Methods for treatment using adoptive cell therapy

Abstract

Adoptive cell therapy, including the administration of a dose of cells, and related methods, compositions, uses, and articles of manufacture are provided for treating subjects with diseases and conditions, such as certain B-cell malignancies. The cells generally express a recombinant receptor, such as a chimeric antigen receptor (CAR). In some embodiments, the disease or condition is large B-cell lymphoma, such as diffuse large B-cell lymphoma (DLBCL). Also provided are methods for assessing the risk of developing toxicity associated with cell therapy, as well as methods for identifying and treating subjects based on the risk assessment. TIFF2022513685000129.tif83134

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority from U.S. Provisional Patent Application No. 62 / 774,164, filed on November 30, 2018, entitled "METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY", U.S. Provisional Patent Application No. 62 / 776,415, filed on December 6, 2018, entitled "METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY", U.S. Provisional Patent Application No. 62 / 847,926, filed on May 14, 2019, entitled "METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY", U.S. Provisional Patent Application No. 62 / 854,945, filed on May 30, 2019, entitled "METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY", U.S. Provisional Patent Application No. 62 / 890,600, filed on August 22, 2019, entitled "METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY", and U.S. Provisional Patent Application No. 62 / 931,204, filed on November 5, 2019, entitled "METHODS FOR TREATMENT USING ADOPTIVE CELL THERAPY", the contents of which are hereby incorporated by reference in their entirety.

[0002] Incorporation by reference of the sequence listing This application is filed with an electronic sequence listing. The sequence listing is provided as a file named 735042019640SeqList.txt, created on November 28, 2019, which is 34.2 kilobytes in size. The information in the electronic form of the sequence listing is hereby incorporated by reference in its entirety.

[0003] Field In some aspects, the present disclosure relates to adoptive cell therapy, including administration of a dose of cells for treating a subject having a disease or condition such as certain B cell malignancies, and related methods, compositions, uses, and articles of manufacture. The cells generally express a recombinant receptor such as a chimeric antigen receptor (CAR). In some embodiments, the disease or condition is a large cell type B cell lymphoma, such as diffuse large cell type B cell lymphoma (DLBCL). Also provided are methods for assessing the risk of developing toxicity associated with the cell therapy, and methods for identifying and treating a subject based on the assessment of the risk. BACKGROUND OF THE INVENTION

[0004] Background For treating diseases and conditions, various immunotherapy and / or cell therapy methods are available. For example, in the treatment of cancer or other diseases or disorders, adoptive cell therapy (including adoptive cell therapy involving administration of cells expressing a chimeric receptor specific for the disease or disorder of interest, such as a chimeric antigen receptor (CAR) and / or other recombinant antigen receptors, as well as other adoptive immune cell therapies and adoptive T cell therapies) may be beneficial. Improved approaches are needed. Methods, uses, and articles of manufacture that address such needs are provided. SUMMARY OF THE INVENTION

[0005] Summary Provided herein is a method of treating a subject having or suspected of having a disease or condition that is relapsed or refractory large cell type B cell lymphoma (r / r LBCL). In some portions of any of the provided embodiments, the method comprises administering to the subject a dose of CD4 + T cells and CD8 + T cells, wherein each dose of T cells comprises a chimeric antigen receptor (CAR) that specifically binds to CD19: the dose of T cells being from 1×10 7 cells or about 1×10 7 cells of CAR-expressing T cells to 2×10 8 cells or about 2×108 comprising a number of CAR-expressing T cells (including the values at both ends); the dose of the T cells being such that the ratio of CD4 + T cells:CD8 T cells expressing CAR is approximately 1:1; and the administration comprising administering a plurality of separate compositions, the plurality of separate compositions comprising a first composition comprising CD8 + T cells and a second composition comprising CD4 + T cells, and comprising steps. + Also provided herein is a method of treating a subject having or suspected of having a disease or condition, comprising the following steps: administering to the subject a dose of CD4

[0006] T cells and CD8 + T cells, wherein each of the CD4 + T cells and CD8 + T cells specifically binds to an antigen expressed by the disease or condition or its cells or tissues, such as a target antigen, and / or individually contains a receptor associated with the disease or condition, and the administration comprises administering a plurality of separate compositions, the plurality of separate compositions comprising a first composition comprising CD8 + T cells and a second composition comprising CD4 + T cells. +

[0007] Also provided herein is a method of treating a subject having or suspected of having a disease or condition that is a B cell malignancy, comprising the following steps: administering to the subject a dose of CD4 + T cells and CD8 + T cells, wherein each dose of T cells comprises a recombinant receptor that specifically binds to an antigen expressed by the disease or condition or its cells or tissues, such as a target antigen, and / or is associated with the disease or condition, and the administration comprises administering a plurality of separate compositions, the plurality of separate compositions comprising a first composition comprising CD8 + T cells and a second composition comprising CD4 + T cells.

[0008] Also provided herein is a method of treating a subject having or suspected of having a disease or condition that is a large cell type B cell lymphoma, comprising the following steps: CD4 + T cells and CD8 + Administering to the subject a dose of T cells, wherein each dose of T cells specifically binds to an antigen expressed by the disease or condition or its cells or tissues, e.g., a target antigen, and / or comprises a recombinant receptor associated with the disease or condition, said administration comprising administering a plurality of separate compositions, said plurality of separate compositions comprising a first composition comprising CD8 + T cells and a second composition comprising CD4 + T cells.

[0009] Also provided herein is a method of treating a subject having or suspected of having a disease or condition that is a non-Hodgkin lymphoma (NHL) or a large cell type B cell lymphoma, comprising: administering to the subject a dose of T cells expressing a chimeric antigen receptor (CAR) that specifically binds to an antigen expressed by NHL or large cell type B cell lymphoma, e.g., a target antigen, wherein the dose of T cells contains from 1×10 7 cells or about 1×10 7 cells to 2×10 8 cells or about 2×10 8 cells (including both end values) of CAR-expressing T cells; and wherein the dose of T cells contains CD4 + T cells and CD8 + T cells, and each of the CD4 + T cells and CD8 + T cells individually contains a receptor that specifically binds to an antigen expressed by the disease or condition or its cells or tissues, e.g., a target antigen, and / or is associated with the disease or condition, said administration comprising administering a plurality of separate compositions, said plurality of separate compositions comprising a first composition comprising CD8 + T cells and a second composition comprising CD4 + T cells.

[0010] In some aspects provided, the dose of T cells is a defined ratio of CD4 + cells expressing the CAR: CD8 + cells expressing the CAR, and / or CD4 + cells: CD8 + cells, and the ratio is approximately 1:1 or approximately 1:3 to approximately 3:1.

[0011] Provided herein is a method of treating a subject having a disease or condition that is non-Hodgkin lymphoma (NHL) or large cell type B cell lymphoma, the method comprising: administering to the subject a dose of T cells comprising T cells expressing a chimeric antigen receptor (CAR) that specifically binds to an antigen expressed by NHL or large cell type B cell lymphoma, e.g., a target antigen, wherein the dose of T cells is a defined ratio of CD4 + cells expressing the CAR: CD8 + cells expressing the CAR, and / or CD4 + cells: CD8 + cells, the ratio being approximately 1:1 or 1:1, and the administration comprising administering a plurality of separate compositions, the plurality of separate compositions comprising a first composition comprising CD8 + T cells and a second composition comprising CD4 + T cells.

[0012] Also provided herein is a method of treating a subject having a disease or condition that is non-Hodgkin lymphoma (NHL) or large cell type B cell lymphoma, the method comprising: administering to the subject a dose of T cells comprising T cells expressing a chimeric antigen receptor (CAR) that specifically binds to an antigen expressed by NHL or large cell type B cell lymphoma, e.g., a target antigen, wherein the dose of T cells is from 5×10 7 cells or about 5×10 7 recombinant receptor-expressing T cells to 1.5×10 8 cells or about 1.5×10 8containing the individual recombinant receptor-expressing T cells (including the values at both ends), wherein the dose is a defined ratio of CD4 + cells: CD8 expressing the recombinant receptor + cells, and / or CD4 + cells: CD8 + cells, wherein 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) cytokine release syndrome (CRS) higher than grade 2 and / or neurotoxicity higher than grade 2 in no more than 50% of the subjects, and the administration includes administering a plurality of separate compositions, the plurality of separate compositions including a first composition containing CD8+ T cells and a second composition containing CD4+ T cells, step.

[0013] In some part of any of the provided embodiments, the method includes the following steps: administering to a subject having a disease or condition that is lymphoma a dose of T cells containing T cells expressing a chimeric antigen receptor (CAR) that specifically binds to an antigen expressed by the lymphoma, such as a target antigen, wherein the lymphoma in the subject is accompanied by or includes central nervous system (CNS) complications; and the dose of T cells contains CD4 + T cells and CD8 + T cells, each dose of T cells containing a receptor that specifically binds to an antigen expressed by the disease or condition or its cells or tissues, such as a target antigen, and / or is related to the disease or condition, and the administration includes administering a plurality of separate compositions, the plurality of separate compositions including a first composition containing CD8 + T cells and a second composition containing CD4 +A stage comprising a second composition containing T cells. In some part of any of the provided embodiments, prior to or at the time of administration of the cell dose, the subject has a brain lesion, such as a temporal lobe brain lesion. In some part of any such embodiment, the lymphoma is a B cell malignancy. In some part of any such embodiment, the lymphoma is non-Hodgkin lymphoma (NHL) or large cell type B cell lymphoma.

[0014] A method of treatment comprising the following steps is provided herein: (a) selecting a subject having follicular lymphoma (FL) for treatment; (b) administering to the subject a dose of T cells comprising T cells that specifically bind to an antigen expressed by FL or its cells or tissues, such as a target antigen, and / or express a recombinant receptor associated with FL.

[0015] In some aspects provided, large B-cell lymphoma is selected from aggressive non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), optionally DLBCL NOS (de novo or transformed from indolent), high-grade B-cell lymphoma (HGBCL), double / triple hit lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), transformed follicular lymphoma (tFL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B). In some aspects, large B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL). In some aspects, DLBCL is DLBCL NOS, de novo DLBCL, or DLBCL transformed from indolent lymphoma. In some aspects, DLBCL is de novo DLBCL. In some aspects, DLBCL is DLBCL transformed from indolent lymphoma other than FL. In some aspects, DLBCL is DLBCL transformed from marginal zone lymphoma (tMZL) or DLBCL transformed from chronic lymphocytic leukemia (tCLL; Richter). In some aspects, large B-cell lymphoma is high-grade B-cell lymphoma (HGBCL). In some aspects, HGBCL has rearrangements of MYC and BCL2 and / or BCL6. In some aspects, HGBCL has a DLBCL histology. In some aspects, large B-cell lymphoma is double / triple hit lymphoma. In some aspects, large B-cell lymphoma is primary mediastinal B-cell lymphoma (PMBCL). In some aspects, large B-cell lymphoma is mantle cell lymphoma (MCL). In some aspects, large B-cell lymphoma is not primary central nervous system lymphoma (PCNSL). In some aspects, large B-cell lymphoma is transformed follicular lymphoma (tFL). In some aspects, large B-cell lymphoma is follicular lymphoma (FL).In some embodiments, FL is associated with co-expression of CD10, BCL6, and BCL2 within follicles, and / or rearrangement of t(14;18) / (q32;q21)(IGH-BCL2) and / or BCL6. In some embodiments, large B-cell lymphoma is follicular lymphoma grade 3B (FL3B).

[0016] In some embodiments, the dose of T cells is enriched for CD3+ T cells, CD4+ T cells, CD8+ T cells, or CD4+ T cells and CD8+ T cells. In some embodiments, more than 70%, 75%, 80%, 85%, 90%, 95%, or 98% of the cells in the dose of T cells, or about more than 70%, 75%, 80%, 85%, 90%, 95%, or 98% are CD3+ T cells, CD4+ T cells, CD8+ T cells, or CD4+ T cells and CD8+ T cells. In some embodiments, the dose of T cells is a defined ratio of CD4 + cells: CD8 + cells expressing the receptor, and / or CD4 + T cells: CD8 + T cells, and the ratio is approximately 1:1 or approximately 1:3 to approximately 3:1. In some embodiments, the defined ratio is 1:1 or approximately 1:1. In some embodiments, the dose of T cells is CD4 + T cells and CD8 + T cells, and each dose of T cells contains a recombinant receptor that specifically binds to an antigen expressed by FL or its cells or tissues, such as a target antigen, and / or is associated with FL. Administration includes administering a plurality of separate compositions, the plurality of separate compositions including a first composition containing CD8 + T cells and a second composition containing CD4 + T cells.

[0017] In some of the provided aspects, the initiation of administration of the first composition is carried out before the initiation of administration of the second composition. In some of the provided aspects, the administration of the first composition and the administration of the second composition are carried out at intervals of 48 hours or less. In some of the provided aspects, the administration of the first composition and the administration of the second composition are carried out at intervals of 36 hours or less, 24 hours or less, 12 hours or less, 6 hours or less, 4 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less. In some of the provided aspects, the administration of the first composition and the administration of the second composition are carried out at intervals from 0 or about 0 to 48 hours or about 48 hours, from 0 or about 0 to 36 hours or about 36 hours, from 0 or about 0 to 24 hours or about 24 hours, from 0 or about 0 to 12 hours or about 12 hours, from 0 or about 0 to 6 hours or about 6 hours, from 0 or about 0 to 2 hours or about 2 hours, from 0 or about 0 to 1 hour or about 1 hour, from 0 or about 0 to 30 minutes or about 30 minutes, from 30 minutes or about 30 minutes to 48 hours or about 48 hours, from 30 minutes or about 30 minutes to 36 hours or about 36 hours, from 30 minutes or about 30 minutes to 24 hours or about 24 hours, from 30 minutes or about 30 minutes to 12 hours or about 12 hours, from 30 minutes or about 30 minutes to 6 hours or about 6 hours, from 30 minutes or about 30 minutes to 4 hours or about 4 hours, from 30 minutes or about 30 minutes to 2 hours or about 2 hours, from 30 minutes or about 30 minutes to 1 hour or about 1 hour, from 1 hour or about 1 hour to 48 hours or about 48 hours, from 1 hour or about 1 hour to 36 hours or about 36 hours, from 1 hour or about 1 hour to 24 hours or about 24 hours, from 1 hour or about 1 hour to 12 hours or about 12 hours, from 1 hour or about 1 hour to 6 hours or about 6 hours, from 1 hour or about 1 hour to 4 hours or about 4 hours, from 1 hour or about 1 hour to 2 hours or about 2 hours, from 2 hours or about 2 hours to 48 hours or about 48 hours, from 2 hours or about 2 hours to 36 hours or about 36 hours, from 2 hours or about 2 hours to 24 hours or about 24 hours, from 2 hours or about 2 hours to 12 hours or about 12 hours, from 2 hours or about 2 hours toFrom 6 hours or about 6 hours, 2 hours or about 2 hours to 4 hours or about 4 hours, 4 hours or about 4 hours to 48 hours or about 48 hours, 4 hours or about 4 hours to 36 hours or about 36 hours, 4 hours or about 4 hours to 24 hours or about 24 hours, 4 hours or about 4 hours to 12 hours or about 12 hours, 4 hours or about 4 hours to 6 hours or about 6 hours, 6 hours or about 6 hours to 48 hours or about 48 hours, 6 hours or about 6 hours to 36 hours or about 36 hours, 6 hours or about 6 hours to 24 hours or about 24 hours, 6 hours or about 6 hours to 12 hours or about 12 hours, 12 hours or about 12 hours to 48 hours or about 48 hours, 12 hours or about 12 hours to 36 hours or about 36 hours, 12 hours or about 12 hours to 24 hours or about 24 hours, 24 hours or about 24 hours to 48 hours or about 48 hours, 24 hours or about 24 hours to 36 hours or about 36 hours, or 36 hours or about 36 hours to 48 hours or about 48 hours.

[0018] In some of the provided embodiments, the administration of the first composition and the administration of the second composition are carried out on the same day and at intervals of about 0 to about 12 hours, about 0 to about 6 hours, or about 0 to 2 hours; or the start of the administration of the first composition and the start of the administration of the second composition are carried out at intervals of about 1 minute to about 1 hour, or about 5 minutes to about 30 minutes. In some of the provided embodiments, the first composition and the second composition are administered at intervals of 2 hours or less, 1 hour or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less.

[0019] In some of the provided embodiments, CD4 + The receptor contained by T cells and / or CD8 + The receptor contained by T cells contains the same recombinant receptor, and / or CD4 + T cells and / or CD8 + T cells are genetically engineered to express the same recombinant receptor.

[0020] In some part of any of the provided embodiments, CD4 + T cells and CD8 + The dosage of T cells is 1:1 or approximately 1:1, or approximately 1:3 to approximately 3:1, of the defined ratio of CD4 + cells expressing the recombinant receptor: CD8 + cells, and / or CD4 + cells: CD8 + cells; and / or CD4 + T cells containing the receptor in one of the first composition and the second composition, and CD8 + T cells containing the receptor in the other of the first composition and the second composition are present in a defined ratio of 1:1 or approximately 1:1, or approximately 1:3 to approximately 3:1; and / or CD4 + T cells containing the receptor and CD8 + T cells are present in a defined ratio, which is 1:1 or approximately 1:1, or approximately 1:3 to approximately 3:1. In some part of any of the provided embodiments, the defined ratio is 1:1 or approximately 1:1.

[0021] In some part of any of the provided embodiments, CD4 + T cells and CD8 + The dosage of T cells is 1×10 7 or about 1×10 7 to 2×10 8 or about 2×10 8 total recombinant receptor-expressing T cells (including both end values); 2.5×10 7 or about 2.5×10 7 to 1.5×10 8 or about 1.5×10 8 total recombinant receptor-expressing T cells (including both end values); 5×10 7 or about 5×10 7 to 1×108 one or about 1×10 8 total recombinant receptor-expressing T cells (including the values at both ends); 5×10 7 one or about 5×10 7 total recombinant receptor-expressing T cells; 1×10 8 one or about 1×10 8 total recombinant receptor-expressing T cells; or 1.5×10 8 one or about 1.5×10 8 total recombinant receptor-expressing T cells. In some parts of any such embodiment, CD4 + T cells and CD8 + T cell doses include 5×10 7 one or about 5×10 7 total recombinant receptor-expressing T cells. In some parts of any such embodiment, CD4 + T cells and CD8 + T cell doses include 1×10 8 one or about 1×10 8 total recombinant receptor-expressing T cells. In some parts of any such embodiment, CD4 + T cells and CD8 + T cell doses include 1.5×10 8 one or about 1.5×10 8 total recombinant receptor-expressing T cells.

[0022] In some parts of any of the provided embodiments, CD4 + T cells and CD8 + T cell doses are from 1×10 7 one or about 1×10 7 to 1×10 8 one or about 1×10 8 recombinant receptor-expressing CD8 + T cells (including the values at both ends); 1.25×10 7 one or about 1.25×10 7 to 7.5×10 7 one or about 7.5×10 7 recombinant receptor-expressing CD8 + T cells (including the values at both ends); 2.5×10 7 one or about 2.5×107 from, 5×10 7 to, or about 5×10 7 receptor-expressing CD8 + T cells (including the values at both ends); 2.5×10 7 to, or about 2.5×10 7 receptor-expressing CD8 + T cells; 5×10 7 to, or about 5×10 7 receptor-expressing CD8 + T cells; or 7.5×10 7 to, or about 7.5×10 7 receptor-expressing CD8 + T cells. In some parts of any such embodiment, CD4 + T cells and CD8 + T cell doses are 2.5×10 7 or about 2.5×10 7 receptor-expressing CD8 + T cells. In some parts of any such embodiment, CD4 + T cells and CD8 + T cell doses are 5×10 7 or about 5×10 7 receptor-expressing CD8 + T cells. In some parts of any such embodiment, CD4 + T cells and CD8 + T cell doses are 7.5×10 7 or about 7.5×10 7 receptor-expressing CD8 + T cells.

[0023] In some parts of any of the provided embodiments, the recombinant receptor specifically binds to an antigen that is associated with a disease or condition or is expressed in cells in the environment of a lesion associated with a disease or condition.

[0024] In some of the provided embodiments, the disease or condition is cancer. In some of any such embodiments, the disease or condition is a B cell malignancy. In some of any such embodiments, the disease or condition is myeloma, leukemia, or lymphoma. In some of the provided embodiments, the disease or condition is a B cell malignancy and / or is acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), or large B cell lymphoma. In some of the provided embodiments, the disease or condition is large B cell lymphoma. In some of the provided embodiments, the disease or condition such as large B cell lymphoma is diffuse large B cell lymphoma (DLBCL). In some of the provided embodiments, DLBCL is DLBCL (not otherwise specified (NOS)), de novo DLBCL, or DLBCL transformed from indolent lymphoma. In some of the provided embodiments, DLBCL is de novo DLBCL. In some of the provided embodiments, DLBCL is DLBCL transformed from follicular lymphoma (tFL). In some of the provided embodiments, DLBCL is DLBCL transformed from marginal zone lymphoma (tMZL) or DLBCL transformed from chronic lymphocytic leukemia (tCLL; Richter). In some of the provided embodiments, the disease or condition is primary mediastinal B cell lymphoma (PMBCL) or follicular lymphoma (FL), such as follicular lymphoma grade 3B (FL3B). In some of any embodiments, the disease or condition is follicular lymphoma (FL). In some of the provided embodiments, NHL or large B cell lymphoma is selected from the group consisting of aggressive NHL, diffuse large B cell lymphoma (DLBCL), NOS (de novo or transformed from indolent), primary mediastinal large B cell lymphoma (PMBCL), mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), such as follicular lymphoma grade 3B (FL3B). In some of any embodiments, the disease or condition is follicular lymphoma (FL).In some aspects, FL is associated with co-expression of CD10, BCL6, and BCL2 within follicles, and / or rearrangement of t(14;18) / (q32;q21)(IGH-BCL2) and / or BCL6. In some aspects, the disease or condition is mantle cell lymphoma (MCL).

[0025] In some of any such aspects, the target antigen is a B cell antigen. In some of any of the provided aspects, the antigen is CD19.

[0026] In some aspects, at the time of or immediately prior to administration of the dose of cells, the subject has relapsed following remission after treatment with two, three, four, or more previous therapies for the disease or condition other than another dose of cells expressing the CAR, or is resistant thereto.

[0027] In some aspects, the previous therapies include anthracyclines and CD20 targeting agents. In some aspects, one or more CD20 targeting agents include rituximab. In some aspects, one or more CD20 targeting agents include R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (oncovin), and prednisone).

[0028] In some aspects, the previous therapies include allogeneic or autologous hematopoietic stem cell transplantation (HSCT). In some aspects, the subject has relapsed within or less than 1 year after receiving HSCT.

[0029] In some aspects, the subject has not achieved a complete remission (CR) in response to previous therapies.

[0030] In some aspects, at the time of or prior to administration of the dose of cells, the subject is identified as having an aggressive or high-risk disease or having a poor prognosis.

[0031] In some aspects, at the time of or prior to administration of the cell dose, the subject is identified as having a chemoresistant disease or having a persistent or recurrent disease after chemotherapy. In some aspects, at the time of or prior to administration of the cell dose, the subject is identified as having a chemoresistant lymphoma, optionally a chemoresistant DLBCL.

[0032] In some aspects, at the time of or prior to administration of the cell dose, the subject is identified as having a lymphoma with or including a central nervous system (CNS) complication, or secondary CNS lymphoma. In some aspects, at the time of or prior to administration of the cell dose, the subject is identified as having a lymphoma with or including a central nervous system (CNS) complication, or secondary CNS lymphoma; and / or, at least 70%, at least 80%, at least 90%, or at least 95% of the subjects treated according to a method identified or identified as showing a lymphoma with CNS complication or secondary CNS lymphoma at the time of or prior to administration of the cell dose achieved resolution of the CNS disease.

[0033] In some aspects, the subject is 65 years of age or older. In some aspects, among the subjects treated, more than 35% or about more than 35%, more than 40% or about more than 40%, more than 45% or about more than 45%, or more than 50% or about more than 50%, or any value between any of the foregoing, are 65 years of age or older. In some aspects, the subject is 70 years of age or older.

[0034] In some embodiments, at the time of or prior to administration of the cell dose, the subject is identified as having or is identified with cardiac dysfunction, optionally with a left ventricular ejection fraction (LVEF) of less than 50% or about less than 50%. In some embodiments, at the time of or prior to administration of the cell dose, the subject is identified as having or is identified with renal dysfunction, optionally with a calculated creatinine clearance of less than 60 mL / min or about less than 60 mL / min. In some embodiments, at the time of or prior to administration of the cell dose, the subject is identified as having or is identified with pulmonary dysfunction, optionally with a diffusing capacity of the lung for carbon monoxide (DLCO) of 60% or less or about 60% or less. In some embodiments, at the time of or prior to administration of the cell dose, the subject is identified as having or is identified with liver dysfunction, optionally with an aspartate aminotransferase (AST) and alanine aminotransferase (ALT) greater than 2 times the upper limit of normal (ULN) or about greater than 2 times the upper limit of normal (ULN).

[0035] In some embodiments, at the time of or prior to administration of the cell dose, the subject is CD4 + T cell and CD8 + undergoing leukapheresis to generate a dose of T cells and CD4 + T cell and CD8 + receiving bridging chemotherapy between the dose of T cells and the administration of the dose of CD8 T cells. In some embodiments, at the time of or prior to administration of the cell dose, the subject is receiving bridging chemotherapy for disease control after previous therapy. In some embodiments, the bridging chemotherapy is selected from one or more of the following: rituximab - gemcitabine + oxaliplatin, dexamethasone, radiation therapy, rituximab, prednisone, BR, lenalidomide, gemcitabine + oxaliplatin, brentuximab vedotin, ibrutinib, bendamustine, and / or gemcitabine + rituximab.

[0036] In some aspects, the subject is identified as having an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0, 1, or 2. In some aspects, the subject is identified as having an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. In some aspects, the subject is identified as having an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2.

[0037] In some aspects, prior to administration of the cell dose, the subject has a sum of products dimensions (SPD) of the tumor in the subject of 50 cm 2 or more or about 50 cm 2 or more.

[0038] In some aspects of the provided aspects, the recombinant receptor is a chimeric antigen receptor (CAR). In some aspects of the provided aspects, the CAR contains an extracellular antigen recognition domain that specifically binds to an antigen, and an intracellular signaling domain containing a CD3-zeta (CD3ζ) chain, and a co-stimulatory signaling region that is a signaling domain of CD28 or 4-1BB.

[0039] In some aspects of the provided aspects, the T cell is a primary T cell obtained from the subject. In some aspects of the provided aspects, the T cell is autologous to the subject.

[0040] In some part of any of the provided aspects, at least 40%, at least 50%, at least 60%, at least 70% of the subjects identified as having or having had double / triple hit lymphoma, or recurrence after administration of autologous stem cell transplantation (ASCT), at the time of or prior to administration of the cell dose, achieved an OR, or an OR that was persistent over 3 months or more than 3 months or 6 months or more than 6 months.

[0041] In some part of any of the provided aspects, at least 35%, at least 40%, or at least 50% of the subjects treated according to the method achieve a complete response (CR); at least 60%, 70%, 80%, 90%, or 95% of the subjects who achieved CR show a persistent CR over 3 months or more than 3 months or 6 months or more than 6 months; and / or at least 60%, 70%, 80%, 90%, or 95% of the subjects who achieved CR by 1 month and / or by 3 months remain in response, remain in CR, and / or are alive or alive without progression for 3 months or more than 3 months and / or 6 months or more than 6 months and / or more than 9 months after achieving CR; and / or at least 50%, at least 60%, or at least 70% of the subjects treated according to the method achieve an objective response (OR); at least 60%, 70%, 80%, 90%, or 95% of the subjects who achieved OR show a persistent OR over 3 months or more than 3 months or 6 months or more than 6 months; and / or at least 35%, at least 40%, or at least 50% of the subjects who achieved OR remain in response or are alive for 3 months or more than 3 months and / or 6 months or more than 6 months after achieving OR; and / or at least 40%, at least 50%, at least 60%, at least 70% of the subjects identified as having or having had double / triple hit lymphoma, or recurrence after administration of autologous stem cell transplantation (ASCT), at the time of or prior to administration of the cell dose, achieved an OR, or an OR that was persistent over 3 months or more than 3 months or 6 months or more than 6 months.

[0042] In some part of any of the provided aspects, the cells are autologous to the subject, and any minimum absolute lymphocyte count (ALC) for apheresis is not required and / or not specified for the generation of the therapy; and / or the cells are generated by a process that can produce cell products for administration according to the method for at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of subjects having a disease or condition or of a selected population of subjects.

[0043] In some part of any of the provided aspects, more than 50% or about more than 50%, about more than 60% or about more than 60%, about more than 70% or about more than 70%, or about more than 80% or about more than 80% of the subjects treated according to the method do not exhibit cytokine release syndrome (CRS) of grade 3 or higher and / or do not exhibit neurotoxicity of grade 3 or higher, and / or more than 40% or more than 50% or more than 55% do not exhibit any neurotoxicity or CRS.

[0044] In some part of any of the provided aspects, CR or OR is persistent 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 the subjects treated according to the method achieve a CR that is persistent for more than 3 months or more than 6 months; and / or at least 60%, 70%, 80%, 90%, or 95% of the subjects treated by the method and achieving CR remain in CR, or remain effective, or remain alive for 3 months or more than 3 months or 6 months or more than 6 months or 9 months or more than 9 months; and / or at least 60%, 70%, 80%, 90%, or 95% of the subjects treated by the method and achieving CR by 1 month and / or by 3 months remain effective, remain in CR, and / or remain alive or survive without progression for a period longer than 3 months or more than 3 months and / or 6 months or more than 6 months and / or more than 9 months; and / or at least 50%, at least 60%, or at least 70% of the subjects treated according to the method achieve an objective response (OR); at least 60%, 70%, 80%, 90%, or 95% of the subjects achieve an OR that is persistent for 3 months or more than 3 months or 6 months or more than 6 months; and / or at least, at least 35%, at least 40%, or at least 50% of the subjects treated by the method and achieving OR remain effective or remain alive for 3 months or more than 3 months and / or 6 months or more than 6 months.

