treatments, the subject's medical history and response to the cells, and the discretion of the attending physician. In several embodiments, the composition and cells are appropriately administered to the subject in a single dose or in a series of treatments.

[0253] In some embodiments, cells are administered as part of a concomitant treatment, for example, concurrently with another therapeutic intervention or additional therapeutic intervention (e.g., an antibody or modified cells or receptors or activators, e.g., cytotoxic agents or therapeutic agents), or sequentially in any order. In some embodiments, cells are co-administered with one or more additional therapeutic agents, or in conjunction with another therapeutic intervention, either concurrently or sequentially in any order. In some embodiments, the additional therapeutic agent is any of the interventions or activators described herein, e.g., any of the interventions or activators described in Section II of this specification, e.g., that can alleviate symptoms of toxicity. In some situations, cells are co-administered with another therapeutic treatment in close proximity in time so that the cell population enhances the effect of one or more additional therapeutic agents, or vice versa. In some embodiments, cells are administered before the one or more additional therapeutic agents. In some embodiments, cells are administered after the one or more additional therapeutic agents. In some embodiments, the one or more additional activators include, for example, cytokines for enhancing persistence, e.g., IL-2. In some embodiments, the method includes the administration of a chemotherapeutic agent.

[0254] In some embodiments, the method includes, for example, the administration of a chemotherapeutic agent, such as a pre-treatment chemotherapeutic agent, to reduce the tumor burden before the administration.

[0255] Pre-treatment of subjects undergoing immunodepletion (e.g., lymphocyte apheresis) therapy may improve the efficacy of adoptive cell therapy (ACT) in several aspects.

[0256] Accordingly, in some embodiments, the method includes administering a pre-treatment agent, such as a lymphocyte scavenger or a chemotherapeutic agent, such as cyclophosphamide, fludarabine, or a combination thereof, to the subject before the initiation of cell therapy. For example, the pre-treatment agent may be administered to the subject at least two days before the initiation of cell therapy, for example, at least three days, at least four days, at least five days, at least six days, or at least seven days before. In some embodiments, the pre-treatment agent is administered to the subject within seven days of the initiation of cell therapy, for example, within six, five, four, three, or two days.

[0257] In some embodiments, subjects are pre-treated with cyclophosphamide at a dose of 20 mg / kg or approximately 20 mg / kg to 100 mg / kg, for example, 40 mg / kg or approximately 40 mg / kg to 80 mg / kg or approximately 80 mg / kg. In some embodiments, subjects are pre-treated with 60 mg / kg or approximately 60 mg / kg of cyclophosphamide. In some embodiments, cyclophosphamide may be administered in a single dose or in multiple doses, for example, daily, every other day, or every three days. In some embodiments, cyclophosphamide is administered once daily over one or two days. In some embodiments, if the lymphocyte scavenging agent contains cyclophosphamide, the cyclophosphamide dose is 100 or approximately 100 mg / m². 2 ~500 or approximately 500 mg / m² 2 For example, 200 or approximately 200 mg / m² 2 ~400 or approximately 400 mg / m² 2 , or 250 or approximately 250 mg / m² 2 ~350 or approximately 350 mg / m² 2 The drug is administered to the subject at the following doses (including the values ​​at both ends). In some cases, the subject is given approximately 300 mg / m². 2Cyclophosphamide is administered. In some embodiments, cyclophosphamide may be administered in a single dose or in multiple doses, for example, daily, every other day, or every three days. In some embodiments, cyclophosphamide is administered daily, for example, for 1 to 5 days, or for example, for 3 to 5 days. In some cases, approximately 300 mg / m² is administered before the start of cell therapy. 2 The patient is administered cyclophosphamide daily for three days.

