Methods and uses related to T cell therapy, and their production

Abstract

This specification provides for the use of T cells, such as chimeric antigen receptor (CAR) T cells, for treating a tumor or cancer (e.g., B cell-related cancer, such as multiple myeloma), wherein the subject to be treated has previously received a topoisomerase inhibitor, a proteasome inhibitor, an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent therapy.

Description

Technical Field

[0001] Cross-reference to related applications This application claims priority from U.S. Provisional Patent Application No. 63 / 340,914, filed May 11, 2022, and No. 63 / 345,865, filed May 25, 2022, both entitled "METHODS AND USES RELATED TO T CELL THERAPY AND PRODUCTION OF SAME", the contents of which are incorporated herein by reference in their entirety.

[0002] Incorporation by reference of the sequence listing This application is filed with a sequence listing in electronic format. The sequence listing is provided as a file entitled 683772002440SeqList.xml created on May 10, 2023, and its size is 421,486 bytes. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

[0003] Field The disclosure presented herein relates to methods for treating a tumor or cancer (e.g., B cell-related cancer, such as multiple myeloma). More specifically, the disclosure relates to improved methods for treating a tumor or cancer (e.g., B cell-related cancer, such as multiple myeloma) using immune effector cells (e.g., T cells), where the subject to be treated has previously received prior therapy. The disclosure also relates to methods for treating a tumor or cancer (e.g., B cell-related cancer, such as multiple myeloma) using a chimeric antigen receptor (CAR) comprising an antibody or an antigen-binding fragment thereof (e.g., an anti-BCMA antibody or an antigen-binding fragment thereof), and immune effector cells (e.g., T cells) genetically modified to express these CARs. The disclosure also relates to methods for manufacturing T cells and CARs comprising an antibody or an antigen-binding fragment thereof (e.g., an anti-BCMA antibody or an antigen-binding fragment thereof) for treating a tumor or cancer (e.g., B cell-related cancer, such as multiple myeloma).

Background Art

[0004] For example, many options such as traditional chemotherapy approaches as well as immunotherapies (e.g., chimeric antigen receptor (CAR) T cell therapy) are currently available for cancer treatment approaches. In certain instances, the use of a particular therapy or approach may render subsequent treatment administrations suboptimal. Thus, there is a need to optimize the administration of such therapies when cancer therapies, such as T cell therapies like CAR-T therapy, are administered to a patient, for example, when administered in sequence with other cancer therapies or approaches related to cancer therapy.

Summary of the Invention

[0005] The present disclosure generally provides improved methods for treating B cell-related cancers, such as tumors or cancers such as multiple myeloma.

[0006] In one aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the method comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating the tumor or cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, step (a) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the subject has received the prior therapy.

[0007] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the method comprising: (a) administering to the subject a topoisomerase inhibitor therapy or a proteasome inhibitor therapy; (b) obtaining T cells from the subject at least about 6 months after the administration in step (a); (c) manufacturing T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (d) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, in step (a), a topoisomerase inhibitor therapy is administered to the subject. In certain embodiments, in step (a), a proteasome inhibitor therapy is administered to the subject. In certain embodiments, step (b) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the administration in step (a).

[0008] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the subject having been administered a prior therapy selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy, the method comprising: (a) selecting a subject who was administered the prior therapy at a time point more than 6 months ago; (b) obtaining T cells from the subject, wherein the obtaining is performed at least about 6 months after the prior therapy was administered to the subject; (c) manufacturing T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (d) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, the prior therapy is a topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is a proteasome inhibitor therapy. In certain embodiments, in step (a), the prior therapy is administered at a time point more than 7 months, more than 8 months, or more than 9 months ago. In certain embodiments, in step (b), the obtaining is performed at least about 7 months, at least about 8 months, or at least about 9 months after the prior therapy was administered to the subject.

[0009] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the method comprising administering to the subject T cells produced from peripheral blood mononuclear cells (PBMCs) isolated from the patient, wherein the subject has been administered a prior therapy selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and at the time the PBMCs are isolated, the subject had last received the prior therapy at least about 6 months prior to the time the PBMCs were isolated. In certain embodiments, the subject has been administered topoisomerase inhibitor therapy. In certain embodiments, the subject has been administered proteasome inhibitor therapy. In certain embodiments, the subject had last received the prior therapy at least about 7 months, at least about 8 months, or at least about 9 months prior to the time the PBMCs were isolated.