[0045] In some part of any of the provided aspects, at the time of or prior to administration of the cell dose, the subject is identified or has been identified as having a lymphoma with or including a central nervous system (CNS) complication; and / or at least 70%, at least 80%, at least 90%, or at least 95% of the subjects treated according to the method, who were identified or shown to have a lymphoma with a CNS complication at the time of or prior to administration of the cell dose, achieved resolution of the CNS disease.

[0046] In some of the provided embodiments, the administration of the first composition and the administration of the second composition are performed at intervals of 48 hours or less. In some of the provided embodiments, the administration of the first composition and the administration of the second composition are performed at intervals of 36 hours or less, 24 hours or less, 12 hours or less, 6 hours or less, 4 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less.

[0047] In some part of any of the provided aspects, the administration of the first composition and the administration of the second composition are from 0 or about 0 to 48 hours or about 48 hours, from 0 or about 0 to 36 hours or about 36 hours, from 0 or about 0 to 24 hours or about 24 hours, from 0 or about 0 to 12 hours or about 12 hours, from 0 or about 0 to 6 hours or about 6 hours, from 0 or about 0 to 2 hours or about 2 hours, from 0 or about 0 to 1 hour or about 1 hour, from 0 or about 0 to 30 minutes or about 30 minutes, from 30 minutes or about 30 minutes to 48 hours or about 48 hours, from 30 minutes or about 30 minutes to 36 hours or about 36 hours, from 30 minutes or about 30 minutes to 24 hours or about 24 hours, from 30 minutes or about 30 minutes to 12 hours or about 12 hours, from 30 minutes or about 30 minutes to 6 hours or about 6 hours, from 30 minutes or about 30 minutes to 4 hours or about 4 hours, from 30 minutes or about 30 minutes to 2 hours or about 2 hours, from 30 minutes or about 30 minutes to 1 hour or about 1 hour, from 1 hour or about 1 hour to 48 hours or about 48 hours, from 1 hour or about 1 hour to 36 hours or about 36 hours, from 1 hour or about 1 hour to 24 hours or about 24 hours, from 1 hour or about 1 hour to 12 hours or about 12 hours, from 1 hour or about 1 hour to 6 hours or about 6 hours, from 1 hour or about 1 hour to 4 hours or about 4 hours, from 1 hour or about 1 hour to 2 hours or about 2 hours, from 2 hours or about 2 hours to 48 hours or about 48 hours, from 2 hours or about 2 hours to 36 hours or about 36 hours, from 2 hours or about 2 hours to 24 hours or about 24 hours, from 2 hours or about 2 hours to 12 hours or about 12 hours, from 2 hours or about 2 hours to 6 hours or about 6 hours, from 2 hours or about 2 hours to 4 hours or about 4 hours, from 4 hours or about 4 hours to 48 hours or about 48 hours, from 4 hours or about 4 hours to 36 hours or about 36 hours, from 4 hours or about 4 hours to 24 hours or about 24 hours, from 4 hours or about 4 hours to 12 hours or about 12 hours, from 4 hours or about 4 hours to 6 hours or about 6 hours, from 6 hours or about 6 hours to 48 hours or about 48 hours, from 6 hours or about 6 hours to 36 hours or about 36 hours,It is carried out for 6 hours or about 6 hours to 24 hours or about 24 hours, 6 hours or about 6 hours to 12 hours or about 12 hours, 12 hours or about 12 hours to 48 hours or about 48 hours, 12 hours or about 12 hours to 36 hours or about 36 hours, 12 hours or about 12 hours to 24 hours or about 24 hours, 24 hours or about 24 hours to 48 hours or about 48 hours, 24 hours or about 24 hours to 36 hours or about 36 hours, or 36 hours or about 36 hours to 48 hours or about 48 hours.,

[0048] In some of the provided embodiments, the administration of the first composition and the administration of the second composition are carried out on the same day and at intervals of about 0 to about 12 hours, about 0 to about 6 hours, or about 0 to 2 hours; or the start of the administration of the first composition and the start of the administration of the second composition are carried out at intervals of about 1 minute to about 1 hour, or about 5 minutes to about 30 minutes.

[0049] In some of the provided embodiments, the first composition and the second composition are administered at intervals of 2 hours or less, 1 hour or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less.

[0050] In some of the provided embodiments, CD4 + The receptors contained by T cells and / or CD8 + The receptors contained by T cells contain the same recombinant receptor, and / or CD4 + T cells and / or CD8 + T cells are genetically engineered to express the same recombinant receptor.

[0051] In some of the provided embodiments, the lymphoma is a B-cell malignancy. In some of the provided embodiments, the lymphoma is non-Hodgkin lymphoma (NHL).

[0052] In some part of any of the provided aspects, at least 35%, at least 40%, or at least 50% of the subjects treated according to the method achieve a complete response (CR) or remission of the CNS disease; at least 60%, 70%, 80%, 90%, or 95% of the subjects who achieve CR remain in CR for 3 months or more or 6 months or more; and / or at least 60%, 70%, 80%, 90%, or 95% of the subjects who achieve CR or remission of the CNS disease by 1 month and / or by 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 the subjects treated according to the method achieve an objective response (OR) or remission of the CNS disease; at least 60%, 70%, 80%, 90%, or 95% of the subjects achieve OR for 3 months or more or 6 months or more; and / or at least 60%, 70%, 80%, 90%, or 95% of the subjects who achieve OR or remission of the CNS disease remain in response or survive for 3 months or more and / or 6 months or more; and / or the brain lesion is reduced in size or volume by 25%, 50%, 75%, or more, or about 25%, 50%, 75%, or more; and / or the reduction or remission or clearance of the CNS disease is achieved in at least 35%, at least 40%, or at least 50% of the subjects treated according to the method.

[0053] In some part of any of the provided aspects, more than 30%, 35%, 40%, or 50% of the subjects treated according to the method, or more than about 30%, 35%, 40%, or 50% do not exhibit any grade of cytokine release syndrome (CRS) or neurotoxicity; and / or at least 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the subjects treated according to the method, or at least about 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% do not show the onset of CRS earlier than 3 days after the start of administration and / or do not show the onset of neurotoxicity earlier than 5 days after the start of administration; and / or the median onset of neurotoxicity among the subjects treated according to the method is at or after the median peak of CRS or the median time to resolution of CRS in the subjects treated according to the method, and / or the median onset of neurotoxicity among the subjects treated according to the method is greater than 8, 9, 10, or 11 days, or greater than about 8, 9, 10, or 11 days.

[0054] In some aspects, more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the subjects treated according to the method, or more than about 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% show an improvement of 10 points or more in the general health status at 6 or 12 months after administration compared to the score before treatment or at 1 month after treatment, as measured by the European Organization for Research and Treatment Core Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30). In some aspects, more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the subjects treated according to the method, or more than about 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% show an improvement of 10 points or more in the physical function at 6 or 12 months after administration compared to the score before treatment or at 1 month after treatment, as measured by the EORTC QLQ-C30. In some aspects, more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the subjects treated according to the method, or more than about 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% show an improvement of 10 points or more in the fatigue at 6 or 12 months after administration compared to the score before treatment or at 1 month after treatment, as measured by the EORTC QLQ-C30. In some aspects, more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the subjects treated according to the method, or more than about 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% show an improvement of 10 points or more in the pain at 6 or 12 months after administration compared to the score before treatment or at 1 month after treatment, as measured by the EORTC QLQ-C30.In some aspects, more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the subjects treated according to the method, or about more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% show an improvement of 10 points or more in the EORTC QLQ-C30 in pain at 6 or 12 months after administration, compared to the score before treatment or 1 month after treatment.

[0055] In some aspects, the mean 5-level EuroQol-5D (EQ-5D-5L) score among the subjects treated according to the method is the same or higher at 6 or 12 months after administration compared to the score before treatment or 1 month after treatment. In some aspects, the mean EuroQol general visual analog scale (EQ-VAS) score among the subjects treated according to the method is the same or higher at 6 or 12 months after administration compared to the score before treatment or 1 month after treatment.

[0056] In some aspects of any of the provided aspects, prior to the initiation of administration of the dose of cells, the subject has not been administered an agent or treatment that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of onset of toxicity after administration of the dose of cells.

[0057] In some aspects of any of the provided aspects, the agent is or comprises an anti-IL-6 antibody, an anti-IL-6 receptor antibody, or a steroid. In some aspects of any of the provided aspects, the agent is or comprises tocilizumab, siltuximab, dexamethasone, or methylprednisolone.

[0058] In some part of any of the provided aspects, administration and any follow-up are carried out on an outpatient basis and / or without the need for hospitalization or an overnight stay in a hospital; and if the subject exhibits persistent fever, or a fever that does not decrease or decreases by more than 1 °C after treatment with an antipyretic, the subject is hospitalized or stays overnight in a hospital and / or is administered an agent or treatment for the treatment, prevention, reduction or attenuation of neurotoxicity and / or cytokine release syndrome or the risk thereof.

[0059] In some part of any of the provided aspects, NHL is selected from the group consisting of aggressive NHL, diffuse large B-cell lymphoma (DLBCL), NOS (de novo or transformed from indolent), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), such as follicular lymphoma grade 3B (FL3B). In some part of any aspect, the subject has follicular lymphoma (FL). In some part of any of the provided aspects, NHL is DLBCL. In some part of any of the provided aspects, DLBCL is DLBCL (not otherwise specified (NOS)), de novo DLBCL, or DLBCL transformed from indolent lymphoma. In some part of any of the provided aspects, DLBCL is de novo DLBCL. In some part of any of the provided aspects, DLBCL is DLBCL transformed from follicular lymphoma (tFL). In some part of any of the provided aspects, DLBCL is DLBCL transformed from marginal zone lymphoma (tMZL) or DLBCL transformed from chronic lymphocytic leukemia (tCLL; Richter). In some part of any of the provided aspects, NHL is primary mediastinal B-cell lymphoma (PMBCL) or follicular lymphoma (FL), such as follicular lymphoma grade 3B (FL3B). In some part of any aspect, the subject has follicular lymphoma (FL).

[0060] In some aspects provided, the subject is identified as having or is identified with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) status of 0, 1, or 2. In some aspects, the subject is identified as having or is identified with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.

[0061] In some aspects provided, at the time of or immediately prior to administration of the dose of the cells, the subject has relapsed following remission after treatment with one or more prior therapies for a disease or condition such as large cell type B cell lymphoma or NHL, or is resistant thereto. In some aspects, the one, two, or three prior therapies are other than another dose of cells expressing a CAR.

[0062] In some aspects, at the time of or immediately prior to administration of the dose of the cells, the subject has relapsed following remission after treatment with one prior therapy for a disease or condition other than another dose of cells expressing a CAR, or is resistant thereto. In some aspects, at the time of or immediately prior to administration of the dose of the cells, the subject has relapsed following remission after treatment with two or more prior therapies for a disease or condition other than another dose of cells expressing a CAR, or is resistant thereto. In some aspects, at the time of or immediately prior to administration of the dose of the cells, the subject is identified as ineligible for high-dose chemotherapy. In some aspects, at the time of or immediately prior to administration of the dose of the cells, the subject is identified as ineligible for hematopoietic stem cell transplantation (HSCT). In some aspects, at the time of or immediately prior to administration of the dose of the cells, the subject is identified as ineligible for both high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT).

[0063] In some aspects, the subject has relapsed / refractory NHL and, at or immediately prior to administration of the cell dose, the subject is identified as or has been identified as ineligible for both high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT), and the subject has relapsed following remission after treatment with one prior therapy for the disease or condition other than another dose of cells expressing a CAR or has become resistant thereto. In some aspects, at or prior to administration of the cell dose, the subject is identified as or has relapsed / refractory large cell type B-cell lymphoma; and / or the subject has been treated or is being treated with an anthracycline and one or more CD20 targeting agents; and / or the subject has or has a relapsed / refractory disease after two or more lines of therapy or after autologous HSCT; and / or the subject is identified as or has an ECOG performance status of 1 or 2; and / or if the subject has received a prior CD19-targeted therapy, a biological sample obtained from the subject after the prior CD19-targeted therapy contains cells expressing CD19; and administration of the cell dose is via an allogeneic patient delivery.

[0064] In some aspects of any of the provided aspects, at or prior to administration of the cell dose, the subject is identified as or has double / triple hit lymphoma; and / or the subject is identified as or has chemotherapy-resistant lymphoma, such as chemotherapy-resistant DLBCL; and / or the subject has not achieved a complete remission (CR) in response to prior therapy; and / or the subject has relapsed within or less than one year after receiving autologous stem cell transplantation (ASCT).

[0065] In some aspects, at or prior to administration of the cell dose, the subject has a positron emission tomography (PET)-positive disease.

[0066] In some aspects, at the time of or prior to administration of a dose of cells, the subject is or has been treated with an anthracycline and one or more CD20 targeting agents. In some aspects, the one or more CD20 targeting agents include rituximab. In some aspects, the one or more CD20 targeting agents include R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (oncovin), and prednisone).

[0067] In some aspects of any of the provided aspects, prior to administration of a dose of cells, the step of identifying or selecting a subject having: double / triple hit lymphoma; chemotherapy-resistant lymphoma, such as chemotherapy-resistant DLBCL; a disease or disorder, such as a malignancy like NHL or large cell type B cell lymphoma, that has not achieved a complete remission (CR) in response to previous therapy for treating the disease or disorder; and / or has relapsed within or less than 1 year after receiving autologous stem cell transplantation (ASCT); and / or has a lymphoma with or including central nervous system (CNS) complications, for administration of a dose of cells.

[0068] In some aspects of any of the provided aspects, prior to administration of a dose of cells, the provided aspects include the step of identifying or selecting a subject having follicular lymphoma (FL), such as co-expression of CD10, BCL6, and BCL2 within the follicles, and / or FL associated with rearrangement of t(14;18) / (q32;q21) (IGH-BCL2) and / or BCL6, for administration of a dose of cells.

[0069] In some aspects, at the time of or prior to administration of a dose of cells, if the subject has received a previous CD19-targeted therapy, a biological sample obtained from the subject after the previous CD19-targeted therapy includes cells that express CD19.

[0070] In some aspects, at the time of or prior to administration of the cell dose: the subject is identified as having or suspected of having relapsed or refractory large B-cell lymphoma; and / or the subject has been or is being treated with an anthracycline and one or more CD20-targeted agents; and / or the subject has or is suspected of having a relapsed or refractory disease after two or more lines of therapy or after autologous HSCT; and / or the subject is identified as having an ECOG performance status of 1 or 2; and / or if the subject has received a prior CD19-targeted therapy, a biological sample obtained from the subject after the prior CD19-targeted therapy contains cells that express CD19.

[0071] In some aspects, administration of the cell dose is via delivery for an outpatient.

[0072] In some aspects, at the time of or prior to administration of the cell dose: the subject is identified as having or suspected of having relapsed or refractory large B-cell lymphoma; and / or the subject has been or is being treated with an anthracycline and one or more CD20-targeted agents; and / or the subject has or is suspected of having a relapsed or refractory disease after two or more lines of therapy or after autologous HSCT; and / or the subject is identified as having an ECOG performance status of 1 or 2; and / or if the subject has received a prior CD19-targeted therapy, a biological sample obtained from the subject after the prior CD19-targeted therapy contains cells that express CD19; and administration of the cell dose is via delivery for an outpatient.

[0073] In part of any aspect, prior to administration of a dose of the cells, identifying or selecting a subject who has relapsed / refractory NHL; is identified as or is ineligible for both high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT); and has relapsed following remission or become resistant to one prior therapy for the disease or condition other than another dose of cells expressing a CAR, for administration of a dose of the cells.

[0074] In part of any aspect, prior to administration of a dose of the cells, identifying or selecting a subject who, prior to administration of a dose of the cells, is or has: an age of 70 years or older; and / or an ECOG performance status of 2; and / or a pulmonary dysfunction with an optional carbon monoxide diffusing capacity of the lung (DLCO) of 60% or less or about 60% or less; and / or a cardiac dysfunction with an optional left ventricular ejection fraction (LVEF) of less than 50% or about 50% or less; and / or a renal dysfunction with an optional calculated creatinine clearance of less than 60 mL / min or about 60 mL / min or less; and / or a hepatic dysfunction with an optional aspartate aminotransferase (AST) and alanine aminotransferase (ALT) more than 2 times the upper limit of normal (ULN) or about 2 times the upper limit of normal (ULN), for administration of a dose of the cells.

[0075] In part of any aspect, prior to administration of a dose of the cells via delivery for an outpatient, identifying or selecting a subject who, prior to administration of a dose of the cells, is or has: relapsed or refractory large B-cell lymphoma; and / or an anthracycline and one or more CD20-targeting agents; and / or a disease that is relapsed or refractory after two or more lines of therapy or after autologous HSCT; and / or an ECOG performance status of 1 or 2; and / or if the subject has received a prior CD19-targeted therapy, a biological sample obtained from the subject after the prior CD19-targeted therapy contains cells expressing CD19, for administration of a dose of the cells.

[0076] In some aspects, prior to administration, the subject is preconditioned with a lymphodepleting therapy that includes administration of fludarabine and / or cyclophosphamide. In some aspects, the method also includes administering to the subject a lymphodepleting therapy that includes administration of fludarabine and / or cyclophosphamide immediately prior to administration of the cell dose.

[0077] In some aspects, administration of the cell dose and / or the lymphodepleting therapy is performed via delivery for outpatients. In some aspects, administration of the cell dose and / or the lymphodepleting therapy is performed at a non-tertiary medical center. In some aspects, after administration of the cell dose, the subject is monitored in an outpatient setting, optionally via telephone contact and / or a visit by a healthcare professional.

[0078] In some aspects of any of the provided aspects, the method further includes administering an additional therapeutic agent or therapy to the subject. In some aspects, the additional agent or therapy is a therapy other than cell therapy, such as CAR + therapy other than T cell therapy.

[0079] In some aspects of any of the provided aspects, the CAR includes an extracellular antigen-binding domain specific for an antigen, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, which may be 4-1BB, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which may be CD3 zeta; the CAR includes, in order, an extracellular antigen-binding domain specific for an antigen, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule; or the CAR includes an extracellular antigen recognition domain that specifically binds to an antigen, and an intracellular signaling domain that includes the CD3-zeta (CD3ζ) chain, and a costimulatory signaling region that is the signaling domain of CD28 or 4-1BB.

[0080] In some part of any of the provided embodiments, the antigen-binding domain is a scFv. In some part of any such embodiment, the scFv has the amino acid sequence of RASQDISKYLN (SEQ ID NO: 35), the amino acid sequence of SRLHSGV (SEQ ID NO: 36), and / or the amino acid sequence of GNTLPYTFG (SEQ ID NO: 37), and / or the amino acid sequence of DYGVS (SEQ ID NO: 38), the amino acid sequence of TIFF0007695882000001.tif4128, and / or the amino acid sequence of YAMDYWG (SEQ ID NO: 40), or the scFv contains the variable heavy chain region of FMC63 and the variable light chain region of FMC63, and / or the CDRL1 sequence of FMC63, the CDRL2 sequence of FMC63, the CDRL3 sequence of FMC63, the CDRH1 sequence of FMC63, the CDRH2 sequence of FMC63, and the CDRH3 sequence of FMC63, or binds to the same epitope as any of the foregoing or competes with it for binding, and, optionally, the scFv, in order, contains V H , optionally a linker containing SEQ ID NO: 24, and V L and, and / or the scFv contains a flexible linker and / or contains the amino acid sequence shown as SEQ ID NO: 43,

[0081] In some part of any of the provided embodiments, the co-stimulatory signaling region is the signaling domain of CD28 or 4-1BB. In some part of any such embodiment, the co-stimulatory signaling region is the signaling domain of 4-1BB. In some part of any such embodiment, the co-stimulatory domain contains SEQ ID NO: 12, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity thereto.

[0082] In some parts of any of the provided embodiments, the primary signaling domain is the CD3 zeta signaling domain. In some parts of any such embodiment, the primary signaling domain comprises SEQ ID NO: 13, 14, or 15, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity thereto. In some parts of any of the provided embodiments, the CAR further comprises a spacer between the transmembrane domain and the scFv. In some parts of any such embodiment, the spacer is a polypeptide spacer comprising or consisting of all or a portion of an immunoglobulin hinge or a modified version thereof, optionally an IgG4 hinge or a modified version thereof.

[0083] In some parts of any such embodiment, the spacer is 15 amino acids or fewer and does not include the CD28 extracellular region or the CD8 extracellular region. In some parts of any such embodiment, the spacer is 12 amino acids in length or about 12 amino acids in length. In some parts of any such embodiment, the spacer has or consists of any of the foregoing variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to the sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34; and / or the spacer comprises or consists of the formula X1PPX2P, wherein in the sequence, X1 is glycine, cysteine, or arginine, and X2 is cysteine or threonine.

[0084] In some part of any of the provided embodiments, the CAR contains a single-chain variable fragment (scFv) specific for an antigen, a transmembrane domain, a cytoplasmic signaling domain derived from a co-stimulatory molecule, which may or may not be 4-1BB or contain it, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which may or may not be the CD3 zeta signaling domain or contain it, and may further contain a spacer between the transmembrane domain and the scFv; the CAR contains, in order, an scFv specific for an antigen, a transmembrane domain, a cytoplasmic signaling domain derived from a co-stimulatory molecule, which may or may not be the 4-1BB signaling domain or contain it, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which may or may not be the CD3 zeta signaling domain; or the CAR contains, in order, an scFv specific for an antigen, a spacer, a transmembrane domain, a cytoplasmic signaling domain derived from a co-stimulatory molecule, which may or may not be the 4-1BB signaling domain, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which may or may not be the CD3 zeta signaling domain or contain it; and the spacer contains (a) all or part of an immunoglobulin hinge or a modified version thereof, or consists of, or contains about 15 amino acids or less and does not contain the extracellular region of CD28 or CD8, (b) all or part of an immunoglobulin hinge, which may be an IgG4 hinge or a modified version thereof, or consists of, and / or contains about 15 amino acids or less and does not contain the extracellular region of CD28 or CD8, or (c) is 12 amino acids in length or about 12 amino acids in length, and / or may contain all or part of an immunoglobulin hinge, which may be an IgG4 hinge or a modified version thereof, or consists of.or (d) the sequence of SEQ ID NO: 1, the sequences encoded by SEQ ID NO: 2, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, or any variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity thereto, or (e) a polypeptide spacer that contains or consists of the formula X1PPX2P, wherein in the sequence, X1 is glycine, cysteine, or arginine and X2 is cysteine or threonine; and / or, the co-stimulatory domain contains SEQ ID NO: 12 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity thereto; and / or, the primary signaling domain includes SEQ ID NO: 13, 14, or 15 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity thereto; and / or, the scFv has the amino acid sequence of RASQDISKYLN (SEQ ID NO: 35), the amino acid sequence of SRLHSGV (SEQ ID NO: 36), and / or the amino acid sequence of GNTLPYTFG (SEQ ID NO: 37), and / or the amino acid sequence of DYGVS (SEQ ID NO: 38); The amino acid sequence of TIFF0007695882000002.tif4128, and / or the amino acid sequence of YAMDYWG (SEQ ID NO: 40), and / or the scFv comprises the variable heavy chain region of FMC63 and the variable light chain region of FMC63, and / or the CDRL1 sequence of FMC63, the CDRL2 sequence of FMC63, the CDRL3 sequence of FMC63, the CDRH1 sequence of FMC63, the CDRH2 sequence of FMC63, and the CDRH3 sequence of FMC63, or binds to the same epitope as any of the foregoing or competes therewith for binding, and optionally, the scFv comprises, in order, V H , optionally a linker comprising SEQ ID NO: 24, and V L and / or the scFv comprises a flexible linker and / or comprises the amino acid sequence shown as SEQ ID NO: 24.

[0085] In some part of any of the provided embodiments, the antigen is a B cell antigen. In some part of any such embodiment, the antigen is CD19. In some part of any of the provided embodiments, prior to administration, the subject is pre-conditioned with lymphodepletion therapy comprising administration of fludarabine and / or cyclophosphamide. In some part of any of the provided embodiments, the step of subjecting the subject to lymphodepletion therapy immediately prior to administration comprises administration of fludarabine and / or cyclophosphamide. In some part of any of the provided embodiments, the administration of the cell dose and / or the lymphodepletion therapy is performed via allogeneic patient delivery; and if the subject exhibits persistent fever, or a fever that does not decrease or decreases by more than 1 °C after treatment with an antipyretic, then the subject is hospitalized or stays overnight in the hospital and / or is administered an agent or treatment for the treatment or prevention or reduction or attenuation of neurotoxicity and / or cytokine release syndrome or the risk thereof.

[0086] In some of the provided embodiments, the cell dosage is administered parenterally. In some of any such embodiments, the cell dosage is administered intravenously. In some of the provided embodiments, the T cells are primary T cells obtained from the subject. In some of the provided embodiments, the T cells are autologous to the subject. In some of the provided embodiments, the subject is a human subject.

[0087] Also provided herein is a manufactured article containing a composition containing genetically engineered cells expressing a recombinant receptor. In some of any such embodiments, the manufactured article also contains instructions for administering a cell dosage according to any of the methods provided herein.

[0088] Provided herein is a method for assessing the risk of developing toxicity after cell therapy, comprising the following steps: (a) assessing one or more parameters in a subject, wherein the one or more parameters are selected from the levels, amounts, or concentrations of LDH, ferritin, or C-reactive protein (CRP) in a biological sample from the subject, or the sum of product dimensions (SPD) of tumors in the subject; the subject is a candidate for treatment with cell therapy, the cell therapy contains a dosage of genetically engineered cells expressing a recombinant receptor; and the assessing step is performed before the cell therapy is administered, and / or the biological sample or tumor does not contain the recombinant receptor and / or the engineered cells; and (b) determining whether the subject is at risk of toxicity, wherein if one or more parameters are above a threshold level, the subject is at risk of toxicity, and if one or more parameters are below the threshold level, the subject is not at risk of toxicity, wherein (i) if the parameter is the sum of product dimensions (SPD), the threshold level is greater than 30 cm 2 , 40 cm 2 , 50 cm 2 , 60 cm 2 , or 70 cm 2 or greater, or about 30 cm2 、 40 cm 2 、 50 cm 2 、 60 cm 2 、 or 70 cm 2 or above; (ii) the parameter is LDH and the threshold level is above 300 units / liter, 400 units / liter, 500 units / liter, or 600 units / liter, or about above 300 units / liter, 400 units / liter, 500 units / liter, or 600 units / liter; (iii) the parameter is ferritin and the threshold level is above 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter, or 8000 nanograms / milliliter, or about above 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter, or 8000 nanograms / milliliter; and / or (iv) the parameter is CRP and the threshold level is above 5 milligrams / liter, 10 milligrams / liter, 15 milligrams / liter, 20 milligrams / liter, 25 milligrams / liter, 30 milligrams / liter, 40 milligrams / liter, or 50 milligrams / liter, or about above 5 milligrams / liter, 10 milligrams / liter, 15 milligrams / liter, 20 milligrams / liter, 25 milligrams / liter, 30 milligrams / liter, 40 milligrams / liter, or 50 milligrams / liter, stage.

[0089] Also provided is a method of identifying a subject, comprising the following steps: (a) evaluating one or more parameters in the subject, wherein the one or more parameters are selected from the level, amount, or concentration of LDH, ferritin, or C-reactive protein (CRP) in a biological sample derived from the subject, or the sum of product dimensions (SPD) of a tumor in the subject; the subject is a candidate for treatment with cell therapy, the cell therapy contains a dose of genetically engineered cells that express a recombinant receptor; and the evaluating step is performed before the cell therapy is administered and / or the biological sample or tumor does not contain the recombinant receptor and / or the engineered cells; and (b) identifying a subject at risk of developing toxicity after administration of the cell therapy, wherein if one or more parameters are above a threshold level, the subject is at risk of toxicity, and if one or more parameters are below the threshold level, the subject is not at risk of toxicity, wherein (i) the parameter is the sum of product dimensions (SPD), and the threshold level is greater than 30 cm 2 , 40 cm 2 , 50 cm 2 , 60 cm 2 , or 70 cm 2 or greater than about 30 cm 2 , 40 cm 2 , 50 cm 2 , 60 cm 2 , or 70 cm 2above; (ii) the parameter is LDH and the threshold level is above 300 units / liter, 400 units / liter, 500 units / liter, or 600 units / liter, or about above 300 units / liter, 400 units / liter, 500 units / liter, or 600 units / liter; (iii) the parameter is ferritin and the threshold level is above 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter, or 8000 nanograms / milliliter, or about above 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter, or 8000 nanograms / milliliter; and / or (iv) the parameter is CRP and the threshold level is above 5 milligrams / liter, 10 milligrams / liter, 15 milligrams / liter, 20 milligrams / liter, 25 milligrams / liter, 30 milligrams / liter, 40 milligrams / liter, or 50 milligrams / liter, or about above 5 milligrams / liter, 10 milligrams / liter, 15 milligrams / liter, 20 milligrams / liter, 25 milligrams / liter, 30 milligrams / liter, 40 milligrams / liter, or 50 milligrams / liter, stage.

