Combination therapy with immunomodulatory compounds

Abstract

This disclosure provides methods, compositions, and uses encompassing immunotherapy (e.g., adoptive cell therapy, e.g., T-cell therapy) and immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or inhibitors of E3-ubiquitin ligase. [Solution] A pharmaceutical for the treatment of a disease or condition in a subject, wherein the pharmaceutical comprises an immunomodulatory compound, and at the time of initiation of administration of the immunomodulatory compound, the subject has previously been administered a T-cell therapy composition containing T cells for the treatment of the disease or condition, the immunomodulatory compound is a thalidomide analog or thalidomide derivative that promotes the degradation of Icarus and / or Aeolus, and the administration of the immunomodulatory compound is initiated at least one week after the initiation of administration of the T-cell therapy composition.

Description

[Technical Field]

[0001] Cross-reference of related applications This application is based on the following U.S. provisional applications: U.S. provisional application number 62 / 492,947 filed on May 1, 2017, titled "COMBINATION OF A CELL THERAPY AND AN IMMUNOMODULATORY COMPOUND"; U.S. provisional application number 62 / 538,670 filed on July 29, 2017, titled "COMBINATION OF A CELL THERAPY AND AN IMMUNOMODULATORY COMPOUND"; U.S. provisional application number 62 / 549,390 filed on August 23, 2017, titled "COMBINATION OF A CELL THERAPY AND AN IMMUNOMODULATORY COMPOUND"; U.S. provisional application number 62 / 580,433 filed on November 1, 2017, titled "COMBINATION OF A CELL THERAPY AND AN IMMUNOMODULATORY COMPOUND"; and "COMBINATION OF Priority is claimed from U.S. Provisional Application No. 62 / 596,753, filed on December 8, 2017, entitled “A CELL THERAPY AND AN IMMUNOMODULATORY COMPOUND,” the entire contents of which are incorporated by reference.

[0002] Inclusion by referencing sequence listings This application is filed together with an electronic sequence listing. The sequence listing is provided as a file named 735042009640SeqList.TXT, created on April 30, 2018, and is 328,355 bytes in size. The information in the electronic sequence listing is incorporated entirely by reference.

[0003] field This disclosure relates in several aspects to methods, compositions and uses encompassing immunotherapy (e.g., adoptive cell therapy, e.g., T cell therapy) and immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or inhibitors of E3-ubiquitin ligase. The methods, compositions and uses provided include methods, compositions and uses for combination therapy encompassing the administration or use of one or more immunomodulatory compounds in combination with T cell therapy, such as genetically modified T cell therapy, which involves cells engineered with recombinant receptors such as chimeric antigen receptor (CAR) expressing T cells. Also provided are compositions for use in the methods, methods of administration to subjects, manufacturing articles and kits. In several aspects, the features of the methods and cells provide increased or improved activity, potency, persistence, enlargement and / or proliferation of endogenous T cells mobilized by T cells for adoptive cell therapy or immunotherapeutic agents. [Background technology]

[0004] background With regard to immunotherapy, for example, with regard to immunotherapy involving the administration of engineered T cells for adoptive therapy, various strategies are available. For example, strategies are available for engineering T cells that express genetically engineered antigen receptors such as CARs, and for administering compositions containing such cells to a target. When administered to a target, there is a need for improved strategies to enhance the efficacy of the cells, for example, by improving the persistence, activity, and / or proliferation of the cells. Methods, compositions, kits, and systems are provided to meet such needs. [Overview of the project]

[0005] overview This specification provides combination therapies comprising immunotherapy encompassing T cell function or activity, such as T cell therapy, and the administration of immunomodulatory compounds, such as structural or functional analogs or derivatives of thalidomide and / or E3-ubiquitin ligase inhibitors. In some aspects, the methods provided enhance or modulate T cell proliferation and / or activity related to the administration of immunotherapy or immunotherapy agents (e.g., compositions comprising cells (e.g., CAR-expressing T cells) for adoptive cell therapy (e.g., T cell therapy)). In some embodiments, the combination therapy generally comprises the administration of immunomodulatory compounds, such as structural or functional analogs of thalidomide and / or E3-ubiquitin ligase inhibitors (e.g., lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione)) and T cell therapy (e.g., compositions comprising cells (e.g., CAR-expressing T cells) for adoptive cell therapy (e.g., T cell therapy)).

[0006] This specification provides a method of treatment comprising (a) administering T-cell therapy to a subject having a disease or condition; and (b) administering an immunomodulatory compound to the subject.

[0007] Provided herein is a method of treatment comprising administering T-cell therapy to a subject having a disease or condition, wherein at the start of administration of T-cell therapy, the subject has been administered an immunomodulatory compound and / or has been treated with an immunomodulatory compound and / or the subject's blood or biopsy sample contains detectable levels of manipulated T-cell therapy T cells.

[0008] Provided herein is a method of treatment comprising administering an immunomodulatory compound to a subject having a disease or condition, wherein, at the commencement of administration of the immunomodulatory compound, the subject has previously received T-cell therapy for the treatment of the disease or condition, and / or a blood or biopsy sample of the subject contains detectable levels of manipulated T-cell therapy T cells. In some embodiments, the method thereby prevents, reduces or improves one or more symptoms or outcomes of the disease or condition.

[0009] In some embodiments of any method provided herein, (a) the amount of immunomodulatory compound administered is insufficient to improve, reduce or prevent a disease or condition or its symptoms or outcome, as a monotherapy and / or in the absence of T-cell therapy; and / or (b) the amount of immunomodulatory compound administered is insufficient to improve, reduce or prevent a disease or condition or its symptoms or outcome in a subject, as a monotherapy and / or in the absence of T-cell therapy; and / or (c) the method thereby improves, reduces or prevents a disease or condition or its symptoms or outcome. The load is reduced or improved to a degree exceeding the combination of (i) the degree of reduction or improvement in a population of subjects having the disease or condition, optionally on average, achieved by the administration of an immunomodulator alone, and (ii) the degree of reduction or improvement in a population of subjects having the disease or condition, optionally on average, achieved by the administration of T-cell therapy alone; and / or (d) the amount of the immunomodulatory compound administered in the method, or administered in one or more doses, is a maintenance level dose of the compound, or equivalent to the dose of the compound administered to subjects who demonstrated a response, optionally a complete response, after administration of the compound for treatment.

[0010] In some embodiments of any method provided herein, a disease or condition is refractory or resistant to an immunomodulatory compound and / or becomes refractory or resistant thereto after treatment with an immunomodulatory compound; and / or, a subject or disease or condition is determined to have a mutation or factor that confers resistance to treatment with an immunomodulatory compound to the disease or condition.

[0011] In some embodiments of any method provided herein, the immunomodulatory compound is selected from immunomodulatory drugs (IMiDs), thalidomide analogs, thalidomide derivatives, compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex, inhibitors of Ikaros (IKZF1), inhibitors of Aiolos (IKZF3), and compounds that enhance or promote the ubiquitination and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3).

[0012] This specification provides a method of treatment comprising (a) administering T-cell therapy to a subject having a disease or condition; and (b) administering an immunomodulatory compound to the subject, wherein the immunomodulatory compound is selected from the group consisting of lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or avadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof.

[0013] This specification describes a method of treatment comprising administering T-cell therapy to a subject having a disease or condition, wherein at the start of administration of T-cell therapy, the subject has been administered an immunomodulatory compound and / or has been treated with an immunomodulatory compound and / or the subject's blood or biopsy sample contains detectable levels of manipulated T-cell therapy T cells, wherein the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-I A method is provided, selected from the group consisting of (p)piperidine-2,6-dione, pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers, or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof.

[0014] This specification describes a method of treatment comprising administering an immunomodulatory compound to a subject having a disease or condition, wherein, at the start of administration of the immunomodulatory compound, the subject has previously received T-cell therapy for the treatment of the disease or condition, and / or the subject's blood or biopsy sample contains detectable levels of manipulated T-cell therapy T cells, and the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)pipette A method is provided, selected from the group consisting of lysine-2,6-dione, pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers, or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof.

[0015] In this specification, a method of treatment comprising (a) administering T-cell therapy to a subject having a disease or condition; and (b) administering an immunomodulatory compound to the subject, wherein the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl- The administration of an immunomodulatory compound selected from the group consisting of 4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers, or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, and the initiation of administration of the immunomodulatory compound is (1) at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks after the initiation of T-cell therapy, and / or 2 to 2 weeks after the initiation of T-cell therapy. This is performed 8 days later or 7 to 21 days later; and / or (2) or less: (i) the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) the number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, and is reduced compared to any preceding point in time after T-cell therapy administration; (iii) the number of detectable T-cell therapy cells in the blood becomes undetectable compared to the peak level of detectable T-cell therapy cells in the subject's blood after the start of T-cell therapy administration. (iv) At the point after the peak or maximum level of T cells in the T-cell therapy becomes detectable in the subject's blood, the number of detectable T cells or cells derived therefrom in the subject's blood is less than 10%, less than 5%, less than 1%, or 0% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood.A method is provided in which the percentage of subjects becomes less than 1%; (v) a subject shows disease progression and / or relapse following remission after treatment with T-cell therapy; and / or (iv) a subject shows an increased tumor volume compared to the tumor volume at the time before or after T-cell administration and before the initiation of immunomodulatory compound administration, or thereafter, optionally immediately thereafter or within 1-3 days thereafter.

[0016] This specification includes a method of treatment comprising administering an immunomodulatory compound to a subject who is receiving T-cell therapy to treat a disease or condition prior to the commencement of administration of the immunomodulatory compound, wherein the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino- The administration of an immunomodulatory compound selected from the group consisting of 2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers, or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, is initiated at (1) at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks after the initiation of T-cell therapy, and / or the initiation of T-cell therapy. This is performed 2 to 28 days or 7 to 21 days after; and / or (2) or less: (i) the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) the number of detectable T-cell therapy cells in the blood is reduced compared to any preceding point in time after T-cell therapy administration, after becoming undetectable or reduced after becoming detectable in the blood; (iii) the number of detectable T-cell therapy cells in the blood is reduced compared to the number of detectable T-cell therapy cells in the subject's blood after the start of T-cell therapy administration. (iv) At the point after the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood, the number of detectable T cells or cells derived from the subject in the subject's blood is less than 10%, less than 5%, less than 1%, or 0% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood.A method is provided in which the percentage of subjects becomes less than 1%; (v) a subject shows disease progression and / or relapse following remission after treatment with T-cell therapy; and / or (iv) a subject shows an increased tumor volume compared to the tumor volume at the time before or after T-cell administration and before the initiation of immunomodulatory compound administration, or thereafter, optionally immediately thereafter or within 1-3 days thereafter.

[0017] In this specification, a therapeutically effective dose of an immunomodulatory compound selected from the group consisting of lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers, or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, is administered before initiating administration of the immunomodulatory compound to treat a disease or illness. A method of treatment is provided, which includes administering T-cell therapy to a subject receiving T-cell therapy for treating a disease or condition, wherein the subject is such that, on day 12 to 15 or approximately day 12 to 15, optionally day 14 or approximately day 14, after the start of administration of T-cell therapy for treating a disease or condition: (i) the number of T-cell therapy cells in the subject is less than 75% of the average number of T-cell therapy cells at the same time in multiple subjects who have received the same or similar dose of T-cell therapy; and / or (ii) the number of CD3+ or CD8+ cells, optionally CAR+ T-cells in the blood of the T-cell therapy is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL.

[0018] In this specification, (a) selecting subjects such as (a) on days 12 to 15 or approximately 12 to 15, optionally on day 14 or approximately 14, after the initiation of T-cell therapy to treat a disease or condition: (i) the number of T-cell therapy cells in a subject is less than 75% of the average number of T-cell therapy cells at the same time in multiple subjects administered the same or similar dose of T-cell therapy; and / or (ii) the number of CD3+ or CD8+ cells, optionally CAR+ T-cells in the blood of the T-cell therapy is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL; and (b) lenalidomide (3-(4-amino A method of treatment is provided, which involves administering a therapeutically effective dose of an immunomodulatory compound selected from the group consisting of (1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers, or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof.

[0019] This specification describes a method of treatment comprising administering T-cell therapy to a subject having a disease or condition, wherein, before initiating T-cell therapy, lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers, or mixtures of enantiomers, A method is provided in which an immunomodulatory compound selected from the group consisting of pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof is administered to a subject, and the immunomodulatory compound is administered in a cycle comprising (i) a maximum of 21 consecutive days of administration, including more than 30 days starting from the commencement of administration of the immunomodulatory compound; and / or (ii) a cycle comprising administration over several consecutive days followed by a rest period in which the immunomodulatory compound is not administered, with the rest period exceeding 14 consecutive days; and / or (iii) a cycle comprising administration for 14 consecutive days or less.

[0020] This specification includes a method of treatment comprising administering an immunomodulatory compound to a subject having a disease or condition and being administered T-cell therapy, wherein the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers, or mirror images. A method is provided in which an immunomodulatory compound is administered in a cycle comprising (i) a cycle comprising administration of the immunomodulatory compound for up to 21 consecutive days, comprising more than 30 days starting from the commencement of administration of the immunomodulatory compound; and / or (ii) a cycle comprising administration of the immunomodulatory compound over several consecutive days followed by a rest period in which the immunomodulatory compound is not administered, wherein the rest period exceeds 14 consecutive days; and / or (iii) a cycle comprising administration of the immunomodulatory compound for 14 consecutive days or less.

[0021] In some embodiments of any method provided herein, the administration of an immunomodulatory compound includes (i) at least one cycle of more than 30 days from the start of administration of the immunomodulatory compound, comprising administration of the compound optionally daily or at least daily for up to 21 consecutive days, and / or the last administration of the compound in the cycle being 21 days or less after the first administration of the compound in the cycle; and / or (ii) at least two cycles, each comprising administration of the compound over several consecutive days followed by a rest period in which the immunomodulatory compound is not administered, the rest period being more than 14 consecutive days; and / or (iii) a cycle comprising administration optionally daily or at least daily for 14 consecutive days or less.

[0022] In some embodiments of any method provided herein, the initiation of administration of an immunomodulatory compound, or the initiation of administration of the compound in at least one cycle, and the initiation of administration of T-cell therapy are optionally performed on the same day or on consecutive days, in parallel; and / or at least one dose of the immunomodulatory compound is administered on the same day as, or within one or two days thereafter, before or after, an administration of a certain dose of T-cell therapy.

[0023] In some embodiments of any method provided herein, the initiation of administration of the immunomodulatory compound, or the initiation of administration of the compound for at least one cycle, is prior to the initiation of administration of T-cell therapy.

[0024] This specification provides a method of treatment comprising administering T-cell therapy to a subject having a disease or condition, wherein an immunomodulatory compound has been administered to the subject prior to the commencement of T-cell therapy, and the cycle comprises (i) a cycle comprising administration for up to 21 consecutive days and including more than 30 days starting from the commencement of administration of the immunomodulatory compound; and / or (ii) a cycle comprising administration for several consecutive days followed by a rest period in which the immunomodulatory compound is not administered, with the rest period exceeding 14 consecutive days; and / or (iii) a cycle comprising administration for 14 consecutive days or less. In some embodiments, the commencement of administration of the immunomodulatory compound occurs within 14 days prior to the commencement of T-cell therapy.

[0025] In any part of the embodiments provided herein, the immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3).

[0026] In some embodiments of any method provided herein, the administration of an immunomodulatory compound is initiated prior to the administration of T cell therapy, (i) at the time when a sample containing T cells to be processed and / or manipulated to bring about the therapy is collected from a subject, or within one week before or after the time, and optionally the sample is an apheresis sample; and / or (ii) within 14 days prior to the commencement of administration of T cell therapy.

[0027] In some embodiments of any method provided herein, T cell therapy comprises cells engineered to express recombinant receptors. In some embodiments, the engineering is one or more steps of an ex vivo manufacturing process, optionally comprising: (1) isolating cells from a biological sample by leukocyte apheresis or apheresis; (2) selecting or concentrating cells by an immunoaffinity-based method; (3) introducing recombinant nucleic acid, optionally a viral vector, into the cells; (4) optionally incubating the engineered cells in the presence of one or more stimulating conditions; (5) formulating the cells in the presence of a cryoprotective substance; and / or (6) formulating the cells for administration to a subject, optionally in the presence of pharmaceutically acceptable excipients.

[0028] In some embodiments of any method provided herein, the method comprises carrying out the manufacturing process and / or manipulating T cells to express recombinant receptors to thereby generate T cell therapy. In some embodiments of any method provided herein, the method comprises contacting cells and immunomodulatory compounds during one or more steps of an ex vivo manufacturing process.

[0029] In some embodiments of any method provided herein, T cell therapy comprises engineered T cells produced by a manufacturing process that includes incubating cells ex vivo in the presence of an immunomodulatory compound.

[0030] In some embodiments of any method provided herein, the method comprises incubating cells in the presence of one or more stimulating conditions, which is carried out in the presence of an immunomodulatory compound.

[0031] In some embodiments of any method provided herein, the administration of the immunomodulatory compound is initiated within 10, 7, 4, 3, or 2 days prior to the initiation of T-cell therapy. In some embodiments of any method provided herein, the administration of the immunomodulatory compound is initiated at least once per cycle after the initiation of T-cell therapy.

[0032] Provided herein is a method of treatment comprising administering an immunomodulatory compound to a subject having a disease or condition and being treated with T-cell therapy, wherein the immunomodulatory compound is administered in cycles of (i) administration of the immunomodulatory compound for up to 21 consecutive days, including more than 30 days starting from the commencement of administration of the immunomodulatory compound; and / or (ii) administration of the immunomodulatory compound over several consecutive days followed by a rest period in which the immunomodulatory compound is not administered, with the rest period exceeding 14 consecutive days; and / or (iii) administration of the immunomodulatory compound for 14 consecutive days or less.

[0033] In some embodiments of any method provided herein, the T cell therapy is a T cell therapy in which the peak number of cells in the blood of the therapy population, optionally CD3+ or CD8+ cells and / or optionally CAR+ T cells, is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL (on average, in multiple subjects treated with T cell therapy in the absence of immunomodulatory compound administration, or in subjects after administration of T cell therapy).

[0034] In some embodiments of any method provided herein, T cell therapy comprises a recombinant receptor and optionally cells expressing a CAR. In some embodiments of any method provided herein, the recombinant receptor comprises an antigen-binding domain specific to a B cell maturation antigen (BCMA).

[0035] In some aspects of any method provided herein, the administration of the immunomodulatory compound is initiated in at least one cycle after the initiation of T-cell therapy. In some aspects of any method provided herein, the administration of the immunomodulatory compound is initiated at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks after the initiation of or final dose of T-cell therapy, and / or 2 to 28 days or 7 to 21 days after the initiation of or final dose of T-cell therapy.

[0036] In this specification, a method of treatment comprising (a) administering T-cell therapy to a subject having a disease or condition; and (b) administering an immunomodulatory compound to the subject, wherein the administration of the immunomodulatory compound is initiated (a) at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks or at least 4 weeks after the initiation of T-cell therapy, and / or 2 to 28 days or 7 to 21 days after the initiation of T-cell therapy; and / or (b) below: (i) the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) the number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally reduced compared to a preceding point in time after the administration of T-cell therapy; (iii) the number of detectable T-cell therapy cells in the blood becomes undetectable or reduced in the subject's blood after the initiation of T-cell therapy. A method is provided in which the peak or maximum number of cells in the T-cell therapy decreases by 1.5 times or more, 2.0 times or more, 3.0 times or more, 4.0 times or more, 5.0 times or more, 10 times or more, or more than 10 times; (iv) at a point after the peak or maximum level of cells in the T-cell therapy becomes detectable in the subject's blood, the number of detectable T cells or cells derived therefrom in the subject's blood is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) the subject shows disease progression after treatment with T-cell therapy and / or relapses following remission; and / or (iv) the subject shows an increased tumor volume compared to the tumor volume at a point in time or thereafter, optionally immediately thereafter or within 1-3 days thereafter, compared to the tumor volume at a point in time or thereafter, optionally immediately thereafter or within 1-3 days thereafter.

[0037] In this specification, a method of treatment comprising administering an immunomodulatory compound to a subject receiving T-cell therapy to treat a disease or condition prior to the commencement of administration of the immunomodulatory compound, wherein the commencement of administration of the immunomodulatory compound occurs at a time at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks or at least 4 weeks after the commencement of T-cell therapy, and / or 2 to 28 days or 7 to 21 days after the commencement of T-cell therapy; and / or (b) below: (i) the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) the number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally reduced compared to a preceding time after administration of T-cell therapy; (iii) the number of detectable T-cell therapy cells in the blood becomes undetectable or reduced in the subject's blood after the commencement of administration of T-cell therapy A method is provided in which the number of detectable T-cell therapy cells decreased by 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or more than 3.0 times, 4.0 times or more than 4.0 times, 5.0 times or more than 5.0 times, 10 times or more than 10 times or more, or more than 10 times; (iv) at a point after the peak or maximum level of T-cell therapy cells became detectable in the subject's blood, the number of detectable T cells or cells derived therefrom in the subject's blood was less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) the subject showed disease progression after treatment with T-cell therapy and / or relapse following remission; and / or (iv) the subject showed an increased tumor volume at a point in time or thereafter, optionally immediately thereafter or within 1 to 3 days thereafter, compared to the tumor volume at a point in time before or after T-cell administration and before the initiation of immunomodulatory compound administration.

[0038] In some embodiments of any method provided herein, the administration of the immunomodulatory compound is initiated at a time after 14 days or about 14 days, after 15 days or about 15 days, after 16 days or about 16 days, after 17 days or about 17 days, after 18 days or about 18 days, after 19 days or about 19 days, after 20 days or about 20 days, after 21 days or about 21 days, after 24 days or about 24 days, or after 28 days or about 28 days.

[0039] In some embodiments of any method provided herein, before the initiation of administration of the immunomodulatory compound, (i) the peak or maximum level of T-cell therapy cells is detectable in the blood of the subject; (ii) the number of detectable T-cell therapy cells in the blood is, optionally, reduced compared to a preceding point in time after administration of the T-cell therapy, and becomes undetectable or reduced after becoming detectable in the blood; (iii) the number of detectable T-cell therapy cells in the blood is 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or more than 3.0 times, or 4.0 times the peak or maximum number of detectable T-cell therapy cells in the blood of the subject after the initiation of administration of the T-cell therapy. Select subjects who: (iv) have decreased by more than 4.0 times, 5.0 times or more, 10 times or more or more; (iv) at the time after the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood, the number of detectable T cells or cells derived from the subject in the subject's blood is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) have shown disease progression after treatment with T-cell therapy and / or have relapsed following remission; and / or (iv) show an increased tumor volume compared to the tumor volume before or after T-cell administration and before the initiation of immunomodulatory compound administration.

[0040] This specification provides a method of treatment which includes administering a therapeutically effective dose of an immunomodulatory compound to a subject who is receiving T-cell therapy to treat a disease or condition prior to the commencement of administration of the immunomodulatory compound, wherein the subject is such that, on days 12 to 15 or approximately 12 to 15, optionally on day 14 or approximately 14, after the commencement of administration of T-cell therapy to treat a disease or condition: (i) the number of T-cell therapy cells in the subject is less than 75% of the average number of T-cell therapy cells at the same time in multiple subjects who have received the same or similar dose of T-cell therapy; and / or (ii) the number of CD3+ or CD8+ cells, optionally CAR+ T-cells in the blood of the T-cell therapy is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL.

[0041] This specification provides a method of treatment comprising (a) selecting a subject on day 12 to 15 or approximately day 12 to 15, optionally day 14 or approximately day 14, after the start of administration of T-cell therapy to treat a disease or condition: (i) the number of T-cell therapy cells in the subject is less than 75% of the average number of T-cell therapy cells at the same time in multiple subjects administered the same or similar dose of T-cell therapy; and / or (ii) the number of CD3+ or CD8+ T-cells, optionally CAR+ T-cells in the blood of the T-cell therapy is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL; and (b) administering a therapeutically effective dose of an immunomodulatory compound to the subject. In some embodiments of any method provided herein, the immunomodulatory compound is administered daily, optionally once daily.

[0042] In some embodiments of any method provided herein, the immunomodulatory compound is administered for more than 7 consecutive days or approximately 7 consecutive days, more than 14 consecutive days or approximately 14 consecutive days, more than 21 consecutive days or approximately 21 consecutive days, more than 21 consecutive days or approximately 21 consecutive days, or more than 28 consecutive days or approximately 28 consecutive days. In some embodiments of any method provided herein, the immunomodulatory compound is administered in a cycle comprising daily administration over several consecutive days followed by a rest period in which the immunomodulatory compound is not administered. In some embodiments, the rest period in which the immunomodulatory compound is not administered is more than 7 consecutive days, more than 14 consecutive days, more than 21 days, or more than 28 days.

[0043] In some aspects of any method provided herein, the cycle of administration of the immunomodulatory compound is repeated at least once. In some aspects, the immunomodulatory compound is administered for at least two cycles, at least three cycles, at least four cycles, at least five cycles, at least six cycles, at least seven cycles, at least eight cycles, at least nine cycles, at least ten cycles, at least eleven cycles, or at least twelve cycles.

[0044] In some embodiments of any method provided herein, administration of an immunomodulatory compound is performed at least from the initiation of T cell administration until the number of detectable T-cell therapy-derived cells in the blood of the subject increases compared to the subject at a preceding time immediately prior to the administration of the immunomodulatory compound or compared to a preceding time after the administration of T-cell therapy; the number of detectable T-cell therapy-derived cells in the blood is within 2.0 times (greater than or less than) the peak or maximum number observed in the subject's blood after the initiation of T cell administration. The treatment continues until the number of detectable T-cell therapy cells in the subject's blood is greater than 10% or approximately 10%, greater than 15% or approximately 15%, greater than 20% or approximately 20%, greater than 30% or approximately 30%, greater than 40% or approximately 40%, greater than 50% or approximately 50%, or greater than 60% or approximately 60% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; and / or until the subject shows a reduction in tumor volume compared to the tumor volume immediately before administration of the T-cell therapy or immediately before administration of the immunomodulatory compound; and / or until the subject achieves complete remission or clinical remission.

[0045] In some embodiments of any method provided herein, the immunomodulatory compound binds to cereblon (CRBN) and / or the CRBN E3 ubiquitin-ligase complex; and / or is an inhibitor of the IKZF1 or Aeolus (IKZF3) transcription factor; and / or enhances the ubiquitination or degradation of IKZF1 or Aeolus (IKZF3).

[0046] In some aspects of any method provided herein, the immunomodulatory compound is thalidomide or a derivative or analog of thalidomide. In some aspects, the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione) or pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)piperidine-2,6-dione), lenalidomide (3-(4-amino These are stereoisomers of (no-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), and abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), or their pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In some embodiments, the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), a stereoisomer of lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion compound, or polymorph.

[0047] In some of the embodiments provided herein, the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), lenalidomide (3 These are stereoisomers of (4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof.

[0048] In some embodiments, the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, or its stereoisomer, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof. In some embodiments, the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione. In some embodiments, the immunomodulatory compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or its stereoisomer, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof. In some embodiments, the immunomodulatory compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

[0049] In some embodiments of any method provided herein, the immunomodulatory compound is administered orally, subcutaneously, or intravenously. In some embodiments, the immunomodulatory compound is administered orally. In some embodiments, the immunomodulatory compound is administered in the form of capsules or tablets.

[0050] In some embodiments of any method provided herein, the immunomodulatory compound is present in amounts of 0.1 mg to 100 mg or about 0.1 mg to about 100 mg, 0.1 mg to 50 mg or about 0.1 mg to 50 mg, 0.1 mg to 25 mg or about 0.1 mg to 25 mg, 0.1 mg to 10 mg or about 0.1 mg to 10 mg, 0.1 mg to 5 mg or about 0.1 mg to 5 mg, 0.1 mg to 1 mg or about 0.1 mg to 1 mg, 1 mg to 100 mg or about 1 mg to 100 mg, 1 mg to 50 mg or about 1 mg to 50 mg, 1 mg to 25 mg or about 1 mg to 25 mg, 1 mg to 10 mg or Payment will be made in amounts of approximately 1 mg to 10 mg, 1 mg to 5 mg or approximately 1 mg to 5 mg, 5 mg to 100 mg or approximately 5 mg to 100 mg, 5 mg to 50 mg or approximately 5 mg to 50 mg, 5 mg to 25 mg or approximately 5 mg to 25 mg, 5 mg to 10 mg or approximately 5 mg to 10 mg, 10 mg to 100 mg or approximately 10 mg to 100 mg, 10 mg to 50 mg or approximately 10 mg to 50 mg, 10 mg to 25 mg, 25 mg to 100 mg or approximately 25 mg to 100 mg, 25 mg to 50 mg or approximately 25 mg to 50 mg, or 50 mg to 100 mg or approximately 50 mg to 100 mg.