[0010] In another aspect, provided herein is a method for treating cancer caused by B cell maturation antigen (BCMA) - expressing cells in a subject in need thereof, the method comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (c) administering the manufactured BCMA CAR T cells to the subject for treating the cancer. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, step (a) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the subject has received the prior therapy.

[0011] In another aspect, the present disclosure provides a method for treating cancer caused by B cell maturation antigen (BCMA)-expressing cells in a subject in need thereof, the method comprising: (a) administering to the subject a topoisomerase inhibitor therapy or a proteasome inhibitor therapy; (b) obtaining T cells from the subject at least about 6 months after the administration in step (a); (c) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (d) administering to the subject the manufactured BCMA CAR T cells for treating cancer. In certain embodiments, in step (a), the topoisomerase inhibitor therapy is administered to the subject. In certain embodiments, in step (a), the proteasome inhibitor therapy is administered to the subject. In certain embodiments, step (b) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the administration in step (a).

[0012] In another aspect, provided herein is a method for treating cancer caused by B cell maturation antigen (BCMA)-expressing cells in a subject in need thereof, wherein the subject has been administered a prior therapy selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy as part of the treatment of the cancer, and the method comprises: (a) selecting a subject who was administered the prior therapy more than 6 months ago; (b) obtaining T cells from the subject, wherein the obtaining is performed at least about 6 months after the prior therapy was administered to the subject; (c) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured T cells comprise a recombinant receptor directed to cancer cells; and (d) administering the manufactured BCMA CAR T cells to the subject for treating the cancer. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, in step (a), the prior therapy is administered more than 7 months, more than 8 months, or more than 9 months ago. In certain embodiments, in step (b), the obtaining is performed at least about 7 months, at least about 8 months, or at least about 9 months after the prior therapy was administered to the subject.

[0013] In another aspect, the present disclosure provides a method for treating cancer caused by B cell maturation antigen (BCMA) - expressing cells in a subject in need thereof, the method comprising administering to the subject chimeric antigen receptor (CAR) T cells directed to BCMA produced from peripheral blood mononuclear cells (PBMCs) isolated from the patient, wherein the subject has been administered a prior therapy selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and at the time the PBMCs are isolated, the subject had last received the prior therapy at least about 6 months prior to the time the PBMCs were isolated. In certain embodiments, the subject has been administered topoisomerase inhibitor therapy. In certain embodiments, the subject has been administered proteasome inhibitor therapy. In certain embodiments, the subject had last received the prior therapy at least about 7 months, at least about 8 months, or at least about 9 months prior to the time the PBMCs were isolated.

[0014] In another aspect, provided herein is a method of reducing the time for a subject to recover from neutropenia after T cell therapy, wherein the T cell therapy comprises: (a) obtaining T cells from a subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. In another aspect, provided herein is a method of reducing the time for a subject to recover from thrombocytopenia after T cell therapy, wherein the T cell therapy comprises: (a) obtaining T cells from a subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing the T cells for treating the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, step (a) is performed at least about 7 months before step (a), 8 months before step (a), or at least about 9 months after the subject has received the prior therapy.

[0015] In another aspect, provided herein is a method of reducing the time to recovery from neutropenia following T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from a subject, wherein the subject has previously received a prior therapy for treating a cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured T cells comprise a recombinant receptor directed to cancer cells; and (c) administering the manufactured BCMA CAR T cells to the subject for treating the cancer. In another aspect, provided herein is a method of reducing the time to recovery from thrombocytopenia following T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from a subject, wherein the subject has previously received a prior therapy for treating a cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (c) administering the manufactured BCMA CAR T cells to the subject for treating the cancer. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, step (a) is performed at least about 7 months before step (a), 8 months before step (a), or at least about 9 months after the subject has received the prior therapy.

[0016] In another aspect, provided herein is a method for manufacturing T cells from a subject, the method comprising: (a) obtaining T cells from the subject, wherein the subject has previously received prior therapy for treating a tumor or cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; and (b) manufacturing T cells comprising a recombinant receptor. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, step (a) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the subject has received the prior therapy.