[0090] Also provided herein is a method of treatment comprising the following steps: (a) evaluating one or more parameters in a subject, wherein the one or more parameters are selected from the level, amount, or concentration of LDH, ferritin, or C-reactive protein (CRP) in a biological sample derived from the subject, or the sum of product dimensions (SPD) of a tumor in the subject; the subject being a candidate for treatment with cell therapy, the cell therapy comprising a dose of genetically engineered cells that express a recombinant receptor; and the evaluating step being performed before the cell therapy is administered and / or the biological sample or tumor not containing the recombinant receptor and / or the engineered cells; and (b) determining whether the subject is at risk of toxicity, wherein if one or more parameters are above a threshold level, the subject is at risk of toxicity, and if one or more parameters are below the threshold level, the subject is not at risk of toxicity, wherein (i) the parameter is the sum of product dimensions (SPD) and the threshold level is greater than 30 cm 2 , 40 cm 2 , 50 cm 2 , 60 cm 2 , or 70 cm 2 or greater than about 30 cm 2 , 40 cm 2 , 50 cm 2 , 60 cm 2 , or 70 cm 2above; (ii) the parameter is LDH and the threshold level is above 300 units / liter, 400 units / liter, 500 units / liter, or 600 units / liter, or about above 300 units / liter, 400 units / liter, 500 units / liter, or 600 units / liter; (iii) the parameter is ferritin and the threshold level is above 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter, or 8000 nanograms / milliliter, or about above 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter, or 8000 nanograms / milliliter; and / or (iv) the parameter is CRP and the threshold level is above 5 milligrams / liter, 10 milligrams / liter, 15 milligrams / liter, 20 milligrams / liter, 25 milligrams / liter, 30 milligrams / liter, 40 milligrams / liter, or 50 milligrams / liter, or about above 5 milligrams / liter, 10 milligrams / liter, 15 milligrams / liter, 20 milligrams / liter, 25 milligrams / liter, 30 milligrams / liter, 40 milligrams / liter, or 50 milligrams / liter, stage; and (c) a stage of subjecting the subject to cell therapy after the evaluation or based on the result of the evaluation. In some parts of any such aspect, the method also includes a stage of administering an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity.

[0091] In some part of any of the provided aspects, the parameter in the provided method is SPD and the threshold level is 50 cm 2It is so. In some part of any of the provided methods, the parameter in the provided method is LDH, and the threshold level is 500 units / liter. In some part of any of the provided embodiments, one or more parameters in the provided method are SPD and LDH, and the threshold level for SPD is 50 cm 2 and the threshold level for LDH is 500 units / liter. In some part of any of the provided embodiments, the parameter in the provided method is ferritin, and the threshold level is 5000 nanograms / milliliter. In some part of any of the provided embodiments, the parameter in the provided method is CRP, and the threshold level is 10 milligrams / liter. In some part of any of the provided embodiments, one or more parameters in the method are ferritin and CRP, the threshold level for ferritin is 5000 nanograms / milliliter, and the threshold level for CRP is 10 milligrams / liter.

[0092] In some part of any of the provided embodiments, the biological sample in the provided method is a blood or plasma sample. In some part of any of the provided embodiments, the SPD in the provided method is measured based on CT and / or MRI imaging of the body or other imaging. In some part of any of the provided embodiments, the level, amount, or concentration of one or more analytes and / or SPD is measured before treatment, before apheresis, or before cell product manufacture.

[0093] Also provided herein is a method for assessing the risk of developing toxicity after cell therapy, comprising the following steps: (a) assessing the peak concentration of genetically engineered cells expressing a recombinant receptor in a biological sample from a subject who has previously received cell therapy containing genetically engineered cells; and (b) determining whether the subject is at risk of toxicity, wherein if one or more parameters, such as the peak concentration of genetically engineered cells, are above a threshold level, the subject is at risk of toxicity, and if the peak concentration of genetically engineered cells is below the threshold level, the subject is not at risk of toxicity, and the threshold level is above 300 cells / microliter, 400 cells / microliter, 500 cells / microliter, 600 cells / microliter, 700 cells / microliter, 800 cells / microliter, 900 cells / microliter, or 1000 cells / microliter, or is about 300 cells / microliter, 400 cells / microliter, 500 cells / microliter, 600 cells / microliter, 700 cells / microliter, 800 cells / microliter, 900 cells / microliter, or 1000 cells / microliter.

[0094] Also provided herein is a method of identifying a subject, comprising the following steps: (a) evaluating the peak concentration of genetically engineered cells expressing a recombinant receptor in a biological sample from a subject who has previously received a cell therapy containing the genetically engineered cells; and (b) identifying a subject at risk of developing toxicity after the cell therapy, wherein if one or more parameters, such as the peak concentration of the genetically engineered cells, are above a threshold level, the subject is at risk of toxicity, and if the peak concentration of the genetically engineered cells is below the threshold level, the subject is not at risk of toxicity, wherein the threshold level is above 300 cells / microliter, 400 cells / microliter, 500 cells / microliter, 600 cells / microliter, 700 cells / microliter, 800 cells / microliter, 900 cells / microliter, or 1000 cells / microliter, or about above 300 cells / microliter, 400 cells / microliter, 500 cells / microliter, 600 cells / microliter, 700 cells / microliter, 800 cells / microliter, 900 cells / microliter, or 1000 cells / microliter.

[0095] Also provided herein is a method of treatment comprising the following steps: (a) assessing the peak concentration of genetically engineered cells expressing a recombinant receptor in a biological sample from a subject previously administered a cell therapy comprising the genetically engineered cells; and (b) determining whether the subject is at risk of toxicity, wherein if one or more parameters, such as the peak concentration of the genetically engineered cells, are above a threshold level, the subject is at risk of toxicity, and if the peak concentration of the genetically engineered cells is below the threshold level, the subject is not at risk of toxicity, wherein the threshold level is above 300 cells / microliter, 400 cells / microliter, 500 cells / microliter, 600 cells / microliter, 700 cells / microliter, 800 cells / microliter, 900 cells / microliter, or 1000 cells / microliter, or about above 300 cells / microliter, 400 cells / microliter, 500 cells / microliter, 600 cells / microliter, 700 cells / microliter, 800 cells / microliter, 900 cells / microliter, or 1000 cells / microliter, and (c) administering a cell therapy to the subject after or based on the assessment. In some aspects of any such embodiment, the method also includes administering an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity. In some aspects of any of the provided embodiments, the threshold level in the provided method is 500 cells / microliter.

[0096] Also provided herein is a method further comprising monitoring the subject for symptoms of toxicity if the subject is identified as having received a cell therapy and being at risk of developing toxicity.

[0097] In some of the provided embodiments, the toxicity is neurotoxicity or CRS. In some of the provided embodiments, the toxicity is grade 1 or higher neurotoxicity or CRS. In some of the provided embodiments, the toxicity is severe neurotoxicity or grade 2 or higher neurotoxicity, grade 3 or higher neurotoxicity, or grade 4 or higher neurotoxicity. In some of the provided embodiments, the toxicity is grade 1 or higher neurotoxicity. In some of the provided embodiments, the toxicity is severe neurotoxicity or grade 3 or higher neurotoxicity. In some of the provided embodiments, the toxicity is severe CRS or grade 2 or higher CRS, grade 3 or higher CRS, or grade 4 or higher CRS. In some of the provided embodiments, the toxicity is grade 1 or higher CRS. In some of the provided embodiments, the toxicity is severe CRS or grade 3 or higher CRS.

[0098] Also provided herein is a method of treatment for a subject to be subjected to the following, when the subject is identified as having a risk of developing toxicity: (a) (1) an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of toxicity or the risk of onset of toxicity, and (2) a cell therapy, wherein the administration of the agent should be administered (i) prior to the initiation of, (ii) within 1, 2, or 3 days of the initiation of, (iii) concurrently with the initiation of, and / or (iv) at the first fever after the initiation of, the cell therapy to the subject; and / or (b) a cell therapy at a reduced dose or at a dose not associated with the risk of developing toxicity or severe toxicity after the cell therapy has been administered, or in the majority of subjects not associated with the risk of developing toxicity or severe toxicity, and / or in the majority of subjects having or suspected of having a disease or condition that the subject has; and / or (c) the administration of a cell therapy to a subject in the context of an inpatient setting and / or involving hospitalization of the subject in a hospital for one or more days. In some parts of any such embodiment, the cell therapy should otherwise be administered to the subject on an outpatient basis or without involving hospitalization of the subject in a hospital for one or more days.

[0099] In some part of any of the provided aspects, the agent or other treatment is an anti-IL-6 antibody or an anti-IL-6 receptor antibody. In some part of any of the provided aspects, the agent or other treatment is an agent selected from or containing tocilizumab, siltuximab, clazakizumab, sarilumab, olokizumab (CDP6038), elsilimomab, ALD518 / BMS-945429, silkumab (CNTO 136), CPSI-2634, ARGX-109, FE301, and FM101. In some part of any of the provided aspects, the agent or other treatment is tocilizumab. In some part of any of the provided aspects, the agent or other treatment is or contains one or more steroids. In some part of any of the provided aspects, the steroid is dexamethasone or methylprednisolone. In some part of any of the provided aspects, the steroid is dexamethasone. In some part of any of the provided aspects, the agent or other treatment contains administration of a pressor agent. In some part of any of the provided aspects, the agent or other treatment includes intubation. In some part of any of the provided aspects, the agent or other treatment includes dialysis.

[0100] In some part of any of the provided embodiments, the recombinant receptor specifically binds to an antigen (e.g., a target antigen) that is associated with a disease or condition or is expressed in cells in the context of a lesion associated with a disease or condition. In some part of any such embodiment, the antigen is a B cell antigen. In some part of any such embodiment, the antigen is CD19. In some part of any of the provided embodiments, the disease or condition is cancer. In some part of any of the provided embodiments, the disease or condition is multiple myeloma, leukemia, or lymphoma. In some part of any of the provided embodiments, the disease or condition is a B cell malignancy and / or acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), or large B cell lymphoma. In some part of any such embodiment, the disease or condition is large B cell lymphoma. In some part of any of the provided embodiments, a disease or condition such as large B cell lymphoma is diffuse large B cell lymphoma (DLBCL). In some part of any of the provided embodiments, DLBCL is DLBCL (not otherwise specified (NOS)), de novo DLBCL, or DLBCL transformed from indolent lymphoma. In some part of any of the provided embodiments, DLBCL is de novo DLBCL. In some part of any of the provided embodiments, DLBCL is DLBCL transformed from follicular lymphoma (tFL). In some part of any of the provided embodiments, DLBCL is DLBCL transformed from marginal zone lymphoma (tMZL) or DLBCL transformed from chronic lymphocytic leukemia (tCLL; Richter). In some part of any of the provided embodiments, the disease or condition is primary mediastinal B cell lymphoma (PMBCL) or follicular lymphoma (FL), such as follicular lymphoma grade 3B (FL3B). In some part of any embodiment, the disease or condition is follicular lymphoma (FL). In some part of any embodiment, the disease or condition is follicular lymphoma (FL).In some aspects, FL is associated with co-expression of CD10, BCL6, and BCL2 within follicles, and / or rearrangement of t(14;18) / (q32;q21) (IGH-BCL2) and / or BCL6. In some aspects, the disease or condition is mantle cell lymphoma (MCL).

[0101] In some aspects of any of the provided aspects, the recombinant receptor is a chimeric antigen receptor (CAR). In some aspects of any of the provided aspects, the engineered cell is a T cell, e.g., CD4 + T cell and / or CD8 + T cell. In some aspects of any of the provided aspects, the cell therapy is CD4 + T cell and CD8 + T cell at a stage of administration to a subject, wherein each dose of T cell specifically binds to an antigen expressed by the disease or condition or its cells or tissues, e.g., a target antigen, and / or contains a receptor associated with the disease or condition, and the administration includes administering a plurality of separate compositions, the plurality of separate compositions including a first composition containing CD8 + T cell and a second composition containing CD4 + T cell.

[0102] In some aspects of any of the provided aspects, the initiation of administration of the first composition is performed before the initiation of administration of the second composition. In some aspects of any of the provided aspects, the administration of the first composition and the administration of the second composition are performed at an interval of 48 hours or less. In some aspects of any of the provided aspects, the administration of the first composition and the administration of the second composition are performed at an interval of 36 hours or less, 24 hours or less, 12 hours or less, 6 hours or less, 4 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less.

[0103] In some aspects of any of the provided aspects, the receptor contained by CD4 + T cell and / or CD8 +The receptors contained by T cells include the same recombinant receptor and / or CD4 + T cells and / or CD8 + The T cells are genetically engineered to express the same recombinant receptor.

[0104] In some part of any of the provided embodiments, CD4 + T cells and CD8 + The dose of T cells is 1:1 or approximately 1:1, or approximately 1:3 to approximately 3:1, of the defined ratio of CD4 cells expressing the recombinant receptor: CD8 cells expressing the recombinant receptor, and / or CD4 cells: CD8 cells, which contain; or, CD4 T cells containing the receptor in one of the first composition and the second composition, and CD8 T cells containing the receptor in the other of the first composition and the second composition. + cells: CD8 cells expressing the recombinant receptor + cells, and / or CD4 + cells: CD8 + cells; and / or, CD4 T cells containing the receptor in one of the first composition and the second composition, and CD8 T cells containing the receptor in the other of the first composition and the second composition. + T cells, and CD8 T cells containing the receptor in the other of the first composition and the second composition. + The T cells are present in a defined ratio that is 1:1 or approximately 1:1, or approximately 1:3 to approximately 3:1; and / or, CD4 T cells containing the receptor and CD8 T cells containing the receptor are administered in the first composition and the second composition. + T cells and CD8 T cells containing the receptor. + The T cells are present in a defined ratio, which is 1:1 or approximately 1:1, or approximately 1:3 to approximately 3:1. In some part of any of the provided embodiments, the defined ratio is 1:1 or approximately 1:1.

[0105] In some part of any of the provided embodiments, CD4 + T cells and CD8 + The dose of T cells is from 1×10 7 cells or about 1×10 7 cells to 2×10 8 cells or about 2×10 8 cells of total recombinant receptor-expressing T cells (including both end values); 2.5×10 7 cells or about 2.5×10 7from 1.5×10 8 to 1.5×10 8 total recombinant receptor-expressing T cells (including the values at both ends); 5×10 7 to 5×10 7 from 1×10 8 to 1×10 8 total recombinant receptor-expressing T cells (including the values at both ends); 5×10 7 to 5×10 7 total recombinant receptor-expressing T cells; 1×10 8 to 1×10 8 total recombinant receptor-expressing T cells; or 1.5×10 8 to 1.5×10 8 total recombinant receptor-expressing T cells. In some parts of any such embodiment, CD4 + T cells and CD8 + T cell doses include 5×10 7 to 5×10 7 total recombinant receptor-expressing T cells. In some parts of any such embodiment, CD4 + T cells and CD8 + T cell doses include 1×10 8 to 1×10 8 total recombinant receptor-expressing T cells. In some parts of any such embodiment, CD4 + T cells and CD8 + T cell doses include 1.5×10 8 to 1.5×10 8 total recombinant receptor-expressing T cells.

[0106] In some parts of any of the provided embodiments, CD4 + T cells and CD8 + T cell doses are from 1×10 7 to 1×10 7 to 1×10 8 to 1×10 8 recombinant receptor-expressing CD8 + T cells (including the values at both ends); 1.25×10 7 to 1.25×10 7from, 7.5×10 7 to, or about 7.5×10 7 receptor-expressing CD8 + T cells (including the values at both ends); 2.5×10 7 to, or about 2.5×10 7 to, 5×10 7 to, or about 5×10 7 receptor-expressing CD8 + T cells (including the values at both ends); 2.5×10 7 to, or about 2.5×10 7 receptor-expressing CD8 + T cells; 5×10 7 to, or about 5×10 7 receptor-expressing CD8 + T cells; or 7.5×10 7 to, or about 7.5×10 7 receptor-expressing CD8 + T cells. In some parts of any such embodiment, CD4 + T cells and CD8 + T cell dosages are 2.5×10 7 or about 2.5×10 7 receptor-expressing CD8 + T cells. In some parts of any such embodiment, CD4 + T cells and CD8 + T cell dosages are 5×10 7 or about 5×10 7 receptor-expressing CD8 + T cells. In some parts of any such embodiment, CD4 + T cells and CD8 + T cell dosages are 7.5×10 7 or about 7.5×10 7 receptor-expressing CD8 + T cells.

[0107] In some parts of any of the provided embodiments, the T cells are primary T cells obtained from the subject or are autologous to the subject.