[0051] In some aspects of any method provided herein, the immunomodulatory compound is administered once daily, twice daily, three times daily, four times daily, five times daily, or six times daily. In some aspects, the immunomodulatory compound is administered in a total daily dose of at least 0.1 mg / day or at least about 0.1 mg / day, at least 0.5 mg / day or at least about 0.5 mg / day, at least 1.0 mg / day or at least about 1.0 mg / day, at least 2.5 mg / day or at least about 2.5 mg / day, at least 5 mg / day or at least about 5 mg / day, at least 10 mg / day or at least about 10 mg / day, at least 25 mg / day or at least about 25 mg / day, at least 50 mg / day or at least about 50 mg / day, or at least 100 mg / day or at least about 100 mg / day.

[0052] In some embodiments of any method provided herein, the immunomodulatory compound is administered in amounts greater than or about 1 mg, greater than or about 2.5 mg, greater than or about 5 mg, greater than or about 7.5 mg, greater than or about 10 mg, greater than or about 15 mg and less than 25 mg; or the immunomodulatory compound is administered in amounts greater than or about 1 mg / day, greater than or about 2.5 mg / day and about 2.5 mg / day, greater than or about 5 mg / day, greater than or about 7.5 mg / day and about 7.5 mg / day, greater than or about 10 mg / day and about 15 mg / day and less than 25 mg / day.

[0053] In some embodiments of any method provided herein, administration of a therapeutically effective dose of an immunomodulatory compound stimulates an increase in T cell growth associated with T cell therapy compared to the increase after administration of T cell therapy in the absence of the immunomodulatory compound.

[0054] In some embodiments of any method provided herein, administration of a therapeutically effective dose of an immunomodulatory compound stimulates an increase in T cell-mediated cytolytic activity of T cells associated with T cell therapy, compared to cytolytic activity after administration of T cells in the absence of the immunomodulatory compound.

[0055] In some aspects of any method provided herein, administration of a therapeutically effective dose of an immunomodulatory compound stimulates an increase in T cell cytokine production associated with T cell therapy compared to cytokine production after T cell administration in the absence of the immunomodulatory compound. In some aspects, the increase is greater than 1.5 times or about 1.5 times, greater than 2.0 times or about 2.0 times, greater than 3.0 times or about 3.0 times, greater than 4.0 times or about 4.0 times, greater than 5.0 times or about 5.0 times, greater than 10.0 times or about 10.0 times or greater.

[0056] In some aspects of any method provided herein, T cell therapy is or comprises tumor-infiltrating lymphocyte (TIL) therapy or genetically engineered cells expressing recombinant receptors that specifically bind to antigens. In some aspects of any method provided herein, T cell therapy is or comprises genetically engineered cells expressing recombinant receptors that specifically bind to antigens. In some aspects, T cell therapy comprises cells expressing recombinant receptors that are or contain functional non-TCR antigen receptors or TCRs or antigen-binding fragments thereof. In some aspects, the recombinant antigen receptor is a chimeric antigen receptor (CAR).

[0057] In some embodiments of any method provided herein, T-cell therapy comprises a recombinant antigen receptor comprising an extracellular domain containing an antigen-binding domain that specifically binds to an antigen. In some embodiments, the antigen is associated with, specific to, and / or expressed on cells or tissues of a disease, disorder, or pathological condition. In some embodiments, the disease, disorder, or pathological condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or cancer. In some embodiments, the antigen is a tumor antigen.

[0058] In some embodiments of any method provided herein, the antigens include ROR1, B cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), tEGFR, Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, antifolate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, and EGFR. vIII, Folate-binding protein (FBP), FCRL5, FCRH5, Fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, Kinase insert domain receptor (kdr), Kappa light chain, Lewis Y, L1-cell adhesion molecule (L1-CAM), Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, Melanoma preferential expression antigen (PRAME), Survivin, TAG72, B7-H6, IL-13 receptor alpha2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, dual antigen, cancer testicular antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, G protein-binding receptor 5D (GPCR5D), tumor fetal antigen, R The antigens are selected from OR1, TAG72, VEGF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, optionally any of the aforementioned human antigens; pathogen-specific antigens; and antigens associated with the universal tag. In some embodiments, the antigen is CD19, optionally human CD19, or contains it.In some embodiments, the antigen is or comprises multiple myeloma-associated antigen, optionally BCMA, optionally human BCMA.

[0059] In some embodiments of any method provided herein, the antigen-binding domain is or comprises an antibody or an antibody fragment, which is optionally a single-chain fragment. In some embodiments, the fragment comprises an antibody variable region connected by a flexible linker. In some embodiments, the fragment comprises an scFv.

[0060] In some embodiments of any method provided herein, the T cell therapy comprises a recombinant receptor further comprising a spacer, optionally containing a hinge region, optionally derived from immunoglobulin. In some embodiments, the recombinant antigen receptor comprises an intracellular signaling region. In some embodiments, the intracellular signaling region comprises an intracellular signaling domain. In some embodiments, the intracellular signaling domain is or comprises a primary signaling domain, a signaling domain capable of inducing a primary activation signal in T cells, a signaling domain of a T cell receptor (TCR) component, and / or a signaling domain containing an immunoreceptor tyrosine-based activation motif (ITAM). In some embodiments of any method provided herein, the intracellular signaling domain is or comprises an intracellular signaling domain or signaling portion thereof of a CD3 chain, optionally a CD3 zeta (CD3ζ) chain.

[0061] In some embodiments of any method provided herein, the recombinant receptor further comprises a transmembrane domain located between an extracellular domain and an intracellular signaling domain, which is optionally a transmembrane domain of CD8 or CD28. In some embodiments, the intracellular signaling domain further comprises a co-stimulatory signaling domain. In some embodiments, the co-stimulatory signaling domain comprises the intracellular signaling domain or signaling moiety of a T cell co-stimulatory molecule. In some embodiments, the co-stimulatory signaling domain comprises the intracellular signaling domain or signaling moiety of CD28, 4-1BB, or ICOS. In some embodiments, the co-stimulatory signaling domain comprises the intracellular signaling domain of 4-1BB. In some embodiments of any method provided herein, the co-stimulatory signaling domain is located between the transmembrane domain and the intracellular signaling domain.

[0062] In some aspects of any method provided herein, T cell therapy comprises T cells selected from central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells; and / or a plurality of cells comprising at least 50% of a population of cells selected from CD4+ T cells, CD8+ T cells, central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells.

[0063] In some embodiments of any method provided herein, T cell therapy comprises T cells that are CD4+ or CD8+. In some embodiments, T cell therapy comprises primary cells derived from a subject. In some embodiments, T cell therapy comprises cells that are autologous to the subject. In some embodiments, T cell therapy comprises T cells that are allogeneic to the subject. In some embodiments of any method provided herein, the subject is human.

[0064] In some embodiments of any method provided herein, the T cell therapy is 1×105 or more to 1×108 or less or about 1×105 or more to 1×108 or less total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), 5×10 5 or more to 1×10 7 or less or about 5×10 5 or more to 1×10 7 or less total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), or 1×10 6 or more to 1×10 7 or less or about 1×10 6 or more to 1×10 7 or less total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs).

[0065] In some embodiments of any method provided herein, the T cell therapy is 1×10 8 or less total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), 1×10 7 or less total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), 0.5×10 7 or less total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), 1×10 6 or less total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), 0.5×10 6 or less total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs).

[0066] In some embodiments of any method provided herein, the amount of cells administered in the T cell therapy is less than the amount in another method in which the T cell therapy is administered without administration of an immunomodulatory compound and which optionally results in a similar or lower degree of improvement or reduction or prevention of a disease or condition or its symptoms or burden compared to that resulting from the method. In some embodiments, the amount of cells administered is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold or 10-fold less than the amount administered by the other method.

[0067] In some embodiments of any method provided herein, T-cell therapy is administered as a single pharmaceutical composition containing cells. In some embodiments of any method provided herein, T-cell therapy comprises a dose of cells in a divided dose, wherein the dose of cells is administered over a period of three days or less in multiple compositions containing the dose of cells together.

[0068] In some embodiments of any method provided herein, the method further comprises administering lymphocyte depletion chemotherapy prior to the administration of T-cell therapy.

[0069] In some embodiments of any method provided herein, the disease or condition is cancer. In some embodiments, cancer is a B-cell malignancy and / or myeloma, lymphoma, or leukemia. In some embodiments, cancer is mantle cell lymphoma (MCL), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), or diffuse large B-cell lymphoma (DLBCL). In some embodiments, cancer is a non-hematological cancer or a solid tumor.

[0070] In some embodiments of any method provided herein, T-cell therapy exhibits increased or prolonged enlargement and / or persistence in a subject compared to a method in which T-cell therapy is administered to a subject in the absence of an immunomodulatory compound.

[0071] In some embodiments of any method provided herein, the method reduces tumor load to a greater extent and / or over a longer period of time compared to the reduction that would be observed in an equivalent method at any same dose or dosing regimen when T-cell therapy is administered to a subject in the absence of an immunomodulatory compound and / or when an immunomodulatory compound is administered in the absence of T-cell therapy.

[0072] This specification provides a kit comprising a pharmaceutical composition comprising a unit dose of a T-cell therapy; and instructions for administering the composition in combination with the administration of a composition containing an immunomodulatory compound to a subject having a disease or condition, wherein the instructions specify that the immunomodulatory compound be administered in one or more unit doses, in a cycle comprising administration of the immunomodulatory compound for up to 21 consecutive days, including more than 30 days starting from the commencement of administration of the immunomodulatory compound; and / or a cycle comprising administration of the immunomodulatory compound over several consecutive days followed by a rest period in which the immunomodulatory compound is not administered, with the rest period exceeding 14 consecutive days; and / or a cycle comprising administration of the immunomodulatory compound for 14 consecutive days or less.

[0073] Furthermore, this specification provides a kit comprising a pharmaceutical composition containing one or more unit doses of an immunomodulatory compound; and instructions for administering the immunomodulatory compound to a subject having a disease or condition in combination with the administration of a unit dose of the pharmaceutical composition including T-cell therapy, wherein the instructions specify that one or more unit doses of the immunomodulatory compound should be administered according to an administration cycle comprising a cycle of administration of the immunomodulatory compound for up to 21 consecutive days, including more than 30 days starting from the start of administration of the immunomodulatory compound; and / or a cycle comprising administration of the immunomodulatory compound over several consecutive days followed by a rest period in which the immunomodulatory compound is not administered, with the rest period exceeding 14 consecutive days; and / or a cycle comprising administration of the immunomodulatory compound for 14 consecutive days or less.

[0074] In some of such embodiments, the instructions specify that administration of one or more unit doses of the immunomodulatory compound may be initiated on the same day as, or optionally in parallel with, the initiation of T-cell therapy. In some of such embodiments, the instructions specify that administration of one or more unit doses of the immunomodulatory compound may be initiated before the initiation of T-cell therapy.

[0075] In some embodiments, the instructions specify that the administration of one or more unit doses of the immunomodulatory compound should be initiated at the time when a sample containing the T cells to be manipulated is collected from the subject, or within one week prior thereto, and optionally the sample is an apheresis sample; and / or at one or more steps in the ex vivo manufacturing process to produce the manipulated T cell therapy; and / or within 14 days prior to the administration of the T cell therapy.

[0076] In some embodiments, one or more steps of the ex vivo manufacturing process are selected from: isolating cells from a biological sample by leukocyte apheresis or apheresis; selecting or concentrating cells by an immunoaffinity-based method; introducing recombinant nucleic acids, optionally viral vectors, into the cells; optionally incubating the engineered cells in the presence of one or more stimulating conditions; formulating the cells in the presence of a cryoprotective substance; and / or formulating the cells for administration to a subject, optionally in the presence of pharmaceutically acceptable excipients.

[0077] In some of these arbitrary embodiments, the instructions specify that administration of one or more unit doses of the immunomodulatory compound should be initiated within 10, 7, 4, 3, or 2 days prior to the initiation of T-cell therapy. In some examples, the instructions specify that administration of one or more unit doses of the immunomodulatory compound should be initiated after the initiation of T-cell therapy. In some aspects, the instructions specify that administration of one or more unit doses of the immunomodulatory compound should be initiated at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks after the initiation of T-cell therapy, and / or 2 to 28 days or 7 to 21 days after the initiation of T-cell therapy.

[0078] Furthermore, in this specification, a pharmaceutical composition containing a unit dose of T-cell therapy; and a kit containing instructions for administering the composition to a subject with a disease or condition in combination with the administration of an immunomodulatory compound, wherein the instructions specify that the administration of one or more unit doses of the immunomodulatory compound is initiated at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks after the initiation of T-cell therapy, and / or 2 to 28 days or 7 to 21 days after the initiation of T-cell therapy; and / or the following: (i) the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) the number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally reduced compared to a preceding point in time after T-cell therapy administration; (iii) the number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after the initiation of T-cell therapy administration. A kit is provided in which the number of detectable T-cell therapy cells in the subject's blood decreased by 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or more than 3.0 times, 4.0 times or more than 4.0 times, 5.0 times or more than 5.0 times, 10 times or more than 10 times or more than the peak or maximum number of detectable T-cell therapy cells in the subject's blood. (iv) At a point after the peak or maximum level of T-cell therapy cells became detectable in the subject's blood, the number of detectable T-cells or cells derived therefrom in the subject's blood became less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood. (v) The subject showed disease progression after treatment with T-cell therapy and / or relapse following remission. and / or (iv) The subject showed an increased tumor volume at a point in time or thereafter, optionally immediately thereafter or within 1-3 days thereafter, compared to the tumor volume at the time before or after T-cell administration and before the initiation of immunomodulatory compound administration.

[0079] This specification refers to a pharmaceutical composition containing one or more unit doses of immunomodulatory compounds; and instructions for administering the immunomodulatory compounds to a subject with a disease or condition in combination with the administration of a unit dose of a pharmaceutical composition including T-cell therapy, wherein the administration of one or more unit doses of the immunomodulatory compounds is initiated at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks after the initiation of T-cell therapy, and / or 2 to 28 days or 7 to 21 days after the initiation of T-cell therapy; and / or the following: (i) the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) the number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally reduced compared to a preceding point in time after T-cell therapy administration; (iii) the number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after the initiation of T-cell therapy administration. (iv) The number of detectable T cells in the subject's blood decreased by 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or more than 3.0 times, 4.0 times or more than 4.0 times, 5.0 times or more than 5.0 times, 10 times or more than 10 times or more than the peak or maximum number of detectable T cells in the subject's blood. (iv) At a point after the peak or maximum level of T cells in the subject's blood became detectable, the number of detectable T cells or cells derived therefrom in the subject's blood became less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood. (v) The subject showed disease progression after treatment with T cell therapy and / or relapsed following remission. and / or (iv) The subject showed an increased tumor volume at a point in time or thereafter, optionally immediately thereafter or within 1-3 days thereafter, compared to the tumor volume at the time before or after T cell administration and before the initiation of immunomodulatory compound administration.

[0080] In any such form, the instructions specify that administration of one or more unit doses of immunomodulatory compounds should be initiated at a time 14 days or about 14 days after the start of T-cell therapy, 15 days or about 15 days after, 16 days or about 16 days after, 17 days or about 17 days after, 18 days or about 18 days after, 19 days or about 19 days after, 20 days or about 20 days after, 21 days or about 21 days after, 24 days or about 24 days after, or 28 days or about 28 days after. In any such embodiment, the instruction is for a subject for administration of one or more unit doses of an immunomodulatory compound, and after administration of T-cell therapy, (i) the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) the number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally reduced compared to a preceding time after administration of T-cell therapy; (iii) the number of detectable T-cell therapy cells in the blood is 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times, or more than 1.5 times the peak or maximum number of detectable T-cell therapy cells in the subject's blood after the start of administration of T-cell therapy. The criteria specify that subjects should be selected if they have decreased by more than 3.0 times, 4.0 times or more than 4.0 times, 5.0 times or more than 5.0 times, 10 times or more than 10 times or more; (iv) at the time after the peak or maximum level of T-cell therapy cells became detectable in the subject's blood, the number of detectable T cells or cells derived from the subject in the subject's blood was less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) exhibited disease progression and / or relapse following remission after treatment with T-cell therapy; and / or (iv) showed an increased tumor volume compared to the tumor volume before or after T-cell administration and before the initiation of immunomodulatory compound administration.

[0081] This specification provides a kit comprising a pharmaceutical composition containing a unit dose of T-cell therapy; and instructions for administering the composition to a subject having a disease or condition in combination with the administration of an immunomodulatory compound, the instructions specifying that the immunomodulatory compound should be administered to the subject in one or more unit doses on days 12 to 15 or about 12 to 15, optionally on day 14 or about 14, when the number of T-cell therapy cells in the subject is less than 75% of the average number of T-cell therapy cells at the same time in multiple subjects administered the same or similar dose of T-cell therapy; and / or when the number of CD3+ or CD8+ cells, optionally CAR+ T-cells in the blood of the T-cell therapy is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL.

[0082] This specification provides a kit comprising a pharmaceutical composition containing one or more unit doses of immunomodulatory compounds; and instructions for administering one or more unit doses of immunomodulatory compounds to a subject having a disease or condition in combination with the administration of a pharmaceutical composition containing a unit dose of T-cell therapy, wherein the instructions specify that one or more unit doses of immunomodulatory compounds should be administered to the subject on day 12 to 15 or about day 12 to 15, optionally on day 14 or about day 14, when the number of T-cell therapy cells in the subject is less than 75% of the average number of T-cell therapy cells at the same time in multiple subjects who have been administered the same or similar dose of T-cell therapy; and / or when the number of CD3+ or CD8+ cells, optionally CAR+ T-cells in the blood of the T-cell therapy is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL.

[0083] In this specification, (a) a pharmaceutical composition comprising a unit dose of T-cell therapy; and (b) a kit comprising instructions for administering the composition to a subject having a disease or condition in combination with the administration of a composition comprising an immunomodulatory compound, wherein the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers, or mixtures thereof. A kit is provided, which is selected from the group consisting of a substance, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, and the instructions specify that the immunomodulatory compound is to be administered in one or more unit doses according to an administration cycle including (i) a cycle comprising administration of the immunomodulatory compound for up to 21 consecutive days and including more than 30 days starting from the commencement of administration of the immunomodulatory compound; and / or (ii) a cycle comprising administration of the immunomodulatory compound over several consecutive days followed by a rest period in which the immunomodulatory compound is not administered, with the rest period exceeding 14 consecutive days; and / or (iii) a cycle comprising administration of the immunomodulatory compound for 14 consecutive days or less.

[0084] In this specification, (a) a pharmaceutical composition comprising one or more unit doses of an immunomodulatory compound; and (b) a kit comprising instructions for administering the immunomodulatory compound to a subject having a disease or condition in combination with the administration of a unit dose of a pharmaceutical composition comprising T-cell therapy, wherein the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers, or A kit is provided which is selected from the group consisting of a mixture of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, and the instructions specify that one or more unit doses of the immunomodulatory compound are to be administered according to an administration cycle including (i) a cycle of administration of the immunomodulatory compound for up to 21 consecutive days, including more than 30 days starting from the commencement of administration of the immunomodulatory compound; and / or (ii) a cycle of administration of the immunomodulatory compound over several consecutive days followed by a rest period in which the immunomodulatory compound is not administered, with the rest period exceeding 14 consecutive days; and / or (iii) a cycle of administration of the immunomodulatory compound for 14 consecutive days or less.

[0085] In this specification, (a) a pharmaceutical composition comprising a unit dose of T-cell therapy; and (b) a kit comprising instructions for administering the composition in combination with the administration of an immunomodulatory compound to a subject having a disease or condition, wherein the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-A A compound selected from the group consisting of mino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof, and the instruction states that the administration of one or more unit doses of the immunomodulatory compound is initiated at (1) at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks or at least 4 weeks after the initiation of T-cell therapy, and / or performed 2 to 28 days or 7 to 21 days after the start of T-cell therapy administration; and / or (2) less: (i) the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) the number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally reduced compared to a preceding point in time after T-cell therapy administration; (iii) the number of detectable T-cell therapy cells in the blood becomes undetectable in the subject's blood after the start of T-cell therapy administration (iv) At the point after the peak or maximum level of T-cell therapy cells has become detectable in the subject's blood, the number of detectable T cells or cells derived therefrom in the subject's blood is less than 10%, less than 5%, less than 1%, or 0% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood.The kit is provided if the percentage is less than 1%; (v) the subject shows disease progression and / or relapse following remission after treatment with T-cell therapy; and / or (iv) the subject shows an increased tumor volume compared to the tumor volume at the time before or after T-cell administration and before the initiation of immunomodulatory compound administration, and it is specified that this occurs at or after, optionally immediately thereafter or within 1-3 days thereafter.

[0086] In this specification, (a) a pharmaceutical composition comprising one or more unit doses of an immunomodulatory compound, wherein the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, mirror images (b) A pharmaceutical composition selected from the group consisting of isomers or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof; and (b) instructions for administering an immunomodulatory compound to a subject having a disease or condition in combination with the administration of a unit dose of a pharmaceutical composition including T cell therapy, wherein the administration of one or more unit doses of the immunomodulatory compound is initiated at least two days, at least one week, at least two weeks, at least three weeks or at least four weeks after the initiation of T cell therapy. This is a time point later and / or performed 2 to 28 days or 7 to 21 days after the start of T-cell therapy administration; and / or (2) less than: (i) the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) the number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally reduced compared to a preceding time point after T-cell therapy administration; (iii) the number of detectable T-cell therapy cells in the blood becomes undetectable in the subject's blood after the start of T-cell therapy administration. (iv) At the point after the peak or maximum number of T-cell therapy cells has become detectable in the subject's blood, the number of detectable T cells or cells derived therefrom in the subject's blood is less than 10%, less than 5%, less than 1%, or 0% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood.The kit is provided with instructions specifying that the percentage of subjects who experienced a disease progression and / or relapse following remission after T-cell therapy was less than 1%; (v) the subject showed disease progression and / or relapse after T-cell therapy; and / or (iv) the subject showed an increased tumor volume at or after the time of T-cell administration and / or before the initiation of immunomodulatory compound administration, either immediately thereafter or within 1-3 days thereafter.

[0087] In this specification, (a) a pharmaceutical composition comprising a unit dose of T-cell therapy; and (b) a kit comprising instructions for administering the composition to a subject having a disease or condition in combination with the administration of an immunomodulatory compound, wherein the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers, or mixtures of enantiomers, or pharmaceutically acceptable salts or solvates thereof. A kit is provided in which an immunomodulatory compound is administered to a subject in one or more unit doses, selected from the group consisting of hydrates, cocrystals, inclusion compounds, or polymorphs, and the instructions specify that the immunomodulatory compound should be administered to the subject in one or more unit doses on day 12 to 15 or approximately day 12 to 15, optionally on day 14 or approximately day 14, after the start of administration of T cell therapy to treat a disease or condition: (i) the number of T cell therapy cells in the subject is less than 75% of the average number of T cell therapy cells at the same time in multiple subjects who received the same or similar dose of T cell therapy; and / or (ii) the number of CD3+ or CD8+ cells, optionally CAR+ T cells in the blood of the T cell therapy is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL.

[0088] In this specification, (a) a pharmaceutical composition comprising one or more unit doses of an immunomodulatory compound, wherein the immunomodulatory compound is selected from the group consisting of lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers, or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof; and (b) a pharmaceutical composition comprising one or more unit doses of an immunomodulatory compound for a disease Alternatively, a kit is provided, comprising instructions for administration to a subject with a disease condition in combination with the administration of a pharmaceutical composition containing a unit dose of T-cell therapy, wherein the instructions specify that one or more unit doses of an immunomodulatory compound should be administered to the subject on day 12 to 15 or approximately day 12 to 15, optionally on day 14 or approximately day 14, after the start of administration of T-cell therapy to treat the disease or condition: (i) the number of T-cell therapy cells in the subject is less than 75% of the average number of T-cell therapy cells at the same time in multiple subjects who have received the same or similar doses of T-cell therapy; and / or (ii) the number of CD3+ or CD8+ cells, optionally CAR+ T-cells in the blood of the T-cell therapy is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL.

[0089] In any such embodiment, the immunomodulatory compound is formulated in a dose for daily administration and / or the instructions specify that the immunomodulatory compound is administered daily. In any such embodiment, the instructions specify that the immunomodulatory compound is administered for more than 7 consecutive days or approximately 7 consecutive days, more than 14 consecutive days or approximately 14 consecutive days, more than 21 consecutive days or approximately 21 consecutive days, more than 21 consecutive days or approximately 21 consecutive days, or more than 28 consecutive days or approximately 28 consecutive days.

[0090] In some of such embodiments, the instructions specify that the immunomodulatory compound is administered in a dosing cycle comprising daily doses over several consecutive days, followed by rest periods in which the immunomodulatory compound is not administered. In some examples, the instructions specify that the rest periods in which the immunomodulatory compound is not administered are for more than 7 consecutive days, more than 14 consecutive days, more than 21 consecutive days, or more than 28 consecutive days. In some of such embodiments, the instructions specify that the dosing cycle of the immunomodulatory compound is repeated at least once.

[0091] In any such embodiment, the instruction is to administer the immunomodulatory compound at least from the start of T cell administration until the number of detectable T-cell therapy-derived cells in the subject's blood increases compared to the subject at a preceding time immediately prior to the administration of the immunomodulatory compound or compared to a preceding time after the administration of T-cell therapy; until the number of detectable T-cell therapy-derived cells in the blood is within 2.0 times (greater than or less than) the peak number or maximum number observed in the subject's blood after the start of T cell administration; It is specified that the treatment will continue until the number of detectable T-cell therapy cells in the subject's blood is greater than or approximately greater than 10%, greater than or approximately greater than 15%, greater than or approximately greater than 20%, greater than or approximately greater than 30%, greater than or approximately greater than 40%, greater than or approximately greater than 50%, greater than or approximately greater than 50%, or greater than or approximately greater than 60% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; and / or until the subject shows a reduction in tumor burden compared to the tumor burden at the time immediately preceding administration of T-cell therapy or immunomodulatory compound; and / or until the subject shows complete remission or clinical remission.

[0092] In some of such embodiments, the immunomodulatory compound binds to cereblon (CRBN) and / or the CRBN E3 ubiquitin-ligase complex; and / or is an inhibitor of the IKZF1 or Aeolus (IKZF3) transcription factor; and / or enhances the ubiquitination or degradation of IKZF1 or Aeolus (IKZF3). In some of such embodiments, the immunomodulatory compound is thalidomide or a derivative or analog of thalidomide. In any such embodiment, the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione) or pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), lenalidomide (3-( These are stereoisomers of 4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), or their pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In any such embodiment, the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), a stereoisomer of lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion compound, or polymorph.

[0093] In some of such embodiments, the immunomodulatory compound is formulated for oral, subcutaneous, or intravenous administration. In some examples, the immunomodulatory compound is formulated for oral administration. In some of such embodiments, the immunomodulatory compound is formulated in capsules or tablets.

[0094] In some of such embodiments, each of one or more unit doses of an immunomodulatory compound is between 0.1 mg and 100 mg or about 0.1 mg and about 100 mg, between 0.1 mg and 50 mg or about 0.1 mg and 50 mg, between 0.1 mg and 25 mg or about 0.1 mg and 25 mg, between 0.1 mg and 10 mg or about 0.1 mg and 10 mg, between 0.1 mg and 5 mg or about 0.1 mg and 5 mg, between 0.1 mg and 1 mg or about 0.1 mg and 1 mg Below, 1 mg to 100 mg or approximately 1 mg to 100 mg, 1 mg to 50 mg or approximately 1 mg to 50 mg, 1 mg to 25 mg or approximately 1 mg to 25 mg, 1 mg to 10 mg or approximately 1 mg to 10 mg, 1 mg to 5 mg or approximately 1 mg to 5 mg, 5 mg to 100 mg or approximately 5 mg to 100 mg, 5 mg to 50 mg or approximately 5 mg to 50 mg, 5 mg to 25 mg or approximately 5 mg to 25 mg, 5 mg to 1 It contains amounts of 0 mg or less, or approximately 5 mg to 10 mg, 10 mg to 100 mg or approximately 10 mg to 100 mg, 10 mg to 50 mg or approximately 10 mg to 50 mg, 10 mg to 25 mg, 25 mg to 100 mg or approximately 25 mg to 100 mg, 25 mg to 50 mg or approximately 25 mg to 50 mg, or 50 mg to 100 mg or approximately 50 mg to 100 mg; and / or, each of one or more unit doses of an immunomodulatory compound is It contains an amount of at least 0.1 mg or at least about 0.1 mg, at least 0.5 mg or at least about 0.5 mg, at least 1.0 mg or at least about 1.0 mg, at least 2.5 mg or at least about 2.5 mg, at least 5 mg or at least about 5 mg, at least 10 mg or at least about 10 mg, at least 25 mg or at least about 25 mg, at least 50 mg or at least about 50 mg, or at least 100 mg or at least about 100 mg.In some of any such embodiments, one or more unit doses of immunomodulatory compounds contain an amount greater than or about 1 mg, greater than or about 2.5 mg, greater than or about 5 mg, greater than or about 7.5 mg, greater than or about 10 mg, greater than or about 15 mg and less than 25 mg.

[0095] In any such embodiment, T cell therapy is or comprises tumor-infiltrating lymphocytes (TILs) or genetically engineered cells expressing recombinant receptors that specifically bind to antigens.