[0258] In some embodiments, if the lymphocyte-depleting agent contains fludarabine, the amount of fludarabine is 1 or about 1 mg / m². 2 ~100 or approximately 100 mg / m² 2 For example, 10 or approximately 10 mg / m² 2 ~75 or approximately 75 mg / m² 2 15 or approximately 15 mg / m² 2 ~50 or approximately 50 mg / m² 2 20 or approximately 20 mg / m² 2 ~40 or approximately 40 mg / m² 2 , or 24 or approximately 24 mg / m² 2 ~35 or approximately 35 mg / m² 2 The drug is administered to the subject at the following doses (including both extreme values). In some cases, approximately 30 mg / m² 2 Fludarabine is administered to the target. In some embodiments, fludarabine may 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, or for example, for 3 to 5 days. In some cases, approximately 30 mg / m² is administered before the start of cell therapy. 2 Fludarabine is administered to the subjects daily for three days.

[0259] In some embodiments, the lymphocyte scavenging agent includes a combination of agents, for example, a combination of cyclophosphamide and fludarabine. Thus, the combination of agents may include any dose or administration schedule, for example, cyclophosphamide and any dose or administration schedule, for example, fludarabine. For example, in some aspects, before the initial dose or subsequent doses, 60 mg / kg (approximately 2 g / m²) may be administered. 2 ) Cyclophosphamide and 3-5 doses of 25 mg / m² 2 Fludarabine is administered to the target patient.

[0260] Following administration of the cells, the biological activity of the modified cell population in several embodiments is measured by, for example, one of several known methods. Parameters to be evaluated include, for example, the specific binding of modified T cells or native T cells or other immune cells to antigens in vivo by imaging or ex vivo by, for example, ELISA or flow cytometry. In certain embodiments, the ability of modified cells to destroy target cells can be measured using any suitable known method, such as the cytotoxicity assays described in, for example, 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 evaluating clinical outcomes, such as a reduction in tumor burden or tumor cell volume.

[0261] In certain embodiments, modified cells are further modified in any number of ways to enhance their therapeutic or prophylactic efficacy. For example, a modified CAR or TCR expressed by the population may be conjugated to the targeting moiety either directly or indirectly via a linker. The practice of conjugating compounds, e.g., CARs or TCRs, to the targeting moiety is publicly 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, cells are administered as part of a combination treatment, for example, concurrently with another therapeutic intervention (e.g., an antibody or modified cells or receptor or activator, e.g., a cytotoxic agent or therapeutic agent), or sequentially in any order. In some embodiments, cells are co-administered with one or more additional therapeutic agents, or in conjunction with another therapeutic intervention, either concurrently or sequentially in any order. In some situations, cells are co-administered with another therapeutic treatment in sufficiently close time intervals 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 active agents include, for example, cytokines to enhance persistence, such as IL-2.

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

[0263] In some embodiments, the cells in that dose are 2 × 10 5 Or approximately 2 × 105 pieces / kg~2×10 6 Or approximately 2 × 10 6 pieces / kg, for example 4 x 10 5 Or approximately 4 x 10 5 pieces...

Claims

1. A pharmaceutical product for the treatment of a subject having or suspected of having non-Hodgkin lymphoma (NHL), comprising CD8 ＋ The use of a first composition containing T cells, The drug is CD4 ＋ It is characterized by being used together with a second composition containing T cells; Here, CD4 ＋ T cells and the CD8 ＋ Each T cell individually contains a chimeric antigen receptor (CAR) that targets CD19, and this CAR is CD19-specific scFv, including the CDRL1 sequence of RASQDISKYLN (SEQ ID NO:35), the CDRL2 sequence of SRLHSGV (SEQ ID NO:36), the CDRL3 sequence of GNTLPYTFG (SEQ ID NO:37), the CDRH1 sequence of DYGVS (SEQ ID NO:38), the CDRH2 sequence of VIWGSETTYYNSALKS (SEQ ID NO:39), and the CDRH3 sequence of YAMDYWG (SEQ ID NO:40). A spacer consisting only of an immunoglobulin hinge. Transmembrane domain, The cytoplasmic signaling domain derived from the 4-1BB co-stimulatory molecule, and Intracellular signaling domains including the CD3 zeta signaling domain Including; The pharmaceutical is characterized in that it is used to be administered as a plurality of separate compositions, wherein the plurality of separate compositions contain the CD8 ＋ A first composition containing T cells, and the CD4 ＋ The first composition and the second composition are used so as to be administered on the same day, and further, the CD8 ＋ The first composition containing T cells is CD4 ＋ It is administered before the second composition containing T cells. The medicament contains a dose of CD4+ T cells and CD8+ T cells that are viable CAR-expressing T cells of 2.5×10 7 or approximately 2.5×10 7 to 1×10 8 or approximately 1×10 8 cells (including the values at both ends). The doses of CD4+ T cells and CD8+ T cells are uniform doses of cells or fixed doses of cells that are not related to or based on the body surface area or body weight of the subject; and NHL includes diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), DLBCL-NOS (unspecified type), or follicular lymphoma grade 3B (FL3B), aggressive NHL, mantle cell lymphoma (MCL), or high-grade B-cell lymphoma (HGBCL). use.