[0108] Compositions comprising genetically engineered cells that express recombinant receptors; and articles of manufacture containing instructions for assessing the risk of developing toxicity, identifying a subject, or treating a subject according to any of the methods provided herein. In some aspects of any such embodiment, the article of manufacture also contains an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of onset of toxicity. [Inventive concept 1001] A method of treating a subject having or suspected of having a disease or condition that is relapsed or refractory large - cell type B - cell lymphoma (r / r LBCL), comprising the following steps: CD4 + T cells and CD8 + Administering to the subject a dose of T cells, wherein each dose of T cells comprises a chimeric antigen receptor (CAR) that specifically binds to CD19, the dose of T cells being from 1×10 7 or about 1×10 7 CAR - expressing T cells to 2×10 8 or about 2×10 8 CAR - expressing T cells (including both end values); the dose of T cells comprising an approximately 1:1 ratio of CD4 + T cells expressing CAR:CD8 + T cells expressing CAR; and the administration comprising administering a plurality of separate compositions, the plurality of separate compositions comprising a first composition comprising CD8 + T cells and a second composition comprising CD4 + T cells. [Inventive concept 1002] The method of Inventive concept 1001, wherein the large - cell type B - cell lymphoma is selected from aggressive non - Hodgkin lymphoma (NHL), diffuse large - cell type B - cell lymphoma (DLBCL), optionally DLBCL NOS (de novo or transformed from indolent), high - grade B - cell lymphoma (HGBCL), double / triple - hit lymphoma, primary mediastinal large - cell type B - cell lymphoma (PMBCL), mantle cell lymphoma (MCL), transformed follicular lymphoma (tFL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B). [Inventive concept 1003] The method of Inventive concept 1001 or Inventive concept 1002, wherein the large - cell type B - cell lymphoma is diffuse large - cell type B - cell lymphoma (DLBCL). [Inventive concept 1004] The method of Inventive concept 1003, wherein the DLBCL is DLBCL NOS, de novo DLBCL, or DLBCL transformed from indolent lymphoma. [Inventive concept 1005] The method of Inventive concept 1003 or Inventive concept 1004, wherein the DLBCL is de novo DLBCL. [Inventive concept 1006] The method of Inventive concept 1003 or Inventive concept 1004, wherein the DLBCL is DLBCL transformed from indolent lymphoma other than FL. [Inventive concept 1007] The method of the 1003rd or 1004th invention of the present invention, wherein the DLBCL is transformed DLBCL (tMZL) from marginal zone lymphoma or transformed DLBCL (tCLL; Richter) from chronic lymphocytic leukemia. [The 1008th invention of the present invention] The method of the 1001st or 1002nd invention of the present invention, wherein the large cell type B cell lymphoma is high-grade B cell lymphoma (HGBCL). [The 1009th invention of the present invention] The method according to any one of the 1001st, 1002nd, and 1008th inventions of the present invention, wherein the HGBCL has rearrangements of MYC and BCL2 and / or BCL6. [The 1010th invention of the present invention] The method according to any one of the 1001st, 1002nd, 1008th, and 1009th inventions of the present invention, wherein the HGBCL has a DLBCL histological image. [The 1011th invention of the present invention] The method of the 1001st or 1002nd invention of the present invention, wherein the large cell type B cell lymphoma is double / triple hit lymphoma. [The 1012th invention of the present invention] The method of the 1001st or 1002nd invention of the present invention, wherein the large cell type B cell lymphoma is primary mediastinal B cell lymphoma (PMBCL). [The 1013th invention of the present invention] The method of the 1001st or 1002nd invention of the present invention, wherein the large cell type B cell lymphoma is mantle cell lymphoma (MCL). [The 1014th invention of the present invention] The method of the 1001st or 1002nd invention of the present invention, wherein the large cell type B cell lymphoma is not primary central nervous system lymphoma (PCNSL). [The 1015th invention of the present invention] The method of the 1001st or 1002nd invention of the present invention, wherein the large cell type B cell lymphoma is transformed follicular lymphoma (tFL). [The 1016th invention of the present invention] The method of the 1001st or 1002nd invention of the present invention, wherein the large cell type B cell lymphoma is follicular lymphoma (FL). [The 1017th invention of the present invention] A method of treatment comprising the following steps: (a) Selecting a subject having follicular lymphoma (FL) for treatment; (b) A dose of T cells comprising T cells expressing a recombinant receptor that specifically binds to an antigen expressed by FL or its cells or tissues and / or is related to FL is administered to the subject. [The 1018th invention of the present invention] The dose of the T cells comprises a dose of CD4 + T cells and a dose of CD8 + T cells, and each dose of T cells comprises a recombinant receptor that specifically binds to an antigen expressed by FL or its cells or tissues and / or is related to FL , and the administration comprises administering a plurality of separate compositions, the plurality of separate compositions being CD8 ​ + A first composition comprising T cells and a second composition comprising CD4 + T cells, the method of the present invention 1017. [The present invention 1019] The method of the present invention 1017 or the present invention 1018, wherein the recombinant receptor is a chimeric antigen receptor (CAR). [The present invention 1020] The method according to any one of the present inventions 1017 to 1019, wherein the antigen is CD19. [The present invention 1021] The method according to any one of the present inventions 1018 to 1020, comprising identifying or selecting a subject having follicular lymphoma (FL) for administration of the dose of the cells prior to administration of the dose of the cells. [The present invention 1022] The method according to any one of the present inventions 1016 to 1021, wherein the FL is associated with co-expression of CD10, BCL6, and BCL2 in the follicle, and / or rearrangement of t(14;18) / (q32;q21)(IGH-BCL2) and / or BCL6. [The present invention 1023] The method according to any one of the present inventions 1016 to 1022, wherein the FL is follicular lymphoma grade 3B (FL3B). [The present invention 1024] At the time of or immediately prior to administration of the dose of the cells, the subject has relapsed following remission after treatment with two or more previous therapies for a disease or condition other than another dose of cells expressing CAR, or is resistant thereto, the method according to any one of the present inventions 1001 to 1023. [The present invention 1025] At the time of or immediately prior to administration of the dose of the cells, the subject has relapsed following remission after treatment with three or more previous therapies for a disease or condition other than another dose of cells expressing CAR, or is resistant thereto, the method according to any one of the present inventions 1001 to 1024. [The present invention 1026] At the time of or immediately prior to administration of the dose of the cells, the subject has relapsed following remission after treatment with four or more previous therapies for a disease or condition other than another dose of cells expressing CAR, or is resistant thereto, the method according to any one of the present inventions 1001 to 1025. [The present invention 1027] The method according to any one of the present inventions 1024 to 1026, wherein the previous therapy comprises anthracycline and a CD20 targeting agent. [The present invention 1028] The method of the present invention 1027, wherein one or more CD20 targeting agents comprise rituximab. [The present invention 1029] A method of the present invention 1027 or 1028, wherein one or more CD20 targeting agents are included in R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (oncovin), and prednisone). [The present invention 1030] A method according to any one of the present inventions 1024 to 1029, wherein when the previous therapy is a previous CD19-targeted therapy, a biological sample obtained from the subject after the previous CD19-targeted therapy contains cells expressing CD19. [The present invention 1031] A method according to any one of the present inventions 1024 to 1030, wherein the previous therapy includes allogeneic or autologous hematopoietic stem cell transplantation (HSCT). [The present invention 1032] A method of the present invention 1031, wherein the subject relapses within 1 year or less after receiving HSCT. [The present invention 1033] A method according to any one of the present inventions 1024 to 1032, wherein the subject has not achieved a complete remission (CR) in response to the previous therapy. [The present invention 1034] A method according to any one of the present inventions 1001 to 1033, wherein at the time of or prior to administration of the cell dose, the subject is identified as having an aggressive or high-risk disease or having a poor prognosis. [The present invention 1035] A method according to any one of the present inventions 1001 to 1034, wherein at the time of or prior to administration of the cell dose, the subject is identified as having a chemoresistant disease or having a persistent or recurrent disease after chemotherapy. [The present invention 1036] A method according to any one of the present inventions 1001 to 1035, wherein at the time of or prior to administration of the cell dose, the subject is identified as having a chemoresistant lymphoma, optionally chemoresistant DLBCL. [The present invention 1037] A method according to any one of the present inventions 1001 to 1036, wherein at the time of or prior to administration of the cell dose, the subject is identified as having a lymphoma with or including central nervous system (CNS) complications or secondary CNS lymphoma. [The present invention 1038] At the time of or prior to administration of the cell dose, the subject is identified as having or is identified as having a lymphoma with or including central nervous system (CNS) complications or secondary CNS lymphoma; and / or At the time of or before administration of the cell dose, at least 70%, at least 80%, at least 90%, or at least 95% of the subjects treated according to the method, who have been identified or are identified as having lymphoma or secondary lymphoma with CNS complications, have achieved resolution of the CNS disease. Any method of the present invention from 1001 to 1037. [The present invention 1039] Any method of the present invention from 1001 to 1038, wherein the subject is 65 years of age or older. [The present invention 1040] Among the treated subjects, more than 35% or about more than 35%, more than 40% or about more than 40%, more than 45% or about more than 45%, or more than 50% or about more than 50%, or any value between any of the foregoing, are 65 years of age or older. Any method of the present invention from 1001 to 1039. [The present invention 1041] Any method of the present invention from 1001 to 1039, wherein the subject is 70 years of age or older. [The present invention 1042] At the time of or before administration of the cell dose, the subject has a cardiac dysfunction characterized by or identified as having an ejection fraction of the left ventricle (LVEF) of less than 50% or about less than 50% at will. Any method of the present invention from 1001 to 1041. [The present invention 1043] At the time of or before administration of the cell dose, the subject is characterized by or identified as having a renal dysfunction with a calculated creatinine clearance of less than 60 mL / min or about less than 60 mL / min at will. Any method of the present invention from 1001 to 1042. [The present invention 1044] At the time of or before administration of the cell dose, the subject is characterized by or identified as having a pulmonary dysfunction with a carbon monoxide diffusing capacity of the lung (DLCO) of 60% or less or about 60% or less at will. Any method of the present invention from 1001 to 1043. [The present invention 1045] At the time of or before administration of the cell dose, the subject is characterized by or identified as having a liver dysfunction with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) more than 2 times the upper limit of normal value (ULN) or about more than 2 times at will. Any method of the present invention from 1001 to 1044. [The present invention 1046] At the time of or before administration of the cell dose, the subject is CD4 + T cells and CD8 + During leukapheresis for generating doses of T cells and CD4 + T cells and CD8 + Any method of the present invention from 1001 to 1045, wherein the subject is receiving bridging chemotherapy between administration of the T cell dose. [The present invention 1047] Any method of the present invention from 1001 to 1046, wherein the subject is receiving bridging chemotherapy for disease control after previous therapy at the time of or prior to administration of the cell dose. [The present invention 1048] The bridging chemotherapy is as follows: rituximab - gemcitabine + oxaliplatin, dexamethasone, radiotherapy, rituximab, prednisone, BR, lenalidomide, gemcitabine + oxaliplatin, brentuximab vedotin, ibrutinib, bendamustine, and / or gemcitabine + rituximab The method of the present invention 1046 or the method of the present invention 1047, which is selected from one or more of the above. [The present invention 1049] Any method of the present invention from 1001 to 1048, wherein the subject is identified or has been identified as ineligible for high - dose chemotherapy at the time of or immediately prior to administration of the cell dose. [The present invention 1050] Any method of the present invention from 1001 to 1049, wherein the subject is identified or has been identified as ineligible for hematopoietic stem cell transplantation (HSCT) at the time of or immediately prior to administration of the cell dose. [The present invention 1051] The method of the present invention 1049 or the method of the present invention 1050, wherein the subject is identified or has been identified as ineligible for both high - dose chemotherapy and hematopoietic stem cell transplantation (HSCT) at the time of or immediately prior to administration of the cell dose. [The present invention 1052] Any method of the present invention from 1001 to 1051, wherein the subject is identified or has been identified as ineligible for both high - dose chemotherapy and hematopoietic stem cell transplantation (HSCT) at the time of or immediately prior to administration of the cell dose, and the subject has relapsed or become resistant following remission after treatment with one previous therapy for the disease or condition other than another dose of cells expressing CAR. [The present invention 1053] Any method of the present invention from 1001 to 1052, wherein the subject is identified or has been identified as having an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0, 1, or 2. [The present invention 1054] Any of the methods of the present invention 1001 to 1053, wherein the subject is identified as having or is identified as having an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. [The present invention 1055] Any of the methods of the present invention 1001 to 1053, wherein the subject is identified as having or is identified as having an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2. [The present invention 1056] Prior to administration of the dose of cells, the subject has a sum of product dimensions (SPD) of the tumor in the subject of 50 cm 2 or more or about 50 cm 2 or more, and any of the methods of the present invention 1001 to 1055 is identified as having or is identified as having. [The present invention 1057] Any of the methods of the present invention 1001 to 1055, wherein the subject has a positron emission tomography (PET)-positive disease at the time of or prior to administration of the dose of cells. [The present invention 1058] Any of the methods of the present invention 1001 to 1056, wherein prior to administration of the dose of cells, the subject is identified or selected for administration of the dose of cells. [The present invention 1059] Any of the methods of the present invention 1001 to 1057, comprising the step of identifying or selecting, for administration of the dose of cells, a subject having or being the following prior to administration of the dose of cells: Relapsed or refractory large cell type B cell lymphoma; and / or Anthracycline and one or more CD20 targeting agents; and / or Relapsed or refractory disease after two or more lines of treatment or after autologous HSCT; and / or Having an ECOG performance status of 0, 1, or 2; and / or If the subject has received a previous CD19-targeted therapy, a biological sample obtained from the subject after the previous CD19-targeted therapy contains cells expressing CD19. [The present invention 1060] Any of the methods of the present invention 1001 to 1057, comprising the step of identifying or selecting, for administration of the dose of cells, a subject having or being the following prior to administration of the dose of cells: An age of 70 years or older; and / or An ECOG performance status of 2; and / or Optionally, a pulmonary function disorder with a carbon monoxide diffusing capacity of the lung (DLCO) of 60% or less or about 60% or less; and / or Cardiac dysfunction, optionally with a left ventricular ejection fraction (LVEF) of less than 50% or about less than 50%; and / or Renal dysfunction, optionally with a calculated creatinine clearance of less than 60 mL / min or about less than 60 mL / min; and / or Liver dysfunction, optionally with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) more than 2 times the upper limit of normal (ULN) or about more than 2 times the ULN. [Inventive concept 1061] Any method of Inventive concepts 1001 - 1057, comprising identifying or selecting a subject having the following prior to administration of a dose of cells for administration of the dose of cells: Double / triple hit lymphoma; Chemotherapy-resistant lymphoma, optionally chemotherapy-resistant DLBCL; A malignancy, optionally failure to achieve a complete remission (CR) in response to previous therapy for treating NHL; and / or Relapse within or less than 1 year after receiving autologous stem cell transplantation (ASCT); and / or Having lymphoma with or including central nervous system (CNS) complications. [Inventive concept 1062] Any method of Inventive concepts 1001 - 1061, wherein the dose of T cells is enriched for CD3+ T cells, CD4+ T cells, CD8+ T cells, or both CD4+ T cells and CD8+ T cells, and optionally more than 70%, 75%, 80%, 85%, 90%, 95%, or 98% of the cells in the dose of T cells, or about more than 70%, 75%, 80%, 85%, 90%, 95%, or 98% of the cells in the dose of T cells, are CD3+ T cells, CD4+ T cells, CD8+ T cells, or both CD4+ T cells and CD8+ T cells. [Inventive concept 1063] Any method of Inventive concepts 1001 - 1017 and 1019 - 1062, wherein initiation of administration of the first composition is performed prior to initiation of administration of the second composition. [Inventive concept 1064] Any method of Inventive concepts 1001 - 1017 and 1019 - 1063, wherein administration of the first composition and administration of the second composition are performed at intervals of 48 hours or less. [Inventive concept 1065] The method according to any one of the present inventions 1001 to 1017 and 1019 to 1064, wherein the administration of the first composition and the administration of the second composition are carried out at intervals of 36 hours or less, 24 hours or less, 12 hours or less, 6 hours or less, 4 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less. [The present invention 1066] The administration of the first composition and the administration of the second composition are carried out on the same day and at intervals of about 0 to about 12 hours, about 0 to about 6 hours, or about 0 to 2 hours; or The method according to any one of the present inventions 1001 to 1017 and 1019 to 1064, wherein the start of the administration of the first composition and the start of the administration of the second composition are carried out at intervals of about 1 minute to about 1 hour, or about 5 minutes to about 30 minutes. [The present invention 1067] The method according to any one of the present inventions 1001 to 1017 and 1019 to 1064, wherein the first composition and the second composition are administered at intervals of 2 hours or less, 1 hour or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less. [The present invention 1068] CD4 + The recombinant receptor contained by T cells and / or CD8 + The recombinant receptor contained by T cells is the same recombinant receptor, and / or CD4 + T cells and / or CD8 + The method according to any one of the present inventions 1001 to 1067, wherein the CD4 T cells and / or the CD8 T cells are genetically engineered to express the same recombinant receptor. [The present invention 1069] CD4 + The dosage of CD4 T cells and CD8 T cells is + from 2.5×10 7 individuals or about 2.5×10 7 individuals to 1.5×10 8 individuals or about 1.5×10 8 individuals of total recombinant receptor-expressing T cells (including both end values); 5×10 7 from 7 individuals or about 5×10 8 individuals to 1×10 8 individuals or about 1×10 5×10 7 individuals of total recombinant receptor-expressing T cells (including both end values); 7 individuals or about 5×10 1×10 8 individuals of total recombinant receptor-expressing T cells; 8 individuals or about 1×10 1.5×10 8 individuals of total recombinant receptor-expressing T cells; or 8 individuals or about 1.5×10 individuals of total recombinant receptor-expressing T cells [The present invention 1070] CD4 + The dosage of CD4 T cells and CD8 T cells is +5×10 7 individuals or about 5×10 7 individuals of total recombinant receptor-expressing T cells, and the method according to any one of the present inventions 1001 to 1069. [The present invention 1071] CD4 + The dosage of CD4 T cells and CD8 T cells is + 1×10 8 individuals or about 1×10 8 individuals of total recombinant receptor-expressing T cells, and the method according to any one of the present inventions 1001 to 1069. [The present invention 1072] CD4 + T cells and CD8 + The dose of T cells is 1.5×10 8 cells or about 1.5×10 8 cells of total recombinant receptor-expressing T cells, in any of the methods of the present invention from 1001 to 1069. [The present invention 1073] CD4 + T cells and CD8 + The dose of T cells is 1.25×10 7 cells or about 1.25×10 7 cells to 7.5×10 7 cells or about 7.5×10 7 cells of recombinant receptor-expressing CD8 + T cells (including both end values); 2.5×10 7 cells or about 2.5×10 7 cells to 5×10 7 cells or about 5×10 7 cells of recombinant receptor-expressing CD8 + T cells (including both end values); 2.5×10 7 cells or about 2.5×10 7 cells of recombinant receptor-expressing CD8 + T cells; 5×10 7 cells or about 5×10 7 cells of recombinant receptor-expressing CD8 + T cells; or 7.5×10 7 cells or about 7.5×10 7 cells of recombinant receptor-expressing CD8 + T cells in any of the methods of the present invention from 1001 to 1069. [The present invention 1074] CD4 + T cells and CD8 + The dose of T cells is 2.5×10 7 cells or about 2.5×10 7 cells of recombinant receptor-expressing CD8 + T cells, in any of the methods of the present invention from 1001 to 1069, 1070, and 1073. [The present invention 1075] CD4 + T cells and CD8 + The dose of T cells is 5×10 7 cells or about 5×10 7 cells of recombinant receptor-expressing CD8 + T cells, in any of the methods of the present invention from 1001 to 1069, 1071, and 1073. [The present invention 1076] CD4 + T cells and CD8 + The dose of T cells is 7.5×10 7 cells or about 7.5×10 7 cells of recombinant receptor-expressing CD8 + T cells, in any of the methods of the present invention from 1001 to 1069, 1072, and 1073. [The present invention 1077] Before administration, the subject is preconditioned with lymphodepletion therapy including administration of fludarabine and / or cyclophosphamide, in any of the methods of the present invention from 1001 to 1076. [The present invention 1078] Further comprising the step of subjecting the subject to lymphodepletion therapy including administration of fludarabine and / or cyclophosphamide immediately before administration of the dose of cells, in any of the methods of the present invention from 1001 to 1077. [The present invention 1079] The administration of the dose of cells and / or the lymphodepletion therapy is performed via delivery for foreign patients, the method of the present invention 1077 or the method of the present invention 1078. [The present invention 1080] The administration of the dose of cells and / or the lymphodepletion therapy is performed at a non-tertiary medical center, the method of the present invention 1079. [The present invention 1081] Administration and any follow-up are conducted as an outpatient and / or do not require hospitalization or an overnight stay in the hospital; and if the subject exhibits persistent fever or fever that does not decrease or decreases by more than 1°C after treatment with an antipyretic, the subject is hospitalized or stays overnight in the hospital and / or is administered an agent or treatment for the treatment, prevention, reduction, or attenuation of neurotoxicity and / or cytokine release syndrome or the risk thereof, any method of the present invention from 1001 to 1080. [The present invention 1082] Any method of the present invention from 1001 to 1081, wherein the subject has not been administered an agent or treatment for the treatment, prevention, reduction, or attenuation of neurotoxicity and / or cytokine release syndrome or the risk thereof before the start of administration of the cell dose. [The present invention 1083] Any method of the present invention from 1001 to 1082, further comprising the step of administering to the subject an agent or treatment for the treatment, prevention, reduction, or attenuation of neurotoxicity and / or cytokine release syndrome or the risk thereof. [The present invention 1084] Any method of the present invention from 1081 to 1083, wherein the agent is or comprises an anti-IL-6 antibody, an anti-IL-6 receptor antibody, or a steroid. [The present invention 1085] Any method of the present invention from 1081 to 1084, wherein the agent is or comprises tocilizumab, siltuximab, dexamethasone, or methylprednisolone. [The present invention 1086] Any method of the present invention from 1081 to 1085, wherein the agent is or comprises tocilizumab. [The present invention 1087] Any method of the present invention from 1081 to 1085, wherein the agent is or comprises dexamethasone. [The present invention 1088] at the time of or before administration of the cell dose, the subject has been or is being treated with an anthracycline and one or more CD20-targeted agents; and / or the subject has or has a disease that is recurrent or resistant after two or more lines of treatment or after autologous HSCT; and / or the subject is identified or has been identified as having an ECOG performance status of 0, 1, or 2; and / or If the subject has received a previous CD19-targeted therapy, a biological sample obtained from the subject after the previous CD19-targeted therapy contains cells expressing CD19; and the administration of the cell dose is performed via delivery for an allogeneic patient, any method of the present invention from 1001 to 1087. [The present invention 1089] Any method of the present invention from 1001 to 1088, wherein the T cells are primary T cells obtained from a subject. [The present invention 1090] Any method of the present invention from 1001 to 1089, wherein the T cells are autologous to the subject. [The present invention 1091] At least 40%, at least 50%, at least 60%, at least 70% of the subjects identified as having or having had double / triple hit lymphoma or relapse after administration of autologous stem cell transplantation (ASCT) achieve an OR, or a persistent OR over 3 months or more than 3 months or 6 months or more than 6 months, at the time of or before administration of the cell dose, any method of the present invention from 1001 to 1090. [The present invention 1092] At least 35%, at least 40%, or at least 50% of the subjects treated according to the method achieve a complete response (CR); At least 60%, 70%, 80%, 90%, or 95% of the subjects who achieved CR show a persistent CR over 3 months or more than 3 months or 6 months or more than 6 months; and / or At least 60%, 70%, 80%, 90%, or 95% of the subjects who achieved CR by 1 month and / or by 3 months remain in response, remain in CR, and / or survive or survive without progression for 3 months or more than 3 months and / or 6 months or more than 6 months and / or 9 months or more after achieving CR; and / or At least 50%, at least 60%, or at least 70% of the subjects treated according to the method achieve an objective response (OR); At least 60%, 70%, 80%, 90%, or 95% of the subjects who achieved OR show a persistent OR over 3 months or more than 3 months or 6 months or more than 6 months; and / or At least 35%, at least 40%, or at least 50% of the subjects who achieved OR remain effective or survive over 3 months or more and / or 6 months or more after achieving OR; and / or At least 40%, at least 50%, at least 60%, at least 70% of the subjects identified as having or having had double / triple hit lymphoma or recurrence after administration of autologous stem cell transplantation (ASCT) at or before administration of the cell dose achieve OR or achieve a persistent OR over 3 months or more or 6 months or more Any method of the present invention from 1001 to 1091 [The present invention 1093] At least 50% of the subjects treated according to the method achieve complete response (CR); At least 60% of the subjects who achieved CR show a persistent CR over 6 months or more; and / or At least 60% of the subjects who achieved CR by 1 month and / or by 3 months remain effective, remain in CR, and / or survive or survive without progression over 6 months or more after achieving CR; and / or At least 70% of the subjects treated according to the method achieve objective response (OR); At least 60% of the subjects who achieved OR show a persistent OR over 6 months or more; and / or At least 50% of the subjects who achieved OR remain effective or survive over 6 months or more after achieving OR; and / or At least 40% of the subjects identified as having or having had double / triple hit lymphoma or recurrence after administration of autologous stem cell transplantation (ASCT) at or before administration of the cell dose achieve OR or achieve a persistent OR over 3 months or more Any method of the present invention from 1001 to 1092 [The present invention 1094] The cells are autologous to the subject, and No minimum absolute lymphocyte count (ALC) for apheresis is required or specified for the generation of the therapy; and / or The cell is generated by a process capable of producing a cell product for administration according to the method for at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of a subject having a disease or condition or of a selected population of subjects. The method according to any one of 1001 to 1093 of the present invention. [The present invention 1095] CR or OR is persistent 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 the subjects treated according to the method achieve a persistent CR for more than 3 months or more than 6 months; and / or At least 60%, 70%, 80%, 90%, or 95% of the subjects treated by the method and achieving CR remain in CR, or remain effective, or remain alive for 3 months or more than 3 months or 6 months or more than 6 months or 9 months or more than 9 months; and / or At least 60%, 70%, 80%, 90%, or 95% of the subjects treated by the method and achieving CR by 1 month and / or by 3 months remain effective, remain in CR, and / or remain alive or survive without deterioration for a longer period than 3 months or more than 3 months and / or 6 months or more than 6 months and / or more than 9 months; and / or At least 50%, at least 60%, or at least 70% of the subjects treated according to the method achieve an objective response (OR). At least 60%, 70%, 80%, 90%, or 95% of the subjects achieve a persistent OR for 3 months or more than 3 months or 6 months or more than 6 months; and / or At least, at least 35%, at least 40%, or at least 50% of the subjects treated by the method and achieving OR remain effective or remain alive for 3 months or more than 3 months and / or 6 months or more than 6 months. The method according to any one of 1092 to 1094 of the present invention. [The present invention 1096] At least 35%, at least 40%, or at least 50% of the subjects treated according to the method achieve a complete response (CR) or remission of the CNS disease. At least 60%, 70%, 80%, 90%, or 95% of the subjects who achieved CR remain in CR for 3 months or more or 6 months or more; and / or At least 60%, 70%, 80%, 90%, or 95% of the subjects who achieved CR or remission of CNS disease by 1 month and / or by 3 months remain in response, remain in CR, and / or are alive or alive without progression for 3 months or more and / or 6 months or more and / or longer than 9 months; and / or At least 50%, at least 60%, or at least 70% of the subjects treated according to the method achieve objective response (OR) or remission of CNS disease; At least 60%, 70%, 80%, 90%, or 95% of the subjects achieve OR for 3 months or more or 6 months or more; and / or At least 60%, 70%, 80%, 90%, or 95% of the subjects who achieved OR or remission of CNS disease remain in response or are alive for 3 months or more and / or 6 months or more; and / or The brain lesion has a size or volume reduction of more than 25%, 50%, 75%, or more, or about more than 25%, 50%, 75%, or more; and / or Reduction or remission or clearance of CNS disease is achieved in at least 35%, at least 40%, or at least 50% of the subjects treated according to the method, Any method of the present invention from 1001 to 1095. [The present invention 1097] More than 50% or about more than 50%, about more than 60% or about more than 60%, about more than 70% or about more than 70%, or about more than 80% or about more than 80% of the subjects treated according to the method do not show cytokine release syndrome (CRS) of grade 3 or higher, and / or do not show neurotoxicity of grade 3 or higher, and / or more than 40% or more than 50% or more than 55% do not show any neurotoxicity or CRS, Any method of the present invention from 1001 to 1096. [The present invention 1098] Any method of the present invention 1001-1097, wherein more than 80% or about 80% or more of the subjects treated according to the method do not exhibit cytokine release syndrome (CRS) of grade 3 or higher and / or do not exhibit neurotoxicity of grade 3 or higher. [The present invention 1099] Any method of the present invention 1001-1098, wherein more than 95% of the subjects treated according to the method do not exhibit CRS of grade 3 or higher. [The present invention 1100] Any method of the present invention 1001-1099, wherein more than 85% of the subjects treated according to the method do not exhibit neurotoxicity of grade 3 or higher. [The present invention 1101] More than 30%, 35%, 40%, or 50% or about more than 30%, 35%, 40%, or 50% of the subjects treated according to the method do not exhibit cytokine release syndrome (CRS) or neurotoxicity of any grade; and / or At least 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or at least about 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the subjects treated according to the method do not exhibit the onset of CRS earlier than 3 days after the start of administration and / or do not exhibit the onset of neurotoxicity earlier than 5 days after the start of administration; and / or The median onset of neurotoxicity among the subjects treated according to the method is at or after the median peak of CRS or the median time to resolution of CRS in the subjects treated according to the method, and / or the median onset of neurotoxicity among the subjects treated according to the method is greater than 8, 9, 10, or 11 days or about greater than 8, 9, 10, or 11 days, Any method of the present invention 1001-1100. [The present invention 1102] More than 50% or about more than 50% of the subjects treated according to the method do not exhibit cytokine release syndrome (CRS) or neurotoxicity of any grade; and / or At least 45% or at least about 45% of the subjects treated according to the method do not exhibit the onset of CRS earlier than 3 days after the start of administration and / or do not exhibit the onset of neurotoxicity earlier than 5 days after the start of administration; and / or The median onset of neurotoxicity among subjects treated according to the method is at or after the median peak of CRS or the median time to resolution of CRS in subjects treated according to the method, and / or the median onset of neurotoxicity among subjects treated according to the method is greater than 8 days or about 8 days. The method of any one of 1001 to 1101 of the present invention. [The present invention 1103] At least 50% of the subjects treated according to the method achieve a complete response (CR); At least 70% of the subjects treated according to the method achieve an objective response (OR); and More than 50% or about more than 50% of the subjects treated according to the method do not show any grade of cytokine release syndrome (CRS) or neurotoxicity; and More than 80% or about more than 80% of the subjects treated according to the method do not show grade 3 or higher cytokine release syndrome (CRS) and / or do not show grade 3 or higher neurotoxicity. The method of any one of 1001 to 1102 of the present invention. [The present invention 1104] More than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% or about more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the subjects treated according to the method show an improvement of 10 points or more in the overall health status of the European Organization for Research and Treatment Core Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30) compared to the score before treatment or 1 month after treatment at 6 months or 12 months after administration; and / or More than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% or about more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the subjects treated according to the method show an improvement of 10 points or more in the physical function of the EORTC QLQ-C30 compared to the score before treatment or 1 month after treatment at 6 months or 12 months after administration; and / or more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the subjects treated according to the method, or about more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% show an improvement of 10 points or more in the EORTC QLQ-C30 in fatigue at 6 or 12 months after administration compared to the score before treatment or 1 month after treatment; and / or more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the subjects treated according to the method, or about more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% show an improvement of 10 points or more in the EORTC QLQ-C30 in pain at 6 or 12 months after administration compared to the score before treatment or 1 month after treatment; and / or more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the subjects treated according to the method, or about more than 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% show an improvement of 10 points or more in the EORTC QLQ-C30 in pain at 6 or 12 months after administration compared to the score before treatment or 1 month after treatment Any method of the present invention 1001 to 1103 [The present invention 1105] The average 5-level EuroQol-5D (EQ-5D-5L) score among the subjects treated according to the method is the same or higher at 6 or 12 months after administration compared to the score before treatment or 1 month after treatment; and / or The average EuroQol general visual analog scale (EQ-VAS) score among the subjects treated according to the method is the same or higher at 6 or 12 months after administration compared to the score before treatment or 1 month after treatment Any method of the present invention 1001 to 1104 [The present invention 1106] The CAR is an extracellular antigen-binding domain specific for an antigen, a transmembrane domain, a cytoplasmic signaling domain derived from a co-stimulatory molecule which is optionally 4-1BB, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule which is optionally CD3 zeta comprising; The CAR is, in order An extracellular antigen-binding domain specific for an antigen, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule comprising; or said CAR being an extracellular antigen recognition domain that specifically binds to an antigen, an intracellular signaling domain comprising a CD3-zeta (CD3ζ) chain, and a costimulatory signaling region that is a signaling domain of 4-1BB comprising, any method of the present invention from 1001 to 1105. [The present invention 1107] said CAR being an extracellular antigen-binding domain specific for CD19, a transmembrane domain, a cytoplasmic signaling domain derived from 4-1BB, and a cytoplasmic signaling domain derived from CD3 zeta comprising, any method of the present invention from 1001 to 1106. [The present invention 1108] The method of the present invention 1107, wherein the antigen-binding domain is an scFv. [The present invention 1109] said scFv being the amino acid sequence of RASQDISKYLN (SEQ ID NO: 35), the amino acid sequence of SRLHSGV (SEQ ID NO: 36), and / or the amino acid sequence of GNTLPYTFG (SEQ ID NO: 37), and / or the amino acid sequence of DYGVS (SEQ ID NO: 38), TIFF0007695882000003.tif4128 the amino acid sequence of, and / or the amino acid sequence of YAMDYWG (SEQ ID NO: 40) comprising, or said scFv being the variable heavy chain region of FMC63 and the variable light chain region of FMC63, and / or comprising the CDRL1 sequence of FMC63, the CDRL2 sequence of FMC63, the CDRL3 sequence of FMC63, the CDRH1 sequence of FMC63, the CDRH2 sequence of FMC63, and the CDRH3 sequence of FMC63, or binding to the same epitope as any of the foregoing or competing therewith for binding, and, optionally, said scFv being, in order, V H and optionally a linker comprising SEQ ID NO: 24, and V L and comprising, and / or said scFv comprising a flexible linker and / or comprising the amino acid sequence shown as SEQ ID NO: 43, The method of the present invention 1108. [The present invention 1110] The method of the present invention 1108 or the present invention 1109, wherein the scFv comprises the variable heavy chain region of FMC63 and the variable light chain region of FMC63. [The present invention 1111] The method according to any one of aspects 1106 to 1110 of the present invention, wherein the co-stimulatory signaling region is the signaling domain of 4-1BB. [Aspect 1112 of the present invention] The method according to any one of aspects 1106 to 1111 of the present invention, wherein the co-stimulatory domain comprises SEQ ID NO: 12 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto. [Aspect 1113 of the present invention] The method according to any one of aspects 1106 to 1112 of the present invention, wherein the primary signaling domain is the CD3 zeta signaling domain. [Aspect 1114 of the present invention] The method according to any one of aspects 1106 to 1113 of the present invention, wherein the primary signaling domain comprises SEQ ID NO: 13, 14, or 15 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto. [Aspect 1115 of the present invention] The method according to any one of aspects 1106 to 1114 of the present invention, wherein the CAR further comprises a spacer between the transmembrane domain and the scFv. [Aspect 1116 of the present invention] The method of aspect 1115 of the present invention, wherein the spacer is a polypeptide spacer comprising all or part of an immunoglobulin hinge or a modified version thereof, optionally an IgG4 hinge or a modified version thereof, or consisting of the foregoing. [Aspect 1117 of the present invention] The method of aspect 1115 or aspect 1116 of the present invention, wherein the spacer is 12 amino acids in length or about 12 amino acids in length. [Aspect 1118 of the present invention] The spacer has or consists of the sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, or a variant of any of the foregoing having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto; and / or The spacer comprises or consists of the formula X 1 PPX 2 P, wherein in the sequence, X 1is glycine, cysteine, or arginine, and X 2 which is cysteine or threonine, any of the methods of the present invention from 1115 to 1117. [The present invention 1119] wherein the spacer is (a) comprises all or a part of an immunoglobulin hinge or a modified version thereof or consists thereof, or contains 15 or fewer amino acids and does not contain the extracellular region of CD28 or CD8 extracellular region, (b) comprises all or a part of an immunoglobulin hinge, optionally an IgG4 hinge, or a modified version thereof or consists thereof, and / or contains 15 or fewer amino acids and does not contain the extracellular region of CD28 or CD8 extracellular region, or (c) is 12 amino acids in length or about 12 amino acids in length, and / or comprises all or a part of an immunoglobulin hinge, optionally IgG4, or a modified version thereof or consists thereof; or (d) the sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, or a sequence encoded thereby, or having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity thereto Any of the foregoing variants or consisting thereof, or (e) formula X 1 PPX 2 containing or consisting of P, in the sequence, X 1 is glycine, cysteine, or arginine, X 2 is cysteine or threonine, a polypeptide spacer ; and / or wherein the co-stimulatory domain is SEQ ID NO: 12 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity thereto ; and / or wherein the primary signaling domain is SEQ ID NO: 13, 14, or 15 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity thereto ; and / or wherein the scFv is The amino acid sequence of RASQDISKYLN (SEQ ID NO: 35), the amino acid sequence of SRLHSGV (SEQ ID NO: 36), and / or the amino acid sequence of GNTLPYTFG (SEQ ID NO: 37), and / or the amino acid sequence of DYGVS (SEQ ID NO: 38), TIFF0007695882000004.tif4128 the amino acid sequence of, and / or the amino acid sequence of YAMDYWG (SEQ ID NO: 40), or wherein the scFv comprises the variable heavy chain region of FMC63 and the variable light chain region of FMC63, and / or comprises the CDRL1 sequence of FMC63, the CDRL2 sequence of FMC63, the CDRL3 sequence of FMC63, the CDRH1 sequence of FMC63, the CDRH2 sequence of FMC63, and the CDRH3 sequence of FMC63, or binds to the same epitope as any of the foregoing or competes therewith for binding, and optionally, the scFv comprises, in order, V H and, optionally, a linker comprising SEQ ID NO: 24, and V L and, and / or the scFv comprises a flexible linker and / or comprises the amino acid sequence shown as SEQ ID NO: 43, any method of any one of 1115 to 1118 of the present invention. [Invention 1120] the spacer is a polypeptide spacer comprising the sequence of SEQ ID NO: 1; the co-stimulatory domain comprises SEQ ID NO: 12; the primary signaling domain comprises SEQ ID NO: 13, 14, or 15; the antigen-binding domain comprises an scFv comprising the variable heavy chain region of FMC63 and the variable light chain region of FMC63, any method of any one of 1115 to 1119 of the present invention. [Invention 1121] Any method of any one of 1001 to 1120 of the present invention, wherein the dose of the cells is administered parenterally, optionally intravenously. [Invention 1122] Any method of any one of 1001 to 1121 of the present invention, wherein the subject is a human subject. [Invention 1123] A composition comprising genetically engineered cells expressing a recombinant receptor; and optionally, an article of manufacture comprising instructions for administering a dose of the cells according to any method of any one of 1001 to 1122 of the present invention. [Invention 1124] A method for evaluating the risk of developing toxicity after cell therapy, comprising the following steps: (a) evaluating one or more parameters in a subject, wherein The one or more parameters are selected from the level, amount, or concentration of LDH, ferritin, or C-reactive protein (CRP) in a biological sample from a subject, or are the sum of product dimensions (SPD) of tumors in a subject; The subject is a candidate for treatment with cell therapy, the cell therapy comprising a dose of genetically engineered cells that express a recombinant receptor; and The evaluating step is performed before administering the cell therapy, and / or the biological sample or tumor does not contain the recombinant receptor and / or the engineered cells, step; and (b) a step of determining whether the subject is at risk of toxicity, wherein if one or more parameters are above a threshold level, the subject is at risk of toxicity, and if one or more parameters are below the threshold level, the subject is not at risk of toxicity, (i) the parameter is ferritin and the threshold level is above 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter, or 8000 nanograms / milliliter, or is above about 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter, or 8000 nanograms / milliliter; and / or (ii) the parameter is CRP and the threshold level is above 5 milligrams / liter, 10 milligrams / liter, 15 milligrams / liter, 20 milligrams / liter, 25 milligrams / liter, 30 milligrams / liter, 40 milligrams / liter, or 50 milligrams / liter, or is above about 5 milligrams / liter, 10 milligrams / liter, 15 milligrams / liter, 20 milligrams / liter, 25 milligrams / liter, 30 milligrams / liter, 40 milligrams / liter, or 50 milligrams / liter, step. [Invention 1125] A method of identifying a subject, comprising the following steps: (a) A step of evaluating one or more parameters in a subject, where the one or more parameters are selected from the levels, amounts, or concentrations of LDH, ferritin, or C-reactive protein (CRP) in a biological sample derived from the subject, or the sum of product dimensions (SPD) of tumors in the subject; the subject is a candidate for treatment with cell therapy, and the cell therapy involves a dose of genetically engineered cells that express a recombinant receptor; and the evaluating step is performed before the cell therapy is administered, and / or the biological sample or tumor does not contain the recombinant receptor and / or the engineered cells, step; and (b) A step of identifying a subject at risk of developing toxicity after receiving cell therapy, where if one or more parameters are above a threshold level, the subject is at risk of toxicity, and if one or more parameters are below the threshold level, the subject is not at risk of toxicity, (i) the parameter is ferritin, and the threshold level is above 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter, or 8000 nanograms / milliliter, or is above about 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter, or 8000 nanograms / milliliter; and / or (ii) The parameter is CRP, and the threshold level is above 5 milligrams per liter, 10 milligrams per liter, 15 milligrams per liter, 20 milligrams per liter, 25 milligrams per liter, 30 milligrams per liter, 40 milligrams per liter, or 50 milligrams per liter, or above about 5 milligrams per liter, 10 milligrams per liter, 15 milligrams per liter, 20 milligrams per liter, 25 milligrams per liter, 30 milligrams per liter, 40 milligrams per liter, or 50 milligrams per liter, step. [Invention 1126] A method of treatment comprising the following steps: (a) Evaluating one or more parameters in a subject, wherein the one or more parameters are selected from the level, amount, or concentration of LDH, ferritin, or C-reactive protein (CRP) in a biological sample from the subject, or the sum of the product dimensions of tumors (SPD) in the subject; the subject is a candidate for treatment with cell therapy, the cell therapy comprising a dose of genetically engineered cells expressing a recombinant receptor; and the evaluating step is performed before administering the cell therapy, and / or the biological sample or tumor does not contain the recombinant receptor and / or the engineered cells, step; and (b) Determining whether the subject is at risk of toxicity, wherein if one or more parameters are above the threshold level, the subject is at risk of toxicity, and if one or more parameters are below the threshold level, the subject is not at risk of toxicity, (i) the parameter is ferritin and the threshold level is above 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter, or 8000 nanograms / milliliter, or about above 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter, or 8000 nanograms / milliliter; and / or (ii) the parameter is CRP and the threshold level is above 5 milligrams / liter, 10 milligrams / liter, 15 milligrams / liter, 20 milligrams / liter, 25 milligrams / liter, 30 milligrams / liter, 40 milligrams / liter, or 50 milligrams / liter, or about above 5 milligrams / liter, 10 milligrams / liter, 15 milligrams / liter, 20 milligrams / liter, 25 milligrams / liter, 30 milligrams / liter, 40 milligrams / liter, or 50 milligrams / liter, stage; and (c) after the evaluation or based on the result of the evaluation, subjecting the subject to cell therapy and optionally an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity step. [Invention 1127] The method according to any one of Inventions 1124 to 1126, wherein the parameter is ferritin and the threshold level is 5000 nanograms / milliliter. [Invention 1128] The method according to any one of Inventions 1124 to 1127, wherein the parameter is CRP and the threshold level is 10 milligrams / liter. [Invention 1129] The method according to any one of Inventions 1124 to 1128, wherein the one or more parameters are ferritin and CRP, the threshold level for ferritin is 5000 nanograms / milliliter, and the threshold level for CRP is 10 milligrams / liter. [Invention 1130] The method according to any one of claims 1124 to 1129 of the present invention, wherein the biological sample is a blood or plasma sample. [The present invention 1131] The method according to any one of claims 1124 to 1130 of the present invention, wherein the level, amount, or concentration of ferritin or CRP is measured before treatment, before apheresis, or before cell product production. [The present invention 1132] A method for assessing the risk of developing toxicity after cell therapy, comprising the following steps: (a) assessing the peak concentration of genetically engineered cells expressing a recombinant receptor in a biological sample from a subject who has previously received cell therapy comprising the genetically engineered cells; and (b) determining whether the subject is at risk of toxicity, wherein if the peak concentration of the genetically engineered cells is above a threshold level, the subject is at risk of toxicity, and if the peak concentration of the genetically engineered cells is below the threshold level, the subject is not at risk of toxicity, wherein the threshold level is above 300 cells / microliter, 400 cells / microliter, 500 cells / microliter, 600 cells / microliter, 700 cells / microliter, 800 cells / microliter, 900 cells / microliter, or 1000 cells / microliter, or about 300 cells / microliter, 400 cells / microliter, 500 cells / microliter, 600 cells / microliter, 700 cells / microliter, 800 cells / microliter, 900 cells / microliter, or 1000 cells / microliter. step. [The present invention 1133] A method for identifying a subject, comprising the following steps: (a) assessing the peak concentration of genetically engineered cells expressing a recombinant receptor in a biological sample from a subject who has previously received cell therapy comprising the genetically engineered cells; and (b) identifying a subject at risk of developing toxicity after cell therapy, wherein if the peak concentration of the genetically engineered cells is above a threshold level, the subject is at risk of toxicity, and if the peak concentration of the genetically engineered cells is below the threshold level, the subject is not at risk of toxicity. The threshold level is above 300 cells / microliter, 400 cells / microliter, 500 cells / microliter, 600 cells / microliter, 700 cells / microliter, 800 cells / microliter, 900 cells / microliter, or 1000 cells / microliter, or is above about 300 cells / microliter, 400 cells / microliter, 500 cells / microliter, 600 cells / microliter, 700 cells / microliter, 800 cells / microliter, 900 cells / microliter, or 1000 cells / microliter, step. [Invention 1134] A method of treatment comprising the following steps: (a) Evaluating the peak concentration of genetically engineered cells expressing a recombinant receptor in a biological sample from a subject previously treated with a cell therapy comprising genetically engineered cells; and (b) Determining whether the subject is at risk of toxicity, wherein if the peak concentration of the genetically engineered cells is above the threshold level, the subject is at risk of toxicity, and if the peak concentration of the genetically engineered cells is below the threshold level, the subject is not at risk of toxicity, wherein the threshold level is above 300 cells / microliter, 400 cells / microliter, 500 cells / microliter, 600 cells / microliter, 700 cells / microliter, 800 cells / microliter, 900 cells / microliter, or 1000 cells / microliter, or is above about 300 cells / microliter, 400 cells / microliter, 500 cells / microliter, 600 cells / microliter, 700 cells / microliter, 800 cells / microliter, 900 cells / microliter, or 1000 cells / microliter, step; and (c) Administering to the subject, after or based on the evaluation, a cell therapy and optionally an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of toxicity or the risk of onset of toxicity step. [Invention 1135] The method according to any one of Inventions 1132 to 1134, wherein the threshold level is 500 cells / microliter. [Invention 1136] If the subject is identified as having received cell therapy and being at risk of developing toxicity, the method according to any one of 1124 to 1135 of the present invention further includes a step of monitoring the subject for symptoms of toxicity. [1137 of the present invention] The method according to any one of 1124 to 1136 of the present invention, wherein the toxicity is neurotoxicity or cytokine release syndrome (CRS). [1138 of the present invention] The method according to any one of 1124 to 1137 of the present invention, wherein the toxicity is grade 1 or higher neurotoxicity or CRS. [1139 of the present invention] The method according to any one of 1124 to 1138 of the present invention, wherein the toxicity is grade 1 or higher neurotoxicity. [1140 of the present invention] The method according to any one of 1124 to 1139 of the present invention, wherein the toxicity is severe neurotoxicity or grade 2 or higher neurotoxicity, grade 3 or higher neurotoxicity, or grade 4 or higher neurotoxicity. [1141 of the present invention] The method according to any one of 1124 to 1140 of the present invention, wherein the toxicity is severe neurotoxicity or grade 3 or higher neurotoxicity. [1142 of the present invention] The method according to any one of 1124 to 1138 of the present invention, wherein the toxicity is grade 1 or higher CRS. [1143 of the present invention] The method according to any one of 1124 to 1138 and 1142 of the present invention, wherein the toxicity is severe CRS or grade 2 or higher CRS, grade 3 or higher CRS, or grade 4 or higher CRS. [1144 of the present invention] The method according to any one of 1124 to 1138, 1142, and 1143 of the present invention, wherein the toxicity is severe CRS or grade 3 or higher CRS. [1145 of the present invention] If the subject is identified as having a risk of developing toxicity, the method according to any one of 1124 to 1144 of the present invention comprises administering to the subject: (a) (1) An agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of toxicity or the risk of onset of toxicity, and (2) A cell therapy, wherein the administration of the agent should be performed (i) before the start of, (ii) within 1, 2, or 3 days of the start of, (iii) concurrently with, and / or (iv) at the first fever after the start of the cell therapy administered to the subject; and / or (b) At a reduced dosage or after administration of cell therapy, a cell therapy that is not associated with the risk of developing toxicity or severe toxicity, or is not associated with the risk of developing toxicity or severe toxicity in the majority of subjects and / or in the majority of subjects having or suspected of having a disease or condition that the subject has; and / or (c) Administration of cell therapy to a subject in a hospital inpatient setting and / or involving hospitalization of the subject for one or more days, optionally, the cell therapy being otherwise administered to the subject as an outpatient or without hospitalization for one or more days. [The present invention 1146] The method of the present invention 1145, wherein the agent or other treatment is an anti-IL-6 antibody or an anti-IL-6 receptor antibody. [The present invention 1147] The method of the present invention 1146, wherein the agent or other treatment is an agent selected from or comprising tocilizumab, siltuximab, clazakizumab, sarilumab, olokizumab (CDP6038), elsilimomab, ALD518 / BMS-945429, silkumab (CNTO 136), CPSI-2634, ARGX-109, FE301, and FM101. [The present invention 1148] The method of the present invention 1146 or 1147, wherein the agent or other treatment is tocilizumab. [The present invention 1149] The method of the present invention 1148, wherein the agent or other treatment is or comprises one or more steroids. [The present invention 1150] The method of the present invention 1149, wherein the steroid is dexamethasone or methylprednisolone. [The present invention 1151] The method of the present invention 1149 or 1150, wherein the steroid is dexamethasone. [The present invention 1152] The recombinant receptor is An antigen that specifically binds to an antigen expressed in cells in the environment of a lesion associated with a disease or condition or associated with a disease or condition The method according to any one of the present inventions 1124 to 1151. [The present invention 1153] The method according to any one of the present inventions 1124 to 1152, wherein the disease or condition is cancer. [The present invention 1154] The method according to any one of the present inventions 1124 to 1153, wherein the disease or condition is myeloma, leukemia, or lymphoma. [The present invention 1155] The method according to any one of 1124 to 1054 of the present invention, wherein the disease or condition is a B-cell malignancy and / or acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), or large cell type B-cell lymphoma. [The present invention 1156] The method according to any one of 1124 to 1155 of the present invention, wherein the disease or condition is large cell type B-cell lymphoma. [The present invention 1157] The method according to 1156 of the present invention, wherein the large cell type B-cell lymphoma is selected from aggressive non-Hodgkin lymphoma (NHL), diffuse large cell type B-cell lymphoma (DLBCL), optionally DLBCL NOS (de novo or transformed from indolent), high-grade B-cell lymphoma (HGBCL), double / triple hit lymphoma, primary mediastinal large cell type B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), transformed follicular lymphoma (tFL), and / or follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B). [The present invention 1158] The method according to 1156 or 1157 of the present invention, wherein the large cell type B-cell lymphoma is diffuse large cell type B-cell lymphoma (DLBCL). [The present invention 1159] The method according to 1156 or 1157 of the present invention, wherein the large cell type B-cell lymphoma is follicular lymphoma (FL). [The present invention 1160] The method according to 1159 of the present invention, wherein the FL is associated with co-expression of CD10, BCL6, and BCL2 in the follicle, and / or rearrangement of t(14;18) / (q32;q21)(IGH-BCL2) and / or BCL6. [The present invention 1161] The method according to 1156 or 1157 of the present invention, wherein the large cell type B-cell lymphoma is mantle cell lymphoma (MCL). [The present invention 1162] The method according to any one of 1036 to 1049 of the present invention, wherein the recombinant receptor binds to a target antigen, and the target antigen is a B-cell antigen, optionally CD19. [The present invention 1163] The method according to any one of 1124 to 1162 of the present invention, wherein the recombinant receptor is a chimeric antigen receptor (CAR). [The present invention 1164] The genetically engineered cell is a T cell, optionally CD4 + T cell and / or CD8 + The method according to any one of 1124 to 1163 of the present invention, comprising T cells. [The present invention 1165] Performing cell therapy is CD4 + T cells and CD8 + administering a dose of T cells, wherein each dose of T cells specifically binds to an antigen expressed by a disease or condition or its cells or tissues and / or is a recombinant receptor associated with a disease or condition and the administration comprises administering a plurality of separate compositions, the plurality of separate compositions comprising a first composition comprising CD8 + T cells and a second composition comprising CD4 + T cells, according to any of the methods of the invention from 1124 to 1163. [Invention 1166] The method of invention 1165, wherein the initiation of administration of the first composition is carried out before the initiation of administration of the second composition. [Invention 1167] The method of invention 1165 or invention 1166, wherein the administration of the first composition and the administration of the second composition are carried out at intervals of 48 hours or less. [Invention 1168] The method according to any of inventions 1165 to 1167, wherein the administration of the first composition and the administration of the second composition are carried out at intervals of 36 hours or less, 24 hours or less, 12 hours or less, 6 hours or less, 4 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less. [Invention 1169] The recombinant receptor comprised by CD4 + T cells and / or the recombinant receptor comprised by CD8 + T cells is or comprises the same recombinant receptor, and / or CD4 + T cells and / or CD8 + T cells are genetically engineered to express the same recombinant receptor, according to any of the methods of the invention from 1124 to 1168. [Invention 1170] The doses of CD4 + T cells and CD8 + T cells are in a defined ratio of 1:1 or approximately 1:1, or approximately 1:3 to approximately 3:1, of CD4 + T cells expressing a receptor:CD8 + T cells expressing a recombinant receptor, and / or CD4 + T cells:CD8 + T cells and / or the CD4 + T cells comprising a recombinant receptor in one of the first composition and the second composition, and the CD8 + T cells comprising a recombinant receptor in the other of the first composition and the second composition are in a defined ratio of 1:1 or approximately 1:1, or approximately 1:3 to approximately 3:1 and / or the CD4 + T cells comprising a receptor and the CD8 T cells comprising a recombinant receptor administered in the first composition and the second composition + T cells are present in a defined ratio, which is 1:1 or approximately 1:1, or approximately 1:3 to approximately 3:1. Any method of the present invention from 1124 to 1169. [The present invention 1171] Any method of the present invention from 1124 to 1170, wherein the defined ratio is 1:1 or approximately 1:1. [The present invention 1172] CD4 + T cells and CD8 + The dosage of T cells is 1×10 7 cells or about 1×10 7 cells to 2×10 8 cells or about 2×10 8 total recombinant receptor-expressing T cells (including both end values); 2.5×10 7 cells or about 2.5×10 7 cells to 1.5×10 8 cells or about 1.5×10 8total recombinant receptor-expressing T cells (including both end values); 5×10 7 cells or about 5×10 7 cells to 1×10 8 cells or about 1×10 8 total recombinant receptor-expressing T cells (including both end values); 5×10 7 cells or about 5×10 7 total recombinant receptor-expressing T cells; 1×10 8 cells or about 1×10 8 total recombinant receptor-expressing T cells; or 1.5×10 8 cells or about 1.5×10 8 total recombinant receptor-expressing T cells Any method of the present invention from 1124 to 1171, comprising. [The present invention 1173] CD4 + T cells and CD8 + The dosage of T cells is 1×10 7 cells or about 1×10 7 cells to 1×10 8 cells or about 1×10 8 recombinant receptor-expressing CD8 + T cells (including both end values); 1.25×10 7 cells or about 1.25×10 7 cells to 7.5×10 7 cells or about 7.5×10 7 recombinant receptor-expressing CD8 + T cells (including both end values); 2.5×10 7 cells or about 2.5×10 7 cells to 5×10 7 cells or about 5×10 7 recombinant receptor-expressing CD8 + T cells (including both end values); 2.5×107 cells or about 2.5×10 7 recombinant receptor-expressing CD8 + T cells; 5×10 7 cells or about 5×10 7 recombinant receptor-expressing CD8 + T cells; or 7.5×10 7 cells or about 7.5×10 7 recombinant receptor-expressing CD8 + T cells Any method of the present invention from 1124 to 1172, comprising. [The present invention 1174] Any method of the present invention from 1124 to 1173, wherein the T cells are primary T cells obtained from a subject or are autologous to the subject. [The present invention 1175] Any method of the present invention from 1124 to 1174, wherein the subject is a human subject. [The present invention 1176] A composition comprising genetically engineered cells that express a recombinant receptor, and optionally, an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of onset of toxicity; and, an article of manufacture comprising instructions for assessing the risk of developing toxicity, identifying a subject, or treating a subject according to any of the methods of the present invention from 1124 to 1175.