[0096] In some of such embodiments, the recombinant receptor is or contains a functional non-TCR antigen receptor or a TCR or its antigen-binding fragment. In some of such embodiments, the recombinant antigen receptor is a chimeric antigen receptor (CAR). In some of such embodiments, the recombinant antigen receptor contains an extracellular domain containing an antigen-binding domain that specifically binds to the antigen.

[0097] In some of any such embodiments, the antigen is associated with, specific to, and / or expressed on cells or tissues of a disease, disorder, or pathological condition. In some situations, the disease, disorder, or pathological condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or cancer.

[0098] In some of such embodiments, the antigen is a tumor antigen. In some of such embodiments, the antigen is ROR1, B cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), tEGFR, Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, antifolate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, EGFR vIII, Folate-binding protein (FBP), FCRL5, FCRH5, Fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, Kinase insert domain receptor (kdr), Kappa light chain, Lewis Y, L1-cell adhesion molecule (L1-CAM), Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, Melanoma preferential expression antigen (PRAME), Survivin, TAG72, B7-H6, IL-13 receptor alpha2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, dual antigen, cancer testicular antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, G protein-binding receptor 5D (GPCR5D), tumor fetal antigen, R The antigens selected are OR1, TAG72, VEGF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, optionally any of the aforementioned human antigens; pathogen-specific antigens; and antigens associated with the universal tag.In some embodiments, the antigen is CD19, optionally human CD19, or includes it. In some embodiments, the antigen is BCMA, optionally human BCMA, or includes it.

[0099] In some of such embodiments, the antigen-binding domain is or contains an antibody or an antibody fragment, which is optionally a single-chain fragment. In some cases, the fragment contains an antibody variable region connected by a flexible linker. In some embodiments, the fragment contains an scFv. In some of such embodiments, the recombinant receptor further contains a spacer, optionally derived from an immunoglobulin, which optionally contains a hinge region.

[0100] In some of such embodiments, the recombinant antigen receptor contains an intracellular signaling region. In some of such embodiments, the intracellular signaling region contains an intracellular signaling domain. In some examples, the intracellular signaling domain is or contains a signaling domain comprising a primary signaling domain, a signaling domain capable of inducing a primary activation signal in T cells, a signaling domain of a T cell receptor (TCR) component, and / or an immunoreceptor tyrosine-based activation motif (ITAM).

[0101] In any such embodiment, the intracellular signaling domain is or contains the intracellular signaling domain or signaling portion of the CD3 chain, optionally the CD3 zeta (CD3ζ) chain. In any such embodiment, the recombinant receptor further contains a transmembrane domain located between the extracellular domain and the intracellular signaling region, which is optionally the transmembrane domain of CD8 or CD28.

[0102] In some of such embodiments, the intracellular signaling region further comprises a co-stimulatory signaling region. In some cases, the co-stimulatory signaling region comprises the intracellular signaling domain or signaling moiety of a T cell co-stimulatory molecule. In some embodiments, the co-stimulatory signaling region comprises the intracellular signaling domain or signaling moiety of CD28, 4-1BB, or ICOS. In some examples, the co-stimulatory signaling region comprises the intracellular signaling domain of 4-1BB. In some of such embodiments, the co-stimulatory signaling region lies between the transmembrane domain and the intracellular signaling region.

[0103] In any such embodiment, the T cell therapy comprises T cells selected from the group consisting of central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells; and / or a plurality of cells comprising at least 50% of a population of cells selected from the group consisting of CD4+ T cells, CD8+ T cells, central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells. In any such embodiment, the T cell therapy comprises T cells that are CD4+ or CD8+.

[0104] In some of such embodiments, the T-cell therapy contains primary cells derived from the subject. In some of such embodiments, the T-cell therapy is autologous to the subject. In some of such embodiments, the T-cell therapy is homogeneous to the subject. In some of such embodiments, the subject is human.

[0105] In some of such embodiments, the unit dose of T-cell therapy is 1 × 10⁻⁶ 5 The above 1 x 10 8 The following or approximately 1 x 10 5 The above 1 x 10 8The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 5 × 10⁶ 5 The above 1 x 10 7 The following or approximately 5 x 10 5 The above 1 x 10 7 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), or 1 × 10⁶ cells. 6 The above 1 x 10 7 The following or approximately 1 x 10 6 The above 1 x 10 7 The following are included: total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs). In any such embodiment, the unit dose of T cell therapy is 1 × 10⁻⁶ 8 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 1 × 10⁶ 7 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 0.5 × 10⁶ 7 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 1 × 10⁶ 6 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 0.5 × 10⁶ 6 This includes administration of total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs).

[0106] In any such embodiment, a unit dose of T-cell therapy is a divided dose containing a dose of cells, wherein the dose of cells is administered over a period of no more than three days in a plurality of compositions containing the dose of cells together.

[0107] In some of such embodiments, the instructions further specify that lymphocyte depletion chemotherapy be administered before T-cell therapy. In some of such embodiments, the disease or condition is cancer. In some of such embodiments, cancer is a B-cell malignancy and / or myeloma, lymphoma, or leukemia. In some embodiments, cancer is mantle cell lymphoma (MCL), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), or diffuse large B-cell lymphoma (DLBCL). In some cases, cancer is a non-hematological cancer or a solid tumor.

[0108] In this specification, a manufactured article containing any of the kits described herein is provided.

[0109] Furthermore, this specification provides pharmaceutical compositions comprising T-cell therapy, immunomodulatory compounds, and pharmaceutically acceptable carriers. In some embodiments, the T-cell therapy is formulated in unit doses. In some cases, the unit dose of the T-cell therapy is 1 × 10⁻⁶. 5 The above 1 x 10 8 The following or approximately 1 x 10 5 The above 1 x 10 8 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 5 × 10⁶ 5 The above 1 x 10 7 The following or approximately 5 x 10 5 The above 1 x 10 7 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), or 1 × 10⁶ cells. 6 The above 1 x 10 7 The following or approximately 1 x 10 6 The above 1 x 10 7 It contains the following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs).

[0110] This specification provides a pharmaceutical composition comprising a T-cell therapy, an immunomodulatory compound, and a pharmaceutically acceptable carrier, wherein the immunomodulatory compound is selected from the group consisting of lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), or abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), its stereoisomers, enantiomers, or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof.

[0111] In some embodiments, the unit dose of T-cell therapy is 1 × 10⁻⁶ 8 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 1 × 10⁶ 7 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 0.5 × 10⁶ 7 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 1 × 10⁶ 6 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 0.5 × 10⁶ 6 The following are included in the administration of total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs).

[0112] In some of such embodiments, the immunomodulatory compound binds to cereblon (CRBN) and / or the CRBN E3 ubiquitin-ligase complex; and / or is an inhibitor of the IKZF1 or Aeolus (IKZF3) transcription factor; and / or enhances the ubiquitination or degradation of IKZF1 or Aeolus (IKZF3). In some of such embodiments, the immunomodulatory compound is thalidomide or a derivative or analog of thalidomide. In any such embodiment, the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione) or pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), lenalidomide (3-( These are stereoisomers of 4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, pomalidomide (4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-1,3-dione), abadomide (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), or their pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In any such embodiment, the immunomodulatory compound is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), a stereoisomer of lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione), or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion compound, or polymorph.

[0113] In some of such embodiments, the immunomodulatory compound is formulated in unit doses. In some of such embodiments, the amount of the immunomodulatory compound in the composition is 0.1 mg to 100 mg or about 0.1 mg to about 100 mg, 0.1 mg to 50 mg or about 0.1 mg to 50 mg, 0.1 mg to 25 mg or about 0.1 mg to 25 mg, 0.1 mg to 10 mg or about 0.1 mg to 10 mg, 0.1 mg to 5 mg or about 0.1 mg to 5 mg, 0.1 mg to 1 mg or about 0.1 mg to 1 mg, 1 mg to 100 mg or approximately 1 mg to 100 mg, 1 mg to 50 mg or approximately 1 mg to 50 mg, 1 mg to 25 mg or approximately 1 mg to 25 mg, 1 mg to 10 mg or approximately 1 mg to 10 mg, 1 mg to 5 mg or approximately 1 mg to 5 mg, 5 mg to 100 mg or approximately 5 mg to 100 mg, 5 mg to 50 mg or approximately 5 mg to 50 mg, 5 mg to 25 mg or approximately 5 mg to 25 mg, 5 mg g or more and 10 mg or less or approximately 5 mg or more and 10 mg or less, 10 mg or more and 100 mg or less or approximately 10 mg or more and 100 mg or less, 10 mg or more and 50 mg or less or approximately 10 mg or more and 50 mg or less, 10 mg or more and 25 mg or less, 25 mg or more and 100 mg or less or approximately 25 mg or more and 100 mg or less, 25 mg or more and 50 mg or less or approximately 25 mg or more and 50 mg or less, or 50 mg or more and 100 mg or less or approximately 50 mg or more and 100 mg or less; and / or the amount of immunomodulatory compound in the composition is small The amount is at least 0.1 mg or at least about 0.1 mg, at least 0.5 mg or at least about 0.5 mg, at least 1.0 mg or at least about 1.0 mg, at least 2.5 mg or at least about 2.5 mg, at least 5 mg or at least about 5 mg, at least 10 mg or at least about 10 mg, at least 25 mg or at least about 25 mg, at least 50 mg or at least about 50 mg, or at least 100 mg or at least about 100 mg.In some of any such embodiments, the amount of the immunomodulatory compound in the composition is greater than or about 1 mg, greater than or about 2.5 mg, greater than or about 5 mg, greater than or about 7.5 mg, greater than or about 10 mg, greater than or about 15 mg and less than 25 mg.

[0114] In some of such embodiments, T cell therapy is or contains tumor-infiltrating lymphocytes (TILs) or genetically engineered cells expressing recombinant receptors that specifically bind to antigens. In some of such embodiments, T cell therapy is or contains genetically engineered cells expressing recombinant receptors that specifically bind to antigens. In some of such embodiments, the recombinant receptor is or contains a functional non-TCR antigen receptor or a TCR or its antigen-binding fragment. In some of such embodiments, the recombinant antigen receptor is a chimeric antigen receptor (CAR).

[0115] In some of such embodiments, the recombinant antigen receptor contains an extracellular domain containing an antigen-binding domain that specifically binds to the antigen. In some of such embodiments, the antigen is associated with, specific to, and / or expressed on cells or tissues of a disease, disorder, or pathological condition. In some cases, the disease, disorder, or pathological condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or cancer.

[0116] In some of such embodiments, the antigen is a tumor antigen. In some of such embodiments, the antigen is ROR1, B cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), tEGFR, Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, antifolate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, EGFR vIII, Folate-binding protein (FBP), FCRL5, FCRH5, Fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, Kinase insert domain receptor (kdr), Kappa light chain, Lewis Y, L1-cell adhesion molecule (L1-CAM), Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, Melanoma preferential expression antigen (PRAME), Survivin, TAG72, B7-H6, IL-13 receptor alpha2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, dual antigen, cancer testicular antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, G protein-binding receptor 5D (GPCR5D), tumor fetal antigen, R The antigens selected are OR1, TAG72, VEGF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, optionally any of the aforementioned human antigens; pathogen-specific antigens; and antigens associated with the universal tag.In some of such embodiments, the antigen is CD19, optionally human CD19, or contains it. In some embodiments, the antigen is BCMA, optionally human BCMA, or contains it.

[0117] In some of such embodiments, the antigen-binding domain is or contains an antibody or an antibody fragment, which is optionally a single-chain fragment. In some examples, the fragment contains an antibody variable region connected by a flexible linker. In some embodiments, the fragment contains an scFv. In some of such embodiments, the recombinant receptor further contains a spacer, optionally derived from an immunoglobulin, which optionally contains a hinge region.

[0118] In some of such embodiments, recombinant antigen receptors contain an intracellular signaling region. In some examples, the intracellular signaling region contains an intracellular signaling domain. In some situations, the intracellular signaling domain is or contains a primary signaling domain, a signaling domain capable of inducing a primary activation signal in T cells, a signaling domain of a T cell receptor (TCR) component, and / or a signaling domain containing an immunoreceptor tyrosine-based activation motif (ITAM). In some embodiments, the intracellular signaling domain is or contains an intracellular signaling domain or signaling portion of a CD3 chain, optionally a CD3 zeta (CD3ζ) chain.

[0119] In some of such embodiments, the recombinant receptor further comprises a transmembrane domain positioned between an extracellular domain and an intracellular signaling domain, wherein the transmembrane domain is optionally the transmembrane domain of CD8, CD28, CTLA-4, or PD-1. In some of such embodiments, the intracellular signaling domain further comprises a co-stimulatory signaling domain.

[0120] In some of such embodiments, the co-stimulatory signaling region contains the intracellular signaling domain or signaling moiety of a T cell co-stimulatory molecule. In some embodiments, the co-stimulatory signaling region contains the intracellular signaling domain or signaling moiety of CD28, 4-1BB, or ICOS. In some examples, the co-stimulatory signaling region contains the intracellular signaling domain of 4-1BB. In some of such embodiments, the co-stimulatory signaling region is located between the transmembrane domain and the intracellular signaling region. In some of such embodiments, the recombinant receptor is or includes a chimeric antigen receptor containing an antigen-binding domain, a spacer, a transmembrane domain derived from CD28, an intracellular signaling domain containing a CD3 zeta (CD3ζ) chain, and an intracellular signaling domain derived from 4-1BB.

[0121] In some of any such embodiments, T cell therapy comprises T cells selected from the group consisting of central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells; and / or a plurality of cells comprising at least 50% of a population of cells selected from the group consisting of CD4+ T cells, CD8+ T cells, central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells. In some of any such embodiments, T cell therapy contains T cells that are CD4+ or CD8+. In some examples, the ratio of CD4+ T cells to CD8+ T cells is 1:3 to 3:1 or about 1:3 to 3:1, and optionally 1:1.

[0122] In some of such embodiments, T-cell therapy contains primary cells derived from the subject. In some situations, the subject is human.

[0123] In some of these arbitrary embodiments, the pharmaceutical composition is in the following concentrations: 1 mL to 100 mL or approximately 1 mL to 100 mL, 1 mL to 75 mL or approximately 1 mL to 75 mL, 1 mL to 50 mL or approximately 1 mL to 50 mL, 1 mL to 25 mL or approximately 1 mL to 25 mL, 1 mL to 10 mL or approximately 1 mL to 10 mL, 1 mL to 5 mL or approximately 1 mL to 5 mL, 5 mL to 100 mL or approximately 5 mL to 100 mL, 5 mL to 75 mL or approximately 5 mL to 75 mL, 5 mL to 50 mL or approximately 5 mL to 50 mL, 5 mL to 25 mL or approximately 5 mL to 25 mL, 5 mL to 10 mL or approximately 5 mL It contains volumes of L~10mL, 10mL~100mL or approximately 10mL~100mL, 10mL~75mL or approximately 10mL~75mL, 10mL~50mL or approximately 10mL~50mL, 10mL~25mL or approximately 10mL~25mL, 25mL~100mL or approximately 25mL~100mL, 25mL~75mL or approximately 25mL~75mL, 25mL~50mL or approximately 25mL~50mL, 50mL~100mL or approximately 50mL~100mL, 50mL~75mL or approximately 50mL~75mL, or 75mL~100mL or approximately 75mL~100mL. In any such embodiment, the pharmaceutical composition contains a volume of at least 1 mL or about at least 1 mL or about 1 mL, at least 5 mL or about at least 5 mL or about 5 mL, at least 10 mL or about at least 10 mL or about 10 mL, at least 20 mL or about at least 20 mL or about 20 mL, at least 25 mL or about at least 25 mL or about 25 mL, at least 30 mL or about at least 30 mL or about 30 mL, at least 40 mL or about at least 40 mL or about 40 mL, at least 50 mL or about at least 50 mL or about 50 mL, at least 60 mL or about at least 60 mL or about 60 mL, at least 70 mL or about at least 70 mL or about 70 mL, at least 80 mL or about at least 80 mL or about 80 mL, at least 90 mL or about at least 90 mL or about 90 mL, or at least 100 mL or about at least 100 mL or about 100 mL.

[0124] In some of such embodiments, the pharmaceutical composition further contains a cryoprotective substance. In some of such embodiments, the pharmaceutical composition is sterile.

[0125] This specification provides for manufactured articles containing any of the pharmaceutical compositions described herein.