2. The use according to Claim 1, wherein the subject has at least one poor-risk characteristic selected from the group consisting of double / triple hit occurrence, primary refractory disease, refractory to two or more lines of treatment, failure to achieve complete response (CR), inability to undergo autologous stem cell transplantation (ASCT), and an ECOG Group Performance Score (ECOG PS) of 2.

3. The use according to claim 2, wherein the at least one poor-risk feature predicts a median overall survival (OS) of 3 to 6 months.

4. CD8 ＋ The first composition containing T cells is CD4 ＋ The use according to any one of claims 1 to 3, characterized in that the second composition containing T cells is administered at least 2 hours prior, at least 1 hour prior, at least 30 minutes prior, at least 15 minutes prior, at least 10 minutes prior, or at least 5 minutes prior.

5. The use according to any one of claims 1 to 4, characterized in that the first composition and the second composition are administered with an interval of about 1 minute to about 1 hour, or about 5 minutes to about 30 minutes between them.

6. The aforementioned CD4 ＋ and CD8 ＋ The dose of T cells Having a ratio of CAR-expressing CD4+ cells to CAR-expressing CD8+ cells of 1:1 or approximately 1:1, or approximately 1:3 to approximately 3:1, The use according to any one of claims 1 to 5.

7. The use according to claim 6, wherein the ratio is 1:1 or approximately 1:

1.

8. The aforementioned dose of CD4+ and CD8+ T cells yields approximately 1 × 10⁻⁶ 8 The use according to any one of claims 1 to 7, wherein the CAR-expressing cells are individual cells.

9. The use according to any one of claims 1 to 8, wherein the T cells are the autologous cells of the subject.

10. The use according to any one of claims 1 to 9, wherein the NHL is an aggressive NHL.

11. The use according to any one of claims 1 to 9, wherein the NHL is diffuse large B-cell lymphoma (DLBCL).

12. The use according to any one of claims 1 to 9, wherein the NHL is DLBCL non-specific type (DLBCL-NOS).

13. The use according to any one of claims 1 to 9, wherein the NHL is primary mediastinal large B-cell lymphoma (PMBCL).

14. The use according to any one of claims 1 to 9, wherein the NHL is mantle cell lymphoma (MCL).

15. The use according to any one of claims 1 to 9, wherein the NHL is follicular lymphoma grade 3B (FL3B).

16. (a) The spacer consists of all or part of the hinge of the immunoglobulin and is 15 amino acids or less in length; (b) The spacer is 12 amino acid length or about 12 amino acid length; or (c) The spacer consists of the sequence described in SEQ ID NO:1, The use according to any one of claims 1 to 15.

17. The aforementioned scFv is, (a) V as described in SEQ ID NO:41 H V described in the sequence and SEQ ID NO:42 L Includes an array; or, (b) Including the sequence described in SEQ ID NO:43, The use according to any one of claims 1 to 16.

18. The use according to any one of claims 1 to 17, wherein the subject is pretreated with lymphocyte apheresis comprising fludarabine, cyclophosphamide, or a combination thereof, prior to the use of the pharmacopoeia.