Brief Description of the Drawings

[0109]

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Mode for Carrying Out the Invention

[0110] Detailed Description I. Methods and Uses of Cell Therapy Using Genetically Engineered Cells Methods and uses of engineered cells (e.g., T cells) and / or their compositions for treating a subject having a disease or condition (generally cancer or tumor (e.g., leukemia or lymphoma, most specifically B cell malignancy or non-Hodgkin lymphoma (NHL)) or including the same) are provided. In certain embodiments of any of the provided methods, the T cells are engineered with a chimeric antigen receptor (CAR) against CD19. In some aspects, the disease or condition is B cell lymphoma. In some aspects, the disease or condition is large cell type B cell lymphoma. In some aspects, the disease or condition is diffuse large cell type B cell lymphoma (DLBCL) or a subtype thereof. In some aspects, the methods and uses result in or provide improved efficacy and / or more sustained efficacy or effectiveness and / or 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 method is advantageous by administering a specified number or relative number of engineered cells, administering a particular type of cell in a defined ratio, treating a particular patient population, e.g., a patient population having a particular risk profile, disease stage and / or treatment history and / or a combination thereof.

[0111] Also provided are methods that include evaluating specific parameters that may correlate with the manifestation of toxicity, such as the expression of specific biomarkers or analytes, and treatments for preventing and / or alleviating toxicity, such as methods for interventional therapy. Also provided are methods involving assessing the outcome after immunotherapy and / or cell therapy, such as treatment outcome, such as complete response (CR) or partial response (PR) with durable response, such as durable response lasting at least 3 months, 6 months, or longer in some cases; or safety outcome, such as the manifestation of toxicity, such as specific parameters that may correlate with neurotoxicity or CRS, such as the expression of specific biomarkers or analytes. Also provided are methods for assessing the likelihood of response and / or the likelihood of toxicity risk based on the evaluation of parameters such as biomarker expression or analytes. Also provided are compositions for use in cell therapy. Also provided are manufactured articles and kits for use, for example, in the methods provided herein. In some embodiments, the manufactured articles and kits also include instructions for use according to the methods provided herein.

[0112] In some embodiments, the methods and uses include administering to a subject cells that express a genetically modified (recombinant) cell surface receptor, generally a chimeric receptor, such as a chimeric antigen receptor (CAR), that recognizes an antigen expressed by leukemia or lymphoma and / or the cell type from which it is derived, an antigen related thereto, and / or an antigen specific thereto. The cells are generally administered in a composition formulated for administration; the methods generally involve administering one or more doses of the cells to the subject, the dose(s) being capable of comprising a specified number or relative number of cells or engineered cells and / or two or more subtypes in a defined ratio or composition in the composition (e.g., CD4 T cells and CD8 T cells).

[0113] In some embodiments, the cells, populations, and compositions are administered to a subject having a particular disease or condition to be treated, e.g., by adoptive cell therapy, e.g., adoptive T cell therapy. In some embodiments, the method involves treating a subject having lymphoma or leukemia, or a B cell malignancy, e.g., large cell type B cell lymphoma or non-Hodgkin lymphoma (NHL), with a dose of antigen receptor-expressing cells (e.g., CAR-expressing cells).

[0114] In some embodiments, the provided methods involve treating subjects in a particular group or subset, such as subjects identified as having a high-risk disease, such as high-risk NHL or high-risk large cell type B-cell lymphoma. In some aspects, the methods treat subjects having B-cell non-Hodgkin lymphoma (NHL) in an aggressive and / or poor-prognosis form, such as NHL that is refractory or resistant (R / R) to standard treatment and / or has a poor prognosis. In some aspects, the methods treat subjects having large cell type B-cell lymphoma that is refractory or resistant (R / R) to standard treatment. In some cases, the overall response rate (ORR; also known as objective response rate in some cases) to available treatment, to standard of care (SOC), or to reference treatment indicated for the disease and / or patient population is less than 40%, and / or the complete response (CR; also known as complete remission in some cases) is less than 20%. In some embodiments, in chemotherapy-resistant DLBCL, the ORR with reference treatment or treatment with available or standard treatment is about 26% and the CR rate is about 8% (Crump et al. Outcomes in refractory aggressive diffuse large B-cell lymphoma (DLBCL): Results from the international SCHOLAR study. ASCO 2016 [Abstract 7516]). In some aspects, the provided methods, compositions, uses, and articles of manufacture provide improved and superior responses relative to available treatment. In some embodiments, the improved or excellent response is relative to the current standard of care (SOC).In some embodiments, the current SOC for the treatment of B-cell malignancies, such as B-cell NHL, non-Hodgkin lymphoma (NHL), is either up to 3 cycles of rituximab, dexamethasone, cytarabine (AraC) and cisplatin (R-DHAP), rituximab, ifosfamide, carboplatin and etoposide (R-ICE), or rituximab, gemcitabine, dexamethasone and cisplatin (R-GDP), followed by response-adapted carmustine, etoposide, cytarabine and melphalan (BEAM) high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT) (see, e.g., Crump et al., J Clin Oncol. 2014; 32(31):3490-6; Gisselbrecht, et al., J Clin Oncol. 2010;28(27):4184-90; van Imhoff et al., J Clin Oncol. 2017;35(5):544-51).

[0115] Large B-cell lymphoma (LBCL) is the most common subtype of non-Hodgkin lymphoma (NHL). With current frontline treatment, approximately 60% of patients are cured; however, approximately 30% of patients relapse and approximately 10% are resistant to frontline treatment. Salvage chemotherapy (CT) is primarily included in the treatment options for patients with relapsed / refractory (R / R) disease, particularly as third-line or greater (3L+) treatment. Two chimeric antigen receptor (CAR) T-cell products and an antibody-drug conjugate have been approved as third-line treatment. Unmet medical needs within second-line and greater (2L+) or 3L+ treatment of R / R LBCL were identified based on a systematic literature review (SLR) of the evidence regarding the clinical outcomes of LBCL patients, including the new therapies described above.

[0116] Based on an illustrative SLR conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and European Union Health Technology Assessment requirements to screen 8,683 database records and additional sources, 103 publications were identified that covered 78 unique studies. In this review, randomized and non-randomized / observational studies within relapsed / refractory large B-cell lymphoma (R / R LBCL) were identified, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma grade 3B (FL3B), primary mediastinal large B-cell lymphoma (PMBCL), DLBCL transformed from indolent lymphoma, and R / R DLBCL involving secondary central nervous system (SCNS). The sources reviewed included EMBASE, MEDLINE, The Cochrane Library, and clinical conferences (ASCO, ESMO, EHA, ASH, ICML, AACR, and EORTC). An illustrative schematic diagram representing the SLR is depicted in Figure 47. The identified studies were characterized by treatment regimens and R / R LBCL subtypes. The observed OS, PFS, DOR, OR, and safety from the identified studies were described. The disease subtypes, eligibility criteria for subjects, and follow-up periods differed particularly among the studies.

[0117] Based on the exemplary SLR, in the 3L+ cohort, survival outcomes were reported in 11 salvage CT and 2 CAR T cell therapy studies. In salvage CT, the ORR reported across the studies ranged from 0% to 54%, while the CR ranged from 5.6% to 31%. The median OS (mOS) ranged from 3 to 9 months, and in one outlier study, mOS was reported at 20 months. The median PFS (mPFS) reported in the salvage CT studies ranged from 2 to 6 months. Among CAR T cell therapies, subjects treated with anti-CD19 CAR T cell therapy (n = 101) reported a CR rate of 58%, and the median DOR (mDOR) was 11.1 months after a median follow-up of 27.1 months. The mPFS was 5.9 months, and mOS was not reached. At a median follow-up of 19.3 months, subjects treated with another anti-CD19 CAR T cell therapy (n = 115) had a CR of 40%, but did not reach mDOR. The mOS was 11.1 months in all infused patients.

[0118] In the 2L+ transplant-eligible cohort (36 studies), subjects who received high-dose CT + HSCT achieved mOS between 9 months and 5 years. In the transplant-ineligible cohort, 16 studies reported mOS between 3 and 20 months. In studies with a mix of transplant-eligible and ineligible cohorts (30 studies), mOS of 1 to 17 months was reported.

[0119] In several studies with limited sample sizes, outcomes of LBCL subtypes (e.g., PMBCL, SCNS lymphoma, DLBCL transformed from non-FL indolent lymphoma, FL3B) were found to be reported. In the 3L+ setting, one study reported not reaching mOS after a median of 6.6 months. In the 2L+ setting, 4 studies reported mPFS and mOS outcomes in the ranges of 2 to 9 months and 10 to 16 months, respectively.

[0120] In studies evaluating the safety of salvage chemotherapy in R / R LBCL, neutropenia, leukopenia, thrombocytopenia, and infections were the most commonly reported adverse events (AEs), with neutropenia being the most reported. Among three studies reporting the safety outcomes of CAR T cell therapy, the data showed that hematological AEs (presumably related to lymphodepleting CT), cytokine release syndrome, and neurotoxicity were the most reported.

[0121] Based on exemplary studies, less than 50% of patients with relapsed / refractory large B-cell lymphoma (LBCL) achieve a response to third or subsequent treatment (Van Den Neste et al. Bone Marrow Transplant. 2016;51:51-7; Gonzalez-Barca E et al. Bone Marrow Transplant 2019). High-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) remains the standard of care at first relapse in transplant-eligible patients with chemotherapy-sensitive disease (National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. March 6, 2019), but most patients will not be cured with this approach (Van Den Neste et al. Bone Marrow Transplant. 2016;51:51-7; Gonzalez-Barca E et al. Bone Marrow Transplant 2019, National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. March 6, 2019, Gisselbrecht C et al. J Clin Oncol. 2010; 28:4184-90). In several studies, the outcomes of subjects with chemotherapy-resistant disease have been poor, with a complete response (CR) rate of 7% and an overall survival (OS) of 6 months to conventional treatment. (Crump et al. Blood. 2017;130:1800-8). Adverse outcomes were associated with older age, central nervous system (CNS) involvement (Thanarajasingam et al. Br J Haematol. 2018;183:149-52; Nabhan et al. J Clin Oncol. 2018; 36:7545) and comorbidities (Pfreundschuh Blood. 2010;116:5103-10).

[0122] Certain CD19-directed CAR-T cell therapies, including axi-cel and tisagenlecleucel, are available for the treatment of B-cell lymphoma. In one exemplary study, subjects who received axi-cel achieved a CR rate (per investigator) of 54% and had a durable response (median follow-up, 15.4 months) of 40% (Neelapu et al. N Engl Med. 2017. 377;2531-44). Most subjects expressed CRS (93%) and NE (64%), with median times to onset of 2 days and 5 days, respectively, for grade 3 or higher CRS (Lee grading criteria (Lee et al. Blood. 2014;124:188-95)) and NE occurring in 13% and 28%, respectively, with 43% receiving tocilizumab (27% receiving corticosteroids). In another exemplary study, approximately one-third of patients who received tisagenlecleucel maintained a durable response at 1 year (Schuster et al. N Engl J Med. 2019. 380:45-56). Most subjects (58%) expressed CRS and 21% had NE. Grade 3 or higher CRS (Penn grading criteria, Porter et al. J Hematol Oncol. 2018;11:35) and NE were reported in 22% and 12% of patients, respectively (Schuster et al. N Engl J Med. 2019. 380:45-56). Additionally, these therapies do not include the treatment of certain high-risk patients, including those with PMBCL, DLBCL transformed from indolent lymphoma other than FL, patients with FL3B, and those with certain high-risk features such as secondary CNS lymphoma, moderate renal / heart comorbidities, and the need for bridge therapy.

[0123] From the current evidence-based SLR and investigations, there is an important and unmet high need for additional treatment options that provide favorable benefit / risk and durable responses, which are not met by the available treatments for subjects with 2L+ and 3L+ LBCL. Furthermore, limited data were available for the rarer LBCL subtypes. These findings have revealed an important treatment gap for R / R LBCL that needs to be addressed, and the need for improvement of existing treatments. Aspects are provided herein that can meet such needs.

[0124] In some aspects, the methods, uses, and articles of manufacture are used in the treatment of a subject involving, or involving the selection or identification of, a particular group or subset of subjects, based on, for example, a particular type of disease, diagnostic criteria, previous treatment, and / or response to previous treatment. In some aspects, the methods involve treating a subject who has relapsed following remission after treatment with one or more previous therapies or who has become resistant to such treatment; or a subject who is relapsed or resistant (R / R) to one or more previous therapies, such as one or more standard lines of treatment.

[0125] In some embodiments, the subject has a B cell malignancy, such as B cell lymphoma and / or non-Hodgkin lymphoma (NHL). In some embodiments, the subject has a B cell malignancy, such as large cell type B cell lymphoma, such as relapsed / refractory (R / R) large cell type B cell lymphoma. In some embodiments, the subject has large cell type B cell lymphoma, such as diffuse large cell type B cell lymphoma (DLBCL) (e.g., DLBCL of unknown specific type (NOS; de novo or transformed from indolent) or other DLBCL). In some embodiments, the subject has primary mediastinal B cell lymphoma (PMBCL) or follicular lymphoma, such as follicular lymphoma grade 3B (FL3B). In some aspects, the B cell lymphoma is, or includes, diffuse large cell type B cell lymphoma (DLBCL), follicular lymphoma or PBMCL. In some aspects, the subject has DLBCL that is DLBCL of unknown specific type (NOS). In some embodiments, the lymphoma, such as DLBCL, is de novo. In some embodiments, the lymphoma, such as DLBCL, is transformed from another indolent lymphoma. In some embodiments, the lymphoma, such as DLBCL, is transformed from follicular lymphoma (tFL). In some of any of the embodiments, the subject has follicular lymphoma (FL).

[0126] In certain embodiments, the methods provided herein are based on administering a CD19-directed CAR T cell therapy, wherein the CAR comprises a CD19-directed scFv antigen-binding domain (e.g., from FMC63). The CAR further comprises an intracellular signaling domain that includes a signaling domain from CD3 zeta, and also incorporates a 4-1BB co-stimulatory domain that has been associated with a lower incidence of CRS and NE compared to constructs that include CD28 (Lu et al. J Clin Oncol. 2018;36:3041). In some embodiments, the methods provided herein include CD8+ and CD4+ T cell subsets that are transduced and expanded separately in vitro and administered at an equal (about 1:1) target dose. In some embodiments, the total dose administered and the variability in the CD8+ CAR+ T cell dose, two parameters associated with increased toxicity in previous studies, are low (Neelapu et al. N Engl Med. 2017. 377;2531-44; Turtle et al. Sci Transl Med. 2016;8:355ra116; Hay et al. Blood. 2017;130:2295-306).

[0127] In certain embodiments, the provided methods can be used to treat specific LBCL subtypes or high-risk groups, such as elderly patients and patients with comorbidities or CNS involvement, where the available treatment options remain limited. For example, existing CAR T cell therapies are associated with severe CAR T cell-related toxicities, including cytokine release syndrome (CRS) and neurological events (NE), which can limit their application to specialized treatment centers (Yescarta Risk Evaluation and Mitigation Strategy (REMS). Gilead Pharma September 10, 2019; Kymriah Risk Evaluation and Mitigation Strategy (REMS) Novartis September 10, 2019), affecting their use in difficult-to-treat patients. CAR T cell therapies with favorable benefit / risk profiles, particularly those with high efficacy and low incidences of severe CRS and NE, may enable broader inclusion of the target subgroup and outpatient management / monitoring.