[0126] Furthermore, methods of treatment are provided, comprising administering one of the pharmaceutical compositions described herein to a subject for treating a disease or condition. In some cases, the disease or condition is cancer. In some situations, cancer is a B-cell malignancy and / or myeloma, lymphoma, or leukemia. In some embodiments, cancer is mantle cell lymphoma (MCL), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLB), or follicular lymphoma (FL). [Invention 1001] (a) administering T-cell therapy to subjects with a disease or condition; and (b) Administer an immunomodulatory compound to the subject. A method of treatment including, A method wherein the immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of Ikaros (IKZF1) and / or Aiolos (IKZF3). [Invention 1002] The method of the present invention 1001, wherein the administration of an immunomodulatory compound for at least one cycle is initiated after the initiation of T-cell therapy. [Invention 1003] A method of treatment comprising administering T-cell therapy to a subject having a disease or condition, At the start of T-cell therapy administration, the subject has been administered an immunomodulatory compound and / or has been treated with an immunomodulatory compound and / or the subject's blood or biopsy sample contains detectable levels of manipulated T-cell therapy T cells. A method wherein the immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3). [Invention 1004] A method of treatment comprising administering an immunomodulatory compound to a subject having a disease or condition, At the start of administration of the immunomodulatory compound, if the subject has previously received T-cell therapy for the treatment of a disease or condition, and / or if the subject's blood or biopsy sample contains detectable levels of manipulated T-cell therapy T cells, A method wherein the immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3). [Invention 1005] (a) administering T-cell therapy to subjects with a disease or condition; and (b) Administer an immunomodulatory compound to the subject. A method of treatment including, The immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3), and The initiation of immunomodulatory compound administration, (1) at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks or at least 4 weeks after the start of T-cell therapy, and / or performed 2 to 28 days or 7 to 21 days after the start of T-cell therapy; and / or (2)(i) The peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) The number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally reduced compared to a preceding time point after administration of T-cell therapy; (iii) The number of detectable T-cell therapy cells in the blood decreased by 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or more than 3.0 times, 4.0 times or more than 4.0 times, 5.0 times or more than 5.0 times, 10 times or more than 10 times or more than the peak number or maximum number of detectable T-cell therapy cells in the subject's blood after the start of T-cell therapy administration; (iv) At the point after the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood, the number of detectable T cells or cells derived from the subject's blood is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) The subject has shown disease progression after treatment with T-cell therapy and / or has relapsed following remission; and / or (iv) The subjects showed an increased tumor volume compared to the tumor volume before or after T cell administration and before the initiation of immunomodulatory compound administration. The method, either at that time or thereafter, optionally immediately after or within 1-3 days thereafter. [Invention 1006] A method of treatment comprising administering an immunomodulatory compound to a subject who is receiving T-cell therapy to treat a disease or condition prior to the initiation of administration of the immunomodulatory compound, The immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3), and The initiation of immunomodulatory compound administration, (1) at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks or at least 4 weeks after the start of T-cell therapy, and / or performed 2 to 28 days or 7 to 21 days after the start of T-cell therapy; and / or (2)(i) The peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) The number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally reduced compared to a preceding time point after administration of T-cell therapy; (iii) The number of detectable T-cell therapy cells in the blood decreased by 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or more than 3.0 times, 4.0 times or more than 4.0 times, 5.0 times or more than 5.0 times, 10 times or more than 10 times or more than the peak number or maximum number of detectable T-cell therapy cells in the subject's blood after the start of T-cell therapy administration; (iv) At the point after the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood, the number of detectable T cells or cells derived from the subject's blood is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) The subject has shown disease progression after treatment with T-cell therapy and / or has relapsed following remission; and / or (iv) The subjects showed an increased tumor volume compared to the tumor volume before or after T cell administration and before the initiation of immunomodulatory compound administration. The method, either at that time or thereafter, optionally immediately after or within 1-3 days thereafter. [Invention 1007] The method according to any one of 1002, 1005, and 1006 of the present invention, wherein the administration of the immunomodulatory compound is initiated at a time when the administration of the immunomodulatory compound is initiated at or after 14 days or approximately 14 days, at or after 15 days or approximately 15 days, at or after 16 days, at or after 17 days or approximately 17 days, at or after 18 days or approximately 18 days, at or after 19 days or approximately 19 days, at or after 20 days or approximately 20 days, at or after 21 days or approximately 21 days, at or after 24 days or approximately 24 days, or at or after 28 days or approximately 28 days. [Invention 1008] Before initiating administration of immunomodulatory compounds, (i) The peak or maximum level of T-cell therapy cells is detectable in the target blood; (ii) The number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally reduced compared to a preceding point in time after administration of T-cell therapy; (iii) The number of detectable T-cell therapy cells in the blood decreases by 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or more than 3.0 times, 4.0 times or more than 4.0 times, 5.0 times or more than 5.0 times, 10 times or more than 10 times or more than the peak number or maximum number of detectable T-cell therapy cells in the subject's blood after the start of T-cell therapy administration; (iv) At the time after the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood, the number of detectable T cells or cells derived from the subject in the subject's blood is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) The disease has progressed after treatment with T-cell therapy and / or has relapsed following remission; and / or (iv) The tumor volume shown is the increased tumor volume compared to the tumor volume before or after T cell administration and before the initiation of immunomodulatory compound administration. A method of the present invention, including selecting a target, as described in 1002 and any of 1005-1007. [Invention 1009] A method of treatment comprising administering a therapeutically effective dose of an immunomodulatory compound to a subject who is receiving T-cell therapy to treat a disease or condition prior to the initiation of administration of the immunomodulatory compound, The immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3). The subjects are those who, on days 12 to 15 or approximately 12 to 15 after the start of T-cell therapy to treat a disease or condition, optionally on day 14 or approximately 14, (i) The number of T-cell therapy cells in a subject is less than 75% of the average number of T-cell therapy cells at the same time point in multiple subjects who received the same or similar dose of T-cell therapy; and / or (ii) The number of CD3+ or CD8+ cells, or optionally CAR+ T cells, in the blood for T-cell therapy is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL. The subject, the method. [Invention 1010] (a) On day 12 to 15 or approximately day 12 to 15 after the start of administration of T-cell therapy to treat the disease or condition, optionally on day 14 or approximately day 14, (i) The number of T-cell therapy cells in a subject is less than 75% of the average number of T-cell therapy cells at the same time point in multiple subjects who received the same or similar dose of T-cell therapy; and / or (ii) The number of CD3+ or CD8+ cells, or optionally CAR+ T cells, in the blood for T-cell therapy is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL. Selecting a target; and (b) Administration of a therapeutically effective dose of an immunomodulatory compound selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that interact with and / or bind to one or more members of cerebron (CRBN) and / or the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3). A method of treatment, including [the specified part of the procedure]. [Invention 1011] A method according to any of items 1001 to 1010 of the present invention for preventing, reducing, or improving one or more symptoms or outcomes of a disease or condition. [Invention 1012] (a) The amount of immunomodulatory compound administered is insufficient to improve, reduce or prevent the disease or condition or its symptoms or outcome, both as a monotherapy and / or in the absence of T-cell therapy; and / or (b) The amount of immunomodulatory compound administered is insufficient to improve, reduce or prevent the disease or condition or its symptoms or outcome in the subject, both as a monotherapy and / or in the absence of T-cell therapy; and / or (c) The method described above causes symptoms, outcomes, or burdens of a disease or condition, (i) The degree of reduction or improvement achieved by the administration of an immunomodulator alone in a population of subjects having the disease or condition, on an arbitrary and average basis, (ii) The degree of reduction or improvement in a population of subjects with the disease or condition, on average, as a result of T-cell therapy alone. To reduce or improve to an extent that exceeds the combination of; and / or (d) The amount of the immunomodulatory compound administered in the method described above, or administered in one or more doses, is a maintenance level dose of the compound, or is equivalent to the dose of the compound administered to a subject who showed a response, optionally a complete response, after administration of the compound for treatment. Any method according to invention 1001 to 1011. [Invention 1013] A disease or condition is refractory or resistant to an immunomodulatory compound, and / or becomes refractory or resistant to it after treatment with an immunomodulatory compound; and / or The subject, disease, or condition has been determined to have a mutation or factor that confers resistance to treatment with immunomodulatory compounds to the disease or condition. Any method according to invention 1001 to 1012. [Invention 1014] Administration of immunomodulatory compounds (i) at least one cycle of more than 30 days beginning with the commencement of administration of an immunomodulatory compound, the cycle comprising administration of the compound optionally daily or at least daily for up to 21 consecutive days, and / or the last administration of the compound in the cycle is 21 days or less after the first administration of the compound in the cycle; and / or (ii) at least two cycles, each comprising administration of the compound over several consecutive days followed by a rest period in which no immunomodulatory compound is administered, the rest period exceeding 14 consecutive days; and / or (iii) Optionally administered daily or at least daily for 14 consecutive days or less. A method of the present invention, including any of the methods described in items 1001 to 1013. [Invention 1015] The initiation of administration of an immunomodulatory compound or the initiation of administration of said compound for at least one cycle, and the initiation of administration of T-cell therapy, may be performed on the same day or on consecutive days, or optionally in parallel; and / or At least one dose of an immunomodulatory compound is administered on the same day as, or within one or two days of, an administration of a certain dose of T-cell therapy, before, or immediately thereafter. Any method of the present invention 1001 to 1014. [Invention 1016] Any method of the present invention 1001 to 1015, wherein the initiation of administration of an immunomodulatory compound, or the initiation of administration of said compound for at least one cycle, is prior to the initiation of T-cell therapy. [Invention 1017] A method of treatment comprising administering T-cell therapy to a subject having a disease or condition, Immunomodulatory compounds were administered to the target before the initiation of T-cell therapy. The immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3), and Immunomodulatory compounds, (i) A cycle comprising up to 21 consecutive days of administration, including more than 30 days beginning with the commencement of administration of the immunomodulatory compound; and / or (ii) A cycle comprising administration over several consecutive days followed by a rest period during which no immunomodulatory compound is administered, wherein the rest period exceeds 14 consecutive days; and / or (iii) Cycles including administration for 14 consecutive days or less It is administered as follows: method. [Invention 1018] The method according to any one of the present invention 1001, 1003, and 1011-1017, wherein the administration of the immunomodulatory compound is initiated within 14 days prior to the initiation of T-cell therapy. [Invention 1019] Administration of immunomodulatory compounds before administration of T-cell therapy, (i) the time at which a sample containing T cells to be processed and / or manipulated to bring about the therapy is collected from the subject, or within one week before or after that time, and optionally the time at which the sample is an apheresis sample; and / or (ii) Within 14 days prior to the start of T-cell therapy A method of the present invention, any of 1001, 1003, and 1011-1018, starting from the present invention. [Invention 1020] A method according to any one of the invention 1001 to 1019, wherein T cell therapy comprises cells engineered to express recombinant receptors. [Invention 1021] The operation is optional. (1) The process of isolating cells from a biological sample by leukocyte apheresis or apheresis; (2) A step of selecting or concentrating cells by an immunoaffinity-based method; (3) Steps to introduce recombinant nucleic acid, and optionally a viral vector, into cells; (4) Incubating optionally manipulated cells in the presence of one or more stimulating conditions; (5) The process of formulating cells in the presence of a cryoprotective substance; and / or (6) The process of formulating cells for administration to a subject in the presence of optionally pharmaceutically acceptable excipients. The method of the present invention 1020, comprising one or more steps of an ex vivo manufacturing process selected from among. [Invention 1022] The method of the present invention 1021, further comprising contacting cells with an immunomodulatory compound during one or more steps of an ex vivo manufacturing process. [Invention 1023] Any method of the present invention 1001 to 1020, wherein the T cell therapy comprises engineered T cells produced by a manufacturing process comprising incubating cells ex vivo in the presence of an immunomodulatory compound. [Invention 1024] The method of the present invention 1022 or 1023, wherein the incubation of cells in the presence of one or more stimulating conditions is carried out in the presence of an immunomodulatory compound. [Invention 1025] The method according to any one of the present invention 1001-1003 and 1011-1024, wherein the administration of the immunomodulatory compound is initiated within 10, 7, 4, 3, or 2 days prior to the initiation of T-cell therapy. [Invention 1026] A method of treatment comprising administering an immunomodulatory compound to a subject who has a disease or condition and is receiving T-cell therapy, The immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3), and Immunomodulatory compounds, (i) a cycle comprising administration of an immunomodulatory compound for up to 21 consecutive days, including more than 30 days starting from the commencement of administration of the immunomodulatory compound; and / or (ii) A cycle comprising administration of an immunomodulatory compound over several consecutive days and a subsequent rest period during which no immunomodulatory compound is administered, wherein the rest period exceeds 14 consecutive days; and / or (iii) A cycle including administration of an immunomodulatory compound for 14 consecutive days or less. The method of administration. [Invention 1027] T-cell therapy, The peak number in the blood of the cell population for the therapy, optionally consisting of CD3+ or CD8+ cells and / or optionally CAR+ T cells, (a) On average, in multiple subjects treated with T-cell therapy in the absence of immunomodulatory compound administration, (b) In subjects after administration of T-cell therapy, T-cell therapy with fewer than 10 cells per μL, fewer than 5 cells per μL, or fewer than 1 cell per μL. The present invention relates to any of the methods described in 1001 to 1026. [Invention 1028] A method according to any of items 1001 to 1027 of the present invention, wherein T cell therapy comprises a recombinant receptor and optionally cells expressing CAR. [Invention 1029] The method of the present invention 1028, wherein the recombinant receptor contains an antigen-binding domain specific to B cell maturation antigen (BCMA). [Invention 1030] The method according to any of items 1001, 1002, 1004-1017, 1020-1024 and 1025-1029 of the present invention, wherein the administration of the immunomodulatory compound is initiated at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks after the initiation or final dose of T-cell therapy, and / or 2 to 28 days or 7 to 21 days after the initiation or final dose of T-cell therapy. [Invention 1031] A method according to any one of the present invention 1001 to 1030, wherein an immunomodulatory compound is administered for more than 7 consecutive days or approximately 7 consecutive days, more than 14 consecutive days or approximately 14 consecutive days, more than 21 consecutive days or approximately 21 consecutive days, more than 21 consecutive days or approximately 21 consecutive days, or more than 28 consecutive days or approximately 28 consecutive days. [Invention 1032] A method according to any one of items 1001 to 1031 of the present invention, wherein the immunomodulatory compound is administered in a cycle comprising daily administration over several consecutive days, followed by a rest period during which the immunomodulatory compound is not administered. [Invention 1033] The method of the present invention 1032, wherein the rest period during which no immunomodulatory compound is administered is more than 7 consecutive days, more than 14 consecutive days, more than 21 consecutive days, or more than 28 consecutive days. [Invention 1034] A method according to any one of the present invention 1002, 1007, 1008 and 1014-1033, wherein the cycle of administration of the immunomodulatory compound is repeated at least once. [Invention 1035] A method according to any of the present invention 1002, 1007, 1008 and 1014-1034, wherein the immunomodulatory compound is administered for at least two cycles, at least three cycles, at least four cycles, at least five cycles, at least six cycles, at least seven cycles, at least eight cycles, at least nine cycles, at least ten cycles, at least eleven cycles, or at least twelve cycles. [Invention 1036] Administration of immunomodulatory compounds, at least from the start of T cell administration, Until the number of detectable T-cell therapy-derived or administered T-cell therapy cells in the subject's blood increases compared to the subject at a preceding time point immediately prior to administration of the immunomodulatory compound or compared to a preceding time point after administration of the T-cell therapy; Until the number of detectable T-cell therapy cells or cells derived therefrom in the blood is no more than 2.0 times (greater than or less than) the peak or maximum number observed in the subject's blood after the start of T-cell administration; Until the number of detectable T-cell therapy cells in the blood of the subject is greater than or approximately greater than 10%, greater than or approximately greater than 15%, greater than or approximately greater than 20%, greater than or approximately greater than 30%, greater than or approximately greater than 40%, greater than or approximately greater than 50%, or greater than or approximately greater than 60% of the total peripheral blood mononuclear cells (PBMCs) in the blood of the subject; and / or Until the subject shows a reduction in tumor volume compared to the tumor volume immediately before administration of T-cell therapy or immediately before administration of immunomodulatory compounds; and / or Until the subject shows complete remission or clinical remission A method of any of the present invention 1001 to 1035, which is continued. [Invention 1037] Any method of the present invention 1001 to 1036, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, pomalidomide, or 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione; a stereoisomer of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, pomalidomide, or 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione; or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof. [Invention 1038] The method according to any of items 1001 to 1037 of the present invention, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof. [Invention 1039] A method according to any of the present invention 1001 to 1038, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione. [Invention 1040] The method according to any one of the present invention 1001 to 1037, wherein the immunomodulatory compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof. [Invention 1041] The method according to any one of invention 1001 to 1037 and 1040, wherein the immunomodulatory compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. [Invention 1042] A method according to any one of items 1001 to 1041 of the present invention, wherein an immunomodulatory compound is administered orally, subcutaneously, or intravenously. [Invention 1043] The method of the present invention 1042, wherein an immunomodulatory compound is administered orally. [Invention 1044] A method according to any one of items 1001 to 1043 of the present invention, wherein an immunomodulatory compound is administered in the form of a capsule or tablet. [Invention 1045] The immunomodulatory compound, including the values ​​at both ends, is in the following ranges: 0.1 mg to approximately 100 mg or approximately 0.1 mg to approximately 100 mg, 0.1 mg to 50 mg or approximately 0.1 mg to 50 mg, 0.1 mg to 25 mg or approximately 0.1 mg to 25 mg, 0.1 mg to 10 mg or approximately 0.1 mg to 10 mg, 0.1 mg to 5 mg or approximately 0.1 mg to 5 mg, 0.1 mg to 1 mg or approximately 0.1 mg to 5 mg, 0.1 mg to 1 mg or approximately 0.1 mg to 1 mg, 1 mg to 100 mg or approximately 1 mg to 100 mg, 1 mg to 50 mg or approximately 1 mg to 50 mg, 1 mg to 25 mg or approximately 1 mg to 25 mg, 1 mg to 10 mg or approximately 1 mg to 10 mg, and 1 mg to 5 mg. Any method of the present invention described in 1001 to 1044, wherein the amount is less than or approximately 1 mg to 5 mg, 5 mg to 100 mg or approximately 5 mg to 100 mg, 5 mg to 50 mg or approximately 5 mg to 50 mg, 5 mg to 25 mg or approximately 5 mg to 25 mg, 5 mg to 10 mg or approximately 5 mg to 10 mg, 10 mg to 100 mg or approximately 10 mg to 100 mg, 10 mg to 50 mg or approximately 10 mg to 50 mg, 10 mg to 25 mg, 25 mg to 100 mg or approximately 25 mg to 100 mg, 25 mg to 50 mg or approximately 25 mg to 50 mg, or 50 mg to 100 mg or approximately 50 mg to 100 mg. [Invention 1046] A method according to any one of the present invention 1001 to 1045, wherein the immunomodulatory compound is administered once, twice, three times, four times, five times, or six times a day. [Invention 1047] A method according to any one of the present invention 1001 to 1046, wherein the immunomodulatory compound is administered in a total daily dose of at least 0.1 mg / day or at least about 0.1 mg / day, at least 0.5 mg / day or at least about 0.5 mg / day, at least 1.0 mg / day or at least about 1.0 mg / day, at least 2.5 mg / day or at least about 2.5 mg / day, at least 5 mg / day or at least about 5 mg / day, at least 10 mg / day or at least about 10 mg / day, at least 25 mg / day or at least about 25 mg / day, at least 50 mg / day or at least about 50 mg / day, or at least 100 mg / day or at least about 100 mg / day. [Invention 1048] The immunomodulatory compound is administered in an amount greater than 1 mg or about 1 mg, greater than 2.5 mg or about 2.5 mg, greater than 5 mg or about 5 mg, greater than 7.5 mg or about 7.5 mg, greater than 10 mg or about 10 mg, greater than 15 mg or about 15 mg, and less than 25 mg; or The immunomodulatory compound is administered in doses greater than 1 mg / day or approximately greater than 1 mg / day, greater than 2.5 mg / day or approximately greater than 2.5 mg / day, greater than 5 mg / day or approximately greater than 5 mg / day, greater than 7.5 mg / day or approximately greater than 7.5 mg / day, greater than 10 mg / day or approximately greater than 10 mg / day, greater than 15 mg / day or approximately greater than 15 mg / day, and less than 25 mg / day. Any method of the present invention 1001 to 1047. [Invention 1049] Any method of the present invention 1001 to 1048, wherein the administration of a therapeutically effective dose of an immunomodulatory compound stimulates an increase in T cell growth associated with T cell therapy compared to the increase after administration of T cell therapy in the absence of the immunomodulatory compound. [Invention 1050] A method according to any one of the present invention 1001 to 1049, wherein the administration of a therapeutically effective dose of an immunomodulatory compound stimulates an increase in the T cell-mediated cytolytic activity of T cells associated with T cell therapy, compared to the cytolytic activity of T cells after administration in the absence of the immunomodulatory compound. [Invention 1051] Any method of the present invention 1001 to 1050, wherein the administration of a therapeutically effective dose of an immunomodulatory compound stimulates increased cytokine production of T cells associated with T cell therapy, compared to cytokine production after T cell administration in the absence of the immunomodulatory compound. [Invention 1052] The method according to any of the invention 1049 to 1051, wherein the increase is more than 1.5 times or approximately more than 1.5 times, more than 2.0 times or approximately more than 2.0 times, more than 3.0 times or approximately more than 3.0 times, more than 4.0 times or approximately more than 4.0 times, more than 5.0 times or approximately more than 5.0 times, more than 10.0 times or approximately more than 10.0 times, or greater than that. [Invention 1053] A method according to any one of the present invention 1001 to 1052, wherein the T cell therapy is tumor-infiltrating lymphocyte (TIL) therapy or genetically modified cells expressing recombinant receptors that specifically bind to an antigen, or comprising such T cell therapy. [Invention 1054] A method of the present invention 1001 to 1053, wherein the T cell therapy is genetically modified cells expressing recombinant receptors that specifically bind to an antigen, or comprises such cells. [Invention 1055] T-cell therapy, Cells expressing functional non-TCR antigen receptors or recombinant receptors that are TCRs or their antigen-binding fragments, or that contain them. A method of the present invention, including any of the methods described in items 1001 to 1054. [Invention 1056] The method of the present invention 1055, wherein the recombinant antigen receptor is a chimeric antigen receptor (CAR). [Invention 1057] T-cell therapy, Recombinant antigen receptors, which include an extracellular domain containing an antigen-binding domain that specifically binds to the antigen. A method of the present invention, including any of the methods described in items 1001 to 1056. [Invention 1058] A method according to either Invention 1056 or Invention 1057, wherein the antigen is associated with, specific to, and / or expressed on cells or tissues of a disease, disorder, or pathological condition. [Invention 1059] The method of the present invention 1058, wherein the disease, disorder, or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or cancer. [Invention 1060] A method according to any of the present invention 1056 to 1059, wherein the antigen is a tumor antigen. [Invention 1061] Antigens include ROR1, B cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, antifolate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, and EGFR. vIII, Folate-binding protein (FBP), FCRL5, FCRH5, Fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, Kinase insert domain receptor (kdr), Kappa light chain, Lewis Y, L1-cell adhesion molecule (L1-CAM), Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, Melanoma preferential expression antigen (PRAME), Survivin, TAG72, B7-H6, IL-13 receptor alpha2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, biantigen, cancer testicular antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, G protein-binding receptor 5D (GPCR5D), tumor fetal antigen, ROR1, TAG72, Any method of the present invention 1056 to 1060, wherein the antigen is selected from VEGF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, and optionally any of the aforementioned human antigens; pathogen-specific antigens; and antigens associated with the universal tag. [Invention 1062] A method according to any one of the present invention 1056 to 1061, wherein the antigen is CD19, optionally human CD19, or comprises the same. [Invention 1063] A method according to any one of items 1056 to 1061 of the present invention, wherein the antigen is multiple myeloma-associated antigen, optionally BCMA, optionally human BCMA, or comprising the same. [Invention 1064] A method according to any one of the present invention 1056 to 1063, wherein the antigen-binding domain is an antibody, or optionally a fragment of that antibody which is a single-chain fragment. [Invention 1065] The method of the present invention 1064, wherein the fragment comprises an antibody variable region connected by a flexible linker. [Invention 1066] A method of the present invention 1064 or 1065, wherein the fragment comprises scFv. [Invention 1067] T-cell therapy, Recombinant receptors further comprising spacers, optionally including a hinge region and optionally derived from immunoglobulin. Any method of the present invention 1056 to 1066, including the above. [Invention 1068] A method according to any one of the present invention 1056 to 1067, wherein the recombinant antigen receptor includes an intracellular signaling region. [Invention 1069] The method of the present invention 1068, wherein the intracellular signaling region includes an intracellular signaling domain. [Invention 1070] The method of the present invention 1069, wherein the intracellular signaling domain is or comprises a primary signaling domain, a signaling domain capable of inducing a primary activation signal in a T cell, a signaling domain of a T cell receptor (TCR) component, and / or a signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM). [Invention 1071] The method of Invention 1069 or Invention 1070, wherein the intracellular signaling domain is or comprises the intracellular signaling domain or signaling portion of a CD3 chain, optionally a CD3 zeta (CD3ζ) chain. [Invention 1072] The method according to any one of the invention 1069 to 1071, wherein the recombinant receptor further comprises a transmembrane domain positioned between an extracellular domain and an intracellular signaling domain, and the transmembrane domain is optionally a CD8 or CD28 transmembrane domain. [Invention 1073] A method according to any one of the present invention 1069 to 1072, wherein the intracellular signaling region further comprises a co-stimulatory signaling region. [Invention 1074] The method of the present invention 1073, wherein the co-stimulatory signaling region includes the intracellular signaling domain or signaling portion of a T cell co-stimulatory molecule. [Invention 1075] The method of the present invention 1073 or 1074, wherein the co-stimulatory signaling region includes an intracellular signaling domain or signaling portion of CD28, 4-1BB, or ICOS. [Invention 1076] A method according to any one of the present invention 1073 to 1075, wherein the co-stimulatory signaling region includes an intracellular signaling domain at 4-1BB. [Invention 1077] A method according to any one of the present invention 1073 to 1076, wherein the co-stimulatory signaling region is located between the transmembrane domain and the intracellular signaling region. [Invention 1078] T-cell therapy, T cells selected from the group consisting of central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells; and / or Multiple cells, including at least 50% of a population of cells selected from the group consisting of CD4+ T cells, CD8+ T cells, central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells. A method of the present invention, including any of the methods described in items 1001 to 1077. [Invention 1079] Any method of the present invention 1001 to 1078, wherein the T cell therapy comprises T cells that are CD4+ or CD8+. [Invention 1080] A method of T-cell therapy comprising primary cells derived from the subject, as described in any of the invention items 1001 to 1079. [Invention 1081] A method of T-cell therapy comprising cells that are autologous to the target, as described in any of items 1001 to 1080 of the present invention. [Invention 1082] A method of T cell therapy comprising T cells of the same type as the target, as described in any of the invention items 1001 to 1081. [Invention 1083] Any method according to invention 1001 to 1082, wherein the subject is a human. [Invention 1084] T-cell therapy, including the values ​​at both ends, 1 × 10 5 The above 1 x 10 8 The following or approximately 1 x 10 5 The above 1 x 10 8 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 5 × 10⁶ 5 The above 1 x 10 7 The following or approximately 5 x 10 5 The above 1 x 10 7 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), or 1 × 10⁶ cells. 6 The above 1 x 10 7 The following or approximately 1 x 10 6 The above 1 x 10 7 Any method 1001 to 1083 of the present invention, comprising the administration of total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs). [Invention 1085] T cell therapy, 1 x 10 8 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 1 × 10⁶ 7 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 0.5 × 10⁶ 7 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 1 × 10⁶ 6 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 0.5 × 10⁶ 6 Any method of the present invention 1001 to 1084, comprising the administration of total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs). [Invention 1086] Any method of the present invention 1001 to 1085, wherein the amount of cells administered in T-cell therapy is less than the amount in another method in which T-cell therapy is administered without the administration of an immunomodulatory compound, and optionally, the other method brings about a similar or lower degree of improvement, reduction, or prevention of a disease or condition or its symptoms or burden compared to that resulting from the other method. [Invention 1087] The method of the present invention 1086, wherein the amount of cells administered is 1.5 times, 2 times, 3 times, 4 times, 5 times, or 10 times less than the amount administered by other methods. [Invention 1088] A method according to any one of the present invention 1001 to 1087, wherein T-cell therapy is administered as a single pharmaceutical composition containing cells. [Invention 1089] Any method of the present invention 1001 to 1088, wherein the T-cell therapy comprises a divided dose of cells, and the dose of cells is administered over a period of three days or less in multiple compositions comprising the dose of cells together. [Invention 1090] Any method of the present invention 1001 to 1089, further comprising administering lymphocyte depletion chemotherapy before administering T cell therapy. [Invention 1091] A method according to any of the present invention 1001 to 1090, wherein the disease or condition is cancer. [Invention 1092] A method according to any one of the present invention 1001 to 1091, wherein the cancer is a B-cell malignant tumor and / or myeloma, lymphoma, or leukemia. [Invention 1093] The method of Invention 1091 or Invention 1092, wherein the cancer is mantle cell lymphoma (MCL), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), or follicular lymphoma (FL). [Invention 1094] The method of the present invention 1091, wherein the cancer is a non-hematological cancer or a solid tumor. [Invention 1095] Any method of the present invention 1001 to 1094, wherein T cell therapy exhibits increased or prolonged enlargement and / or persistence in a subject compared to a method in which T cell therapy is administered to a subject in the absence of an immunomodulatory compound. [Invention 1096] Any method of the Invention 1001-1095, optionally reducing tumor load to a greater extent and / or over a longer period of time compared to the reduction that would be observed in an equivalent manner in which T-cell therapy is administered to a subject in the absence of an immunomodulatory compound and / or the immunomodulatory compound is administered in the absence of T-cell therapy, at the same dose or dosing regimen. [Invention 1097] (a) Pharmaceutical compositions comprising a unit dose of T-cell therapy; and (b) Instructions for administering the composition to a subject having a disease or condition in combination with the administration of a composition containing an immunomodulatory compound. A kit that includes, The immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3), and The instructions state that the immunomodulatory compound should be administered in one or more unit doses. (i) a cycle comprising administration of an immunomodulatory compound for up to 21 consecutive days, including more than 30 days starting from the commencement of administration of the immunomodulatory compound; and / or (ii) A cycle comprising administration of an immunomodulatory compound over several consecutive days and a subsequent rest period during which no immunomodulatory compound is administered, wherein the rest period exceeds 14 consecutive days; and / or (iii) A cycle including administration of an immunomodulatory compound for 14 consecutive days or less. The kit specifies that it should be administered according to the included dosing cycle. [Invention 1098] (a) A pharmaceutical composition comprising one or more unit doses of an immunomodulatory compound; and (b) Instructions for administering immunomodulatory compounds to subjects with a disease or condition in combination with a unit dose of a pharmaceutical composition including T-cell therapy. A kit that includes, The immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3), and The instructions specify one or more unit doses of immunomodulatory compounds. (i) a cycle comprising administration of an immunomodulatory compound for up to 21 consecutive days, including more than 30 days starting from the commencement of administration of the immunomodulatory compound; and / or (ii) A cycle comprising administration of an immunomodulatory compound over several consecutive days and a subsequent rest period during which no immunomodulatory compound is administered, wherein the rest period exceeds 14 consecutive days; and / or (iii) A cycle including administration of an immunomodulatory compound for 14 consecutive days or less. The kit specifies that it should be administered according to the included dosing cycle. [Invention 1099] A kit according to Invention 1097 or Invention 1098, wherein the instructions specify that administration of one or more unit doses of immunomodulatory compounds may be optionally initiated concurrently with the initiation of T-cell therapy on the same day. [Invention 1100] A kit according to Invention 1097 or Invention 1098, wherein the instructions specify that administration of one or more unit doses of immunomodulatory compounds should be initiated before the start of T-cell therapy. [Invention 1101] The instruction sheet specifies the administration of one or more unit doses of immunomodulatory compounds. (1) The time at which the sample containing the T cells to be manipulated is collected from the subject, or within one week prior thereto, and optionally the time at which the sample is an apheresis sample; and / or (2) At one or more steps in the ex vivo manufacturing process to produce an engineered T cell therapy; and / or (3) Within 14 days prior to administering T-cell therapy A kit of the present invention 1100, which specifies that it will be started at [time]. [Invention 1102] One or more steps in the ExVivo manufacturing process (1) The process of isolating cells from a biological sample by leukocyte apheresis or apheresis; (2) A step of selecting or concentrating cells by an immunoaffinity-based method; (3) Steps to introduce recombinant nucleic acid, and optionally a viral vector, into cells; (4) Incubating optionally manipulated cells in the presence of one or more stimulating conditions; (5) The process of formulating cells in the presence of a cryoprotective substance; and / or (6) The process of formulating cells for administration to the target in the presence of optionally pharmaceutically acceptable excipients. A kit of the present invention 1101, selected from the following. [Invention 1103] A kit according to any of Invention 1097-1102, wherein the instructions specify that administration of one or more unit doses of immunomodulatory compounds should be initiated within 10, 7, 4, 3, or 2 days prior to the start of T-cell therapy. [Invention 1104] A kit according to Invention 1097 or Invention 1098, wherein the instructions specify that the administration of one or more unit doses of immunomodulatory compounds should be initiated after the start of T-cell therapy. [Invention 1105] The instruction sheet is, Administration of one or more unit doses of immunomodulatory compounds shall be initiated at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks after the initiation of T-cell therapy, and / or 2 to 28 days or 7 to 21 days after the initiation of T-cell therapy. The kit of Invention 1104, which clearly states the following. [Invention 1106] (a) Pharmaceutical compositions comprising a unit dose of T-cell therapy; and (b) Instructions for administering the composition to a subject having a disease or condition in combination with the administration of an immunomodulatory compound. A kit that includes, The immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3), and The instruction sheet states that the initiation of administration of one or more unit doses of immunomodulatory compounds is (1) at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks or at least 4 weeks after the start of T-cell therapy, and / or performed 2 to 28 days or 7 to 21 days after the start of T-cell therapy; and / or (2)(i) The peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) The number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally reduced compared to a preceding time point after administration of T-cell therapy; (iii) The number of detectable T-cell therapy cells in the blood decreased by 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or more than 3.0 times, 4.0 times or more than 4.0 times, 5.0 times or more than 5.0 times, 10 times or more than 10 times, or more than the peak number or maximum number of detectable T-cell therapy cells in the subject's blood after the start of T-cell therapy administration; (iv) At the time after the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood, the number of detectable T cells or cells derived from the subject in the subject's blood is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) The subject has shown disease progression after treatment with T-cell therapy and / or has relapsed following remission; and / or (iv) The subjects showed an increased tumor volume compared to the tumor volume before or after T cell administration and before the initiation of immunomodulatory compound administration. At that time or thereafter, optionally immediately after or within 1-3 days thereafter A kit that clearly states that it is. [Invention 1107] (a) A pharmaceutical composition comprising one or more unit doses of an immunomodulatory compound, wherein the immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3); and (b) Instructions for administering an immunomodulatory compound to a subject with a disease or condition in combination with the administration of a unit dose of a pharmaceutical composition including T-cell therapy, wherein the initiation of administration of one or more unit doses of the immunomodulatory compound is (1) at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks or at least 4 weeks after the start of T-cell therapy, and / or performed 2 to 28 days or 7 to 21 days after the start of T-cell therapy; and / or (2)(i) The peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) The number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally reduced compared to a preceding time point after administration of T-cell therapy; (iii) The number of detectable T-cell therapy cells in the blood decreased by 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or more than 3.0 times, 4.0 times or more than 4.0 times, 5.0 times or more than 5.0 times, 10 times or more than 10 times, or more than the peak number or maximum number of detectable T-cell therapy cells in the subject's blood after the start of T-cell therapy administration; (iv) At the time after the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood, the number of detectable T cells or cells derived from the subject in the subject's blood is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) The subject has shown disease progression after treatment with T-cell therapy and / or has relapsed following remission; and / or (iv) The subjects showed an increased tumor volume compared to the tumor volume before or after T cell administration and before the initiation of immunomodulatory compound administration. At that time or thereafter, optionally immediately after or within 1-3 days thereafter The instruction manual clearly states that A kit that includes this. [Invention 1108] The instruction sheet is, Administration of one or more unit doses of immunomodulatory compounds shall be initiated at a time 14 days or approximately 14 days after the start of T-cell therapy, 15 days or approximately 15 days after, 16 days or approximately 16 days after, 17 days or approximately 17 days after, 18 days or approximately 18 days after, 19 days or approximately 19 days after, 20 days or approximately 20 days after, 21 days or approximately 21 days after, 24 days or approximately 24 days after, or 28 days or approximately 28 days after. A kit according to Invention 1106 or Invention 1107, which explicitly states the following. [Invention 1109] The instruction manual specifies that the patient should be selected for administration of one or more unit doses of immunomodulatory compounds after T-cell therapy has been administered, and here, (i) The peak or maximum level of T-cell therapy cells is detectable in the target blood; (ii) The number of detectable T-cell therapy cells in the blood becomes undetectable or reduced after becoming detectable in the blood, and optionally reduced compared to a preceding point in time after administration of T-cell therapy; (iii) The number of detectable T-cell therapy cells in the blood decreases by 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or more than 3.0 times, 4.0 times or more than 4.0 times, 5.0 times or more than 5.0 times, 10 times or more than 10 times, or more than the peak number or maximum number of detectable T-cell therapy cells in the subject's blood after the start of T-cell therapy administration; (iv) After the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood, the number of detectable T cells or cells derived from the subject in the subject's blood is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) The subject shows disease progression after treatment with T-cell therapy and / or relapses following remission; and / or (iv) The subject shows an increased tumor volume compared to the tumor volume before or after T cell administration and before the initiation of immunomodulatory compound administration. A kit according to any of inventions 1106 to 1108. [Invention 1110] (a) Pharmaceutical compositions comprising a unit dose of T-cell therapy; and (b) Instructions for administering the composition to subjects with a disease or condition in combination with the administration of an immunomodulatory compound. A kit that includes, The immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3), and On days 12 to 15 or approximately 12 to 15 after the start of T-cell therapy to treat a disease or condition, optionally on day 14 or approximately 14, (i) The number of T-cell therapy cells in a subject is less than 75% of the average number of T-cell therapy cells at the same time point in multiple subjects who received the same or similar dose of T-cell therapy; and / or (ii) The number of CD3+ or CD8+ cells, or optionally CAR+ T cells, in the blood for T-cell therapy is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL. In such cases, the immunomodulatory compound may be administered in one or more unit doses. This is a kit, as clearly stated in the instructions. [Invention 1111] (a) A pharmaceutical composition comprising one or more unit doses of an immunomodulatory compound, wherein the immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of IKZF1; inhibitors of Aeolus (IKZF3); and compounds that enhance or promote the ubiquitination and / or degradation of IKZF1 and / or Aeolus (IKZF3); and (b) Instructions for administering one or more unit doses of immunomodulatory compounds to a subject with a disease or condition in combination with the administration of a pharmaceutical composition containing a unit dose of T-cell therapy, wherein the administration is performed on day 12 to 15 or approximately day 12 to 15 after the start of administration of T-cell therapy to treat the disease or condition, optionally on day 14 or approximately day 14, (i) The number of T-cell therapy cells in a subject is less than 75% of the average number of T-cell therapy cells at the same time point in multiple subjects who received the same or similar dose of T-cell therapy; and / or (ii) The number of CD3+ or CD8+ cells, or optionally CAR+ T cells, in the blood for T-cell therapy is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL. In some cases, the instruction sheet specifies that one or more unit doses of an immunomodulatory compound should be administered to the target patient. A kit that includes this. [Invention 1112] A kit according to any of Invention 1097 to 1111, wherein the immunomodulatory compound is formulated in a daily dose and / or the instructions specify that the immunomodulatory compound should be administered daily. [Invention 1113] A kit according to any of Invention 1097 to 1112, wherein the instructions specify that the immunomodulatory compound be administered for more than 7 consecutive days or approximately more than 7 consecutive days, more than 14 consecutive days or approximately more than 14 consecutive days, more than 21 consecutive days or approximately more than 21 consecutive days, more than 21 consecutive days or approximately more than 21 consecutive days, or more than 28 consecutive days or approximately more than 28 consecutive days. [Invention 1114] A kit according to any of Invention 1097 to 1113, wherein the instructions specify that the immunomodulatory compound is administered in a dosing cycle that includes daily administration over several consecutive days, followed by a rest period during which the immunomodulatory compound is not administered. [Invention 1115] The kit of Invention 1114, wherein the instructions specify that the rest period during which no immunomodulatory compound is administered is more than 7 consecutive days, more than 14 consecutive days, more than 21 consecutive days, or more than 28 consecutive days. [Invention 1116] A kit according to any of Invention 1097 to 1115, wherein the instructions specify that the administration cycle of the immunomodulatory compound is repeated at least once. [Invention 1117] Administration of immunomodulatory compounds should begin at least after the initiation of T cell administration. Until the number of detectable T-cell therapy-derived or administered T-cell therapy cells in the subject's blood increases compared to the subject at a preceding time point immediately prior to administration of the immunomodulatory compound or compared to a preceding time point after administration of the T-cell therapy; Until the number of detectable T-cell therapy cells or cells derived therefrom in the blood is no more than 2.0 times (greater than or less than) the peak or maximum number observed in the subject's blood after the start of T-cell administration; Until the number of detectable T-cell therapy cells in the blood of the subject is greater than or approximately greater than 10%, greater than or approximately greater than 15%, greater than or approximately greater than 20%, greater than or approximately greater than 30%, greater than or approximately greater than 40%, greater than or approximately greater than 50%, or greater than or approximately greater than 60% of the total peripheral blood mononuclear cells (PBMCs) in the blood of the subject; and / or Until the subject shows a reduction in tumor volume compared to the tumor volume immediately before administration of T-cell therapy or immediately before administration of immunomodulatory compounds; and / or Until the subject shows complete remission or clinical remission A kit according to any of Invention 1097-1116, in which the instructions specify that it should be continued. [Invention 1118] A kit according to any of Invention 1097 to 1117, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, pomalidomide, or 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione; a stereoisomer of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, pomalidomide, or 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione; or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof. [Invention 1119] A kit according to any of Invention 1097 to 1118, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof. [Invention 1120] A kit according to any of Invention 1097 to 1119, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione. [Invention 1121] A kit according to any of Invention 1097 to 1118, wherein the immunomodulatory compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof. [Invention 1122] A kit according to any one of Invention 1097-1118 and 1121, wherein the immunomodulatory compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. [Invention 1123] A kit according to any one of Invention 1097 to 1122, wherein an immunomodulatory compound is formulated for oral, subcutaneous, or intravenous administration. [Invention 1124] A kit according to the present invention 1123, wherein an immunomodulatory compound is formulated for oral administration. [Invention 1125] A kit according to any of Invention 1097 to 1124, wherein an immunomodulatory compound is formulated in a capsule or tablet. [Invention 1126] Each of one or more unit doses of an immunomodulatory compound, including the values ​​at both ends, is between 0.1 mg and approximately 100 mg or approximately 0.1 mg and approximately 100 mg, between 0.1 mg and 50 mg or approximately 0.1 mg and 50 mg, between 0.1 mg and 25 mg or approximately 0.1 mg and 25 mg, between 0.1 mg and 10 mg or approximately 0.1 mg and 10 mg, between 0.1 mg and 5 mg or approximately 0.1 mg and 5 mg, between 0.1 mg and 1 mg or approximately 0.1 mg and 1 mg, between 1 mg and 100 mg or approximately 1 mg and 100 mg, between 1 mg and 50 mg or approximately 1 mg and 50 mg, between 1 mg and 25 mg or approximately 1 mg and 25 mg, between 1 mg and 10 mg or approximately 1 mg. Including amounts of 10 mg or less, 1 mg to 5 mg or approximately 1 mg to 5 mg, 5 mg to 100 mg or approximately 5 mg to 100 mg, 5 mg to 50 mg or approximately 5 mg to 50 mg, 5 mg to 25 mg or approximately 5 mg to 25 mg, 5 mg to 10 mg or approximately 5 mg to 10 mg, 10 mg to 100 mg or approximately 10 mg to 100 mg, 10 mg to 50 mg or approximately 10 mg to 50 mg, 10 mg to 25 mg, 25 mg to 100 mg or approximately 25 mg to 100 mg, 25 mg to 50 mg or approximately 25 mg to 50 mg, or 50 mg to 100 mg or approximately 50 mg to 100 mg; and / or Each of one or more unit doses of an immunomodulatory compound contains an amount of at least 0.1 mg or at least about 0.1 mg, at least 0.5 mg or at least about 0.5 mg, at least 1.0 mg or at least about 1.0 mg, at least 2.5 mg or at least about 2.5 mg, at least 5 mg or at least about 5 mg, at least 10 mg or at least about 10 mg, at least 25 mg or at least about 25 mg, at least 50 mg or at least about 50 mg, or at least 100 mg or at least about 100 mg. A kit according to any of inventions 1097 to 1125. [Invention 1127] A kit according to any one of Invention 1097 to 1126, wherein each of one or more unit doses of an immunomodulatory compound contains an amount greater than or about 1 mg, greater than or about 2.5 mg, greater than or about 5 mg, greater than or about 7.5 mg, greater than or about 10 mg, greater than or about 15 mg, and less than 25 mg. [Invention 1128] A kit according to any of Invention 1097-1127, wherein the T-cell therapy is tumor-infiltrating lymphocyte (TIL) therapy or genetically modified cells expressing recombinant receptors that specifically bind to an antigen. [Invention 1129] A kit according to any of Invention 1097-1128, wherein the T cell therapy is genetically modified cells expressing recombinant receptors that specifically bind to an antigen, or comprises such cells. [Invention 1130] A kit according to Invention 1128 or Invention 1129, wherein the recombinant receptor is a functional non-TCR antigen receptor or a TCR or its antigen-binding fragment, or comprises the same. [Invention 1131] A kit according to any of the present invention 1128 to 1130, wherein the recombinant antigen receptor is a chimeric antigen receptor (CAR). [Invention 1132] A kit according to any one of the invention 1128 to 1131, wherein the recombinant antigen receptor comprises an extracellular domain containing an antigen-binding domain that specifically binds to an antigen. [Invention 1133] A kit according to any of Invention 1128-1132, wherein the antigen is associated with, specific to, and / or expressed on cells or tissues of a disease, disorder, or pathological condition. [Invention 1134] A kit according to the present invention 1133, wherein the disease, disorder, or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or cancer. [Invention 1135] A kit according to any of the present invention 1128 to 1134, wherein the antigen is a tumor antigen. [Invention 1136] Antigens include ROR1, B cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, antifolate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, and EGFR. vIII, Folate-binding protein (FBP), FCRL5, FCRH5, Fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, Kinase insert domain receptor (kdr), Kappa light chain, Lewis Y, L1-cell adhesion molecule (L1-CAM), Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, Melanoma preferential expression antigen (PRAME), Survivin, TAG72, B7-H6, IL-13 receptor alpha2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, dual antigen, cancer testicular antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, G protein-binding receptor 5D (GPCR5D), tumor fetal antigen, ROR1, TAG72, V A kit according to any of Invention 1128-1135, selected from EGF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, optionally any of the aforementioned human antigens; pathogen-specific antigens; and antigens associated with the universal tag. [Invention 1137] A kit according to any of Invention 1128-1136, wherein the antigen is CD19, optionally human CD19, or contains the same. [Invention 1138] A kit according to any of Invention 1128-1137, wherein the antigen is BCMA, optionally human BCMA, or contains the same. [Invention 1139] A kit according to any one of Invention 1128-1138, wherein the antigen-binding domain is an antibody or an antibody fragment, which is optionally a single-chain fragment. [Invention 1140] The kit of the present invention 1139, wherein the aforementioned fragment comprises an antibody variable region connected by a flexible linker. [Invention 1141] The aforementioned fragment is a kit of invention 1139 or invention 1140, comprising scFv. [Invention 1142] A kit according to any one of the inventions 1128 to 1141, further comprising a recombinant receptor, optionally comprising a spacer optionally derived from immunoglobulin, optionally including a hinge region. [Invention 1143] A kit according to any of Invention 1128 to 1142, wherein the recombinant antigen receptor includes an intracellular signaling region. [Invention 1144] A kit according to the present invention 1143, wherein the intracellular signaling region includes an intracellular signaling domain. [Invention 1145] The kit of the present invention 1144, wherein the intracellular signaling domain is or comprises a primary signaling domain, a signaling domain capable of inducing a primary activation signal in T cells, a signaling domain of a T cell receptor (TCR) component, and / or a signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM). [Invention 1146] A kit according to Invention 1144 or Invention 1145, wherein the intracellular signaling domain is or comprises the intracellular signaling domain or signaling portion of a CD3 chain, optionally a CD3 zeta (CD3ζ) chain. [Invention 1147] A kit according to any one of the inventions 1144 to 1146, wherein the recombinant receptor further comprises a transmembrane domain positioned between an extracellular domain and an intracellular signaling region, and the transmembrane domain is optionally a CD8 or CD28 transmembrane domain. [Invention 1148] A kit according to any one of the present inventions 1144 to 1147, wherein the intracellular signaling region further comprises a co-stimulatory signaling region. [Invention 1149] A kit according to Invention 1148, wherein the co-stimulatory signaling region includes the intracellular signaling domain or signaling portion of a T cell co-stimulatory molecule. [Invention 1150] A kit according to Invention 1148 or Invention 1149, wherein the co-stimulatory signaling region comprises an intracellular signaling domain or signaling portion of CD28, 4-1BB, or ICOS. [Invention 1151] A kit according to any of Invention 1148 to 1150, wherein the co-stimulatory signaling region includes an intracellular signaling domain at 4-1BB. [Invention 1152] A kit according to any of invention 1148 to 1151, wherein the co-stimulatory signaling region is located between the transmembrane domain and the intracellular signaling region. [Invention 1153] T-cell therapy, T cells selected from the group consisting of central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells; and / or Multiple cells, including at least 50% of a population of cells selected from the group consisting of CD4+ T cells, CD8+ T cells, central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells. A kit comprising any of inventions 1097 to 1152. [Invention 1154] A kit according to any of Invention 1097 to 1153, comprising T cells that are CD4+ or CD8+. [Invention 1155] A kit from any of the 97-154 of the present invention, comprising T-cell therapy and primary cells derived from the target. [Invention 1156] A kit according to any of Invention 1097-1155, which is autologous to the target of T-cell therapy. [Invention 1157] Any method 1097 to 1156 of the present invention, wherein T-cell therapy is homogeneous for the target. [Invention 1158] A kit according to any of Invention 1097 to 1157, for use with humans. [Invention 1159] The unit dose of T-cell therapy, including both extreme values, is 1 × 10⁻⁶. 5 The above 1 x 10 8 The following or approximately 1 x 10 5 The above 1 x 10 8 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 5 × 10⁶ 5 The above 1 x 10 7 The following or approximately 5 x 10 5 The above 1 x 10 7 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), or 1 × 10⁶ cells. 6 The above 1 x 10 7 The following or approximately 1 x 10 6 The above 1 x 10 7 A kit according to any of Invention 1097 to 1158, comprising total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs). [Invention 1160] The unit dose of T-cell therapy is 1 × 10 8 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 1 × 10⁶ 7 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 0.5 × 10⁶ 7 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 1 × 10⁶6 The following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 0.5 × 10⁶ 6 A kit according to any of Invention 1097 to 1159, comprising the administration of total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs). [Invention 1161] A kit according to any one of the present inventions 1097 to 1160, wherein the unit dose of T cell therapy contains a dose of cells that is a divided dose, and the dose of cells is administered over a period of three days or less in multiple compositions containing the said dose of cells together. [Invention 1162] A kit according to any of Invention 1097-1161, wherein the instructions further specify that lymphocyte depletion chemotherapy should be administered before the administration of T-cell therapy. [Invention 1163] A kit according to any of invention 1097 to 1162, wherein the disease or condition is cancer. [Invention 1164] A kit according to any of Invention 1097-1163, wherein the cancer is a B-cell malignant tumor and / or myeloma, lymphoma, or leukemia. [Invention 1165] A kit according to Invention 1163 or Invention 1164, wherein the cancer is mantle cell lymphoma (MCL), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), or follicular lymphoma (FL). [Invention 1166] A kit according to the present invention 1163, wherein the cancer is a non-hematological cancer or a solid tumor. [Invention 1167] A manufactured article comprising any kit according to Invention 1097 to 1166. [Invention 1168] A pharmaceutical composition comprising a T-cell therapy, an immunomodulatory compound, and a pharmaceutically acceptable carrier, An immunomodulatory compound is selected from the group consisting of thalidomide analogs; thalidomide derivatives; compounds that bind to cereblon (CRBN) and / or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of ikaros (IKZF1); inhibitors of aiolos (IKZF3); and compounds that enhance or promote ubiquitination and / or degradation of ikaros (IKZF1) and / or aiolos (IKZF3). A pharmaceutical composition. [Inventive concept 1169] The pharmaceutical composition of Inventive concept 1168, wherein the T cell therapy is formulated in a unit dose. [Inventive concept 1170] The unit dose of the T cell therapy includes values at both ends and is 1×10 5 or more to 1×10 8 or less, or about 1×10 5 or more to 1×10 8 or less of total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 5×10 5 or more to 1×10 7 or less, or about 5×10 5 or more to 1×10 7 or less of total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), or 1×10 6 or more to 1×10 7 or less, or about 1×10 6 or more to 1×10 7 or less of total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), and includes the pharmaceutical composition of Inventive concept 1169. [Inventive concept 1171] The unit dose of the T cell therapy is 1×10 8 or less of total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 1×10 7 or less of total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 0.5×10 7 or less of total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 1×10 6 or less of total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 0.5×106 A pharmaceutical composition according to Invention 1169 or Invention 1170, comprising the administration of the following total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs). [Invention 1172] A pharmaceutical composition according to any of the Invention 1168 to 1171, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, pomalidomide, or 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione; a stereoisomer of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, pomalidomide, or 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof. [Invention 1173] A pharmaceutical composition according to any of the Invention 1168 to 1172, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof. [Invention 1174] A pharmaceutical composition according to any of invention 1168 to 1173, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione. [Invention 1175] A pharmaceutical composition according to any of the Invention 1168 to 1172, wherein the immunomodulatory compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof. [Invention 1176] A pharmaceutical composition according to any one of invention 1168 to 1172 and 1175, wherein the immunomodulatory compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. [Invention 1177] Pharmaceutical compositions according to inventions 1168-1173, wherein immunomodulatory compounds are formulated in unit doses. [Invention 1178] The amount of immunomodulatory compound in the composition, including the values ​​at both ends, is between 0.1 mg and about 100 mg or about 0.1 mg and about 100 mg, between 0.1 mg and 50 mg or about 0.1 mg and 50 mg, between 0.1 mg and 25 mg or about 0.1 mg and 25 mg, between 0.1 mg and 10 mg or about 0.1 mg and 10 mg, between 0.1 mg and 5 mg or about 0.1 mg and 5 mg, between 0.1 mg and 1 mg or about 0.1 mg and 1 mg, between 1 mg and 100 mg or about 1 mg and 100 mg, between 1 mg and 50 mg or about 1 mg and 50 mg, between 1 mg and 25 mg or about 1 mg and 25 mg, between 1 mg and 10 mg or about 1 mg and 10 ≤ mg, 1 mg to 5 mg or approximately 1 mg to 5 mg, 5 mg to 100 mg or approximately 5 mg to 100 mg, 5 mg to 50 mg or approximately 5 mg to 50 mg, 5 mg to 25 mg or approximately 5 mg to 25 mg, 5 mg to 10 mg or approximately 5 mg to 10 mg, 10 mg to 100 mg or approximately 10 mg to 100 mg, 10 mg to 50 mg or approximately 10 mg to 50 mg, 10 mg to 25 mg, 25 mg to 100 mg or approximately 25 mg to 100 mg, 25 mg to 50 mg or approximately 25 mg to 50 mg, or 50 mg to 100 mg or approximately 50 mg to 100 mg; and / or A pharmaceutical composition according to any of the Invention 1168 to 1177, wherein the amount of the immunomodulatory compound in the composition is at least 0.1 mg or at least about 0.1 mg, at least 0.5 mg or at least about 0.5 mg, at least 1.0 mg or at least about 1.0 mg, at least 2.5 mg or at least about 2.5 mg, at least 5 mg or at least about 5 mg, at least 10 mg or at least about 10 mg, at least 25 mg or at least about 25 mg, at least 50 mg or at least about 50 mg, or at least 100 mg or at least about 100 mg. [Invention 1179] A pharmaceutical composition according to Invention 1177 or Invention 1178, wherein the amount of the immunomodulatory compound in the composition is greater than 1 mg or about 1 mg, greater than 2.5 mg or about 2.5 mg, greater than 5 mg or about 5 mg, greater than 7.5 mg or about 7.5 mg, greater than 10 mg or about 10 mg, greater than 15 mg or about 15 mg, and less than 25 mg. [Invention 1180] A pharmaceutical composition according to any one of the Invention 1168 to 1179, wherein the T cell therapy is tumor-infiltrating lymphocyte (TIL) therapy or genetically modified cells expressing recombinant receptors that specifically bind to an antigen, or comprising such cells. [Invention 1181] A pharmaceutical composition according to any one of the present inventions 1168 to 1180, wherein the T cell therapy is genetically modified cells expressing recombinant receptors that specifically bind to an antigen, or comprises such cells. [Invention 1182] A pharmaceutical composition of the present invention 1180 or 1181, wherein the recombinant receptor is a functional non-TCR antigen receptor or a TCR or its antigen-binding fragment, or comprises the same. [Invention 1183] A pharmaceutical composition according to any of the invention 1180 to 1182, wherein the recombinant antigen receptor is a chimeric antigen receptor (CAR). [Invention 1184] A pharmaceutically acceptable composition according to any one of the invention 1180 to 1183, wherein the recombinant antigen receptor comprises an extracellular domain containing an antigen-binding domain that specifically binds to an antigen. [Invention 1185] A pharmaceutical composition according to any of the present invention 1180 to 1184, wherein the antigen is associated with, specific to, and / or expressed on cells or tissues of a disease, disorder, or pathological condition. [Invention 1186] A pharmaceutical composition of the present invention 1185, wherein the disease, disorder, or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or cancer. [Invention 1187] A pharmaceutical composition according to any of the present invention 1180 to 1185, wherein the antigen is a tumor antigen. [Invention 1188] Antigens include ROR1, B cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, antifolate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, and EGFR. vIII, Folate-binding protein (FBP), FCRL5, FCRH5, Fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, Kinase insert domain receptor (kdr), Kappa light chain, Lewis Y, L1-cell adhesion molecule (L1-CAM), Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, Melanoma preferential expression antigen (PRAME), Survivin, TAG72, B7-H6, IL-13 receptor alpha2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, dual antigen, cancer testicular antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, G protein-binding receptor 5D (GPCR5D), tumor fetal antigen, ROR1, TAG72, VE A pharmaceutical composition according to any of the Invention 1180 to 1187, selected from GF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, and optionally any of the aforementioned human antigens; pathogen-specific antigens; and antigens associated with the universal tag. [Invention 1189] A pharmaceutical composition according to any of the Invention 1180 to 1188, wherein the antigen is CD19, optionally human CD19, or contains the same. [Invention 1190] A pharmaceutical composition according to any of the inventions 1180 to 1189, wherein the antigen is BCMA, optionally human BCMA, or contains the same. [Invention 1191] A pharmaceutical composition according to any one of the present invention 1180 to 1190, wherein the antigen-binding domain is an antibody or an antibody fragment, which is optionally a single-chain fragment, or comprises such an antibody. [Invention 1192] The pharmaceutical composition of the present invention 1191, wherein the aforementioned fragment comprises an antibody variable region connected by a flexible linker. [Invention 1193] The aforementioned fragment comprises scFv, and is part of a pharmaceutical composition according to invention 1191 or invention 1192. [Invention 1194] A pharmaceutically acceptable composition according to any of invention 1180 to 1193, further comprising a recombinant receptor, optionally comprising a spacer, optionally derived from immunoglobulin, optionally comprising a hinge region. [Invention 1195] A pharmaceutically acceptable composition according to any of invention 1180 to 1194, wherein the recombinant antigen receptor includes an intracellular signaling region. [Invention 1196] A pharmaceutical composition according to Invention 1195, wherein the intracellular signaling region includes an intracellular signaling domain. [Invention 1197] A pharmaceutical composition of the present invention 1196, wherein the intracellular signaling domain is a primary signaling domain, a signaling domain capable of inducing a primary activation signal in T cells, a signaling domain of a T cell receptor (TCR) component, and / or a signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM). [Invention 1198] A pharmaceutical composition according to Invention 1196 or Invention 1197, wherein the intracellular signaling domain is or comprises the intracellular signaling domain or signaling portion of a CD3 chain, optionally a CD3 zeta (CD3ζ) chain. [Invention 1199] A pharmaceutically acceptable composition according to any one of the invention 1195 to 1198, further comprising a transmembrane domain positioned between an extracellular domain and an intracellular signaling region, wherein the transmembrane domain is optionally a CD8 or CD28 transmembrane domain. [Invention 1200] A pharmaceutical composition according to any one of the present invention 1195 to 1199, wherein the intracellular signaling region further comprises a co-stimulatory signaling region. [Invention 1201] A pharmaceutical composition of the present invention 1200, wherein the co-stimulatory signaling region comprises the intracellular signaling domain or signaling portion of a T cell co-stimulatory molecule. [Invention 1202] A pharmaceutical composition according to Invention 1200 or Invention 1201, wherein the co-stimulatory signaling region comprises an intracellular signaling domain or signaling portion of CD28, 4-1BB, or ICOS. [Invention 1203] A pharmaceutical composition according to any one of the invention 1200 to 1202, wherein the co-stimulatory signaling region includes an intracellular signaling domain at 4-1BB. [Invention 1204] A pharmaceutical composition according to any one of the invention 1200 to 1203, wherein the co-stimulatory signaling region is located between the transmembrane domain and the intracellular signaling region. [Invention 1205] Recombinant receptors A chimeric antigen receptor comprising an antigen-binding domain, a spacer, a CD28-derived transmembrane domain, an intracellular signaling domain including a CD3 zeta (CD3ζ) chain, and an intracellular signaling domain derived from 4-1BB. A pharmaceutical composition according to any of the Invention 1200 to 1204, which is or contains the same. [Invention 1206] T-cell therapy, T cells selected from the group consisting of central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells; and / or Multiple cells, including at least 50% of a population of cells selected from the group consisting of CD4+ T cells, CD8+ T cells, central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells. A pharmaceutical composition according to any of invention 1168 to 1205, comprising [the specified element]. [Invention 1207] A pharmaceutical composition according to any of the present invention 1168 to 1206, comprising T cells that are CD4+ or CD8+. [Invention 1208] The pharmaceutical composition of Invention 1207, wherein the ratio of CD4+ T cells to CD8+ T cells is 1:3 to 3:1 or approximately 1:3 to 3:1, or optionally 1:1. [Invention 1209] A pharmaceutical composition according to any of Invention 1168 to 1208, comprising primary cells derived from the subject, for T-cell therapy. [Invention 1210] A pharmaceutical composition according to Invention 1209, for use in humans. [Invention 1211] 1mL to 100mL or approximately 1mL to 100mL, 1mL to 75mL or approximately 1mL to 75mL, 1mL to 50mL or approximately 1mL to 50mL, 1mL to 25mL or approximately 1mL to 25mL, 1mL to 10mL or approximately 1mL to 10mL, 1mL to 5mL or approximately 1mL to 5mL, 5mL to 100mL or approximately 5mL to 100mL, 5mL to 75mL or approximately 5mL to 75mL, 5mL to 50mL or approximately 5mL to 50mL, 5mL to 25mL or approximately 5mL to 25mL, 5mL to 10mL or approximately 5mL to 10mL, 10mL to 100mL or approximately 10mL A pharmaceutical composition according to any of the Invention 1168 to 1210, comprising a volume of ~100 mL, 10 mL to 75 mL or approximately 10 mL to 75 mL, 10 mL to 50 mL or approximately 10 mL to 50 mL, 10 mL to 25 mL or approximately 10 mL to 25 mL, 25 mL to 100 mL or approximately 25 mL to 100 mL, 25 mL to 75 mL or approximately 25 mL to 75 mL, 25 mL to 50 mL or approximately 25 mL to 50 mL, 50 mL to 100 mL or approximately 50 mL to 100 mL, 50 mL to 75 mL or approximately 50 mL to 75 mL, or 75 mL to 100 mL or approximately 75 mL to 100 mL. [Invention 1212] A pharmaceutical composition according to any of the Invention 1168 to 1211, comprising a volume of at least 1 mL or about at least 1 mL or about 1 mL, at least 5 mL or about at least 5 mL or about 5 mL, at least 10 mL or about at least 10 mL or about 10 mL, at least 20 mL or about at least 20 mL or about 20 mL, at least 25 mL or about at least 25 mL or about 25 mL, at least 30 mL or about at least 30 mL or about 30 mL, at least 40 mL or about at least 40 mL or about 40 mL, at least 50 mL or about at least 50 mL or about 50 mL, at least 60 mL or about at least 60 mL or about 60 mL, at least 70 mL or about at least 70 mL or about 70 mL, at least 80 mL or about at least 80 mL or about 80 mL, at least 90 mL or about at least 90 mL or about 90 mL, or at least 100 mL or about at least 100 mL or about 100 mL. [Invention 1213] A pharmaceutical composition according to any of invention 1168 to 1212, further comprising a cryoprotective substance. [Invention 1214] A sterile pharmaceutical composition according to any of the inventions 1168 to 1213. [Invention 1215] A manufactured article comprising any of the pharmaceutical compositions of Invention 1168 to 1213. [Invention 1216] A method of treatment comprising administering any of the pharmaceutical compositions of the present invention 1168 to 1215 to a subject for the treatment of a disease or condition. [Invention 1217] The method of the present invention 1216, wherein the disease or condition is cancer. [Invention 1218] The method of the present invention 1217, wherein the cancer is a B-cell malignant tumor and / or myeloma, lymphoma, or leukemia. [Invention 1219] The method of Invention 1217 or Invention 1218, wherein the cancer is mantle cell lymphoma (MCL), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), or follicular lymphoma (FL). [Invention 1220] The method of the present invention 1217, wherein the cancer is a non-hematological cancer or a solid tumor. [Brief explanation of the drawing]