19. A first composition comprising CD8+ T cells for use in a method of treating a subject having or suspected of having non-Hodgkin lymphoma (NHL), The first composition is characterized by being used together with a second composition containing CD4+ T cells; Here, Each of the CD4+ T cells and the CD8+ T cells individually contains a chimeric antigen receptor (CAR) that targets CD19, and the CAR is CD19-specific scFv, including the CDRL1 sequence of RASQDISKYLN (SEQ ID NO:35), the CDRL2 sequence of SRLHSGV (SEQ ID NO:36), the CDRL3 sequence of GNTLPYTFG (SEQ ID NO:37), the CDRH1 sequence of DYGVS (SEQ ID NO:38), the CDRH2 sequence of VIWGSETTYYNSALKS (SEQ ID NO:39), and the CDRH3 sequence of YAMDYWG (SEQ ID NO:40). A spacer consisting only of an immunoglobulin hinge. Transmembrane domain, The cytoplasmic signaling domain derived from the 4-1BB co-stimulatory molecule, and Intracellular signaling domains including the CD3 zeta signaling domain Including; The first composition and the second composition are used to be administered as a plurality of separate compositions, wherein the plurality of separate compositions comprise a first composition containing CD8+ T cells and a second composition containing CD4+ T cells, wherein the first composition and the second composition are used to be administered on the same day, and further wherein the first composition containing CD8+ T cells is administered before the second composition containing CD4+ T cells. The first and second compositions are characterized by containing doses of 2.5 × 10⁷ or approximately 2.5 × 10⁷ to 1 × 10⁸ or approximately 1 × 10⁸ viable CAR-expressing T cells, namely CD4+ T cells and CD8+ T cells. The doses of CD4+ T cells and CD8+ T cells are uniform doses of cells or fixed doses of cells that are not related to or based on the body surface area or body weight of the subject; and NHL includes diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), DLBCL-NOS (unspecified type), or follicular lymphoma grade 3B (FL3B), aggressive NHL, mantle cell lymphoma (MCL), or high-grade B-cell lymphoma (HGBCL). The first composition.

20. The composition according to claim 19, characterized in that the first composition comprising CD8+ T cells is administered two hours or less, one hour or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less before the second composition comprising CD4+ T cells.

21. The composition according to claim 19 or 20, characterized in that the first composition and the second composition are administered with an interval of about 1 minute to about 1 hour, or about 5 minutes to about 30 minutes between them.

22. The dose of the CD4+ and CD8+ T cells is Having a ratio of CAR-expressing CD4+ cells to CAR-expressing CD8+ cells of 1:1 or approximately 1:1, or approximately 1:3 to approximately 3:1, The composition according to any one of claims 19 to 21.

23. The composition according to claim 22, wherein the ratio is 1:1 or about 1:

1.

24. The composition according to any one of claims 19 to 23, wherein the dose of CD4+ and CD8+ T cells is approximately 1 × 10⁸ CAR-expressing cells.

25. The composition according to any one of claims 19 to 24, wherein the T cells are the target autologous cells.

26. The composition according to any one of claims 19 to 25, wherein the NHL is aggressive NHL.

27. ​​The composition according to any one of claims 19 to 25, wherein the NHL is diffuse large B-cell lymphoma (DLBCL).

28. The composition according to any one of claims 19 to 25, wherein the NHL is DLBCL non-specific type (DLBCL-NOS).

29. The composition according to any one of claims 19 to 25, wherein the NHL is primary mediastinal large B-cell lymphoma (PMBCL).

30. The composition according to any one of claims 19 to 25, wherein the NHL is mantle cell lymphoma (MCL).

31. The composition according to any one of claims 19 to 25, wherein the NHL is follicular lymphoma grade 3B (FL3B).

32. (a) The spacer is all or part of the hinge of the immunoglobulin and has a length of 15 amino acids or less; (b) The spacer is 12 amino acid length or approximately 12 amino acid length; or (c) The spacer consists of the sequence indicated by SEQ ID NO:1, The composition according to any one of claims 19 to 31.

33. The scFv is (a) VH indicated by SEQ ID NO:41 and VL indicated by SEQ ID NO:42; or (b) Sequence indicated by SEQ ID NO:43 A composition according to any one of claims 19 to 32, comprising:

34. The composition according to any one of claims 19 to 33, wherein the subject is pretreated with a lymphocyte apheresis comprising fludarabine, cyclophosphamide, or a combination thereof before using the first composition together with the second composition.

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