[0128] In certain embodiments, the provided method results in favorable outcomes in subjects with LBCL, including certain subjects previously excluded from treatment by other therapies, including other anti-CD19 CAR-T cell therapies. Treatment with CD19-directed CAR T cells in subjects with LBCL in the groups of subjects shown herein resulted in durable responses, including responses associated with increased in vivo CAR T cell expansion, and the CAR T cells persisted for extended periods after infusion. In some embodiments, the provided method demonstrated favorable outcomes in highly pretreated patients with aggressive high-risk diseases, including patients who were chemotherapy resistant or who required immediate treatment for disease control with bridging therapy. The findings herein support treating subjects with aggressive high-risk diseases with CD19-directed CAR T cell therapy according to the provided method. For example, PMBCL, DLBCL transformed from indolent lymphoma other than FL, subjects with FL3B, and patients with certain high-risk features such as secondary CNS lymphoma, moderate renal / heart comorbidities, and patients in need of bridging therapy can be treated according to the provided method. In some embodiments, the provided method can be used to treat highly pretreated subjects (e.g., with two, three, or more previous therapies to treat the disease). Among the subgroups that can be treated by the provided method is a subgroup of elderly subjects 65 years of age or older, including those over 75 years of age. The findings herein demonstrate that ORR and CR, including durable responses, were observed across all subgroups with a low incidence of severe CRS and NE.

[0129] In some embodiments, less than half of all subjects treated by the methods provided herein express CRS or NE. In some embodiments, the incidence of grade 3+ CRS and NE is low (2% and 10%, respectively), and no fatal CRS or NE occurred in the group of subjects treated as described in the examples. In some embodiments, the low overall incidence and severity of CRS and NE, along with their late onset (median, 5 days and 9 days, respectively), support outpatient administration / monitoring in selected subjects. In some embodiments, the safety and efficacy outcomes in subjects administered CAR T cell compositions in an outpatient setting are similar to those of the overall treated population. In some embodiments, chimeric antigen receptor (CAR) T cell therapy has generally been limited to the treatment of inpatients at academic medical centers; however, most patients in the United States with relapsed / refractory (R / R) diffuse large B cell lymphoma (DLBCL) are treated at medical centers outside of academia where outpatient delivery of cancer treatment is common. In some embodiments of any of the methods provided herein, the infusion and management of CAR T cell therapy in an outpatient setting results in improved broader utilization and access at community / non-academic centers.

[0130] In some embodiments, treatment by any of the methods provided herein results in a high durable CR rate and a low incidence of severe CRS and NE among subjects with high-risk, aggressive relapsed / refractory LBCL in this study. In some embodiments, clinically meaningful activity is observed across subgroups of subjects with unmet medical needs, including those with rare LBCL histological subtypes and poor prognostic features. In some embodiments, the low incidence and late time to onset of severe CRS and NE enable outpatient administration / monitoring. In some embodiments, the unique risk / benefit profile of any of the methods provided herein may enable inclusion of more patients and potential care settings.

[0131] In some embodiments, the method involves treating a subject having an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or 0-2. In some embodiments, the method treats DLBCL patients or a poor prognosis population of such subjects who generally have an inadequate response to treatment or a particular reference treatment, for example, DLBCL patients or a poor prognosis population of such subjects having one or more, for example two or three chromosomal translocations (e.g., DLBCL patients or a poor prognosis population of such subjects having so-called "double hit" or "triple hit" lymphomas; DLBCL patients or a poor prognosis population of such subjects having a translocation of the MYC / 8q24 locus, usually in combination with the t(14;18)(q32;q21) bcl-2 gene and / or a BCL6 / 3q27 chromosomal translocation; see, for example, Xu et al. (2013) Int J Clin Exp Pathol. 6(4):788-794), and / or DLBCL patients or a poor prognosis population of such subjects who relapse (e.g., within 12 months) after autologous stem cell transplantation (ASCT), and / or DLBCL patients or a poor prognosis population of such subjects who are considered to be chemotherapy resistant.

[0132] In some aspects, the provided embodiments are based on the observation that the provided methods can be used to obtain high efficacy with high persistence compared to certain methods available for cell therapy without high toxicity risk. In some embodiments, the provided methods enable long-term persistence and / or low toxicity expression rates of cells engrafted for cell therapy in a subject. In some embodiments, the methods can be used to select a subject likely to respond to treatment or possibly respond to treatment for treatment with cell therapy, and / or to determine an appropriate dose or dosing regimen for minimal toxicity risk but high efficacy and / or more persistent efficacy. In some aspects, the provided embodiments are based on the finding that subjects showing improved efficacy such as complete response (CR) exhibit gene expression patterns more similar to those of follicular lymphoma (FL) compared to diffuse large B-cell lymphoma (DLBCL). The provided embodiments and such methods can provide information for a rational strategy to facilitate safe and effective clinical application of adoptive cell therapy, such as CAR-T cell therapy.

[0133] In some aspects, the subject has transplant-ineligible (TNE) lymphoma; for example, the subject is ineligible for high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT). In some embodiments, the subject has TNE relapsed / refractory (R / R) aggressive large B-cell NHL. In some aspects, subjects with R / R aggressive large B-cell NHL who are refractory to first-line treatment with immunochemotherapy and ineligible for high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT) have a poor prognosis. In some aspects, treatment options available to these subjects include platinum / gemcitabine-based or bendamustine-based regimens in combination with rituximab, with or without radiotherapy. However, in some aspects, the long-term outcomes of available therapies remain inadequate due to lack of treatment options. The provided methods provide improved treatment for such subjects.

[0134] In some embodiments, the provided embodiments confer the benefit of improved health-related quality of life (HRQoL), as reported by a subject receiving the provided CAR-expressing T cell therapy. In some aspects, early in the course of treatment, e.g., within 1 month of administration, the subject may be experiencing adverse events (e.g., toxicities) associated with undergoing the cell therapy and may still be recovering from the administration. The provided methods and use of the cell therapy have been observed to result in a marked improvement in HRQoL reported by the patient, particularly over a long period (e.g., at the 12-month time point or after undergoing the cell therapy). The provided methods confer improved treatment outcomes, including improved HRQoL, to a variety of subjects.

[0135] In some embodiments, the antigen receptor (e.g., CAR) specifically binds to a target antigen associated with the disease or condition, e.g., a target antigen associated with a B cell malignancy, e.g., a large cell type B cell lymphoma or 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. In some embodiments, the antigen associated with the disease or disorder, e.g., a B cell malignancy, e.g., a large cell type B cell lymphoma, is CD19.

[0136] In some embodiments, the method comprises an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the expression of toxicity or the risk of expression of toxicity for use in a method of reducing toxicity after cell therapy, where the method comprises: (a) a step of evaluating one or more parameters in a subject, where the one or more parameters are selected from the level, amount, or concentration of ferritin or C-reactive protein (CRP) in a biological sample from the subject; where the subject is a candidate for treatment by cell therapy, the cell therapy comprising a dose of genetically engineered cells that express a recombinant receptor; and where the evaluating step is performed before the cell therapy is administered and / or the biological sample or tumor does not contain the recombinant receptor and / or the engineered cells; the step; (b) a step of determining whether the subject is at risk of toxicity, where the subject is at risk of toxicity if the one or more parameters are above a threshold level and the subject is not at risk of toxicity if the one or more parameters are at or below the threshold level; the step; (c) a step of administering the cell therapy to the subject following or based on the results of the evaluation.

[0137] In some embodiments, the method includes a cell therapy for use in a method of treatment, wherein the method includes the step of administering the cell therapy to a subject, wherein the subject has been identified as having a risk of toxicity, and wherein the step of identifying the subject comprises: (a) evaluating one or more parameters in the subject, wherein the one or more parameters are selected from the level, amount or concentration of a tumor in the subject, LDH, ferritin or C-reactive protein (CRP) in a biological sample derived from the subject; wherein the subject is a candidate for treatment by the cell therapy, and the cell therapy comprises a dose of genetically engineered cells that express a recombinant receptor; and wherein the evaluating step is performed prior to administering the cell therapy, and / or the biological sample or tumor does not contain the recombinant receptor and / or the engineered cells; and (b) determining whether the subject is at risk of toxicity, wherein the subject is at risk of toxicity if the one or more parameters are above a threshold level, and the subject is not at risk of toxicity if the one or more parameters are at or below the threshold level, wherein: (i) the parameter is ferritin, and the threshold level is above 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter or 8000 nanograms / milliliter, or about 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter or 8000 nanograms / milliliter;and / or (ii) the parameter is CRP and the threshold level is above 5 milligrams per liter, 10 milligrams per liter, 15 milligrams per liter, 20 milligrams per liter, 25 milligrams per liter, 30 milligrams per liter, 40 milligrams per liter or 50 milligrams per liter, or about above 5 milligrams per liter, 10 milligrams per liter, 15 milligrams per liter, 20 milligrams per liter, 25 milligrams per liter, 30 milligrams per liter, 40 milligrams per liter or 50 milligrams per liter; and where (c) subsequent to or based on the result of the assessment, administering to the subject the cell therapy and, optionally, an agent or other treatment capable of treating, preventing, delaying, reducing or attenuating the expression of toxicity or the risk of expression of toxicity.

[0138] An agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the manifestation of toxicity or the risk of manifestation of toxicity for use in a method of treatment, wherein the method comprises the step of administering the agent or other treatment to a subject, wherein the subject has been identified as having a risk of manifesting toxicity, and wherein the step of identifying the subject comprises: (a) a step of evaluating one or more parameters in the subject, wherein the one or more parameters are selected from the level, amount, or concentration of ferritin or C-reactive protein (CRP) in a biological sample derived from the subject; wherein the subject is a candidate for treatment by cell therapy, the cell therapy comprising a dose of genetically engineered cells expressing a recombinant receptor; and wherein the step of evaluating is performed prior to the cell therapy, and / or the biological sample or tumor does not contain the recombinant receptor and / or the engineered cells, the step; and (b) a step of determining whether the subject is at risk of toxicity, wherein the subject is at risk of toxicity if the one or more parameters are above a threshold level, and the subject is not at risk of toxicity if the one or more parameters are at or below the threshold level, wherein: (i) the parameter is ferritin and the threshold level is above 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter or 8000 nanograms / milliliter, or about 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter or 8000 nanograms / milliliter;and / or (ii) the parameter is CRP and the threshold level is above 5 milligrams per liter, 10 milligrams per liter, 15 milligrams per liter, 20 milligrams per liter, 25 milligrams per liter, 30 milligrams per liter, 40 milligrams per liter or 50 milligrams per liter, or about above 5 milligrams per liter, 10 milligrams per liter, 15 milligrams per liter, 20 milligrams per liter, 25 milligrams per liter, 30 milligrams per liter, 40 milligrams per liter or 50 milligrams per liter; and where (c) subsequent to or based on the result of the assessment, administering to the subject an agent or other treatment that can treat, prevent, delay, reduce or attenuate the cell therapy and the expression of toxicity or the risk of expression of toxicity.

[0139] An agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the expression of toxicity or the risk of expression of toxicity for use in a method of reducing toxicity after cell therapy, wherein the method comprises: (a) a step of evaluating one or more parameters in a subject, wherein the one or more parameters are selected from the level, amount, or concentration of ferritin or C-reactive protein (CRP) in a biological sample derived from the subject; wherein the subject is a candidate for treatment by cell therapy, the cell therapy comprising a dose of genetically engineered cells expressing a recombinant receptor; and wherein the evaluating step is performed before the cell therapy is administered, and / or the biological sample or tumor does not contain the recombinant receptor and / or the engineered cells; and (b) a step of determining whether the subject is at risk of toxicity, wherein the subject is at risk of toxicity if the one or more parameters are above a threshold level, and the subject is not at risk of toxicity if the one or more parameters are at or below the threshold level, wherein: (i) the parameter is ferritin and the threshold level is above 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter or 8000 nanograms / milliliter, or about 1000 nanograms / milliliter, 2000 nanograms / milliliter, 3000 nanograms / milliliter, 4000 nanograms / milliliter, 5000 nanograms / milliliter, 6000 nanograms / milliliter, 7000 nanograms / milliliter or 8000 nanograms / milliliter;and / or (ii) the parameter is CRP and the threshold level is greater than 5 milligrams per liter, 10 milligrams per liter, 15 milligrams per liter, 20 milligrams per liter, 25 milligrams per liter, 30 milligrams per liter, 40 milligrams per liter or 50 milligrams per liter, or about greater than 5 milligrams per liter, 10 milligrams per liter, 15 milligrams per liter, 20 milligrams per liter, 25 milligrams per liter, 30 milligrams per liter, 40 milligrams per liter or 50 milligrams per liter; and here (c) subsequent to or based on the result of the assessment, administering to the subject an agent or other treatment that can treat, prevent, delay, reduce or attenuate the cell therapy and the expression of toxicity or the risk of expression of toxicity.

[0140] In some embodiments, the method includes administering to a subject, tissue, or cell (e.g., one having, at risk of, or suspected of having a disease, condition, or disorder) a cell or composition comprising a cell. In some embodiments, the subject is an adult subject. In some embodiments, the subject is over 30 years old, 40 years old, 50 years old, 60 years old or 70 years old, or about over 30 years old, 40 years old, 50 years old, 60 years old or 70 years old.

[0141] In some embodiments, the method includes administering the cells to a subject selected or identified as having a particular prognosis or risk of a B cell malignancy, such as a large cell type B cell lymphoma (e.g., DLBCL). In some embodiments, the method includes administering the cells to a subject selected or identified as having non-Hodgkin lymphoma (NHL). Lymphomas, such as non-Hodgkin lymphoma (NHL) or large cell type B cell lymphoma, can be diverse diseases. Some subjects with NHL may survive without treatment, while other subjects may require immediate intervention. In some cases, subjects with NHL can be classified into groups that can provide information on disease prognosis and / or recommended treatment strategies. In some cases, such groups can be "low risk", "intermediate risk", "high risk" and / or "very high risk", and patients can be classified as such groups according to several factors, such as, but not limited to, genetic abnormalities and / or morphological or physical characteristics. In some embodiments, the subject to be treated according to the method and / or by the manufactured article or composition is classified or identified based on the risk of NHL. In some embodiments, the subject is a subject having high risk NHL.

[0142] In some embodiments, the subject has been previously treated with a therapy or therapeutic agent that targets the disease or condition, such as large cell type B cell lymphoma or NHL, prior to administration of the cells expressing the recombinant receptor. In some embodiments, the subject has been previously treated with a hematopoietic stem cell transplantation (HSCT), such as an allogeneic HSCT or an autologous HSCT. In some embodiments, the subject has a poor prognosis after treatment with standard therapies and / or the previous therapy, primary or subsequent, has been ineffective. In some embodiments, the subject has been treated with or has previously received at least one, two, three, or four, or at least about one, two, three, or four, or about one, two, three, or four other therapies, other than lymphodepleting therapy, for treating a disease or disorder, such as large cell type B cell lymphoma or NHL, and / or administration of a dose of the cells expressing the antigen receptor. In some embodiments, the subject has been treated with or has previously received a therapy comprising anthracycline, a CD20-targeting agent, and / or ibrutinib.

[0143] In some embodiments, the subject has been previously treated with chemotherapy or radiation therapy. In some aspects, the subject is resistant or non-responsive to other therapies or therapeutic agents. In some embodiments, the subject has a persistent or relapsed disease, for example, after treatment with another therapy or therapeutic intervention, such as chemotherapy or radiation.

[0144] In some embodiments, the subject is a subject eligible for transplantation, such as a subject eligible for a hematopoietic stem cell transplantation (HSCT), such as an allogeneic HSCT. In some embodiments, the subject is a subject eligible for transplantation, such as a subject eligible for an autologous HSCT. In some such embodiments, the subject has not previously undergone transplantation, despite being eligible, prior to administration of the engineered cells (e.g., CAR-T cells) or composition comprising the cells to the subject as described herein.

[0145] In some embodiments, the subject is a subject who is not eligible for hematopoietic stem cell transplantation (HSCT), such as allogeneic HSCT, i.e., not eligible for transplantation (not transplant eligible, also known as TNE). In some embodiments, to such a subject, engineered cells (e.g., CAR-T cells) or a composition comprising such cells are administered according to the embodiments provided herein.

[0146] In some embodiments, the subject is a subject who is not eligible for hematopoietic stem cell transplantation because the subject meets at least one of the following criteria: age 70 years or older, ECOG PS 2, and / or impaired lung function (DLCO ≤ 60%, provided that SaO2 ≥ 92% on room air and CTCAE ≤ 1 for dyspnea), heart function (LVEF ≥ 40% and < 50%), renal function (creatinine clearance > 30 and < 60 mL / min), or liver function (AST / ALT > 2 and ≤ 5 x ULN).

[0147] In some of any of the embodiments, at the time of administration of the cell dose or immediately prior thereto, the subject is identified as or is being identified as ineligible for high-dose chemotherapy. In some of any of the embodiments, at the time of administration of the cell dose or immediately prior thereto, the subject is identified as or is being identified as ineligible for hematopoietic stem cell transplantation (HSCT). In some of any of the embodiments, at the time of administration of the cell dose or immediately prior thereto, the subject is identified as or is being identified as ineligible for both high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT).

[0148] In some of any of the embodiments, the subject has relapsed / refractory NHL, and at the time of administration of the cell dose or immediately prior thereto, the subject is identified as or is being identified as ineligible for both high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT), and the subject has relapsed following remission after treatment with one previous therapy for the disease or condition other than another dose of cells expressing a CAR, or has become resistant to such treatment.

[0149] In some of any aspects, at the time of or before administration of the cell dose, the subject is identified as or is being 70 years of age or older. In some of any aspects, the subject is identified as or is being with an ECOG performance status of 2. In some of any aspects, the subject is identified as or is being with impaired lung function, optionally using a carbon monoxide diffusing capacity of the lung (DLCO) of 60% or less or about 60% or less. In some of any aspects, the subject is identified as or is being with impaired cardiac function, optionally using a left ventricular ejection fraction (LVEF) of less than 50% or about 50% or less. In some of any aspects, the subject is identified as or is being with impaired renal function, optionally using a calculated creatinine clearance of less than 60 mL / min or about 60 mL / min or less. In some of any aspects, the subject is identified as or is being with impaired liver function, optionally using an aspartate aminotransferase (AST) and alanine aminotransferase (ALT) greater than 2 times the upper limit of normal (ULN) or about 2 times the upper limit of normal (ULN).

[0150] In some aspects, the subject has lymphoma associated with or accompanied by involvement of the central nervous system (CNS), and the subject has been previously treated with an anticonvulsant such as levetiracetam.

[0151] In some embodiments, the method includes administering cells to a subject selected or identified as having high-risk large B-cell lymphoma or high-risk NHL. In some embodiments, the subject exhibits one or more cytogenetic abnormalities associated with, for example, B-cell malignancies such as high-risk B-cell lymphoma or high-risk NHL. In some embodiments, the subject is selected or identified based on having a disease or condition that is histologically diagnosed or determined to be an 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 (BL), mantle cell lymphoma (MCL), and / or follicular lymphoma (FL). In certain embodiments, subjects treated using the methods provided herein include subjects having aggressive large B-cell lymphoma or aggressive NHL, particularly subjects having diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS; de novo and transformed from indolent), primary mediastinal B-cell lymphoma (PMBCL), or follicular lymphoma grade 3B (FL3B). In some of any of the embodiments, the subject has follicular lymphoma (FL). In certain embodiments, subjects treated using the methods provided herein include subjects having follicular lymphoma (FL) or DLBCL transformed from another indolent lymphoma. In certain embodiments, subjects treated using the methods provided herein include subjects having DLBCL transformed from an indolent histologic type (tDLBCL). In some embodiments, the subject has DLBCL transformed from marginal zone lymphoma (MZL) or chronic lymphocytic leukemia (CLL) (e.g., Richter). In some embodiments, subjects having transformation from CLL may exhibit Richter syndrome (RS) defined as transformation of CLL to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL) (see, e.g., Parikh et al. Blood 2014 123:1647-1657).

[0152] In some embodiments, the subject has mantle cell lymphoma (MCL). In some embodiments, MCL is characterized by the chromosomal translocation t(11;14)(q13;q32) (Vose JM, et al. Am J Hematol. 2017; 92:806-813). In some embodiments, the subject has poor risk factors including TP53 mutations and / or a high proliferation index (Ki67>30%). In some embodiments, the subject has poor risk factors including prior bone marrow lesions, prior pleural effusions, and / or CNS disease. In some embodiments, the subject has poor risk factors including MCL variants. In some embodiments, the subject has a blastoid cell variant of MCL. In some embodiments, the subject has a polymorphic variant of MCL. In some embodiments, the subject has relapsed / refractory (R / R) mantle cell lymphoma (MCL) that is refractory after prior treatment with 1 or more lines of therapy. In some embodiments, the subject has relapsed / refractory (R / R) mantle cell lymphoma (MCL) that is refractory after prior treatment with 1, 2, 3, 4, 5, 6, or 7 lines of therapy. In some embodiments, the subject has previously received ibrutinib and / or venetoclax. In some embodiments, the subject has MCL that relapsed after administration of ibrutinib and / or venetoclax. In some embodiments, the subject has received 1 or more prior lines of immunochemotherapy including anthracyclines and CD20-targeted agents (e.g., R-CHOP). In some embodiments, the subject has previously received hematopoietic stem cell therapy (HSCT), e.g., allogeneic HSCT or autologous HSCT. In some embodiments, the subject has been confirmed to have cyclin D1-expressing MCL with R / R disease.

[0153] In some of any aspect, at the time of or prior to administration of the cell dose, the subject is or has been treated with an anthracycline and one or more CD20 targeting agents. In some of any aspect, the one or more CD20 targeting agents include rituximab. In some of any aspect, the one or more CD20 targeting agents include R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (Oncovin) and prednisone).

[0154] In some aspects, the subject has a poor performance status. In some scenarios, the population to be treated includes subjects having an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 - 2. In any other scenario of any aspect, the subjects to be treated include subjects with an ECOG of 0 - 1 or do not include subjects with an ECOG of 2. In some scenarios of any aspect, the subjects to be treated have had two or more previous therapies that were ineffective. In some aspects, the subject does not have diffuse large B-cell lymphoma (DLBCL) transformed from marginal zone lymphoma (MZL) and chronic lymphocytic leukemia (CLL, such as Richter). In some aspects, the subject has the characteristic of being correlated with poor overall survival. In some aspects, the subject has not achieved a complete response (CR), has not received autologous stem cell transplantation (ASCT), is resistant to one or more second-line therapies, has primary refractory disease, and / or has an ECOG performance score of 2 or an ECOG score of 0 - 1. In some aspects, the subject is identified as having an ECOG performance status of 0 or 1 or has been so identified.

[0155] In some embodiments, the subject to be treated includes subjects with diffuse large B-cell lymphoma (DLBCL), transformed (not otherwise specified, NOS) from de novo or indolent lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3b (FL3B) after failure of two lines of treatment, and an ECOG score of 0-2, and the subject may optionally have been previously treated with allogeneic stem cell transplantation (SCT). In some of any of the embodiments, the subject to be treated has follicular lymphoma (FL). In some embodiments, such a group of subjects may be referred to as "full cohort". In some embodiments, a subject is selected for treatment with adoptive cell therapy if the subject meets the criteria. In some embodiments, within the said group ("full cohort"), a subject is not selected for treatment or excluded from treatment if the subject has a poor performance status (e.g., ECOG 2) and / or has DLBCL transformed from marginal zone lymphoma (MZL) or chronic lymphocytic leukemia (CLL, Richter). Thus, in some embodiments, a subject is selected for treatment if the subject has diffuse large B-cell lymphoma (DLBCL), transformed (NOS) from de novo or indolent lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3b (FL3B) after failure of two lines of treatment, and an ECOG score of 0 or 1, and the subject may optionally have been previously treated with allogeneic stem cell transplantation (SCT), but does not have DLBCL transformed from marginal zone lymphoma (MZL) or chronic lymphocytic leukemia (CLL, Richter). In some embodiments, a subject is selected for treatment if the subject has follicular lymphoma (FL).

[0156] In some of any of the aspects, at the time of or before administration of the cell dose, the subject is identified as having, or is identified to have, double / triple hit lymphoma. In some of any of the aspects, the subject is identified as having, or is identified to have, chemotherapy-resistant lymphoma, optionally chemotherapy-resistant DLBCL. In some of any of the aspects, the subject has not achieved a complete remission (CR) in response to previous therapy. In some of any of the aspects, the subject has relapsed within 1 year or less than 1 year after receiving autologous stem cell transplantation (ASCT).

[0157] In some aspects, such a group of subjects may be referred to as the "core cohort". In some aspects, the subject to be treated is a subject of the "core cohort". In some aspects, the provided aspect is based on the observation that a specific population of subjects, such as the "core cohort" subjects, who have received a specific dose of cell therapy, has a complete response (CR) rate of more than 55% and an overall response rate (ORR) of more than 80% with high durability, for example, maintained over a long period, for example longer than 3 months, and shows a response with a 3-month ORR of more than 65% and a 3-month CR rate of about 50%. In particular, the provided observations show that the 3-month ORR is high in subjects with two or three chromosomal translocations ("double hit" or "triple hit" lymphoma; translocations of the MYC / 8q24 locus, usually in combination with the t(14;18)(q32;q21) bcl-2 gene, and / or having BCL6 / 3q27 chromosomal translocations; see, for example, Xu et al. (2013) Int J Clin Exp Pathol. 6(4):788-794), primary resistant lymphoma, subjects with chemotherapy-resistant DLBCL, and subjects who have never achieved CR before.

[0158] In some aspects, provided are compositions, methods, and uses for administration at a specific dose associated with high efficacy and / or high durability of efficacy and low toxicity levels and / or toxicity incidence of a cell therapy of defined composition. In some embodiments, the composition or dose administered is a uniform dose and / or a fixed dose of cells and / or one or more cells having a specific phenotype, e.g., a strictly uniform dose, e.g., a value with a variation or dispersion within a specific range and / or degree compared to a specific number or target numerical value of such cells. In some embodiments, the composition or dose administered comprises a defined ratio of CD4 + cells to CD8 + cells (e.g., a ratio of CD4 + CAR + T cells:CD8 + CAR + T cells of 1:1), and / or a ratio with a variation from said ratio within a specific degree (e.g., within ±10%, e.g., within ±8%), e.g., a ratio with a degree of variation or dispersion of ±10% or less, e.g., ±8% or less. In some embodiments, CD4 + cells and CD8 +Cells are formulated and administered individually. In some embodiments, the cells administered exhibit consistent activity and / or function, such as cytokine production, apoptosis and / or expansion. In some embodiments, the provided composition exhibits highly consistent defined activity, as well as little variation between cells, for example, in terms of cell number, cell function and / or cell activity in the composition, or little variation between preparations. In some embodiments, the consistency in activity and / or function, for example, little variation between preparations of the composition, enables improvement in efficacy and / or safety. In some embodiments, administration of a defined composition results in lower variability of the product and lower toxicity, such as CRS or neurotoxicity, compared to administration of a cell composition with high heterogeneity. Also, in some embodiments, a defined consistent composition also exhibits consistent cell expansion. Such consistency can facilitate determination of dosage, therapeutic range, evaluation of dose response and identification of subject factors that may correlate with safety or toxicity outcomes.

[0159] In some embodiments, in a particular cohort of subjects receiving a single infusion at a particular dose level, a sustained response rate of greater than 60% can be obtained after 6 months. In some embodiments, in some cohorts of subjects, an overall response rate (ORR, also known as objective response rate in some cases) of greater than 80%, a complete response (CR) rate of greater than 60% and / or a high sustained CR rate at 6 months can be obtained. In some embodiments, subjects receiving a defined dose show improvement in safety outcomes, for example, more than two-thirds of the subjects do not exhibit any CRS or NT. In some aspects, the proportion of severe CRS or severe NT is low. In some embodiments, the high exposure (e.g., C max and AUC 0-28 ) observed at a particular defined dose is not associated with an increase in toxicity, such as CRS or NT. In some embodiments, a particular subject factor, such as a particular biomarker, can be used to predict the toxicity risk. In some embodiments, using the provided embodiments, a high response rate can be obtained with a low toxicity risk.

[0160] In some embodiments, for the compositions, articles of manufacture, kits, methods, and subjects treated using the uses provided, the agent (e.g., tocilizumab and / or dexamethasone) for alleviating, treating, or preventing toxicity is administered either before or after the administration of the cell therapy at 25% or less, 20% or less, 15% or less, 10% or less, or 5% or less. In some embodiments, no prophylactic treatment is performed on the subject prior to receiving the administration of the engineered cells (e.g., CAR-T cells).

[0161] In some aspects, the provided aspects provide advantages, for example, enabling the administration of cell therapy on an outpatient basis. CAR T cell therapy has generally been administered in a setting of inpatients, such as at a university medical center. However, many subjects with R / R diffuse large B cell lymphoma are treated at medical centers where outpatient delivery of cancer treatment is performed. In some respects, the infusion and management of CAR T cell therapy in an outpatient setting can improve access to such therapies, including wider use of outpatient treatment at centers other than community / university centers. In some aspects, the administration of the cell dose and / or lymphodepletion therapy is performed at a non-tertiary medical center. In some aspects, cell therapy, for example, the administration of a dose of T cells according to the provided aspects, can be performed on an outpatient basis or does not require the subject to be hospitalized, for example, for a one-night stay at a hospital. In some aspects, such outpatient administration can allow for increased accessibility and cost reduction while maintaining a low toxicity and high sustained efficacy rate. In some respects, outpatient treatment can be advantageous for subjects who are already immunosuppressed in some other way, for example, by previous treatment after lymphodepletion, and who have an increased risk of exposure in a hospital stay or inpatient situation. Also, in some respects, outpatient treatment increases the treatment options available to subjects who may not have access to inpatients, hospital settings or transplant centers, thereby expanding the availability of treatment. In some aspects, after administration of a dose of cells, the subject is monitored in an outpatient setting, optionally via telephone contact and / or via a visit by a medical professional.