[0127] [Figure 1A] Figure 1A shows surface BCMA expression in multiple myeloma cell lines (RPMI-8226, MM1.S, and OPM-2). The dotted line indicates the background, and BCMA-negative cell lines were stained with anti-BCMA antibody. MFI, median fluorescence intensity. [Figure 1B] Figure 1B shows the percentage reduction in BCMA expression target cells (RPMI-8226) by anti-BCMA CAR+ T cells in the presence and absence of lenalidomide (10 μM) after co-culture for 6 days. [Figure 1C] Figure 1C shows the effect of lenalidomide on the cytolytic activity of anti-BCMA CAR+ T cells against RPMI-8226 target cells. [Figure 2A] Figures 2A-2C show the levels of IL-2 (Figure 2A), IFNγ (Figure 2B), and TNF-α (Figure 2C) observed in the supernatant after incubation of RPMI-8226 target cells and anti-BCMA CAR T cells in the presence and absence of lenalidomide. [Figure 2B] Figures 2A-2C show the levels of IL-2 (Figure 2A), IFNγ (Figure 2B), and TNF-α (Figure 2C) observed in the supernatant after incubation of RPMI-8226 target cells and anti-BCMA CAR T cells in the presence and absence of lenalidomide. [Figure 2C]Figures 2A-2C show the levels of IL-2 (Figure 2A), IFNγ (Figure 2B), and TNF-α (Figure 2C) observed in the supernatant after incubation of RPMI-8226 target cells and anti-BCMA CAR T cells in the presence and absence of lenalidomide. [Figure 3A] Figure 3A shows the effect of gradually increasing concentrations of lenalidomide on the cytolytic activity of anti-BCMA CAR+ T cells against OPM2 target cells. [Figure 3B] Figures 3B-3D show the levels of IFNγ (Figure 3B), IL-2 (Figure 3C), and TNF-α (Figure 3D) observed in the supernatant after incubation of OPM2 target cells and anti-BCMA CAR T cells in the presence or absence of gradually increasing concentrations of lenalidomide. [Figure 3C] Figures 3B-3D show the levels of IFNγ (Figure 3B), IL-2 (Figure 3C), and TNF-α (Figure 3D) observed in the supernatant after incubation of OPM2 target cells and anti-BCMA CAR T cells in the presence or absence of gradually increasing concentrations of lenalidomide. [Figure 3D] Figures 3B-3D show the levels of IFNγ (Figure 3B), IL-2 (Figure 3C), and TNF-α (Figure 3D) observed in the supernatant after incubation of OPM2 target cells and anti-BCMA CAR T cells in the presence or absence of gradually increasing concentrations of lenalidomide. [Figure 3E] Figure 3E shows the antigen-specific anti-BCMA CAR-T cell lytic activity and cytokine production of anti-BCMA CAR+ T cells from representative healthy donors and multiple myeloma patients against OPM-2 target cells, in the presence or absence of various concentrations of lenalidomide (0.01 μM, 0.1 μM, 1.0 μM, or 10 μM). [Figure 3F]Figure 3F shows the antigen-specific anti-BCMA CAR-T cell lytic activity of anti-BCMA CAR+ T cells derived from three healthy donors and one multiple myeloma patient against OPM-2 and RPMI-8226 target cells in the presence or absence of various concentrations of lenalidomide (0.01 μM, 0.1 μM, 1.0 μM, or 10 μM). [Figure 3G] Figure 3G shows cytokine production of anti-BCMA CAR+ T cells from three healthy donors and one multiple myeloma patient against OPM-2 target cells in the presence or absence of various concentrations of lenalidomide (0.01 μM, 0.1 μM, 1.0 μM, or 10 μM lenalidomide). [Figure 3H] Figure 3H shows cytokine production of anti-BCMA CAR+ T cells from three healthy donors and one multiple myeloma patient against RPMI-8226 target cells in the presence or absence of various concentrations of lenalidomide (0.01 μM, 0.1 μM, 1.0 μM, or 10 μM). [Figure 4A] Figure 4A illustrates the increase in anti-BCMA CAR T cells after restimulation in the presence of various concentrations of lenalidomide. [Figure 4B] Figure 4B depicts the increase in anti-BCMA CAR T cells after restimulation, both in the presence and absence of lenalidomide. [Figure 5A] Figure 5A shows the cell count (estimated population doubling) of anti-BCMA CAR+ T cells from three donors at each time point in the restorative assay in the presence of the vehicle or 0.1 μM lenalidomide. "x" indicates cells unsuitable for replating in the assay. [Figure 5B] Figure 5B shows the central fluorescence intensity (MFI) of CD25 (gated on raw CD3+ CAR+). [Figure 5C]Figure 5C shows cytokine production normalized to the number of plated cells (top and lower left panels) and cytokine production normalized to the median fluorescence intensity (MFI) of CD25 (gated on live CD3+ CAR+) (lower right panel). [Figure 6A] Figure 6A shows the total number of CD3+ cells in cultures on day 2 and day 7 after incubation of anti-BCMA CAR T cells or non-CAR expressing T cells (mocks) in the presence or absence of lenalidomide. [Figure 6B] Figures 6B and 6C show CD25+ expression in CD4+ (Figure 6B) and CD8+ (Figure 6C) T cells in cultures on day 2 and day 7 after incubation of anti-BCMA CAR T cells or non-CAR expressing T cells (mocks) in the presence or absence of lenalidomide. [Figure 6C] Figures 6B and 6C show CD25+ expression in CD4+ (Figure 6B) and CD8+ (Figure 6C) T cells in cultures on day 2 and day 7 after incubation of anti-BCMA CAR T cells or non-CAR expressing T cells (mocks) in the presence or absence of lenalidomide. [Figure 7A] Figure 7A shows the tumor volume over time in mice after administration of low doses of anti-BCMA CAR+ T cells in the presence and absence of lenalidomide. [Figure 7B] Figure 7B shows the survival rates of mice administered low doses of anti-BCMA CAR+ T cells in the presence and absence of lenalidomide. For the control group, non-CAR expressing T cells (mock) were administered in the presence and absence of lenalidomide, and lenalidomide was administered without T cells. [Figure 8A] Figure 8A shows the levels of CD4+ CAR+ T cells in the blood of mice treated with anti-BCMA CAR+ T cells and lenalidomide, compared to other treatment groups on days 7 and 14. [Figure 8B]Figure 8B shows the levels of CD4+ CAR+ T cells in the blood of mice treated with anti-BCMA CAR+ T cells and lenalidomide, compared to other treatment groups on days 21 and 36. [Figure 8C] Figure 8C shows the levels of CD8+ CAR+ T cells in the blood of mice treated with anti-BCMA CAR+ T cells and lenalidomide, compared to other treatment groups on days 7 and 14. [Figure 8D] Figure 8D shows the levels of CD8+ CAR+ T cells in the blood of mice treated with anti-BCMA CAR+ T cells and lenalidomide, compared to other treatment groups on days 21 and 36. [Figure 8E] Figure 8E shows the levels of CD4+ CAR+ T cells in the blood of mice treated with non-CAR+ T cells and lenalidomide, compared to the other treatment group, on days 7 and 14. [Figure 8F] Figure 8F shows the levels of CD4+ CAR+ T cells in the blood of mice treated with non-CAR+ T cells and lenalidomide, compared to the other treatment group on days 21 and 36. [Figure 8G] Figure 8G shows the levels of CD8+ CAR+ T cells in the blood of mice treated with non-CAR+ T cells and lenalidomide, compared to the other treatment group on days 7 and 14. [Figure 8H] Figure 8H shows the levels of CD8+ CAR+ T cells in the blood of mice treated with non-CAR+ T cells and lenalidomide, compared to the other treatment group on days 21 and 36. [Figure 9A] Figures 9A and 9B depict tumor burden results in mice treated under regimen A (LenA), in which mice were administered lenalidomide the day before receiving CAR+ T cells. [Figure 9B] Figures 9A and 9B depict tumor burden results in mice treated under regimen A (LenA), in which mice were administered lenalidomide the day before receiving CAR+ T cells. [Figure 9C] Figure 9C shows the tumor volume of individual mice throughout day 53. [Figure 9D]Figure 9D shows tumor imaging results at 46 days post-CAR+ cell administration for individual mice that received a higher CAR+ dose (1 × 10⁶) with lenalidomide (Len A) on day -1. [Figure 9E] Figure 9E shows tumor imaging results at 46 days post-CAR+ cell administration for individual mice that received a higher CAR+ dose (1 × 10⁶) without lenalidomide (Len A) on day 1. [Figure 9F] Figures 9F and 9G depict tumor burden results in mice treated under regimen B (LenB), initiating lenalidomide administration 14 days after CAR+T administration. [Figure 9G] Figures 9F and 9G depict tumor burden results in mice treated under regimen B (LenB), initiating lenalidomide administration 14 days after CAR+T administration. [Figure 9H] Figure 9H shows the tumor volume of individual mice throughout day 53. [Figure 9I] Figure 9I shows tumor imaging results (46 days after CAR+ cell administration) for individual mice that received a higher CAR+ dose (1 × 10⁶) with lenalidomide (Len A) on day -1. [Figure 9J] Figure 9J shows tumor imaging results (46 days after CAR+ cell administration) for individual mice that received a higher CAR+ dose (1 × 10⁶) without lenalidomide (Len A) on day 1. [Figure 10A] Figures 10A–10D show the survival of mice in the presence or absence of lenalidomide. Lenalidomide was administered via regimen A (Len A; administration of lenalidomide was started on day 1) or regimen B (Len B; administration of lenalidomide was started on day 14) in combination with low (5 × 10⁵ or 5e⁵) doses or high (1 × 10⁶ or 1e⁶) doses of CAR+ T cells. For the control group, non-CAR expressing T cells (mock) were administered via both regimens A and B in the presence and absence of lenalidomide, and lenalidomide was administered via both regimens A and B without T cells. [Figure 10B]Details are shown in Figure 10A. [Figure 10C] Details are shown in Figure 10A. [Figure 10D] Details are shown in Figure 10A. [Figure 10E] Figure 10E shows the results of tumor burden assessment in mice receiving a higher CAR+ dose (1 × 10⁶) and daily intraperitoneal administration of 10 mg / kg of lenalidomide or vehicle control, initiated either day -1 of CAR-T (or mock) cell administration (the day before CAR-T administration), in parallel with it (parallel lenalidomide (C) or vehicle (vehicle (C))), or on day 14 thereafter (delayed lenalidomide (D)). Results are shown up to day 60 as analyzed by bioluminescence measured by flow cytometry. [Figure 10F] Figure 10F shows the survival rates of mice in the presence or absence of lenalidomide. [Figure 10G] Figures 10G and 10H show flow cytometry analyses of mock control cells and CAR-T cells in the blood of mice at 8, 14, 22, and 28 days after injection of CAR-T cells derived from two donors. [Figure 10H] Figures 10G and 10H show flow cytometry analyses of mock control cells and CAR-T cells in the blood of mice at 8, 14, 22, and 28 days after injection of CAR-T cells derived from two donors. [Figure 11] Figure 11 shows the number of CD4+ and CD8+ T cells in cultures of anti-CD19 CAR T cells stimulated with suboptimal concentrations of anti-CD3 in the presence and absence of lenalidomide. [Figure 12A] Figure 12A shows the number of CD3+ / CAR+ T cells in peripheral blood measured at a specific time point after infusion for subjects classified by best overall response. [Figure 12B] Figure 12B shows the peripheral blood CD3+ / CAR+ T cells measured at a specific time point after infusion for subjects that achieved a response classified as having lasted for 3 months. [Figure 12C]Figures 12C–2D show peripheral blood CD4+ / CAR+ T and CD8+ / CAR+ T cell levels measured at specific time points after infusion for subjects that achieved a classified response based on a sustained 3-month response. [Figure 12D] Figures 12C–2D show peripheral blood CD4+ / CAR+ T and CD8+ / CAR+ T cell levels measured at specific time points after infusion for subjects that achieved a classified response based on a sustained 3-month response. [Figure 13A] Figure 13A shows the number of CD3+ / CAR+, CD4+ / CAR+, and CD8+ / CAR+ T cells in the peripheral blood of subjects with chemotherapy-refractory transformed DLBCL, as measured at a specific point in time. [Figure 13B] Figure 13B depicts a pre-treatment axial PET-CT image showing intracranial abnormalities in the right middle cranial fossa and extensive abnormalities in the subcutaneous tissue of the right posterior auricle region. [Figure 13C] Figure 13C is a post-treatment PET-CT image illustrating the resolution of the abnormalities in Figure 13B after treatment with anti-CD19 CAR+ T cells. [Figure 13D] Figure 13D shows a pre-treatment brain MRI (high-resolution T1-weighted image with contrast agent; axial view) revealing a uniformly enhanced mass in the right middle cranial fossa. [Figure 13E] Figure 13E is a post-treatment MRI image showing nearly complete resolution of the densely stained mass. [Figure 13F] Figure 13F is an axial PET-CT image at the time of recurrence, showing a recurrence of a right posterior auricular tumor with extremely strong uptake of 18F-fluorodeoxyglucose (arrow). [Figure 13G] Figure 13G is a PET-CT image showing resolution of the posterior auricular tumor and CAR+ T cell regrowth after incisional biopsy. [Figure 14]Figure 14 shows the levels of viable target cells over approximately 120 hours when anti-CD19 CAR+ T cells were incubated with K562-CD19 effector cells in an effector-to-target cell (E:T) ratio of 5:1, in or without 1 nM, 5 nM, 60 nM, 550 nM, or 5000 nM lenalidomide, or in the absence of lenalidomide (control). [Figure 15A] Figure 15A shows the levels of CD25+ expression in both CD4+ and CD8+ T cells when anti-CD19 CAR+ T cells were incubated with K562-CD19 effector cells in the presence of lenalidomide or alternative compounds targeting kinase. [Figure 15B] Figure 15B shows the levels of CD25+ expression in both CD4+ and CD8+ T cells when anti-CD19 CAR+ T cells were incubated with PD-1 effector cells in the presence of lenalidomide or alternative compounds targeting kinase. [Figure 16] Figure 16 shows the amount of IL-10 in the culture supernatant after incubation of anti-CD19 CAR+ T cells and K562-CD19 effector cells in effector-to-target cell (E:T) ratios of 3:1 or 9:1, in the presence or absence of various concentrations of lenalidomide. [Figure 17A] Figure 17A shows the multiplicative change in cell number after stimulating anti-CD19 CAR+ T cells from two donors (pt 1 and pt 2) with K562-CD19 effector cells, in or out of the presence of 1 μM lenalidomide or alternative compounds targeting 50 nM or 500 nM kinases. [Figure 17B] Figure 17B shows the number of cells that doubled compared to the initial number after the second and fourth stimuli. [Figure 18A] Figure 18A shows the cytolytic activity of anti-CD19 CAR+ T cells derived from two donor cells (pt 1 and pt 2) restimulated using K562-CD19 cells (labeled with NucLight Red (NLR)) in the presence of 1 μM lenalidomide or alternative compounds targeting 50 nM or 500 nM kinases. [Figure 18B] Figure 18B shows the target cell killing rate of anti-CD19 CAR+ T cells derived from two donor cells (1 or 2) restimulated with K562-CD19 cells, compared to a vehicle-only control (set to 100%). [Figure 19A] Figure 19A shows a histogram plot of CTV staining of all cells in an anti-BCMA CAR+ T cell composition after incubation with beads (200 μg / mL BCMA conjugate bead composition) and T cells in a 1:1 ratio, in or without 5 μM lenalidomide. [Figure 19B] Figures 19B and 19C show flow cytometry histograms of CD25 in CD4+ T cells (left panel) or CD8+ T cells (right panel) present in anti-BCMA CAR+ T cell compositions, either in the presence or absence of lenalidomide, after incubation with beads (200 μg / mL BCMA conjugate bead composition) at a T cell-to-bead ratio of 1:1, or after incubation with immobilized anti-CD3. [Figure 19C] Details are shown in Figure 19B. [Figure 20A] Figures 20A–20I show graphs displaying the levels of transcription factors and activation markers in or on CD4+ T cells (left panel) or CD8+ T cells (right panel) present in anti-BCMA CAR+ T cell compositions after incubation in the presence of 0 μM, 0.5 μM, or 50 μM lenalidomide with no stimulation or different amounts of BCMA conjugate beads or anti-CD3 and anti-CD28 conjugate beads. Levels of Blimp1 (Figure 20A), CD25 (Figure 20B), CD31 (Figure 20C), PD-1 (Figure 20D), Tbet (Figure 20E), EOMES (Figure 20F), GATA3 (Figure 20G), Helios (Figure 20H), and Icarus (Figure 20I) are shown. 200 BCMA, 50 BCMA, and 5 BCMA represent BCMA conjugate beads produced by incubating BCMA with beads at amounts of approximately 200, 50, and 5 μg of BCMA per 4 × 10⁸ beads, respectively. [Figure 20B] Details are shown in Figure 20A. [Figure 20C] Details are shown in Figure 20A. [Figure 20D] Details are shown in Figure 20A. [Figure 20E] Details are shown in Figure 20A. [Figure 20F] Details are shown in Figure 20A. [Figure 20G] Details are shown in Figure 20A. [Figure 20H] Details are shown in Figure 20A. [Figure 20I] Details are shown in Figure 20A. [Figure 21A] Figures 21A–C show graphs displaying the levels of extracellular IFN-gamma (Figure 21A), IL-2 (Figure 21B), and TNF-alpha (Figure 21C) from cultures after incubation of an anti-BCMA CAR+ T cell composition with two different amounts of BCMA conjugate beads in the presence or absence of 5 μM lenalidomide. 50 μg BCMA and 5 μg BCMA represent BCMA conjugate beads produced by incubation of BCMA and beads at amounts of 50 and 5 μg BCMA per approximately 4 × 10⁸ beads, respectively. [Figure 21B] Details are shown in Figure 21A. [Figure 21C] Details are shown in Figure 21A. [Figure 21D] Figure 21D shows a graph displaying the levels of extracellular IL-2 from cultures after incubation of anti-BCMA CAR+ T cell compositions derived from two different donors with different amounts of BCMA conjugate beads in the presence of 0 μM, 1 μM, or 5 μM lenalidomide. 200 BCMA and 5 BCMA represent BCMA conjugate beads produced by incubation of BCMA and beads at amounts of approximately 200 μg and 5 μg of BCMA per 4 × 10⁸ beads, respectively. [Figure 21E]Figures 21E and 21F show the total cell count after incubation of anti-BCMA CAR+ T cell compositions for 4 days (Figure 21E) or 7 days (Figure 21F) in the presence of different amounts of BCMA conjugate beads and 5 μM lenalidomide. 50 BCMA and 5 BCMA represent BCMA conjugate beads produced by incubating BCMA antigen and beads at amounts of 50 μg and 5 μg of BCMA per approximately 4 × 10⁸ beads, respectively. [Figure 21F] Details are shown in Figure 21E. [Figure 21G] Figure 21G shows histogram plots of CTV staining of CD4+ T cells or CD8+ T cells in an anti-BCMA CAR+ T cell composition after incubation for 4 or 7 days in the presence or absence of 5 μM lenalidomide with BCMA conjugate beads (vehicle). [Figure 21H] Figures 21H and 21I show graphs displaying the percentage of cells positive for the surrogate marker EGFRt, as determined by anti-EGFR antibody, after incubation of anti-BCMA CAR+ T cell compositions with different amounts of BCMA conjugate beads for 4 days (Figure 21H) or 7 days (Figure 21I) in the presence or absence of 5 μM lenalidomide (vehicle). "50" and "5" represent beads produced by incubation of BCMA and beads at amounts of 50 μg and 5 μg of BCMA per approximately 4 × 10⁸ beads, respectively. [Figure 21I] Details are shown in Figure 21H. [Figure 21J]Figure 21J shows the cytotoxicity rates of RPMI-8226 target cells by anti-BCMA CAR+ T cell effector cells incubated with different amounts of BCMA conjugate beads in the presence or absence of 5 μM lenalidomide (vehicle). It also shows the cytolytic activity of compositions containing effector cell-to-target cell ratios of 3:1 or 1:1, in the presence or absence of further lenalidomide. "50" and "5" indicate BCMA conjugate beads produced by incubating BCMA and beads at amounts of 50 and 5 μg of BCMA per approximately 4 × 10⁸ beads, respectively. [Figure 22A] Figure 22A shows flow cytometry analysis of phosphorylated STAT5 2 hours after CAR stimulation with 50 μg of BCMA beads. The control group (no stimulation) is shown by the dotted line. [Figure 22B] Figure 22B shows flow cytometry analysis of intracellular cytokine levels in representative normal CAR T donors 24 hours after BCMA bead stimulation (gated on transduced live CD3+). [Figure 23A] Figures 23A–23B depict the results of a serial restimulation assay of anti-BCMA CAR T cell compositions incubated with BCMA conjugate beads (50 μg / mL) for 7 days. Results from three different donor compositions are shown. Figures 23A and 23B show the cytolytic activity of anti-BCMA CAR+ T cells at each time point for two different donors. [Figure 23B] Details are shown in Figure 23A. [Figure 24A] Figure 24A shows the results regarding CAR antigen-specific cell lysis activity, and Figure 24B shows the results regarding cytokine production during co-culture of anti-BCMA CAR-T cells pre-stimulated with BCMA beads (compared to newly thawed (unpre-stimulated) anti-BCMA CAR-T cells), comparing cells cultured in the presence or absence of lenalidomide. [Figure 24B]Figure 24A shows the results regarding CAR antigen-specific cell lysis activity, and Figure 24B shows the results regarding cytokine production during co-culture of anti-BCMA CAR-T cells pre-stimulated with BCMA beads (compared to newly thawed (unpre-stimulated) anti-BCMA CAR-T cells), comparing cells cultured in the presence or absence of lenalidomide. [Figure 24C] Figure 24C shows the overall survival rate and cell count evaluated for three anti-BCMA CAR T donors. [Figure 24D] Figure 24D shows the results of flow cytometry analysis of surface CD25 and PD-1 expression (mean fluorescence intensity (MFI)) in CD4+ or CD8+ anti-BCMA CAR T cells after stimulation (pre-treatment) with BCMA beads for 7 days in or without 1 μM lenalidomide. [Figure 24E] Figure 24E shows flow cytometry analysis of the entire CAR T donor for median fluorescence intensity (MFI; CD25 and Tim3) or percentage of positive PD-1 and Lag3 on the surface of T cell markers in the CD4+CAR+ subset and CD8+CAR+ subset (gated on live CD3+ cells). The values ​​shown are percentages relative to baseline (Veh) MFI, survival rate, or count. [Figure 25A] Figure 25A shows the analysis of effector cytokine production after 24 hours of CAR-specific stimulation on 50 μg of BCMA beads in the presence of 1 μM lenalidomide, compared to the baseline (vehicle) response for each of the three donors. [Figure 25B] Figure 25B shows the effect of activated anti-BCMA CAR T cells on BCMA bead production at different concentrations (i.e., 5 μg, 50 μg, and 200 μg) in the presence or absence of lenalidomide (0.1 μM or 1 μM). [Figure 25C]Figure 25C shows cytokine production from representative healthy donor and multiple myeloma patient anti-BCMA CAR T cells stimulated on BCMA beads, with or without the addition of PD-L1 to the beads, in the presence or absence of 1 μM lenalidomide. [Figure 26A] Figures 26A and 26B show the results of principal component analysis (PCA) for gene expression (based on RNA sequencing analysis results; Figure 26A) and chromatin accessibility (based on ATAC sequencing analysis results; Figure 26B) in anti-BCMA CAR-expressing T cells generated from four different donors (Donors 1-4) who were stimulated with BCMA conjugate beads for 24 hours (24hr+stim), stimulated for 7 days (d7+stim), or cultured for 24 hours without stimulation (24hr), in or without lenalidomide. [Figure 26B] Details are shown in Figure 26A. [Figure 27A] Figures 27A and 27B show Volcano plots illustrating the statistical significance of gene expression (log10 adjusted p-values) based on log2 multiplier changes in gene expression, including genes or peaks showing increased (right side) or decreased (left side) expression, in CAR+ T cells stimulated with BCMA conjugate beads for 24 hours (24hr+stim, Figure 27A) or 7 days (d7+stim, Figure 27B) in or without lenalidomide. The table shows the number of genes or peaks showing a statistically significant increase (up) or decrease (down) in expression. [Figure 27B] Details are shown in Figure 27A. [Figure 27C]Figures 27C and 27D show Volcano plots illustrating the statistical significance of expression (log10 adjusted p-values) based on log2 multiplier changes in g chromatin accessibility in CAR+ T cells stimulated with BCMA conjugate beads for 24 hours (24hr+stim, Figure 27C) or 7 days (d7+stim, Figure 27D), including genes or peaks showing increased (right side) or decreased (left side) accessibility. The table shows the number of genes or peaks showing a statistically significant increase (up) or decrease (down) in accessibility. [Figure 27D] Details are shown in Figure 27C. [Figure 28A] Figures 28A and 28B depict the directional and significant expression of genes in biological signaling pathways enriched with gene sets whose expression was statistically significantly increased or decreased in CAR+ T cells stimulated with BCMA conjugate beads for 24 hours (24hr+stim, Figure 28A) or 7 days (d7+stim, Figure 28B). [Figure 28B] Details are shown in Figure 28A. [Figure 29] Figure 29 shows plots comparing individual chromatin accessibility peaks (diamonds) and average chromatin accessibility changes per gene (circles) for selected genes involved in T cell activation and signal transduction with changes in gene expression. [Figure 30] Figure 30 shows the motif enrichment analysis, enrichment log p-value, occurrence rate, and predicted transcription factors that bind to the motif for peaks with increased accessibility in the presence of lenalidomide in cultures on day 7. [Figure 31]Figure 31 shows flow cytometry analysis of intracellular Ikaros expression in both CD4+ anti-CD19 CAR-expressing T cells and CD8+ anti-CD19 CAR-expressing T cells. CAR-expressing T cells were stimulated with CAR-T anti-idiotype antibodies (5 μg / mL) treated with lenalidomide or compound 1 over a certain concentration range. Ikaros central fluorescence intensity (MFI) values ​​were normalized and calculated as relative percentages relative to the vehicle control. [Figure 32A] Figures 32A and 32B show the analysis of cytokine production in anti-CD19 CAR-expressing T cells in the presence of compound 1 (Figure 32A) or lenalidomide (Figure 32B) after incubation with target cells. Multiplex cytokine assay of supernatant collected over 24 hours from 3-well sets of anti-CD19 CAR-expressing T cells co-cultured with K562.CD19 target cells in the presence of several concentrations of compound 1 or lenalidomide. The concentrations of IFN-γ, IL-2, and TNF-α were determined across two E:T ratios for CAR-expressing T cells from three different donors. Data represent the mean + / -SD across the three experiments. [Figure 32B] Details are shown in Figure 32A. [Figure 33] Figure 33 shows the analysis of the cytolytic function of anti-CD19 CAR-expressing T cells in the presence of compound 1 or lenalidomide after incubation with target cells. Anti-CD19 CAR-expressing T cells from three different donors were co-cultured with K562.CD19 target cells in triplicate, at two E:T ratios, for 5 days in the presence of compound 1 or lenalidomide. Results were calculated as a normalized cytotoxicity index. Data represent the mean + / - SD across the three experiments. [Figure 34A]Figures 34A and 34B show the analysis of cytokine production in anti-CD19 CAR-expressing T cells in the presence of compound 1 (Figure 34A) or lenalidomide (Figure 34B) after stimulation with an anti-idiotype antibody. Multiplex cytokine assays were performed on supernatant collected over 24 hours from triple wells of anti-CD19 CAR-expressing T cells co-cultured with an agonist anti-idiotype antibody in the presence of 100 or 1000 nM compound 1 (Figure 34A) or 500 or 5000 nM lenalidomide (Figure 34B). IFN-γ, IL-2, and TNF-α concentrations were determined for CAR-expressing T cells from three different donors. Data represent the mean + / - SD across the three experiments. [Figure 34B] Details are shown in Figure 34A. [Figure 35A] Figures 35A and 35B show the analysis of surface marker expression on CD4+ anti-CD19 CAR-expressing T cells (Figure 35A) and CD8+ anti-CD19 CAR-expressing T cells (Figure 35B) in the presence of compound 1 after stimulation with anti-idiotype antibodies. Anti-CD19 CAR-expressing T cells from three different donors were stimulated with 0, 0.3, 3, or 30 μg / mL anti-idiotype antibodies in the presence of 100 or 1000 nM of compound 1. Cells were analyzed by flow cytometry on day 4. The change in median fluorescence intensity relative to the vehicle control for each concentration of anti-idiotype antibody was calculated. The data are representative of the three experiments. [Figure 35B] Details are shown in Figure 35A. [Figure 36A] Figures 36A and 36B show the analysis of surface marker expression on CD4+ anti-CD19 CAR-expressing T cells (Figure 36A) and CD8+ anti-CD19 CAR-expressing T cells (Figure 36B) in the presence of lenalidomide after stimulation with anti-idiotype antibodies. Anti-CD19 CAR-expressing T cells from three different donors were stimulated with 0, 0.3, 3, or 30 μg / mL anti-idiotype antibodies in the presence of 500 or 5000 nM lenalidomide. Cells were analyzed by flow cytometry on day 4. The change in median fluorescence intensity relative to the vehicle control for each concentration of anti-idiotype antibody was calculated. The data are representative of the three experiments. [Figure 36B]Details are shown in Figure 36A. [Figure 37A] Figures 37A and 37B show the analysis of CD28 surface expression on CD4+ and CD8+ anti-CD19 CAR-expressing T cells in the presence of compound 1 (Figure 37A) or lenalidomide (Figure 37B) after sequential stimulation. Anti-CD19 CAR-expressing T cells from three different donors were stimulated every 3-4 days with K562.CD19 at an E:T ratio of 2.5:1 in the presence of compound 1 (Figure 37A) or lenalidomide (Figure 37B). The percentage of CD28-positive cells was measured by flow cytometry on day 28. [Figure 37B] Details are shown in Figure 37A. [Figure 38] Figure 38 shows the analysis of the cytolytic function of anti-CD19 CAR-expressing T cells in the presence of compound 1 or lenalidomide after serial stimulation. Anti-CD19 CAR-expressing T cells from three different donors and irradiated K562.CD19 target cells were co-cultured in triplicate, at two E:T ratios, in the presence of compound 1 or lenalidomide 24 days after serial stimulation. The results were calculated as a normalized cytotoxicity index. [Figure 39A] Figures 39A and 39B show an analysis of population doubling of anti-CD19 CAR-expressing T cells during a 28-day continuous stimulation period in the presence or absence of compound 1. Anti-CD19 CAR-expressing T cells from three different donors were stimulated every 3-4 days for 28 days (represented by the x-axis) with K562.CD19 target cells in the presence of 500 nM compound 1 at an E:T ratio of 2.5:1 or 10:1. Cells were counted after each stimulation, and cell doubling was calculated (Figure 39A). Figure 39B shows the percentage change in cell doubling at day 24 for continuous stimulation in the presence of 10 nM, 100 nM, or 500 nM compound 1. Data represent the mean + / - SEM of three consecutive treatments from the three donors. Each arrow represents the time of restimulation. [Figure 39B] Details are shown in Figure 39A. [Figure 40A]Figures 40A and 40B show an analysis of population doubling of anti-CD19 CAR-expressing T cells during a 28-day continuous stimulation period in the presence or absence of lenalidomide. Anti-CD19 CAR-expressing T cells from three different donors were stimulated every 3–4 days for 28 days (represented by the x-axis) with K562.CD19 target cells in the presence of 1000 nM lenalidomide at an E:T ratio of 2.5:1 or 10:1. Cells were counted after each stimulation, and cell doubling was calculated (Figure 40A). Figure 40B shows the percentage change in cell doubling at day 24 for continuous stimulation in the presence of 100 nM or 1000 nM lenalidomide. Data represent the mean + / - SEM of three consecutive treatments from the three donors. Each arrow represents the time of restimulation. [Figure 40B] Details are shown in Figure 40A. [Modes for carrying out the invention]