[0162] In some embodiments, the subject treated on an outpatient basis using the provided compositions, manufactured articles, kits, methods and uses remains an outpatient for at least 3 days, or a particular percentage (%) of subjects so treated, such as at least 60%, at least 70%, at least 80%, at least 85%, at least 90% or at least 95% of the subjects remain an outpatient for at least 3 days. In some aspects, the subject remains an outpatient for at least 4 days, 5 days, 6 days, 7 days, 8 days or longer. In some embodiments, the subjects treated using the provided compositions, manufactured articles, kits, methods and uses exhibit a reduction in the duration of hospital stay, such as 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.

[0163] In some embodiments, the methods, cells and compositions can provide a high sustained response rate for a range of patient characteristics and / or tumor burdens. In some embodiments, the methods, cells and compositions can provide a high sustained response rate with a low risk of adverse effects or toxicity for high-risk patients with poor prognoses. In some embodiments, the methods and uses can result in or provide a high response rate and / or more sustained response or efficacy and / or a low risk of toxicity or other side effects associated with cell therapy, such as neurotoxicity (NT) or cytokine release syndrome (CRS). In some aspects, the provided observations show a low percentage of severe NT (sNT) or severe CRS (sCRS) and a high percentage of patients without any toxicity, such as NT or CRS.

[0164] 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 the subjects treated according to the provided method and / or the subjects treated with the provided manufactured article or composition achieve a complete response (CR). In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the subjects treated according to the provided method and / or the subjects treated with the provided manufactured article or composition achieve an objective response (OR). In some embodiments, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or more, of the subjects treated according to the provided method and / or the subjects treated with the provided manufactured article or composition achieve CR or OR by 1 month, by 2 months, or by 3 months.

[0165] In some embodiments, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or more of the subjects treated according to the provided method and / or the subjects treated with the provided manufactured article or composition are still in an effective state, such as still in a CR or OR state, at 3 months, 4 months, 5 months, 6 months, or longer after the initiation of the administration of the cell therapy. In some embodiments, such an efficacy, such as CR or OR, is at least 60% or at least about 60%, at least 70%, at least 80%, at least 90%, at least 95%, or more, or up to 1 month, or up to 3 months, or in such subjects achieving CR by 3 months, and is sustained for at least 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, or 9 months. In some embodiments, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or more, or up to 1 month, or up to 3 months, or such subjects achieving CR of the subjects treated according to the provided method and / or the subjects treated with the provided manufactured article or composition are surviving or surviving without progression for 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, or 9 months or longer, or about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months or longer, or about 9 months or longer.

[0166] In some embodiments, the efficacy as a result observed in such a subject by following the provided method and / or by treatment with the provided manufactured article or composition is associated with any toxicity of low risk or severe toxicity of low risk in most of the treated subjects, or results in any toxicity of low risk or severe toxicity of low risk in most of the treated subjects. In some embodiments, more than 30%, more than 35%, more than 40%, more than 50%, more than 55%, or more than 60%, or about more than 30%, more than 35%, more than 40%, more than 50%, more than 55%, or more than 60% of the subjects treated according to the provided method and / or the subjects treated 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%, more than 60%, more than 70%, or more than 80%, or about more than 50%, more than 60%, more than 70%, or more than 80% of the subjects treated according to the provided method and / or the subjects treated with the provided manufactured article or composition do not exhibit severe CRS or CRS of grade 3 or higher. In some embodiments, more than 50%, more than 60%, more than 70%, or more than 80%, or about more than 50%, more than 60%, more than 70%, or more than 80% of the subjects treated according to the provided method and / or the subjects treated with the provided manufactured article or composition do not exhibit severe neurotoxicity or neurotoxicity of grade 3 or higher, such as grade 4 or 5 neurotoxicity.

[0167] In some embodiments, at least 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or at least about 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the subjects treated according to the method and / or with the provided manufactured article or composition do not exhibit early-onset CRS or neurotoxicity and / or do not exhibit the onset of CRS earlier than day 1, 2, 3, or 4 after the start of the administration. In some embodiments, at least 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or at least about 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the 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 the administration. In some aspects, the median onset of neurotoxicity in the subjects treated according to the method and / or with the provided manufactured article or composition is at or after the median peak of CRS or after the median time to resolution of CRS in the subjects treated according to the method. In some cases, the median onset of neurotoxicity in the subjects treated according to the method is 8, 9, 10, or 11 days or more, or about 8, 9, 10, or 11 days or more, after the start of the treatment.

[0168] In some embodiments, such results are from 5×10 7 or about 5×10 7 to 1.5×10 8 or about 1.5×10 8 cells, such as from 5×10 7 or about 5×10 7 to 1×10 8 or about 1×10 8Individual total recombinant receptor-expressing T cells (e.g., CAR+ T cells), such as those described herein, in a defined ratio (e.g., a ratio of 1:1 or about 1:1), and / or a precise number or uniform number or fixed number of, CAR + T cells or a specific type of CAR + T cells, e.g., CD4 + CAR + T cells and / or CD8 + CAR + T cells, and / or within a specified dispersion range of any such cells, e.g., + or - (plus or minus, sometimes indicated as ±) 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% compared to such a precise number or uniform number or fixed number, administered CD4 + and CD8 + T cells, is observed after administration of a dose of T cells. In some embodiments, such a uniform cell number or fixed cell number is, for example, the total CAR + T cells or CD8 + and / or CD4 + CAR + T cells are 2.5×10 7 、5×10 7 、10×10 7 、15×10 7 、or 20×10 7 cells, or about 2.5×10 7 、5×10 7 、10×10 7 、15×10 7 、or 20×10 7 cells. In some embodiments, the number of cells in the dose is 5×10 7 cells of CD4 + CAR + T cells (in some cases 2.5×10 7 cells of CD4 + CAR + T cells and 2.5×10 7 cells of CD8 + CAR +comprising, consisting of, or consisting essentially of T cells; in some embodiments, this is 10×10 7 CAR + T cells (in some cases 5×10 7 CD4 + CAR + T cells and 5×10 7 CD8 + CAR + T cells); in some aspects, the number of cells administered is within a certain range of dispersion of such numbers in the foregoing embodiments, e.g., within plus or minus (±) 5, 6, 7, 8, 9, or 10% compared to such cell numbers, e.g., within plus or minus 8%. In some aspects, the dosage is such that a correlation (optionally a linear relationship) is observed between such cells (e.g., total CAR + T cells or CD8 + and / or CD4 + CAR + T cells) and one or more outcomes indicating the efficacy or duration of the treatment (e.g., the likelihood of achieving remission, complete remission and / or a specific remission duration) and / or the duration of any of the foregoing. In some aspects, the higher the dosage of cells administered, the greater the efficacy, without or with substantially no or without or with substantially no effect on the incidence or risk of toxicity (e.g., CRS or neurotoxicity) or toxicity in the subject, e.g., the incidence or risk of severe CRS or severe neurotoxicity.

[0169] In some scenarios, the provided method can achieve a high or specific response rate (e.g., the response rate in a population evaluated after a specific period after administration (e.g., after 3 months or 6 months), such as an ORR of 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or 80% or 81%, 82%, 83%, 84%, or 85%, or higher, e.g., 6 - month ORR or 3 - month ORR), and a CR rate of 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 71%, 72%, 73%, or higher, or about 75% or higher (e.g., 6 - month CR rate or 3 - month CR rate). This can also be sustained, for example, over a specific period or at least a specific period, e.g., more than 1 month, 3 months, or 6 months after the start of the therapy, or longer, or 9 months or longer. In some embodiments, such response rates and sustainability are achieved after just one administration or dose of such therapy. Also, the treatment of such a subject by the provided method and / or with the provided manufactured article or composition, in some embodiments, will result in a high response rate in the subject but not show a high incidence of toxicity, e.g., neurotoxicity or CRS, even at high cell doses. In some embodiments, about 50%, 55%, or 60%, or more than 50%, 55%, or 60% of the subjects achieving such a response will not exhibit any grade of toxicity, e.g., will not exhibit any grade of CRS and / or neurotoxicity.

[0170] Thus, in some embodiments, the provided method, manufactured article, and / or composition can provide advantages compared to other available methods or solutions or approaches for treatment, e.g., for adoptive cell therapy. In particular, some of the provided embodiments provide advantages in that for subjects with high - risk NHL, a high rate of sustained response is obtained with a low incidence of toxicity or side effects.

[0171] A. Treatment Method Provided herein are treatment methods involving administering engineered cells such as engineered T cells or compositions comprising engineered cells. Also provided are methods involving administration of engineered cells and / or their compositions, and the use of engineered cells (e.g., T cells) and / or their compositions, e.g., for the treatment of a subject having a disease or condition, such as leukemia or lymphoma or B cell malignancy, such as diffuse large B cell lymphoma (DLBCL) or a subtype thereof, follicular B cell lymphoma and / or non-Hodgkin lymphoma (NHL). In some embodiments, the methods and uses provided may result in improved efficacy and / or more sustained efficacy or effectiveness and / or lower risk of toxicity or other side effects compared to certain alternative methods, e.g., in a particular group of treated subjects. Also provided in some aspects is a method of administering an engineered cell such as an engineered T cell or a composition comprising an engineered cell to a subject, e.g., a subject having a disease or disorder. Also provided in some aspects is the use of an engineered cell such as an engineered T cell or a composition comprising an engineered cell for the treatment of a disease or disorder. Also provided in some aspects is the use of an engineered cell such as an engineered T cell or a composition comprising an engineered cell for the manufacture of a medicament for the treatment of a disease or disorder. Also provided in some aspects is a method of administering an engineered cell such as an engineered T cell or a composition comprising an engineered cell 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 an engineered cell such as an engineered T cell or a composition comprising an engineered cell follows any of the methods described herein.

[0172] Also provided is a method of treatment involving the step of selecting a subject having a disease or condition, such as any disease or condition described herein, and the step of administering to the subject a dose of T cells comprising T cells that specifically bind to a target antigen expressed by the disease or condition or its cells or tissues and / or express a recombinant receptor associated with the disease or condition.

[0173] Engineered cells expressing recombinant receptors such as chimeric antigen receptors (CARs), or compositions containing the same, are useful in a variety of therapeutic, diagnostic, and prophylactic applications. For example, the engineered cells or compositions containing the engineered cells are useful for treating various diseases and disorders in a subject. Such methods and uses include, for example, therapeutic methods and uses involving administration of the engineered cells or compositions containing the same to a subject having a disease, condition, or disorder, such as a B cell malignancy, such as large cell type B cell lymphoma. In some embodiments, the engineered cells or compositions containing the same are administered in an amount effective to effect treatment of a disease or disorder. Uses include the use of the engineered cells or compositions in such methods and treatments, and in the preparation of a medicament for carrying out such therapeutic methods. In some embodiments, the method is carried out by administering the engineered cells, or a composition containing the same, to a subject having or suspected of having a disease or condition. In some embodiments, the method thereby treats a disease, condition, or disorder in the subject.

[0174] General methods for administration of cells for adoptive cell therapy are known and can be used in connection with the provided methods and compositions. For example, methods of adoptive T cell therapy are described, for example, in U.S. Patent Application Publication No. 2003 / 0170238 to Gruenberg et al.; U.S. Patent No. 4,690,915 to Rosenberg; Rosenberg (2011) Nat Rev Clin Oncol. 8(10):577-85). See, for example, Themeli et al. (2013) Nat Biotechnol. 31(10):928-933; Tsukahara et al. (2013) Biochem Biophys Res Commun 438(1):84-9; Davila et al. (2013) PLoS ONE 8(4):e61338.

[0175] The disease or condition to be treated can be any disease, condition or disorder in which the expression of an antigen is associated with and / or involved in the etiology of the disease, condition or disorder, e.g., causes, exacerbates or is otherwise involved in such a disease, condition or disorder. Exemplary diseases and conditions include diseases or conditions associated with malignant tumors or cell transformation (e.g., cancer), autoimmune diseases or inflammatory diseases, or infectious diseases caused by, e.g., bacterial pathogens, viral pathogens or other pathogens. Exemplary antigens including antigens associated with various diseases and conditions that can be treated are described above. In certain embodiments, the chimeric antigen receptor (CAR) or transduced TCR specifically binds to an antigen associated with the disease or condition.

[0176] Among the diseases, conditions, and disorders are tumors, such as solid tumors, hematopoietic malignancies, and melanoma, and, e.g., localized and metastatic tumors, infectious diseases, such as infections by viruses or other pathogens, such as HIV, HCV, HBV, CMV, HPV, and parasitoses, as well as autoimmune diseases and inflammatory diseases.

[0177] In some embodiments, the disease, disorder or condition to be treated is a tumor, cancer, malignant tumor, neoplasm or other proliferative disease or disorder. Such diseases include, but are not limited to, leukemia, lymphoma, e.g., acute myeloid (or myelogenous) leukemia (AML), chronic myeloid (or myelogenous) leukemia (CML), acute lymphocytic (or lymphoblastic) leukemia (ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), anaplastic large cell lymphoma (ALCL), follicular lymphoma (FL), refractory follicular lymphoma, diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM).

[0178] In some embodiments, the disease or condition to be treated is a B cell malignancy. In some embodiments, the disease or condition is a B cell malignancy selected from the group consisting of acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and diffuse large B cell lymphoma (DLBCL). In some embodiments, the disease or condition is NHL. In some embodiments, the disease or condition is large B cell lymphoma. In some embodiments, the disease or condition is DLBCL. In some embodiments, the disease or condition is unclassifiable DLBCL (DLBCL, NOS). In some embodiments, the disease or condition is NHL, and the NHL is selected from the group consisting of aggressive NHL, diffuse large B cell lymphoma (DLBCL), NOS (de novo and transformed from indolent), primary mediastinal large B cell lymphoma (PMBCL), T cell / histiocyte-rich large B cell lymphoma (TCHRBCL), Burkitt lymphoma (BL), mantle cell lymphoma (MCL), and / or follicular lymphoma (FL). In some embodiments, the disease or condition is follicular lymphoma (FL). In some embodiments, the follicular lymphoma is follicular lymphoma grade 3B (FL3B). In some embodiments, the disease or condition is mantle cell lymphoma (MCL).

[0179] In some embodiments, the disease or condition treated according to the provided method, use, or article of manufacture is DLBCL. In some aspects, the DLBCL is unclassifiable (NOS) DLBCL, which in some cases can be characterized as de novo or transformed from an indolent disease.

[0180] In some embodiments, a subject having DLBCL, NOS selected for treatment and / or treated according to any of the provided methods has DLBCL that is not DLBCL with a predominant extranodal location, not DLBCL that is a large cell lymphoma of terminally differentiated B cells, or not DLBCL that is a B cell neoplasm having characteristics intermediate between DLBCL and other lymphoid tumors.

[0181] In some embodiments, a subject having DLBCL, NOS selected for treatment and / or treated according to any of the provided methods has DLBCL that is not T cell / histiocyte-rich large cell B cell lymphoma (TCHRBCL), not primary DLBCL of the central nervous system (CNS), not primary cutaneous DLBCL, leg type, or EBV-positive DLBCL (e.g., EBV-positive DLBCL in the elderly), and in some cases, not DLBCL associated with chronic inflammation.

[0182] In some embodiments, a subject having DLBCL, NOS selected for treatment and / or treated according to any of the provided methods has a high-grade B cell lymphoma that is not B lymphoblastic leukemia / lymphoma (B-LBL), not a high-grade B cell lymphoma that is Burkitt lymphoma, or not a high-grade B cell lymphoma that is a high-grade B cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements. In some aspects, the DLBCL can be characterized as DLBCL, NOS that, in some cases, is a high-grade B cell lymphoma that is not B lymphoblastic leukemia / lymphoma (B-LBL), not a high-grade B cell lymphoma that is Burkitt lymphoma, or not a high-grade B cell lymphoma that is a high-grade B cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements.

[0183] In some embodiments, a subject having DLBCL, NOS selected for treatment and / or treated according to any of the provided methods has DLBCL that is germinal center B-cell-like (GCB) and activated B-cell-like (ABC) based on the molecular and / or cytogenetic characteristics of the originating cells.

[0184] In some embodiments, the DLBCL is de novo or primary DLBCL. In some embodiments, the disease or condition (such as a lymphoma such as DLBCL) is transformed from a different subtype of disease or condition, such as an indolent lymphoma such as follicular lymphoma (FL). In some embodiments, such other indolent lymphomas can include, for example, marginal zone B-cell lymphoma (MZL) and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL). In some embodiments, the disease or condition is transformed follicular lymphoma (tFL) DLBCL; in some aspects, it is DLBCL transformed from another indolent lymphoma. In some embodiments, the subject is suspected of or characterized as having transformed follicular lymphoma (tFL). In some embodiments, the disease or condition is DLBCL transformed from FL. In some aspects, the disease or condition is DLBCL transformed from an indolent lymphoma other than FL.

[0185] In some embodiments, the disease or condition to be treated according to the provided method, use or article of manufacture is DLBCL transformed from another indolent lymphoma, such as DLBCL transformed from marginal zone lymphoma (tMZL) or DLBCL transformed from chronic lymphocytic leukemia (tCLL; Richter). In some cases, the disease or condition is DLBCL tMZL or DLBCL tCLL. In some embodiments, it is a disease or condition transformed from an indolent lymphoma other than FL. In some embodiments, it is DLBCL or large cell type B cell lymphoma, such as DLBCL or large cell type B cell lymphoma transformed from FL or another indolent lymphoma. In some embodiments, the subject is characterized as having DLBCL transformed from another indolent lymphoma, such as DLBCL tMZL or DLBCL tCLL.

[0186] In some embodiments, the disease or condition is follicular lymphoma (FL). In some embodiments, a subject is selected for treatment if the subject has follicular lymphoma (FL). In some embodiments, FL exhibits or is associated with neoplastic follicles showing attenuated mantle zones, loss of polarization, and / or absence of tingible body macrophages. In some embodiments, FL is associated with a mixture of centrocytes and centroblasts. In some embodiments, FL is not associated with centrocytes. In some embodiments, FL is grade 3 FL. In some embodiments, grade 3 FL shows or is associated with more than 15 centroblasts per high power field (HPF). In some embodiments, FL is associated with co-expression of CD10, BCL6, and BCL2 within follicles. In some embodiments, FL is associated with or characterized by t(14;18) / IGH-BCL2 and / or BCL6 rearrangements. In some embodiments, FL is associated with the t(14;18)(q32;q21) translocation. In some aspects, the t(14;18)(q32;q21) translocation places BCL2 expression under the control of the immunoglobulin (Ig) heavy locus (IGH) enhancer. In some aspects, t(14;18) is detected in about 90% of grade 1 and 2 FL, 60 - 70% of grade 3A, and 15 - 30% of grade 3B FL cases. In some embodiments, FL is associated with BCL2 translocations t(2;18) and t(18;22). In some embodiments, FL associated with the t(2;18) and t(18;22) translocations is also associated with BCL6 rearrangements. In some of any of the embodiments, FL is associated with co-expression of CD10, BCL6, and BCL2 within follicles, and / or with t(14;18) / (q32;q21) (IGH-BCL2) and / or BCL6 rearrangements.

[0187] In some embodiments, FL is involved in lymph nodes and / or the spleen, bone marrow, peripheral blood, and other extranodal sites. In some embodiments, FL is involved in lymph nodes. In some aspects, exemplary features associated with FL are those described in Choi et al. (2018) Arch Pathol Lab Med 142:1330-1340; Luminari et al., (2012) Rev. Brad. Hematol. Hemoter., 34:54-59 and Salles (2007) ASH Education Book, 2007:216-25. In some aspects, exemplary parameters used to assess the degree of disease burden in the case of FL include hemoglobin levels (e.g., <12 g / dL or <10 g / dL), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH) levels, and β2-microglobulin (B2M) values, gene expression, single nucleotide polymorphisms (SNPs; e.g., in IL-8, IL-2, Il-12B, and IL1RN), miRNA expression, and protein expression (e.g., CD68, STAT1, FOXP3, CD57), etc. (Salles (2007) ASH Education Book, 2007:216-25). In the case of FL, the degree or burden of the disease can be evaluated by the Ann Arbor staging system, tumor burden, bulky tumor lesions, the number of disease nodules or extranodal sites, and / or bone marrow involvement.

[0188] In some settings, the survival rate of a subject, such as a subject with FL, is based on a scoring system developed by the Italian Lymphoma Intergroup (ILI) and / or the International Follicular Lymphoma Prognostic Factors Project (IFLPFP). (Luminari et al., (2012) Rev. Brad. Hematol. Hemoter., 34:54-59). In some settings, the ILI score is based on the independent prognostic roles of age, gender, B symptoms, number of extranodal sites, erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH). In some settings, the IFLPFP score is based on the risk factors of age, Ann Arbor stage, hemoglobin level, number of nodal site areas, and serum LDH level. In some cases, IFLPFP can be used to characterize or predict the overall survival rate of patients with FL.

[0189] In some embodiments, the provided method comprises: selecting a subject having follicular lymphoma (FL) for treatment; and administering to the subject a dose of T cells comprising T cells that specifically bind to a target antigen expressed by FL or its cells or tissues and / or express a recombinant receptor associated with FL.

[0190] In some of any of the embodiments, the dose of T cells is CD4 + and CD8 + and comprises a dose of T cells, wherein each dose of T cells specifically binds to a target antigen expressed by FL or its cells or tissues and / or comprises a recombinant receptor associated with FL, wherein administration comprises administering a plurality of separate compositions, the plurality of separate compositions comprising a first composition comprising CD8 + T cells and a second composition comprising CD4 + T cells.

[0191] In some embodiments, the disease or condition is an extranodal high-grade non-Hodgkin B-cell lymphoma. In some embodiments, the extranodal high-grade non-Hodgkin B-cell lymphoma is primary central nervous system lymphoma (PCNSL). In some embodiments, PCNSL involves the central nervous system (CNS) in the absence of systemic lymphoma. In some embodiments, PCNSL is limited to the brain, spine, cerebrospinal fluid (CSF), and eyes. In some embodiments, PCNSL is diffuse large B-cell lymphoma (DLBCL). In some embodiments, PCNSL is Burkitt lymphoma, indolent lymphoma or T-cell lymphoma. In some embodiments, PCNSL includes neurological symptoms. In some embodiments, the neurological symptoms include focal neurological deficits, mental state and behavioral changes, symptoms of increased intracranial pressure, and / or seizures. In some embodiments, exemplary features associated with the disease or condition include those described by Grommes et al. (J. Clin Oncol 2017; 35(21):2410-18).

[0192] In some embodiments, the subject being treated by the methods provided herein does not have primary central nervous system lymphoma (PCNSL).

[0193] In some embodiments, the disease or condition is secondary central nervous system lymphoma (SCNSL). In some embodiments, SCNSL is present in a patient with systemic lymphoma. In some embodiments, SCNSL is referred to as metastatic lymphoma. In some embodiments, SCNSL is DLBCL. In some embodiments, SCNSL is an aggressive lymphoma that can involve the brain, meninges, spinal cord, and eyes. In some embodiments, SCNSL includes leptomeningeal spread. In some embodiments, SCNSL includes parenchymal brain disease. In some embodiments, exemplary features associated with the disease or condition include those described by Malikova et al. (Neurophychiatric Disease and Treatment 2018; 14:733-40.).

[0194] In some embodiments, the disease or condition is a high-grade B-cell lymphoma with rearrangement of MYC and BCL2 and / or BCL6, which may optionally have DLBCL histology. In some embodiments, the disease or condition is DLBCL NOS (de novo or transformed from indolent). In some embodiments, the disease or condition is primary mediastinal large B-cell lymphoma (PMBCL) or follicular lymphoma grade 3B (FL3B). In some embodiments, the disease or condition is follicular lymphoma (FL). In some embodiments, it is DLBCL with CNS involvement. In some embodiments, the subject has a recurrence of DLBCL (secondary CNS lymphoma) in the central nervous system. In some embodiments, secondary CNS lymphoma involves the brain parenchyma and / or leptomeninges. In some embodiments, the subject has been treated with or has previously received at least 1, 2, 3, 4, or 5 or at least about 1, 2, 3, 4, or 5 or about 1, 2, 3, 4, or 5 other therapies to treat the disease or disorder. In some embodiments, the subject has received prior methotrexate, thiotepa, and / or cytarabine. In some embodiments, the subject has MCL that recurred after receiving methotrexate, thiotepa, and / or cytarabine. In some embodiments, the subject has received prior hematopoietic stem cell therapy (HSCT), such as allogeneic HSCT or autologous HSCT.

[0195] In some embodiments, the subject has or is identified as having double / triple hit lymphoma or lymphoma of the 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) of MYC (myelocytomatosis oncogene), BCL2 (B-cell lymphoma 2) and / or BCL6 (B-cell lymphoma 6); for example, see Aukema et al., (2011) Blood 117:2319-2331. 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) which involves 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 of MYC, BCL2 and BCL6; for example, see Aukema et al., (2011) Blood 117:2319-2331. In some aspects of such embodiments, the subject is ECOG 0-1 or does not have or is not suspected of having transformed DLBCL from MZL or CLL or is not characterized as having transformed DLBCL from MZL or CLL. In such aspects, the treatment is indicated for such subjects and / or the instructions indicate administration to subjects within such a population. In some embodiments, based on the 2016 WHO criteria (Swerdlow et al., (2016) Blood 127(20):2375-2390), double / triple hit lymphoma can be considered a high-grade B-cell lymphoma with rearrangements (double / triple hit) of MYC as well as BCL2 and / or BCL6 and having DLBCL histology.

[0196] In some embodiments, NHL can be staged based on the Lugano classification (see, e.g., Cheson et al., (2014) JCO 32(27):3059-3067; Cheson, B.D. (2015) Chin Clin Oncol 4(1):5). In some cases, the stage is described by Roman numerals I-IV (1-4), and lymphoma with a localized stage (I or II) in which organs outside the lymphatic system (extranodal organs) are affected is denoted by E. Stage I represents infiltration into one lymph node or adjacent lymph node groups or a single extranodal lesion without lymph node infiltration (IE). Stage 2 represents stage I or II depending on the extent of lymph nodes with infiltration into two or more lymph node groups on the same side of the diaphragm or localized continuous extranodal infiltration (IIE). Stage III represents infiltration into lymph nodes on both sides of the diaphragm or above the diaphragm with splenic infiltration. Stage IV represents infiltration of non-continuous additional extralymphatic infiltration. In addition, "bulky tumor lesion" can be used to indicate a large tumor, particularly in stage II of the chest. The extent of the disease is determined by positron emission tomography (PET)-computed tomography (CT) for aggressive (avid) lymphoma and by CT for non-aggressive histology. In some of any of the embodiments, at the time of or prior to administration of the cell dose, the subject to be treated according to the provided embodiment has a positron emission tomography (PET) positive disease.

[0197] In some of any of the embodiments, at the time of or prior to administration of the cell dose, if the subject has received a previous CD19-targeted therapy, a biological sample obtained from the subject after the previous CD19-targeted therapy contains cells expressing CD19.

[0198] In some embodiments, the Eastern Cooperative Oncology Group (ECOG) performance status metric can be used to assess a subject, such as a subject who has had a poor outcome with previous therapy, or to select a subject, such as a subject who has had a poor outcome with previous therapy, for treatment (see, e.g., Oken et al. (1982) Am J Clin Oncol. 5:649-655). The ECOG scale of performance status indicates the functional level from the perspective of the subject's ability to do things around themselves, daily activities, and physical ability (e.g., walking, working, etc.). In some embodiments, an ECOG performance status of 0 indicates that the subject can perform normal activities. In some situations, a subject with an ECOG performance status of 1 shows some limitation in physical activity but the subject's walking is complete. In some situations, the walking of a patient with an ECOG performance status of 2 is more than 50%. Also, in some cases, a subject with an ECOG performance status of 2 may be able to do things around themselves; see, e.g., Sorensen et al., (1993) Br J Cancer 67(4)773-775. The criteria reflecting the ECOG performance status are shown in Table 1 below.

[0199] (Table 1) ECOG Performance Status Criteria TIFF0007695882000005.tif58160

[0200] In some of any of the aspects, at the time of administration of the dose of the cells or immediately prior to such administration, the subject has relapsed following remission after treatment with one or more previous therapies for the disease or condition other than another dose of the cells expressing the CAR, or has become resistant to such treatment. In some aspects, the subject has relapsed following remission after treatment with one, two or three or more previous therapies (other than another dose of the cells expressing the CAR), or has become resistant to such treatment. In some aspects, the subject has relapsed following remission after treatment with one previous therapy (other than another dose of the cells expressing the CAR), such as, for example, where the dose of the cells is a second treatment, or has become resistant to such treatment. In some aspects, the subject has relapsed following remission after treatment with two or more previous treatments (other than another dose of the cells expressing the CAR), such as, for example, where the dose of the cells is a third or subsequent treatment such as a fourth treatment, or has become resistant to such treatment.