[0128] Detailed explanation This specification provides combination therapies comprising immunotherapy encompassing T cell function or activity, such as T cell therapy, and the administration of immunomodulatory compounds, such as structural or functional analogs or derivatives of thalidomide and / or E3-ubiquitin ligase inhibitors. In some aspects, the methods provided enhance or modulate T cell proliferation and / or activity in relation to the administration of immunotherapy or immunotherapy agents (e.g., compositions comprising cells (e.g., CAR-expressing T cells) for adoptive cell therapy (e.g., T cell therapy)). In some embodiments, the combination therapy comprises the administration of immunomodulatory compounds, such as structural or functional analogs of thalidomide and / or E3-ubiquitin ligase inhibitors, and the administration of T cell therapy (e.g., compositions comprising cells (e.g., CAR-expressing T cells) for adoptive cell therapy (e.g., T cell therapy)).

[0129] T cell-based therapies, such as adoptive T cell therapy (e.g., adoptive T cell therapy involving the administration of cells expressing specific chimeric receptors (e.g., chimeric antigen receptors (CARs) and / or other recombinant antigen receptors) for the target disease or disorder, as well as other adoptive immunotherapy and adoptive T cell therapies), may be effective in treating cancer and other diseases and disorders. The direction of T cell specificity can be altered by the manipulated expression of recombinant receptors (e.g., chimeric antigen receptors (CARs)) on the surface of T cells. In clinical studies, CAR-T cells, such as anti-CD19 CAR-T cells, have resulted in permanent complete responses in both leukemia and lymphoma patients (Porter et al. (2015) Sci Transl Med., 7:303ra139; Kochenderfer (2015) J. Clin. Oncol., 33:540-9; Lee et al. (2015) Lancet, 385:517-28; Maude et al. (2014) N Engl J Med, 371:1507-17).