[0201] In some aspects, the subject to be treated according to the provided embodiments includes adult subjects having relapsed or refractory aggressive large B-cell lymphoma (R / R LBCL). Eligible subjects had diffuse large B-cell lymphoma (DLBCL, not otherwise specified [NOS]; including DLBCL transformed from indolent histology [tDLBCL]), high-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements with DLBCL histology, primary mediastinal B-cell lymphoma (PMBCL), or follicular lymphoma grade 3B after treatment with two or more previous therapies. In some embodiments, subjects having secondary CNS lymphoma may be treated according to the provided embodiments. In some aspects, subjects who achieved a complete response but relapsed after infusion of an anti-CD19 CAR may be treated according to the provided embodiments. In some embodiments, subjects who achieved stable disease (SD) as their best response after the first infusion of a CAR-expressing T-cell therapy, e.g., subjects previously administered engineered T-cells expressing the same CAR+ T-cells, may be treated according to the provided embodiments as a second infusion or cycle of the CAR-expressing T-cell therapy.

[0202] In some embodiments, at the time of or prior to administration of the cell dose, the subject is identified as having or being suspected of having relapsed or refractory large B-cell lymphoma; and / or the subject has been or is being treated with an anthracycline and one or more CD20-targeted agents; and / or the subject has or is suspected of having relapsed or refractory disease after two or more lines of therapy or after autologous HSCT; and / or the subject is identified as having or being suspected of having an ECOG performance status of 1 or 2; and / or if the subject has received a previous CD19-targeted therapy, a biological sample obtained from the subject after the previous CD19-targeted therapy contains cells expressing CD19. In some embodiments, administration of the cell dose is by delivery to an outpatient.

[0203] In some settings, subjects treated according to the provided manner, for example, in an outpatient setting, such as a non-tertiary center, include adult patients with relapsed / refractory B-cell NHL. In some settings, for example, in an outpatient setting, subjects treated according to the provided manner include subjects with diffuse large B-cell lymphoma (DLBCL), transformed DLBCL (tDLBCL) arising from follicular lymphoma, and high-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements with DLBCL histology. In some settings, for example, in an outpatient setting, subjects treated according to the provided manner include subjects who have been treated with anthracycline and rituximab and have relapsed / refractory disease after two or more lines of systemic therapy for DLBCL or after autologous HSCT.

[0204] In some embodiments, prior to administration of the dose of the cells effected by outpatient delivery, the provided manner involves identifying or selecting a subject who is, or has, the following with respect to administration of the dose of the cells: relapsed or refractory large B-cell lymphoma; and / or anthracycline and one or more CD20-targeted agents; and / or relapsed or refractory disease after two or more lines of therapy or after autologous HSCT; and / or an ECOG performance status of 1 or 2; and / or, if the subject has previously received a CD19-targeted therapy, a biological sample obtained from the subject after the previous CD19-targeted therapy contains cells that express CD19.

[0205] In some embodiments, prior to administration of the cell dose, the provided embodiments involve identifying or selecting a subject having, with respect to administration of the cell dose: double / triple hit lymphoma; chemotherapy-resistant lymphoma, optionally chemotherapy-resistant DLBCL; malignancy, optionally not having achieved a complete remission (CR) due to the efficacy of prior therapy for treating NHL; and / or having relapsed within or less than 1 year after undergoing autologous stem cell transplantation (ASCT); and / or having lymphoma associated with or accompanied by involvement of the central nervous system (CNS).

[0206] In some scenarios, the subject to be treated according to the provided modalities includes adult subjects who have relapsed from or are resistant to a single-line immunochemotherapy for aggressive B-cell NHL and are ineligible for HSCT. In some scenarios, the subject to be treated according to the provided modalities includes subjects with diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS; de novo or transformed from follicular lymphoma [tFL]), high-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements with DLBCL histology (double / triple hit lymphoma [DHL / THL]), and subjects with follicular lymphoma grade 3B, following one previous line of immunochemotherapy including anthracycline and CD20-targeted agents. In some scenarios, the subject to be treated according to the provided modalities includes subjects with secondary CNS involvement. In some scenarios, the subject to be treated according to the provided modalities includes subjects who are eligible for CAR T-cell therapy but are ineligible for both high-dose chemotherapy and HSCT and are considered transplant ineligible (TNE). In some scenarios, subjects who are TNE include subjects who meet at least one of the following TNE criteria: (a) age ≥ 70 years; (b) ECOG performance status 2; and / or (c) impaired pulmonary function (diffusing capacity for carbon monoxide [DLCO] ≤ 60%, provided SaO2 ≥ 92% on room air and CTCAE ≤ 1 for dyspnea), cardiac function (left ventricular ejection fraction [LVEF] ≥ 40% and < 50%), renal function (creatinine clearance > 30 and 60 mL / min), or liver function (AST / ALT > 2 and ≤ 5 x ULN). In some scenarios, the subject to be treated according to the provided modalities includes subjects who, for example, as the second infusion of CAR-expressing T-cell therapy, achieved a complete response (CR) after the first infusion but relapsed, and who have previously received engineered T-cells expressing the same CAR+ T-cells, such as CAR-expressing T-cell therapy.

[0207] In some embodiments, prior to administration of the cell dose, the provided embodiments involve identifying or selecting a subject who has relapsed / refractory NHL with respect to administration of the cell dose; is identified or determined to be ineligible for both high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT); and has relapsed following remission after treatment with one prior therapy for the disease or condition other than another dose of cells expressing a CAR, or has become resistant to that therapy.

[0208] In some embodiments, prior to administration of the cell dose, the provided embodiments involve identifying or selecting a subject who, with respect to administration of the cell dose, is or has: age 70 years or older; and / or an Eastern Cooperative Oncology Group (ECOG) performance status of 2; and / or impaired lung function, optionally using a carbon monoxide diffusing capacity of the lung (DLCO) of 60% or less or about 60% or less; and / or impaired cardiac function, optionally using a left ventricular ejection fraction (LVEF) of less than 50% or about 50% or less; and / or impaired renal function, optionally using a calculated creatinine clearance of less than 60 mL / min or about 60 mL / min or less; and / or impaired liver function, optionally using aspartate aminotransferase (AST) and alanine aminotransferase (ALT) more than 2 times the upper limit of normal (ULN) or about 2 times the upper limit of normal.

[0209] In some aspects, the subjects to be treated according to the provided embodiments include subjects with appropriate organ function. In some aspects, exemplary criteria for determining appropriate organ function include saturated O2 concentration SaO2 ≥ 92% in room air and Common Terminology Criteria for Adverse Events (CTCAE) ≤ 1 for dyspnea; LVEF ≥ 40%; calculated creatinine clearance (Cockcroft and Gault) > 30 mL / min; AST / ALT ≤ 5 × ULN; appropriate bone marrow function to receive lymphodepleting chemotherapy; and / or total bilirubin < 2.0 mg / dL (or < 3.0 mg / dL for subjects with Dubin-Johnson syndrome or lymphomatous infiltration of the liver).

[0210] In some embodiments, the disease or condition is an infectious disease or condition, such as, but not limited to, viral infection, retroviral infection, bacterial infection, and protozoal infection, immunodeficiency, cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, BK polyomavirus, or is related thereto. In some embodiments, the disease or condition is an autoimmune or inflammatory disease or condition, such as arthritis, such as rheumatoid arthritis (RA), type I diabetes, systemic lupus erythematosus (SLE), inflammatory bowel disease, psoriasis, scleroderma, autoimmune thyroid disease, Graves' disease, Crohn's disease, multiple sclerosis, asthma, and / or a disease or condition related to transplantation.

[0211] In some embodiments, the antigen associated with the disease or disorder is αvβ6 integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (also known as CA9, CAIX or G250), cancer testis antigen, cancer / testis antigen 1B (also known as CTAG, NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), cyclin, cyclin A2, C-C motif chemokine ligand 1 (CCL-1), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138, CD171, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), epidermal growth factor receptor type III variant (EGFRvIII), 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 (GPRC5D), 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-22Rα), IL-13 receptor alpha2 (IL-13Rα2), kinase insert domain receptor (kdr), kappa light chain, L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, leucine-rich repeat-containing 8 family member A (LRRC8A), Lewis Y, melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligand, Melan-A (MART-1), neural cell adhesion molecule (NCAM), tumor fetal antigen, melanoma-predominantly expressed antigen (PRAME), progesterone receptor, prostate-specific antigen, prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), receptor-type tyrosine kinase-like orphan receptor 1 (ROR1), survivin, trophoblast glycoprotein (TPBGSelected from among tumor - associated glycoprotein 72 (TAG72, also known as 5T4), tyrosinase - related protein 1 (TRP1, also known as TYRP1 or gp75), tyrosinase - related protein 2 (TRP2, also known as dopachrome tautomerase, dopachrome delta - isomerase or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms tumor 1 (WT - 1), pathogen - specific antigen or pathogen - expressed antigen, or antigen related to a universal tag, and / or a biotinylated molecule, and / or a molecule expressed by HIV, HCV, HBV or other pathogens. Antigens targeted by the receptor in some embodiments include antigens associated with B - cell malignancies, such as any of several known B - cell markers. In some embodiments, the antigen is, or comprises, CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30. In some embodiments, the disease or condition is a B - cell malignancy, such as large - cell type B - cell lymphoma (e.g., DLBCL), and the antigen is CD19.

[0212] In some embodiments, the antigen is, or comprises, a pathogen - specific antigen or pathogen - expressed 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. In some embodiments, cell therapy, such as adoptive T - cell therapy, is performed by autologous transfer in which cells are isolated from a subject scheduled to receive the cell therapy, or from a sample derived from such a subject, and / or prepared in another manner. Thus, in some aspects, the cells are derived from a subject in need of treatment, e.g., a patient, and the cells are administered to the same subject after isolation and processing.

[0213] In some embodiments, cell therapy, such as adoptive T cell therapy, is performed by allogeneic transfer in which cells are isolated from and / or prepared in another manner from a subject other than the subject intended to receive the cell therapy or a subject other than the subject ultimately receiving the cell therapy, e.g., a first subject. In such embodiments, the cells are then administered to a different subject of the same species, e.g., a second subject. In some embodiments, the first and second subjects are genetically identical. In some embodiments, the first and second subjects are genetically similar. In some embodiments, the second subject expresses the same HLA class or supertype as the first subject.

[0214] Cells can be administered by any suitable means, e.g., by bolus infusion, injection, e.g., intravenous or subcutaneous injection, intraocular injection, periocular injection, subretinal injection, intravitreal injection, transseptal injection, subtenon injection, retrobulbar injection, peribulbar injection, or posterior juxtascleral delivery. In some embodiments, the cells are administered parenterally, intrapulmonary, and intranasally and, when local treatment is desired, by intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, a given dose is administered by a single bolus injection of the cells. In some embodiments, the dose is administered by, e.g., repeated bolus injection of the cells over a period of 3 days or less or by continuous infusion of the cells. In some embodiments, the administration of the cell dose or any additional treatment, e.g., lymphodepletion therapy, intervention therapy, and / or combination therapy, is performed by delivery for an outpatient.

[0215] In some embodiments, administration of the cell dose or any additional treatment, such as lymphodepletion therapy, interventional therapy, and / or combination therapy, is performed by outpatient visits of inpatients. In some aspects, administration of the cell dose or any additional treatment, such as lymphodepletion therapy, interventional therapy, and / or combination therapy, is performed in the setting of inpatients, for example, at a university medical center. In some aspects, the treatment is received in the setting of outpatients, for example, at a medical center other than a university. In some aspects, administration and management of cell therapy or any additional treatment, such as lymphodepletion therapy, interventional therapy, and / or combination therapy, in the setting of outpatients can lead to broader utilization and improved access in community / non-university centers.

[0216] For the prevention or treatment of a disease, the appropriate dosage may depend on the type of disease being treated, the type of cell or recombinant receptor, whether the cell administration is for prophylactic or therapeutic purposes, the severity and course of the disease, previous tr...

Claims

1. A composition comprising a dose of T cells for use in treating a subject having or suspected of having a disease or condition that is relapsed or refractory large B-cell lymphoma (r / r LBCL), (i) the dose of T cells comprises a chimeric antigen receptor (CAR) that specifically binds to CD19; wherein the CAR comprises an extracellular antigen-binding domain specific for CD19, a transmembrane domain, a cytoplasmic signaling domain derived from 4-1BB, and a cytoplasmic signaling domain derived from CD3 zeta, (ii) the dose of T cells comprises from 1×10 7 cells or about 1×10 7 cells of viable CAR-expressing T cells to 2×10 8 cells or about 2×10 8 cells of viable CAR-expressing T cells, (iii) the dose of T cells comprises a ratio of CD4+ T cells expressing CAR:CD8+ T cells expressing CAR of approximately 1:5 to approximately 5:1, and (iv) at the time of or immediately prior to administration of the dose of cells, the subject is identified or has been identified as ineligible for both high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT), A composition.

2. Use of a composition comprising a dose of T cells in the manufacture of a medicament for treating a subject having or suspected of having a disease or condition that is relapsed or refractory large B-cell lymphoma (r / r LBCL), (i) the dose of T cells comprises a chimeric antigen receptor (CAR) that specifically binds to CD19; wherein the CAR comprises an extracellular antigen-binding domain specific for CD19, a transmembrane domain, a cytoplasmic signaling domain derived from 4-1BB, and a cytoplasmic signaling domain derived from CD3 zeta, (ii) the dose of T cells comprises from 1×10 7 cells or about 1×10 7 cells of viable CAR-expressing T cells to 2×10 8 cells or about 2×10 8 containing up to (iii) the dose of the T cells comprising a ratio of CD4+ T cells expressing CAR:CD8+ T cells expressing CAR of approximately 1:5 to approximately 5:1, and (iv) at the time of administration of the dose of the cells or immediately prior thereto, the subject is identified or has been identified as ineligible for both high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT), Use. Claim 3 (a) the LBCL is selected from aggressive non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), DLBCL transformed from an indolent lymphoma other than FL, DLBCL transformed from marginal zone lymphoma (tMZL), DLBCL transformed from chronic lymphocytic leukemia (tCLL; Richter), high-grade B-cell lymphoma (HGBCL), double / triple hit lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), transformed follicular lymphoma (tFL), and / or follicular lymphoma (FL); or (b) the large B-cell lymphoma is high-grade B-cell lymphoma (HGBCL), (c) the large B-cell lymphoma is double / triple hit lymphoma, (d) the large B-cell lymphoma is primary mediastinal B-cell lymphoma (PMBCL), (e) the large B-cell lymphoma is mantle cell lymphoma (MCL), (f) the large B-cell lymphoma is not primary central nervous system lymphoma (PCNSL), (g) the large B-cell lymphoma is transformed follicular lymphoma (tFL), or (h) the large B-cell lymphoma is follicular lymphoma (FL), The composition according to claim 1. Claim 4 The composition according to claim 3, wherein the DLBCL is DLBCL NOS (de novo or transformed from indolent lymphoma).

5. The composition according to claim 3, wherein the FL is follicular lymphoma grade 3B (FL3B).

6. The HGBCL is (i) having rearrangement of MYC and BCL2 and / or BCL6, and / or (ii) having a DLBCL histological pattern, The composition according to claim 3.

7. The LBCL is FL, and the FL is associated with co-expression of CD10, BCL6, and BCL2 within follicles and / or rearrangement of t(14;18) / (q32;q21) (IGH-BCL2) and / or BCL6, The composition according to claim 3 or 5.

8. At the time of use of the composition in a subject or immediately prior thereto, the subject has relapsed following remission after treatment with two or more previous therapies, three or more previous therapies, or four or more previous therapies for a disease or condition other than another dose of cells expressing a CAR, or is resistant thereto. The composition according to any one of claims 1 and 3 to 7.

9. (a) the previous therapy comprises an anthracycline and one or more CD20 targeting agents, (b) when the previous therapy is a previous CD19 targeted therapy, a biological sample obtained from the subject after the previous CD19 targeted therapy comprises cells expressing CD19, (c) the previous therapy comprises allogeneic or autologous HSCT, and / or (d) the subject has not achieved a complete remission (CR) in response to the previous therapy. The composition according to claim 8.

10. one or more of said CD20 targeting agents being, (i) including rituximab, and / or (ii) R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (oncovin), and prednisone), the composition according to claim 9.

11. the composition according to claim 9, wherein the subject has relapsed within 1 year or less than 1 year after receiving HSCT.

12. (a) at or before use of the composition in a subject, (i) the subject is identified as having an aggressive or high-risk disease or having a poor prognosis, (ii) the subject is identified as having a chemotherapy-resistant disease or having a persistent or recurrent disease after chemotherapy, (iii) the subject is identified as having a chemotherapy-resistant lymphoma, and / or (iv) the subject is identified or is to be identified as having a lymphoma with or including central nervous system (CNS) complications or secondary CNS lymphoma; and / or (b) at or before use of the composition in a subject, at least 70%, at least 80%, at least 90%, or at least 95% of the subjects treated with the composition, who are identified or are to be identified as having a lymphoma with or showing CNS complications or secondary lymphoma, have achieved resolution of the CNS disease, (c) the subject is 65 years of age or older, (d) among the treated subjects, more than 35% or about more than 35%, more than 40% or about more than 40%, more than 45% or about more than 45%, or more than 50% or about more than 50%, or any value between any of the foregoing, are 65 years of age or older, (e) at or before use of the composition in a subject, the subject is identified or is to be identified as having cardiac dysfunction, (f) at the time of or prior to use of the composition in a subject, the subject is identified as having or is identified with renal dysfunction, (g) at the time of or prior to use of the composition in a subject, the subject is identified as having or is identified with pulmonary dysfunction, (h) at the time of or prior to use of the composition in a subject, the subject is identified as having or is identified with hepatic dysfunction, (i) at the time of or prior to use of the composition in a subject, the subject has leukapheresis to generate doses of CD4 + T cells and CD8 + T cells and receives bridging chemotherapy between the administration of doses of CD4 + T cells and CD8 + T cells, (j) at the time of or prior to use of the composition in a subject, the subject has received bridging chemotherapy for disease control after a previous therapy, (k) at the time of or prior to use of the composition in a subject, the subject is identified as ineligible or is identified with respect to high-dose chemotherapy, (l) at the time of or prior to use of the composition in a subject, the subject is identified as ineligible or is identified with respect to hematopoietic stem cell transplantation (HSCT), (m) at the time of or prior to use of the composition in a subject, the subject is identified as ineligible or is identified with respect to both high-dose chemotherapy and HSCT, and / or (n) the subject is identified as having or is identified with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0, 1, or 2, The composition according to any one of claims 1 and 3 to 11.

13. (a) the chemoresistant lymphoma is chemoresistant DLBCL; (b) the subject is identified as having or is identified as having cardiac dysfunction with a left ventricular ejection fraction (LVEF) of less than 50% or about less than 50%; (c) the subject is identified as having or is identified as having renal dysfunction with a calculated creatinine clearance of less than 60 mL / min or about less than 60 mL / min; (d) the subject is identified as having or is identified as having pulmonary dysfunction with a carbon monoxide diffusing capacity of the lung (DLCO) of 60% or less or about 60% or less; (e) the subject is identified as having or is identified as having liver dysfunction with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) more than 2 times the upper limit of normal (ULN) or about more than 2 times; and / or (f) the bridging chemotherapy is one or more of the following: rituximab - gemcitabine + oxaliplatin, dexamethasone, radiotherapy, rituximab, prednisone, BR, lenalidomide, gemcitabine + oxaliplatin, brentuximab vedotin, ibrutinib, bendamustine, and / or gemcitabine + rituximab selected from one or more of: The composition according to claim 12.

14. Before use of the composition in a subject, (a) the subject is identified as having or is identified as having a sum of the product dimensions (SPD) of the tumor in the subject of 50 cm 2 or more or about 50 cm 2 or more, or (b) the subject has a positron emission tomography (PET)-positive disease The composition according to any one of claims 1 and 3 - 13.

15. Prior to use of the composition in a subject, whether the subject has or is the following, the subject has been identified or selected for treatment with the composition: Composition according to any one of claims 1 and 3 - 14 (a) Relapsed or refractory large B-cell lymphoma; and / or Anthracycline and one or more CD20-targeting agents; and / or Relapsed or refractory disease after two or more lines of therapy or after autologous HSCT; and / or Having an ECOG performance status of 0, 1, or 2; and / or If the subject has received a prior CD19-targeted therapy, a biological sample obtained from the subject after the prior CD19-targeted therapy contains cells expressing CD19 (b) An age of 70 years or older; and / or An ECOG performance status of 2; and / or Pulmonary dysfunction; and / or Cardiac dysfunction; and / or Renal dysfunction; and / or Liver dysfunction; and / or (c) Double / triple hit lymphoma Chemotherapy-resistant lymphoma Not achieving a CR in response to a prior therapy for treating a malignancy; and / or Relapsing within 1 year or less than 1 year after receiving autologous stem cell transplantation (ASCT); and / or Having a lymphoma with or including CNS complications.

16. The composition according to claim 15, which is the following: (a) The subject has pulmonary dysfunction with a DLCO of 60% or less or about 60% or less (b) the subject has a cardiac dysfunction with an LVEF of less than 50% or approximately less than 50%; (c) the subject has a renal dysfunction with a calculated creatinine clearance of less than 60 mL / min or approximately less than 60 mL / min; (d) the subject has a liver dysfunction with AST and ALT more than 2 times the ULN or approximately more than 2 times the ULN; (e) the subject has a chemotherapy-resistant lymphoma that is chemotherapy-resistant DLBCL; and / or (f) the subject has a double / triple hit lymphoma that is NHL.

17. The composition according to any one of claims 1 and 3 to 16, wherein the dose of T cells is CD4+ T cells and CD8+ T cells.

18. The composition according to any one of claims 1 and 3 to 17, wherein the composition is formulated as a plurality of separate compositions, and the plurality of separate compositions include a first composition containing the CD8+ T cells and a second composition containing the CD4+ T cells.

19. The composition according to claim 18, wherein the first composition is for administration before the second composition.

20. The composition according to claim 19, wherein the first composition and the second composition are for administration at an interval of 48 hours or less.

21. The CD4 + T cells contain the CD19 CAR, and / or the CD8 + T cells contain the CD19 CAR, the composition according to any one of claims 1 to 20.

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

23. The dose of the T cells is CD4 expressing CAR at a ratio of 1:1 +T cells: CD8 expressing CAR + The composition according to any one of claims 1 and 3 to 22, comprising the ratio of T cells.

24. CD4 + T cells and CD8 + The dose of T cells is 2.5×10 7 cells or about 2.5×10 7 cells to 1.5×10 8 cells or about 1.5×10 8 cells of total recombinant receptor-expressing T cells; 5×10 7 cells or about 5×10 7 cells to 1×10 8 cells or about 1×10 8 cells of total recombinant receptor-expressing T cells; 5×10 7 cells or about 5×10 7 cells of total recombinant receptor-expressing T cells; 1×10 8 cells or about 1×10 8 cells of total recombinant receptor-expressing T cells; or 1.5×10 8 cells or about 1.5×10 8 cells of total recombinant receptor-expressing T cells The composition according to any one of claims 1 and 3 to 23, comprising

25. Before use of the composition in a subject, the subject has been pre-conditioned with a lymphodepleting therapy comprising fludarabine and / or cyclophosphamide. The composition according to any one of claims 1 and 3 to 24.

26. The composition according to claim 25, wherein the dose of the T cells and / or the lymphodepleting therapy is for administration via delivery to an out-patient.

27. The use of the composition in a subject and any follow-up are carried out as an out-patient and / or without the need for hospitalization or an overnight stay in a hospital; and If the subject exhibits persistent fever, or fever that may or may not decrease by more than 1°C after treatment with an antipyretic, the subject is admitted to a hospital or stays overnight in a hospital and / or is administered an agent or treatment for the treatment, prevention, reduction, or attenuation of neurotoxicity and / or cytokine release syndrome or the risk thereof, the composition according to any one of claims 1 and 3 to 26.

28. Before use of the composition in a subject, the subject has not been administered an agent or treatment for the treatment, prevention, reduction, or attenuation of neurotoxicity and / or cytokine release syndrome or the risk thereof, the composition according to any one of claims 1 and 3 to 27.

29. An agent or treatment for the treatment, prevention, reduction, or attenuation of neurotoxicity and / or cytokine release syndrome or the risk thereof is administered to the subject, the composition according to any one of claims 1 and 3 to 28.

30. The agent is or includes an anti-IL-6 antibody, an anti-IL-6 receptor antibody, or a steroid, and / or The agent is or includes tocilizumab, siltuximab, dexamethasone, or methylprednisolone, the composition according to claim 29.

31. At the time of or before use of the composition in a subject, the subject is or has been treated with an anthracycline and one or more CD20-targeted agents; and / or the subject is or has a disease that is refractory or resistant after two or more lines of treatment or after autologous HSCT; and / or the subject is or has been identified as having an ECOG performance status of 0, 1, or 2; and / or If the subject has received a previous CD19-targeted therapy, a biological sample obtained from the subject after the previous CD19-targeted therapy contains cells expressing CD19; and / or The administration of the cell dose is performed via delivery for foreign patients. The composition according to any one of claims 1 and 3 to 30.

32. (a) At least 40%, at least 50%, at least 60%, at least 70% of the subjects identified as having or having had double / triple hit lymphoma, or recurrence after administration of ASCT, before or at the time of use of the composition in the subject achieve an OR, or a persistent OR over 3 months or more or 6 months or more, and / or (b) At least 35%, at least 40%, or at least 50% of the subjects treated with the composition achieve a complete response (CR); At least 60%, 70%, 80%, 90%, or 95% of the subjects achieving CR show a persistent CR over 3 months or more or 6 months or more; and / or At least 60%, 70%, 80%, 90%, or 95% of the subjects achieving CR by 1 month and / or by 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 after achieving CR; and / or At least 50%, at least 60%, or at least 70% of the subjects treated with the composition achieve an objective response (OR); At least 60%, 70%, 80%, 90%, or 95% of the subjects achieving OR show a persistent OR over 3 months or more or 6 months or more; and / or At least 35%, at least 40%, or at least 50% of the subjects who achieved an OR remain effective or survive over 3 months or more and / or 6 months or more after achieving the OR; and / or At least 40%, at least 50%, at least 60%, at least 70% of the subjects identified as having or having had double / triple hit lymphoma or recurrence after administration of ASCT, at the time of or prior to use of the composition in the subjects, achieve an OR or a durable OR over 3 months or more or 6 months or more The composition according to any one of claims 1 and 3 to 31.

33. (a) CR or OR is durable over 3 months or more or 6 months or more; and / or At least 20%, at least 25%, at least 35%, at least 40%, or at least 50% of the subjects treated with the composition achieve a durable CR over 3 months or more or 6 months or more; and / or At least 60%, 70%, 80%, 90%, or 95% of the subjects treated with the composition who achieved a CR remain in CR, remain effective, or survive over 3 months or more or 6 months or more or 9 months or more; and / or At least 60%, 70%, 80%, 90%, or 95% of the subjects treated with the composition who achieved a CR by 1 month and / or by 3 months remain effective, remain in CR, and / or survive over a period longer than 3 months or more and / or 6 months or more and / or 9 months or more, or survive without progression; and / or At least 50%, at least 60%, or at least 70% of the subjects treated with the composition achieve an OR; At least 60%, 70%, 80%, 90%, or 95% of the subjects achieve a persistent OR over 3 months or more or 6 months or more; and / or At least, at least 35%, at least 40%, or at least 50% of the subjects treated with the composition and achieving OR remain effective and / or survive over 3 months or more and / or 6 months or more; (b) At least 35%, at least 40%, or at least 50% of the subjects treated with the composition achieve CR or remission of the CNS disease; At least 60%, 70%, 80%, 90%, or 95% of the subjects achieving CR remain in CR over 3 months or more or 6 months or more; and / or At least 60%, 70%, 80%, 90%, or 95% of the subjects achieving CR or remission of the CNS disease by 1 month and / or by 3 months remain effective, remain in CR, and / or survive or survive without progression over 3 months or more and / or 6 months or more and / or longer than 9 months; and / or At least 50%, at least 60%, or at least 70% of the subjects treated with the composition achieve OR or remission of the CNS disease; At least 60%, 70%, 80%, 90%, or 95% of the subjects achieve OR over 3 months or more or 6 months or more; and / or At least 60%, 70%, 80%, 90%, or 95% of the subjects achieving OR or remission of the CNS disease remain effective and / or survive over 3 months or more and / or 6 months or more; and / or The brain lesions are reduced in size or volume by more than 25%, 50%, 75%, or more, or about more than 25%, 50%, 75%, or more; Reduction, remission, or clearance of CNS disease is achieved in at least 35%, at least 40%, or at least 50% of the subjects treated with the composition. (c) More than 50% or about more than 50%, about more than 60% or about more than 60%, about more than 70% or about more than 70%, or about more than 80% or about more than 80% of the subjects treated with the composition do not exhibit cytokine release syndrome (CRS) of grade 3 or higher and / or do not exhibit neurotoxicity of grade 3 or higher, and / or more than 40% or more than 50% or more than 55% do not exhibit any neurotoxicity or CRS, and / or (d) At least 50% of the subjects treated with the composition achieve CR; At least 70% of the subjects treated with the composition achieve OR; and More than 50% or about more than 50% of the subjects treated with the composition do not exhibit any grade of CRS or neurotoxicity; and More than 80% or about more than 80% of the subjects treated with the composition do not exhibit CRS of grade 3 or higher and / or do not exhibit neurotoxicity of grade 3 or higher. The composition according to claim 32.

34. More than 30%, 35%, 40%, or 50%, or about more than 30%, 35%, 40%, or 50% of the subjects treated with the composition do not exhibit any grade of CRS or neurotoxicity; and / or At least 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or at least about 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the subjects treated with the composition do not exhibit the onset of CRS earlier than 3 days after treatment and / or do not exhibit the onset of neurotoxicity earlier than 5 days after treatment; and / or The median onset of neurotoxicity among subjects treated with the composition is at or after the median peak of CRS or the median time to resolution of CRS in subjects treated with the composition, and / or the median onset of neurotoxicity among subjects treated with the composition is greater than 8, 9, 10, or 11 days or greater than about 8, 9, 10, or 11 days. The composition according to claim 33.

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