[0130] In certain circumstances, available approaches to adoptive cell therapy may not always be completely satisfactory. In some situations, optimal efficacy may depend on whether the administered cells can recognize and bind to a target (e.g., a target antigen), reach, localize, and successfully penetrate the appropriate site within the target body, the tumor, and its environment. In some situations, optimal efficacy may depend on whether the administered cells can be activated, proliferate, exert various effector functions, including cytotoxic killing and secretion of various factors (e.g., cytokines), persist over long periods, differentiate into and transition to certain phenotypic states (e.g., a persistent memory state, a poorly differentiated state, and an effector state), or be involved in reprogramming to such phenotypic states, avoid or reduce immunosuppression in the local microenvironment of the disease, produce an effective and robust recall response after clearance and re-exposure to the target ligand or target antigen, and avoid or reduce differentiation into wasting, anergy, peripheral tolerance, terminal differentiation, and / or suppressive states.

[0131] In some embodiments, the exposure and persistence of manipulated cells are reduced or decreased after administration to the subject. However, observations indicate that in some cases, increased exposure of the subject to cells expressing the administered recombinant receptor (e.g., increased cell count or duration over time) may improve the efficacy and therapeutic outcomes in adoptive cell therapy. Preliminary analyses of multiple clinical trials conducted after administration of CAR-expressing T cells targeting different CD19s to subjects with various CD19-expressing cancers have revealed a correlation between greater and / or longer exposure to CAR-expressing cells and treatment outcomes. Such outcomes included patient survival and remission, even in individuals with severe or significant tumor burden.

[0132] In some aspects, the methods and uses provided offer or achieve an improved or more persistent response or efficacy compared to certain alternative methods, for example, in a particular group of treated subjects. In some embodiments, the methods are advantageous by administering T-cell therapy (e.g., a composition comprising cells for adoptive cell therapy (e.g., T-cell therapy) (e.g., CAR-expressing T cells)) and immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or E3 ubiquitin ligase inhibitors, e.g., lenalidomide.

[0133] The methods provided are based on observations that immunomodulatory compounds, such as lenalidomide, including structural or functional analogues or derivatives of thalidomide and / or inhibitors of E3 ubiquitin ligases, improve T cell function, including functions related to T cell enlargement, proliferation, and persistence. Lenalidomide is a recently approved immunomodulatory agent for the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL) and is clinically tested in the treatment of diffuse large B-cell lymphoma with an activated B-cell immunophenotype. In some cases, lenalidomide at least partially increases the antitumor immune response by modulating the activity of the E3 ubiquitin ligase cereblon (CRBN), thereby resulting in increased ubiquitination of Icarus and Aeolus transcription factors, which alters the expression of various receptors on the surface of tumor cells (see, e.g., Otahal et al. (2016) Oncoimmunology., April; 5(4): e1115940).

[0134] The findings provided indicate that combination therapy with immunomodulatory compounds, such as lenalidomide, including structural or functional analogues or derivatives of thalidomide and / or E3 ubiquitin ligase inhibitors, in a manner that includes the administration of T cells, e.g., adoptive T-cell therapy, achieves an improvement in the function of T-cell therapy. In some embodiments, the combination of cell therapy (e.g., administration of engineered T cells) and immunomodulatory compounds, e.g., lenalidomide, improves or enhances one or more functions and / or effects of T-cell therapy, such as persistence, growth, cytotoxicity and / or therapeutic outcomes, e.g., the ability to kill tumor or other disease or target cells or reduce their numbers.

[0135] In certain aspects, immunomodulatory compounds, such as lenalidomide, including structural or functional analogs or derivatives of thalidomide and / or inhibitors of E3 ubiquitin ligases, have been found to promote the continued function and / or survival of T-cell therapy cells (e.g., CAR-T cells) even after activation, including after encounter with an antigen. In some aspects, lenalidomide increases the ability of such T cells to persist or function for extended periods, such as by preventing depletion or cell death. In some embodiments, such improvements can result in combination therapy showing an improved overall response, such as reduced tumor burden and / or increased survival, compared to subjects treated with monotherapy comprising T-cell therapy (e.g., CAR-T cells) or immunomodulatory compounds (e.g., lenalidomide) alone. In some aspects, the methods provided increase the overall response and / or survival by 1.5 times or more, 2.0 times or more, 3.0 times or more, 4.0 times or more, 5.0 times or more, 10 times or more, or more than 10 times, compared to alternative treatments, compared to monotherapy, including, for example, administration of T cell therapy (e.g., CAR-T cells) or immunomodulatory compounds (e.g., lenalidomide) alone.

[0136] In some embodiments, the combination with an immunomodulatory compound improves one or more outcomes or functional attributes without affecting one or more side effects or unwanted T cell changes, for example, not reducing the ability of cells to become activated, to secrete one or more desired cytokines, to increase and / or persist, as measured, for example, by an in vitro assay, compared to such cells cultured under the same conditions except in the absence of the immunomodulatory compound. Thus, in some embodiments, methods and combinations are provided that generally result in improvement of T cell function or phenotype, for example, intrinsic T cell function and / or intrinsic T cell phenotype, without impairing one or more other desired properties of function, for example, CAR-T cell function.

[0137] In some embodiments, the methods provided can enhance T-cell therapy, such as CAR-T cell therapy, thereby improving outcomes to the treatment in some aspects. In some embodiments, the methods are particularly advantageous in subjects where the cells of T-cell therapy show weak growth and depletion, resulting in reduced or decreased persistence, and / or in subjects with cancers that are resistant or refractory to other therapies, invasive or high-risk cancers, and / or cancers that have a relatively low response rate to CAR-T cell therapy administered without immunomodulatory compounds, or are likely to have a relatively low response rate, compared to other types of cancer or compared to the administration of different CAR-T cell therapies.

[0138] In some aspects, the methods provided can overcome, for example, a lack of persistence and / or depletion of T cells in subjects where, for example, less than 10 μL, e.g., less than 5 μL or less than 1 μL of such cells or their CD8+ or CD3+ subsets are detectable in the blood 12–15 days or approximately 12–15 days after the start of administration of T cell therapy. In some embodiments, subjects who have received T cell therapy, e.g., CAR-T cells, are monitored in the subject, e.g., in a biological sample of the subject, e.g., in the subject's blood, for the presence, absence or level of T cells of the therapy. In some embodiments, immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or inhibitors of E3 ubiquitin ligase, e.g., lenalidomide, are administered to subjects receiving T-cell therapy (e.g., CAR-T cells) where such cells are weakly proliferating, and / or where a strong or robust increase in CAR-T cells in a subject is observed, typically at the time that such cells are below a threshold level in a sample of the subject, e.g., a blood sample, when the same T-cell therapy (e.g., the same CAR-T cells) has been administered to multiple subjects. In some cases, immunomodulatory compounds such as lenalidomide, a structural or functional analog or derivative of thalidomide and / or an E3 ubiquitin ligase inhibitor, are administered 12 to 15 days or approximately 12 to 15 days after the initiation of T-cell therapy, when less than 10 μL, e.g., less than 5 μL or less than 1 μL, of such cells or their CD8+ or CD3+ subsets becomes detectable in the blood.

[0139] In certain circumstances, the methods provided can enhance, increase, or intensify T-cell therapy in subjects where a peak response to T-cell therapy has been observed, but the response, e.g., the presence of T cells and / or reduction in tumor burden, is decreasing or no longer detectable. In some circumstances, immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or E3 ubiquitin ligase inhibitors, e.g., lenalidomide, can enhance, increase, or intensify T-cell therapy in subjects where: (i) the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood; (ii) the number of detectable T-cell therapy cells in the blood decreases after becoming detectable in the blood, and subsequently becomes undetectable or reduced, optionally compared to a preceding time after administration of T-cell therapy; or (iii) the number of detectable T-cell therapy cells in the blood increases to 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or 3.0 times the peak or maximum number of detectable T-cell therapy cells in the subject's blood after the start of T-cell therapy administration. (iv) The number of detectable T cells or cells derived from the subject in the subject's blood after the peak or maximum level of T-cell therapy cells has become detectable in the subject's blood is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) The subject has shown disease progression and / or relapse following remission after treatment with T-cell therapy; and / or (iv) The subject is administered within one week, e.g., within one, two, or three days, after showing an increased tumor load compared to the tumor load before or after T-cell administration and before the initiation of immunomodulatory compound administration.

[0140] In some embodiments, the method can be used to treat diseases or conditions, such as B-cell malignancies or hematological malignancies, particularly those in which the response to treatment with T-cell therapy alone (e.g., a composition comprising cells for adoptive cell therapy (e.g., T-cell therapy) (e.g., CAR-expressing T cells)), e.g., complete response, is lower compared to other T-cell therapies or treatments for other diseases or malignancies (e.g., CR in less than 60% or about 60%, less than 50% or about 50%, or less than 45% or about 45% of subjects treated in this manner), and / or the subjects are not responsive to treatment with immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or E3 ubiquitin ligase inhibitors, e.g., lenalidomide alone.

[0141] In some embodiments, the combination therapies provided herein are for use in subjects with cancer who have relapsed following remission after treatment with T-cell therapy (e.g., a composition containing cells for adoptive cell therapy, e.g., CAR-expressing T cells) after initiation of T-cell therapy. In some embodiments, such subjects who have relapsed following remission are administered an immunomodulatory compound, such as lenalidomide, a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase. In some embodiments, the combination therapies provided herein are for use in subjects with a disease or condition, e.g., cancer, where the amount of immunomodulatory compound administered is insufficient to improve, reduce or prevent the disease or condition or its symptoms or outcome as a monotherapy and / or in the absence of T-cell therapy, e.g., insufficient to improve, reduce or prevent the disease or condition or its symptoms or outcome in the subject. In some embodiments, the method thereby reduces or improves the symptoms, outcomes, or burden of a disease or condition to a degree exceeding the combination of (i) the degree of reduction or improvement in a population of subjects having the disease or condition on average achieved by administration of an immunomodulator alone, and (ii) the degree of reduction or improvement in a population of subjects having the disease or condition on average achieved by administration of T-cell therapy alone. In some embodiments, the method reduces or improves such symptoms, outcomes, or burdens of a disease by, for example, more than 1.5 times or about 1.5 times, more than 2.0 times or about 2.0 times, more than 3.0 times or about 3.0 times, more than 4.0 times or about 4.0 times, more than 5.0 times or about 5.0 times, more than 6.0 times or about 6.0 times, more than 7.0 times or about 7.0 times, more than 8.0 times or about 8.0 times, more than 9.0 times or about 9.0 times, more than 10.0 times or about 10.0 times, more than 20.0 times or about 20.0 times, more than 30.0 times or about 30.0 times, more than 40.0 times or about 40.0 times, more than 50.0 times or about 50.0 times, or more, compared to, for example, a population of subjects that, on average, have the disease or condition.

[0142] In some embodiments, the combination therapies offered are used in conjunction with the treatment of certain diseases or conditions, e.g., cancer, where achieving optimal stimulation of recombinant antigen receptors, e.g., CAR-T cells, is difficult and / or not consistently observed. In some embodiments, suboptimal stimulation may result in low or unreachable levels of disease antigens in vivo, e.g., in or on the tumor. In some embodiments, certain cancers, e.g., high-risk or invasive NHL, e.g., DLBCL, and / or chronic lymphocytic leukemia (CLL), may be associated with inherent T-cell dysfunction or reduction, affected in some cases by the disease itself. For example, the pathogenesis of many cancers, such as CLL and NHL, e.g., DLBCL, may be associated with immunodeficiency, leading to enhanced tumor growth and immune evasion, for example, due to T-cell immunosuppression being driven by one or more factors in the tumor microenvironment. In some cases, mitigate the inherent T-cell defects resulting from the cancer of such patients for use in conjunction with adoptive cell therapy, thereby providing a more potent response to adoptive T-cell therapy, such as CAR-T-cell therapy. In some cases, suboptimal stimulation may be due to differences in CAR expression levels on engineered T cells administered to the subject. In any such embodiment, administration of immunomodulatory compounds such as structural or functional analogs or derivatives of thalidomide and / or E3 ubiquitin ligase inhibitors, such as lenalidomide, can enhance the stimulation or activity of such T cells in vivo in the subject.

[0143] In some embodiments of the methods provided, it is possible to improve, increase, or make greater one or more properties of administered genetically modified cells compared to administered cells of a reference composition (e.g., enhanced or longer-lasting expansion and / or persistence of such administered cells in a subject, as well as an increased and greater recall response upon restimulation with an antigen). In some embodiments, the increase may be at least 1.2 times, at least 1.5 times, at least 2 times, and finally 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, or at least 10 times in such properties or features compared to the same properties or features when administered with a reference cell composition. In some embodiments, an increase in one or more such properties or features may be observed or present within 7 days, 14 days, 21 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or 12 months after administration of genetically modified cells and the initiation of administration of immunomodulatory compounds (e.g., structural or functional analogs or derivatives of thalidomide and / or inhibitors of E3 ubiquitin ligase, e.g., lenalidomide).

[0144] In some embodiments, the reference cell composition may be a T cell composition derived from the blood of a subject that does not have or is not suspected of having cancer, or a population of isolated, prepared, prepared, incubated and / or administered T cells obtained under the same or substantially the same conditions, except that they have not been incubated or administered in the presence of immunomodulatory compounds. In some embodiments, the reference cell composition contains genetically modified cells that are substantially the same, including the expression of the same recombinant receptor (e.g., CAR). In some aspects, such T cells are processed identically or substantially identically, for example, prepared in the same way, formulated in the same way, and administered at the same or nearly the same dosage and other similar factors.

[0145] In some embodiments, methods are provided that result in genetically modified cells with increased persistence and / or better efficacy in subjects to which such cells are administered. In some embodiments, the persistence of genetically modified cells (e.g., CAR-expressing T cells) in a subject is greater than the persistence that would be achieved by alternative methods (e.g., methods involving the administration of a reference cell composition, e.g., administration of T-cell therapy without the administration of an immunomodulatory compound). In some such cases, the persistence increases by at least 1.5 times or about at least 1.5 times, at least 2 times or about at least 2 times, at least 3 times or about at least 3 times, at least 4 times or about at least 4 times, at least 5 times or about at least 5 times, at least 6 times or about at least 6 times, at least 7 times or about at least 7 times, at least 8 times or about at least 8 times, at least 9 times or about at least 9 times, at least 10 times or about at least 10 times, at least 20 times or about at least 20 times, at least 30 times or about at least 30 times, at least 50 times or about at least 50 times, at least 60 times or about at least 60 times, at least 70 times or about at least 70 times, at least 80 times or about at least 80 times, at least 90 times or about at least 90 times, at least 100 times or about at least 100 times, or more.

[0146] In some embodiments, the degree or extent of persistence of administered cells can be detected or quantified after administration to a subject. For example, in some cases, quantitative PCR (qPCR) is used to assess the amount of recombinant receptor-expressing cells (e.g., CAR-expressing cells) in the blood or serum or organ or tissue (e.g., disease site) of a subject. In some embodiments, persistence is quantified as the number of copies of receptor-expressing cells (e.g., CAR-expressing cells) per microgram of DNA, or per microliter of sample (e.g., blood or serum), or as the number of receptor-expressing cells (e.g., CAR-expressing cells) relative to the total number of peripheral blood mononuclear cells (PBMCs) or leukocytes or T cells in a microliter of sample. In some embodiments, flow cytometry assays can also be performed to detect receptor-expressing cells, generally using antibodies specific to the receptor. Cell-based assays may also be used to detect the number or proportion of functional cells (e.g., cells capable of binding to disease or pathological cells, and / or neutralizing disease or pathological cells, and / or inducing a response to disease or pathological cells (e.g., a cytotoxic response), or expressing antigens recognized by receptors). In any such embodiment, the degree or level of expression of another marker associated with recombinant receptors (e.g., CAR-expressing cells) can be used to distinguish administered cells from endogenous cells in the subject.

[0147] Furthermore, methods for manipulating, preparing, and producing cells, such as in accordance with a provided combination therapy; compositions containing cells and / or immunomodulatory compounds; kits and devices containing cells and / or inhibitors; and kits and devices for using, producing, and administering cells and / or immunomodulatory compounds.

[0148] All publications referenced in this application, including patent documents, scientific articles, and databases, are incorporated by reference in their entirety for the same degree as each individual publication would have been incorporated by reference individually. If any definition provided herein conflicts with, or otherwise does not conform to, any definition provided in a patent, patent application, published patent application, or other publication incorporated herein by reference, the definition provided herein shall prevail over the definition incorporated herein by reference.

[0149] Section headings used in this specification are for structural purposes only and should not be construed as limiting the subjects described.

[0150] I. Combination Therapy This specification provides methods for combination therapy to treat diseases or disorders, such as cancer or proliferative disorders, comprising 1) administering an immunomodulatory compound, such as lenalidomide, a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, and 2) administering a T-cell therapy, such as a combination therapy of CAR-expressing cells, such as T cells. In some embodiments, the T-cell therapy is adoptive immunotherapy comprising T cells that specifically recognize and / or target antigens associated with the disease or disorder, such as cancer or proliferative disorders. Also provided are combinations and manufactured articles, such as kits, containing compositions comprising T-cell therapy and / or compositions comprising immunomodulatory compounds, as well as the use of such compositions and combinations for treating or preventing diseases, conditions and disorders, including cancer.

[0151] In some embodiments, such a method may include administering an immunomodulatory compound, such as lenalidomide, a structural or functional analog or derivative of thalidomide and / or an inhibitor of E3 ubiquitin ligase, before the administration of T-cell therapy (e.g., CAR-expressing T cells), concurrently with the administration, during the administration, during the course of the administration (including once and / or periodically during the course of the administration), and / or following the administration. In some embodiments, the administration may include sequential or intermittent administration of the immunomodulatory compound and the T-cell therapy.

[0152] In some embodiments, cell therapy is adoptive cell therapy. In some embodiments, cell therapy is or includes recombinant receptor-expressing cell therapy (optionally T-cell therapy), which is tumor-infiltrating lymphocyte (TIL) therapy, transgenic TCR therapy, or optionally chimeric antigen receptor (CAR)-expressing cell therapy. In some embodiments, the therapy is B-cell-targeted therapy. In some embodiments, the therapy targets B-cell maturation antigen (BCMA). In some embodiments, the therapy targets CD19. In some embodiments, the dosing regimen for administering cells and cells may include any of those described under “Administration of T-cell Therapy” in subsection A below.

[0153] In some embodiments, immunomodulatory compounds enhance T cell function. In some embodiments, immunomodulatory compounds promote anti-myeloma activity. In some embodiments, immunomodulatory compounds alter the suppressive microenvironment. In some embodiments, immunomodulatory compounds are structural or functional analogs or derivatives of thalidomide. In some embodiments, immunomodulatory compounds are inhibitors of E3 ubiquitin ligases. In some embodiments, immunomodulatory compounds are lenalidomide or compounds having the same or similar properties as lenalidomide, including analogs or derivatives of lenalidomide, its stereoisomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof. In some embodiments, drug regimens for administering immunomodulatory compounds may include any of those described under “Administration of Immunomodulatory Compounds” in subsection B below.

[0154] In some embodiments, T cell therapy (e.g., CAR-expressing T cells) and immunomodulatory compounds are provided as pharmaceutical compositions for administration to a subject. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of one or both of the active agents for combination therapy (e.g., T cells for adoptive cell therapy and immunomodulatory compounds, as described). In some embodiments, the active agents are formulated for administration in separate pharmaceutical compositions. In some embodiments, any of the pharmaceutical compositions provided herein may be formulated in a dosage form appropriate for the respective route of administration.

[0155] In some embodiments, combination therapy involves administering T-cell therapy containing engineered cells, such as CAR-T cell therapy, and immunomodulatory compounds, and is administered to subjects or patients who have or are at risk of having the disease or condition to be treated (e.g., cancer). In some aspects, the method brings about the treatment of the disease or condition, for example, improvement of one or more symptoms of the disease or condition, for example, by reducing the tumor burden in cancer expressing an antigen recognized by immunotherapy or an immunotherapy agent, for example, an antigen recognized by engineered T cells.

[0156] In some embodiments, the disease or condition being treated may be any of which the expression of an antigen is related to and / or involved in the pathogenesis of the disease, condition, or disorder, for example, causing, exacerbating, or otherwise involved in such disease, condition, or disorder. Exemplary diseases and conditions may include diseases or conditions associated with malignant tumors or cellular transformations (e.g., cancer), autoimmune or inflammatory diseases, or infectious diseases (e.g., infectious diseases caused by bacterial pathogens, viral pathogens, or other pathogens). Exemplary antigens include any of the antigens described herein, including antigens associated with a variety of diseases and conditions that can be treated. In certain embodiments, recombinant receptors expressed on the surface of the manipulated cells of the combination therapy, including chimeric antigen receptors or transgenic TCRs, specifically bind to antigens associated with the disease or condition.

[0157] In some embodiments, the disease or condition is a tumor (e.g., a solid tumor), lymphoma, leukemia, hematological malignancy, metastatic tumor, or other cancer or tumor type.

[0158] In some embodiments, the cancer or proliferative disorder is a B-cell malignancy or a hematological malignancy. In some embodiments, the cancer or proliferative disorder is lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), or chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is CLL. In some embodiments, the method can be used to treat myeloma, lymphoma, or leukemia. In some embodiments, the method can be used to treat non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia (AML), or myeloma (e.g., multiple myeloma (MM)). In some embodiments, the method can be used to treat MM or DBCBL.

[0159] In some embodiments, the antigens associated with the disease or disorder include ROR1, B cell maturation antigen (BCMA), tEGFR, Her2, L1-CAM, CD19, CD20, CD22, mesothelin, CEA, hepatitis B surface antigen, antifolate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, EGP-2, EGP-4, EPHa2, ErbB2, 3 or 4, erbB dimer, EGFR vIII, FBP, FCRL5, FCRH5, fetal acetylcholine e receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, kdr, kappa light chain, Lewis Y, L1-cell adhesion molecule (L1-CAM), melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, melanoma preferential expression antigen (PRAME), survivor, EGP2, EGP40, TAG72, B7-H6, IL-13 receptor a2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, biantigen, and antigens associated with universal tag, cancer testicular antigen, mesothelin, MUC1, MUC16, PSCA, NKG2D ligand, NY-ESO-1, MART-1, gp100, G protein-binding receptor 5D (GPCR5 D) Selected from the group consisting of tumor embryonic antigens, ROR1, TAG72, VEGF-R2, carcinoembryonic antigen (CEA), prostate-specific antigens, PSMA, Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, and pathogen-specific antigens. In some embodiments, the antigen is associated with or is a universal tag.

[0160] In some embodiments, cancer or proliferative disorders express BCMA. In some embodiments, the provided method utilizes recombinant receptor-expressing T cells (e.g., CAR-T cells) that target BCMA.

[0161] In some aspects, the method can be used to treat non-hematological cancers (e.g., solid tumors). In some aspects, the method can be used to treat cancers of the bladder, lung, brain, melanoma (e.g., small cell lung melanoma), breast, cervix, ovaries, colorectal, pancreas, endometrium, esophagus, kidney, liver, prostate, skin, thyroid, or uterus. In some aspects, cancer or proliferative disorder is cancer, and is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, pancreatic cancer, rectal cancer, thyroid cancer, uterine cancer, stomach cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumor, bone cancer, or soft tissue sarcoma.

[0162] In some embodiments, the disease or condition is an infectious disease or condition, such as, for example, viral infections, retroviral infections, bacterial and protozoan infections, immunodeficiency disorders, cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, BK polyomavirus, etc. In some embodiments, the disease or condition is an autoimmune or inflammatory disease or condition, such as arthritis (e.g., rheumatoid arthritis (RA)), type 1 diabetes, systemic lupus erythematosus (SLE), inflammatory bowel disease, psoriasis, scleroderma, autoimmune thyroid disease, Graves' disease, Crohn's disease, multiple sclerosis, asthma, and / or diseases or conditions associated with transplantation.

[0163] For the prevention or treatment of disease, the appropriate dosage of immunomodulatory compounds (e.g., lenalidomide) and / or immunotherapy (e.g., T-cell therapy (e.g., CAR-expressing T cells)) may depend on the type of disease to be treated, the specific immunomodulatory compound, the cells and / or recombinant receptors expressed on the surface of said cells, the severity and course of the disease, the route of administration, whether the immunomodulatory compound and / or T-cell therapy is administered for preventive or therapeutic purposes, previous treatments, frequency of administration, the subject's clinical history and response to cells, and the judgment of the attending physician. The compositions and cells are suitably administered to the patient in a single dose or over a series of treatments in several embodiments. Exemplary dosing plans and schedules for the combination therapies provided are described.

[0164] In some embodiments, T-cell therapy and immunomodulatory compounds are administered as part of further combination therapy, which may be administered concurrently with or sequentially to another therapeutic intervention, in any order. In some situations, T-cell therapy, e.g., engineered T cells (e.g., CAR-expressing T cells), is co-administered with another therapy that is time-sufficiently close to enhance the effect of one or more further therapeutic agents, or in the reverse manner. In some embodiments, the cells are administered prior to the one or more further therapeutic agents. In some embodiments, T-cell therapy, e.g., engineered T cells (e.g., CAR-expressing T cells), is administered after the one or more further therapeutic agents. In some embodiments, the combination therapy method further includes lymphocyte depletion therapy (e.g., administration of chemotherapeutic agents). In some embodiments, the combination therapy further includes the administration of another therapeutic agent (e.g., anticancer agents, checkpoint inhibitors, or other immunomodulatory agents). Uses include the use of combination therapy in such methods and procedures, as well as the use of such compositions in the preparation of pharmaceuticals for carrying out such combination therapy methods. In some embodiments, methods and uses thereby treat a disease or condition or disorder in a subject (e.g., cancer or proliferative disorder).

[0165] In some embodiments, the biological activity of T-cell therapy, e.g., the biological activity of the manipulated cell population, is measured before, during, or after the administration of immunotherapy (e.g., T-cell therapy, e.g., CAR-T-cell therapy) and / or immunomodulatory compounds, by any known method, for example. Parameters for evaluation include the ability of manipulated cells to destroy target cells, the persistence of T-cell activity, and other measures, for example, measured using any suitable method known in the art, such as the assays further described below in Section III. In some embodiments, the biological activity of cells (e.g., T-cells administered for T-cell-based therapy) is measured by assaying cytotoxic cell killing (e.g., upon restimulation with an antigen), the expression and / or secretion, proliferation, or expansion of one or more cytokines. In some aspects, biological activity is measured by evaluating disease burden and / or clinical outcomes (e.g., reduction in tumor burden or tumor cell volume). In some embodiments, the administration of one or both active agents of a combination therapy, and / or any repeated administration of said therapy, can be determined based on the results of assays before, during, over the course of, or after the administration of one or both active agents of the combination therapy.

[0166] In some embodiments, the combined effect of immunomodulatory compounds in combination with cell therapy may be synergistic compared to treatment with immunomodulatory compounds alone or with cell therapy alone. For example, in some embodiments, the methods provided herein result in an increase or improvement in a desired therapeutic effect, such as an increase or improvement in the reduction or suppression of one or more symptoms associated with cancer.

[0167] In some embodiments, immunomodulatory compounds enhance the expansion or proliferation of engineered T cells (e.g., CAR T cells). In some embodiments, the enhancement in expansion or proliferation is observed in vivo when administered to a subject. In some embodiments, the increase in the number of engineered T cells (e.g., CAR-T cells) is greater than 1.2 times or about 1.2 times, greater than 1.5 times or about 1.5 times, greater than 2.0 times or about 2.0 times, greater than 3.0 times or about 3.0 times, greater than 4.0 times or about 4.0 times, greater than 5.0 times or about 5.0 times, greater than 6.0 times or about 6.0 times, greater than 7.0 times or about 7.0 times, greater than 8.0 times or about 8.0 times, greater than 9.0 times or about 9.0 times, greater than 10.0 times or about 10.0 times, or more.

[0168] A. Implementation of T-cell therapy In some aspects of the methods, compositions, combinations, kits, and uses provided herein, combination therapy involves administering an immunotherapy, such as T-cell therapy (e.g., CAR-expressing T cells), to a target. The implementation of such therapy can be initiated before, after, or concurrently with the administration of one or more immunomodulatory compounds, as described herein.

[0169] In some embodiments, cell therapy is or involves the administration of immune cells, such as T cells or NK cells, that target molecules expressed on the surface of lesions, such as tumors or cancer. In some embodiments, the immune cells express T cell receptors (TCRs) or other antigen-binding receptors. In some embodiments, the immune cells express recombinant receptors such as transgenic TCRs or chimeric antigen receptors (CARs). In some embodiments, the cells are autologous to the target. In some embodiments, the cells are homogeneous to the target.

[0170] In some aspects, T-cell therapy is or includes T-cell therapy involving genetically modified cells, such as tumor-infiltrating lymphocyte (TIL) therapy, transgenic TCR therapy, or recombinant receptor-expressing cell therapy. In some embodiments, recombinant receptors specifically bind to ligands that are disease- or pathologically relevant, such as those associated with or expressed on tumor or cancer cells. In some embodiments, T-cell therapy involves administering T cells that have been engineered to express chimeric antigen receptors (CARs).

[0171] In some embodiments, the provided cells express and / or are engineered to express receptors such as recombinant receptors, including T cell receptors (TCRs) and their components, and / or functional non-TCR antigen receptors such as chimeric antigen receptors (CARs), which include a ligand-binding domain or a binding fragment thereof. In some embodiments, the recombinant receptor includes an extracellular ligand-binding domain that specifically binds to an antigen. In some embodiments, the recombinant receptor is a CAR that includes an extracellular antigen-recognizing domain that specifically binds to an antigen. In some embodiments, the ligand, such as an antigen, is a protein expressed on the surface of the cell. In some embodiments, the CAR is a TCR-like CAR, and the antigen is a processed peptide antigen, such as an intracellular protein peptide antigen, which, like a TCR, is recognized on the cell surface in relation to a major histocompatibility complex (MHC) molecule.

[0172] Among the engineered cells, including those containing recombinant receptors, are those described in Section II below. Exemplary recombinant receptors, including CARs and recombinant TCRs, and methods for manipulating and introducing these receptors into cells, are described, for example, in International Publication Nos. 200014257, 2013126726, 2012 / 129514, 2014031687, 2013 / 166321, 2013 / 071154, 2013 / 123061, 2016 / 0046724, 2016 / 014789, 2016 / 090320, 2016 / 094304, 2017 / 025038, 2017 / 173256, and U.S. Patent Application Publication No. 200213. The patents described in Patent No. 1960, No. 2013287748, No. 20130149337, U.S. Patent Nos. 6,451,995, 7,446,190, 8,252,592, 8,339,645, 8,398,282, 7,446,179, 6,410,319, 7,070,995, 7,265,209, 7,354,762, 7,446,191, 8,324,353, 8,479,118, and 9,765,342, as well as those described in European Patent Application No. 2537416, and / or Sadelain This includes those described by et al., Cancer Discov., 3(4):388-398 (2013); Davida et al. PLoS ONE 8(4):e61338 (2013); Turtle et al., Curr. Opin. Immunol., 24(5):633-39 (2012); and Wu et al., Cancer, 18(2):160-75 (2012). In some aspects, genetically engineered antigen receptors include CARs described in U.S. Patent No. 7,446,190 and those described in International Publication No. 2014055668A1.

[0173] In some embodiments, the antigens include αvβ6 integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (also known as CA9, CAIX, or G250), cancer testis antigen, cancer / testis antigen 1B (also known as CTAG, NY-ESO-1, and LAGE-2), carcinoembryonic antigen (CEA), cyclin, cyclin A2, CC motif chemokine ligand 1 (CCL-1), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD123, CD133, CD138, CD171, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), truncated epidermal growth factor protein (tEGFR), and type III epidermal growth factor receptor mutation (EGFR). vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrin B2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor-like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), folate-binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G protein-binding receptor 5D (GPCR5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (er b-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 alpha 2 (IL-13Rα2), kinase insert domain receptor (kdr), kappa light chain, L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, leucine-rich repeat-containing 8 family member A (LRRC8A), Lewis Y, melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, mouse cytomegalovirus (CMV),Mucin 1 (MUC1), MUC16, Natural Killer Group 2 Member D (NKG2D) ligand, Melan A (MART-1), Neuronal Cell Adhesion Molecular (NCAM), Tumor Fetal Antigen, Melanoma Preferred Antigen (PRAME), Progesterone Receptor, Prostate-Specific Antigen, Prostate Stem Cell Antigen (PSCA), Prostate-Specific Membrane Antigen (PSMA), Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1), Survivin, Trophoblastic Glycoprotein (TPBG, also known as 5T4), Tumor-Associated Glycoprotein 72 (TAG72), Tyrosinase-Related Protein 1 (TRP) 1. (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 antigens or pathogen-expressed antigens, or antigens associated with a universal tag, and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV or other pathogens, or comprising the same. Antigens targeted by the receptor include, in some embodiments, antigens associated with B-cell malignancies, such as any number of 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.

[0174] In some embodiments, the antigen is or includes a pathogen-specific antigen or a 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.

[0175] In some embodiments, combination therapy involves administering to a subject cells expressing recombinant receptors, such as T cells, that specifically recognize and / or target antigens associated with cancer and / or present on a universal tag.In some embodiments, antigens recognized or targeted by T cells include ROR1, B cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), tEGFR, Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, antifolate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, and EGFR. vIII, Folate-binding protein (FBP), FCRL5, FCRH5, Fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, Kinase insert domain receptor (kdr), Kappa light chain, Lewis Y, L1-cell adhesion molecule (L1-CAM), Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, Melanoma preferential expression antigen (PRAME), Survivin, TAG72, B7-H6, IL-13 receptor alpha2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE Al, HLA-A2, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, biantigen, cancer testicular antigen, mesothelin, mouse CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, G protein-binding receptor 5D (GPC R5D), tumor embryo antigen, ROR1, TAG72, VEGF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, or any of the aforementioned human antigens; these are pathogen-specific antigens.

[0176] Methods for administering engineered cells for adoptive cell therapy are known and can be used in conjunction with the methods and compositions provided. For example, methods for adoptive T cell therapy are described in, for example, Gruenberg et al., U.S. Patent Application Publication No. 2003 / 0170238; Rosenberg, U.S. Patent No. 4,690,915; Rosenberg (2011) Nat Rev Clin Oncol. 8(10):577-85). See, for example, Themeli et al., (2013) Nat Biotechnol. 31(10):928-933; Tsukahara et al., (2013) Biochem Biophys Res Commun 438(1):84-9; and Davila et al., (2013) PLoS ONE 8(4):e61338.

[0177] In some aspects, cell therapy, such as adoptive T-cell therapy, is carried out by autologous transplantation, in which cells are isolated and / or prepared by other means from or from a sample derived from a subject to receive cell therapy. Thus, in some aspects, the cells are derived from a subject in need of treatment, such as a patient, and are administered to the same subject after isolation and processing.

[0178] In some embodiments, cell therapy, such as adoptive T-cell therapy, is carried out by allogeneic transplantation, in which cells are isolated and / or prepared by other means from a subject other than the subject that is to receive or will ultimately receive cell therapy, e.g., a first subject. In such embodiments, the cells are then administered to a different subject of the same species, e.g., a second subject. In some embodiments, the first and second subjects are genetically identical. In some embodiments, the first and second subjects are genetically similar. In some embodiments, the second subject expresses the same HLA class or supertype as the first subject.

[0179] In a particular embodiment, individual populations of cells, or subtypes of cells, are administered to a subject in a range of approximately 1 million to 100 billion cells and / or such a cell quantity per kilogram of body weight, for example, in the range of 1 million to 50 billion cells (e.g., approximately 5 million cells, approximately 25 million cells, approximately 500 million cells, approximately 1 billion cells, approximately 5 billion cells, approximately 20 billion cells, approximately 30 billion cells, approximately 40 billion cells, or a range defined by any two of the aforementioned values), or in the range of approximately 10 million to 100 billion cells (e.g., approximately 20 million cells, approximately 30 million cells, approximately 40 million cells, approximately 60 million cells, approximately The dosage is administered to the subject in a range of 70 million cells, approximately 80 million cells, approximately 90 million cells, approximately 10 billion cells, approximately 25 billion cells, approximately 50 billion cells, approximately 75 billion cells, approximately 90 billion cells, or any two of the aforementioned values), and in some cases in a range of approximately 100 million to approximately 50 billion cells (e.g., approximately 120 million cells, approximately 250 million cells, approximately 350 million cells, approximately 450 million cells, approximately 650 million cells, approximately 800 million cells, approximately 900 million cells, approximately 3 billion cells, approximately 30 billion cells, approximately 45 billion cells), or any value within these ranges, and / or per kilogram of body weight. The dosage may vary depending on the disease or disorder and / or attributes specific to the patient and / or other treatment.

[0180] In some embodiments, for example, when the subject is human, the dose is approximately 1 × 10⁻⁶ 8 It includes fewer than 1 total recombinant receptor (e.g., CAR) expressing cells, T cells, or peripheral blood mononuclear cells (PBMCs), for example, about 1 × 10⁶ 6 pieces~1×10 8 Individual such cells (for example, 2 × 10 in total) 6 pieces, 5×10 6 pieces, 1×10 7 pieces, 5×10 7 pieces, or 1 x 10 8 The range includes individuals (or such cells, etc.) or a range between any two of the aforementioned values.

[0181] Cells can be administered by any appropriate means. Cells are administered in a dosing regimen to achieve therapeutic effects, such as a reduction in tumor burden. Dosage and administration may, in part, depend on the administration schedule of immunomodulatory compounds, which may be administered before, after, and / or concurrently with the initiation of T-cell therapy. Various dosing schedules for T-cell therapy include, but are not limited to, single or multiple doses, bolus doses, and pulse infusions over various time points.

[0182] 1. Compositions and Formulations In some embodiments, the dose of cells for T-cell therapy, such as T-cell therapy, which includes cells manipulated with recombinant antigen receptors, for example, CAR or TCR, is provided as a composition or formulation, such as a pharmaceutical composition or formulation. Such compositions can be used in the prevention or treatment of diseases, conditions, and disorders, etc., according to the methods provided.

[0183] In some embodiments, T cell therapies, such as those involving engineered T cells (e.g., CAR T cells), are formulated with pharmaceutically acceptable carriers. In some aspects, the choice of carrier is determined, in part, by the specific cells or agent and / or the method of administration. Thus, a variety of suitable formulations exist. For example, a pharmaceutical composition may contain a preservative. Suitable preservatives include, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. In some aspects, a mixture of two or more preservatives is used. The preservative or a mixture thereof is typically present in an amount of about 0.0001% to about 2% by weight of the total composition. Carriers are described, for example, in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). Pharmacochemically acceptable carriers are generally non-toxic to the recipient at the doses and concentrations used and include, but are not limited to, the following: buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, alkylparabens such as butyl or benzyl alcohol, methyl or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol and m-cresol); low-molecular-weight Polypeptides with a small number of residues (less than approximately 10 residues); proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as polyethylene glycol (PEG).

[0184] In some cases, buffers are included in the composition. Suitable buffers include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. In some cases, mixtures of two or more buffers are used. The buffer or mixture is typically present in an amount of about 0.001% to about 4% by weight of the total composition. Methods for preparing administerable pharmaceutical compositions are known. Exemplary methods are described in more detail, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21st ed. (May 1, 2005).

[0185] The formulation may include an aqueous solution. The formulation or composition may also contain multiple active ingredients useful for a specific indication, disease, or condition to be prevented or treated by the cell or agent, provided that their respective activities do not adversely affect each other. Such active ingredients are appropriately present in combination in amounts effective for the intended purpose. Thus, in some embodiments, the pharmaceutical composition may further include other pharmaceutically active agents or drugs such as chemotherapeutic agents, e.g., asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, etc.

[0186] In some embodiments, the pharmaceutical composition contains a quantity of cells effective for treating or preventing a disease or condition, such as a therapeutically effective or prophylactically effective amount. In some embodiments, the effectiveness of treatment or prevention is monitored by periodic evaluation of the subject being treated. For repeated administrations over several days or longer, treatment is repeated, depending on the condition, until the desired suppression of disease symptoms occurs. However, other administration regimens may also be useful and may be determined. The desired dose can be delivered by a single bolus of the composition, by multiple bolus administrations of the composition, or by continuous infusion of the composition.

[0187] Cells may be administered using standard administration techniques, formulations, and / or apparatus. Formulations and apparatus, such as syringes and vials, are provided for the storage and administration of compositions. With respect to cells, administration may be autoadministration or xenoadministration. For example, immune-responsive cells or precursors may be obtained from one subject and administered to the same or different, compatible subjects. Peripheral blood-derived immune-responsive cells or their offspring (e.g., in vivo, ex vivo, or in vitro-derived) may be administered by catheter administration, systemic infusion, local infusion, intravenous injection, or local infusion including parenteral administration. When administering therapeutic compositions (e.g., pharmaceutical compositions containing genetically modified immune-responsive cells), therapeutic compositions are generally formulated in unit-dose injection forms (solutions, suspensions, emulsions).

[0188] Formulations include those for oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, oral, sublingual, or suppository administration. In some embodiments, the agent or cell population is administered parenterally. As used herein, the term “parenteral” includes intravenous, intramuscular, subcutaneous, rectal, vaginal, and intraperitoneal administration. In some embodiments, the agent or cell population is administered to a subject by peripheral systemic delivery via intravenous, intraperitoneal, or subcutaneous injection.

[0189] In some embodiments, the composition is provided as a sterile liquid formulation, such as an isotonic aqueous solution, suspension, emulsion, dispersion, or viscous composition, which can be buffered to a selected pH in some aspects. Liquid formulations are generally easier to prepare than gels, other viscous compositions, and solid compositions. Furthermore, liquid compositions are somewhat more convenient to administer, particularly by injection. On the other hand, viscous compositions can be formulated within a suitable viscosity range that provides a longer contact period with specific tissues. The liquid or viscous composition may contain a carrier, which may be a solvent or dispersion medium containing, for example, water, saline solution, phosphate-buffered saline solution, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol) and suitable mixtures thereof.

[0190] Sterile injection solutions can be prepared by incorporating cells into a solvent such as a mixture with a suitable carrier, diluent, or excipient, e.g., sterile water, saline, glucose, dextrose, e...

Claims

1. A pharmaceutical composition comprising an immunomodulatory compound for use in a method of treating cancer in a subject, wherein the method comprises the step of administering the immunomodulatory compound to a subject having cancer, wherein, at the start of administration of the immunomodulatory compound, the subject has previously received T-cell therapy for the treatment of the cancer, and, This T-cell therapy comprises genetically modified T cells that express a chimeric antigen receptor (CAR) that specifically binds to B cell maturation antigen (BCMA), and The immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, its stereoisomer, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. The aforementioned pharmaceutical composition.

2. A pharmaceutical composition comprising T-cell therapy and immunomodulatory compounds for use in a method of treating cancer in a subject, wherein the method is (a) a step of administering the T-cell therapy to a subject having cancer, wherein the T-cell therapy comprises genetically modified T cells that express a chimeric antigen receptor (CAR) that specifically binds to a B-cell maturation antigen (BCMA); and (b) A step of administering the immunomodulatory compound to a subject, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; including, The aforementioned pharmaceutical composition.

3. A pharmaceutical composition comprising an immunomodulatory compound for use in a method of treating cancer in a subject in combination with T-cell therapy, wherein the method is (a) a step of administering the T-cell therapy to a subject having cancer, wherein the T-cell therapy comprises genetically modified T cells that express a chimeric antigen receptor (CAR) that specifically binds to a B-cell maturation antigen (BCMA); and (b) A step of administering the immunomodulatory compound to a subject, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; including, The aforementioned pharmaceutical composition.

4. A pharmaceutical composition comprising T-cell therapy for use in a method of treating cancer in a subject in combination with an immunomodulatory compound, wherein the method is (a) a step of administering the T-cell therapy to a subject having cancer, wherein the T-cell therapy comprises genetically modified T cells that express a chimeric antigen receptor (CAR) that specifically binds to a B-cell maturation antigen (BCMA); and (b) A step of administering the immunomodulatory compound to a subject, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; including, The aforementioned pharmaceutical composition.

5. The pharmaceutical composition according to any one of claims 2 to 4, wherein the administration of the immunomodulatory compound is initiated in at least one cycle after the initiation of T-cell therapy.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the administration of the immunomodulatory compound is initiated at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks after the initiation of T-cell therapy.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein the administration of the immunomodulatory compound is initiated 2 to 28 days or 7 to 21 days after the initiation of T-cell therapy.

8. The pharmaceutical composition according to any one of claims 1 to 5, wherein administration of the immunomodulatory compound is initiated immediately after or within 1 to 3 days thereafter: (i) The peak or maximum level of T-cell therapy cells became detectable in the target blood; (ii) The number of detectable T-cell therapy cells in the blood becomes undetectable after becoming detectable in the blood, or is reduced compared to a preceding point in time after administration of T-cell therapy; (iii) The number of detectable T-cell therapy cells in the blood decreased by 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or more than 3.0 times, 4.0 times or more than 4.0 times, 5.0 times or more than 5.0 times, 10 times or more than 10 times or more than the peak number or maximum number of detectable T-cell therapy cells in the subject's blood after the start of T-cell therapy administration; (iv) At the time after the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood, the number of detectable T cells or cells derived from the subject in the subject's blood is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) The subject has shown disease progression after treatment with T-cell therapy and / or has relapsed following remission; and / or (vi) The subjects showed an increased tumor volume compared to the tumor volume before or after T cell administration and before the initiation of immunomodulatory compound administration.

9. The pharmaceutical composition according to any one of claims 1 to 5, wherein the administration of the immunomodulatory compound is initiated as follows: (1) 2 to 28 days after the start of T-cell therapy; and (2) (i) The peak or maximum level of T-cell therapy cells became detectable in the subject's blood; (ii) The number of detectable T-cell therapy cells in the blood becomes undetectable after becoming detectable in the blood, or is reduced compared to a preceding point in time after administration of T-cell therapy; (iii) The number of detectable T-cell therapy cells in the blood decreased by 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or more than 3.0 times, 4.0 times or more than 4.0 times, 5.0 times or more than 5.0 times, 10 times or more than 10 times or more than the peak number or maximum number of detectable T-cell therapy cells in the subject's blood after the start of T-cell therapy administration; (iv) At the time after the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood, the number of detectable T cells or cells derived from the subject in the subject's blood is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) The subject has shown disease progression after treatment with T-cell therapy and / or has relapsed following remission; and / or (vi) The subjects showed an increased tumor volume compared to the tumor volume before or after T cell administration and before the initiation of immunomodulatory compound administration. Immediately afterward or within 1-3 days thereafter.

10. The above method, before the start of administration of the immunomodulatory compound, (i) The peak or maximum level of T-cell therapy cells is detectable in the subject's blood; (ii) The number of detectable T-cell therapy cells in the blood becomes undetectable or reduced compared to a preceding point in time after administration of T-cell therapy after becoming detectable in the blood; (iii) The number of detectable T-cell therapy cells in the blood decreases by 1.5 times or more than 1.5 times, 2.0 times or more than 2.0 times, 3.0 times or more than 3.0 times, 4.0 times or more than 4.0 times, 5.0 times or more than 5.0 times, 10 times or more than 10 times or more than the peak number or maximum number of detectable T-cell therapy cells in the subject's blood after the start of T-cell therapy administration; (iv) At the time after the peak or maximum level of T-cell therapy cells becomes detectable in the subject's blood, the number of detectable T cells or cells derived from the subject in the subject's blood is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the subject's blood; (v) The disease has progressed after treatment with T-cell therapy and / or has relapsed following remission; and / or (vi) The tumor volume shown is the increased tumor volume compared to the tumor volume before or after T cell administration and before the initiation of immunomodulatory compound administration. A pharmaceutical composition according to any one of claims 1 to 5, comprising selecting a target.

11. A pharmaceutical composition comprising an immunomodulatory compound for use in a method of treating cancer in a subject, wherein the method comprises administering a therapeutically effective amount of the immunomodulatory compound, wherein The immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, its stereoisomer, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and The subjects have previously received T-cell therapy for the treatment of the cancer prior to the initiation of administration of the immunomodulatory compound, wherein the T-cell therapy comprises genetically modified T cells expressing a chimeric antigen receptor (CAR) that specifically binds to B cell maturation antigen (BCMA), and further, the subjects are those 12 to 15 days or approximately 12 to 15 days after the initiation of administration of T-cell therapy for the treatment of the cancer. (i) The number of T-cells in a subject receiving T-cell therapy is less than 75% of the average number of T-cells in multiple subjects receiving the same or similar doses of T-cell therapy at the same time point; and / or (ii) The number of T-cell therapy CD3+ or CD8+ cells in the blood is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL. The subject, The aforementioned pharmaceutical composition.

12. A pharmaceutical composition comprising an immunomodulatory compound for use in a method of treating cancer in a subject, wherein the method comprises the following: (a) 12 to 15 days after the start of T-cell therapy to treat cancer, (i) The number of T-cells in a subject receiving T-cell therapy is less than 75% of the average number of T-cells in multiple subjects receiving the same or similar doses of T-cell therapy at the same time point; and / or (ii) The number of T-cell therapy CD3+ or CD8+ cells in the blood is less than 10 cells per μL, less than 5 cells per μL, or less than 1 cell per μL. Selecting a target; Here, the T cell therapy includes genetically engineered T cells that express a chimeric antigen receptor (CAR) that specifically binds to B cell maturation antigen (BCMA), and (b) Administering a therapeutically effective dose of the immunomodulatory compound to the target population; wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, its stereoisomer, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

13. A pharmaceutical composition comprising a T-cell therapy for use in a method of treating cancer in a subject, the method comprising the step of administering the T-cell therapy to a subject having cancer, wherein the T-cell therapy comprises genetically engineered T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a B-cell maturation antigen (BCMA), wherein, at the start of administration of the T-cell therapy, the subject has previously been administered an immunomodulatory compound and / or treated with an immunomodulatory compound, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, its stereoisomer, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

14. The initiation of administration of an immunomodulatory compound or the initiation of administration of said compound for at least one cycle, and the initiation of administration of T-cell therapy, occur on the same day or consecutively; and / or At least one dose of an immunomodulatory compound is administered on the same day as, or within one or two days of, an administration of a certain dose of T-cell therapy, before, or immediately thereafter. A pharmaceutical composition according to any one of claims 1 to 4 and 13.

15. The pharmaceutical composition according to any one of claims 2 to 4, wherein the initiation of administration of the immunomodulatory compound, or the initiation of administration of the compound for at least one cycle, is prior to the initiation of administration of T-cell therapy.

16. A pharmaceutical composition comprising a T-cell therapy for use in a method of treating cancer in a subject, the method comprising the step of administering the T-cell therapy to a subject having cancer, wherein the T-cell therapy comprises genetically engineered T cells expressing a chimeric antigen receptor (CAR) that specifically binds to a B-cell maturation antigen (BCMA), wherein the subject has been previously administered an immunomodulatory compound prior to the commencement of administration of the T-cell therapy, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione, its stereoisomer, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, further wherein the immunomodulatory compound is (i) A cycle comprising up to 21 consecutive days of administration, including more than 30 days beginning with the commencement of administration of the immunomodulatory compound; and / or (ii) A cycle comprising administration over several consecutive days followed by a rest period during which no immunomodulatory compound is administered, wherein the rest period exceeds 14 consecutive days; and / or (iii) A cycle including administration for 14 consecutive days or less It is administered as follows: The aforementioned pharmaceutical composition.

17. Administration of immunomodulatory compounds before administration of T-cell therapy, (i) within one week before or after the time when a sample containing T cells to be processed and / or manipulated to produce the therapy is collected from the subject; and / or (ii) Within 14 days prior to the start of T-cell therapy A pharmaceutical composition according to any one of claims 2 to 4, 13 and 16, beginning with

18. The cancer is unresponsive or resistant to immunomodulatory compounds, and / or the subject or cancer is determined to have a mutation or factor that confers resistance to treatment with immunomodulatory compounds. A pharmaceutical composition according to any one of claims 1 to 17.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the immunomodulatory compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione.

20. The pharmaceutical composition according to any one of claims 1 to 18, wherein the immunomodulatory compound is a pharmaceutically acceptable salt of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione.

21. The immunomodulatory compound, including the values ​​at both ends, is in the following ranges: 0.1 mg to approximately 100 mg or approximately 0.1 mg to approximately 100 mg, 0.1 mg to 50 mg or approximately 0.1 mg to 50 mg, 0.1 mg to 25 mg or approximately 0.1 mg to 25 mg, 0.1 mg to 10 mg or approximately 0.1 mg to 10 mg, 0.1 mg to 5 mg or approximately 0.1 mg to 5 mg, 0.1 mg to 1 mg or approximately 0.1 mg to 5 mg, 1 mg to 100 mg or approximately 1 mg to 100 mg, 1 mg to 50 mg or approximately 1 mg to 50 mg, 1 mg to 25 mg or approximately 1 mg to 25 mg, 1 mg to 10 mg or approximately 1 mg to 10 mg, and 1 mg to 5 mg. Alternatively, the pharmaceutical composition according to any one of claims 1 to 20, which is administered in an amount of approximately 1 mg to 5 mg, 5 mg to 100 mg or approximately 5 mg to 100 mg, 5 mg to 50 mg or approximately 5 mg to 50 mg, 5 mg to 25 mg or approximately 5 mg to 25 mg, 5 mg to 10 mg or approximately 5 mg to 10 mg, 10 mg to 100 mg or approximately 10 mg to 100 mg, 10 mg to 50 mg or approximately 10 mg to 50 mg, 10 mg to 25 mg, 25 mg to 100 mg or approximately 25 mg to 100 mg, 25 mg to 50 mg or approximately 25 mg to 50 mg, or 50 mg to 100 mg or approximately 50 mg to 100 mg.

22. A pharmaceutical composition according to any one of claims 1 to 20, wherein the immunomodulatory compound is administered in an amount greater than 1 mg / day and less than 25 mg / day.

23. The pharmaceutical composition according to any one of claims 1 to 22, wherein the immunomodulatory compound is administered once a week, twice a week, three times a week, every other day, once a day, twice a day, three times a day, four times a day, five times a day, or six times a day.

24. A pharmaceutical composition according to any one of claims 1 to 23, wherein the immunomodulatory compound is administered for more than 7 consecutive days.

25. A pharmaceutical composition according to any one of claims 1 to 24, wherein the immunomodulatory compound is administered daily for a maximum of 30 consecutive days.

26. The pharmaceutical composition according to any one of claims 1 to 25, wherein the immunomodulatory compound is administered in a cycle comprising a period of administration during which the immunomodulatory compound is administered, and a subsequent rest period during which the immunomodulatory compound is not administered.

27. The pharmaceutical composition according to claim 26, wherein the rest period is more than one day or more than three consecutive days.

28. The pharmaceutical composition according to claim 26 or 27, wherein the immunomodulatory compound is administered for at least two cycles.

29. A pharmaceutical composition according to any one of claims 1 to 28, wherein the immunomodulatory compound is administered orally.

30. The pharmaceutical composition according to any one of claims 1 to 29 is as follows: The administration of therapeutically effective doses of immunomodulatory compounds stimulates an increase in T cell growth associated with T cell therapy, compared to the increase after administration of T cell therapy in the absence of immunomodulatory compounds; Administration of a therapeutically effective dose of an immunomodulatory compound stimulates an increase in T cell-mediated cytolytic activity of T cells associated with T cell therapy, compared to cytolytic activity after T cell administration in the absence of the immunomodulatory compound; and / or The administration of therapeutically effective doses of immunomodulatory compounds stimulates increased T-cell cytokine production associated with T-cell therapy, compared to cytokine production after T-cell administration in the absence of immunomodulatory compounds.

31. T-cell therapy, T cells selected from the group consisting of central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells; and / or Multiple cells, including at least 50% of a population of cells selected from the group consisting of CD4+ T cells, CD8+ T cells, central memory T cells, effector memory T cells, naive T cells, stem central memory T cells, effector T cells, and regulatory T cells. A pharmaceutical composition according to any one of claims 1 to 30, comprising:

32. The pharmaceutical composition according to any one of claims 1 to 31, wherein the T cell therapy comprises T cells that are CD4+ or CD8+.

33. A pharmaceutical composition according to any one of claims 1 to 32, wherein the T cell therapy includes cells that are autologous to the subject.

34. A pharmaceutical composition according to any one of claims 1 to 32, wherein the T cell therapy comprises T cells that are of the same type as the target.

35. T-cell therapy, including values ​​at both ends, 1 x 10 5 The above 5 x 10 8 The following or approximately 1 x 10 5 The above 5 x 10 8 The following total CAR-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 1 x 10 5 The above 1 x 10 8 The following or approximately 1 x 10 5 The above 1 x 10 8 The following total CAR-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), 5×10 5 1×10 or more 7 5×10 or less or about 5 1×10 or more 7 total CAR-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMC), or 1 x 10 6 The above 1 x 10 7 The following or approximately 1 x 10 6 The above 1 x 10 7 The following total CAR-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), A pharmaceutical composition according to any one of claims 1 to 34, comprising the administration of [a certain substance].

36. The pharmaceutical composition according to any one of claims 1 to 35, wherein the method further comprises administering lymphocyte depletion chemotherapy before administering T cell therapy.

37. The pharmaceutical composition according to any one of claims 1 to 36, wherein the cancer is a B-cell malignant tumor and / or myeloma, lymphoma, or leukemia.

38. The pharmaceutical composition according to claim 37, wherein the cancer is mantle cell lymphoma (MCL), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), or follicular lymphoma (FL).

39. The pharmaceutical composition according to claim 38, wherein the cancer is multiple myeloma (MM).

40. The pharmaceutical composition according to any one of claims 1 to 36, wherein the cancer is a non-hematological cancer or a solid tumor.

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