[0017] In another aspect, provided herein is a method for manufacturing T cells from a subject, the method comprising: (a) administering to the subject a topoisomerase inhibitor therapy or a proteasome inhibitor therapy as part of the treatment of a tumor or cancer; (b) obtaining T cells from the subject at least about 6 months after the administration in step (a); and (c) manufacturing T cells comprising a recombinant receptor. In certain embodiments, in step (a), a topoisomerase inhibitor therapy is administered to the subject. In certain embodiments, in step (a), a proteasome inhibitor therapy is administered to the subject. In certain embodiments, step (b) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the administration in step (a).

[0018] In another aspect, provided herein is a method for manufacturing T cells from a subject, where the subject has been administered a prior therapy selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy as part of the treatment of a tumor or cancer, and the method includes: (a) selecting a subject who was administered the prior therapy more than 6 months ago; (b) obtaining T cells from the subject, where the obtaining is performed at least about 6 months after the prior therapy was administered to the subject; and (c) manufacturing T cells comprising a recombinant receptor. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, the prior therapy is administered more than 7 months, more than 8 months, or more than 9 months ago. In certain embodiments, in step (b), the obtaining is performed at least about 7 months, at least about 8 months, or at least about 9 months after the prior therapy was administered to the subject.

[0019] In another aspect, provided herein is a method for manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells) from a subject, the method including: (a) obtaining T cells from the subject, where the subject has previously received a prior therapy for treating a tumor or cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject received the prior therapy; and (b) manufacturing BCMA CAR T cells comprising a recombinant receptor. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, step (a) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the subject received the prior therapy.

[0020] In another aspect, provided herein is a method for manufacturing chimeric antigen receptor (CAR) T cells directed from a subject to BCMA (BCMA CAR T cells), the method comprising: (a) administering to the subject a topoisomerase inhibitor therapy or a proteasome inhibitor therapy as part of the treatment of cancer; (b) obtaining T cells from the subject at least about 6 months after the administration in step (a); and (c) manufacturing BCMA CAR T cells comprising a recombinant receptor. In certain embodiments, in step (a), a topoisomerase inhibitor therapy is administered to the subject. In certain embodiments, in step (a), a proteasome inhibitor therapy is administered to the subject. In certain embodiments, step (b) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the administration in step (a).

[0021] In another aspect, provided herein is a method for manufacturing chimeric antigen receptor (CAR) T cells directed from a subject to BCMA (BCMA CAR T cells), wherein the subject has been administered a prior therapy selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy, the method comprising: (a) selecting a subject who has been administered the prior therapy at a time point more than 6 months ago; (b) obtaining T cells from the subject, wherein the obtaining is performed at least about 6 months after the prior therapy has been administered to the subject; and (c) manufacturing BCMA CAR T cells comprising a recombinant receptor. In certain embodiments, the prior therapy is a topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is a proteasome inhibitor therapy. In certain embodiments, in step (a), the prior therapy is administered at a time point more than 7 months, more than 8 months, or more than 9 months ago. In certain embodiments, in step (b), the obtaining is performed at least about 7 months, at least about 8 months, or at least about 9 months after the prior therapy has been administered to the subject.

[0022] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the method comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from an anti-CD38 agent therapy, an immunomodulatory agent therapy, or an anti-SLAMF agent therapy, and the T cells are obtained from the subject from about 1 month to up to about 3 months after the subject has received the prior therapy; (b) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, step (a) is performed about 2 months or up to about 3 months after the subject has received the anti-CD38 agent therapy. In certain embodiments, step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received the immunomodulatory agent therapy. In certain embodiments, step (a) is performed about 2 months after the subject has received the anti-SLAMF agent therapy.

[0023] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the method comprising: (a) administering to the subject an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy; (b) obtaining T cells from the subject from about 1 month to up to about 3 months after the administration in step (a); (c) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (d) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, in step (a), the anti-CD38 agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject about 2 months or up to about 3 months after step (a). In certain embodiments, in step (a), the immunomodulatory agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject about 1 month, up to about 2 months, or up to about 3 months after step (a). In certain embodiments, in step (a), the anti-SLAMF agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject about 2 months after step (a).

[0024] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the subject having been administered a prior therapy selected from an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy, the method comprising: (a) selecting a subject who has been administered the prior therapy within the past approximately 1 month to a maximum of within the past approximately 3 months; (b) obtaining T cells from the subject, wherein the obtaining is performed within the past approximately 1 month to a maximum of within the past approximately 3 months; (c) manufacturing T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (d) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, in step (a), the subject has been administered the anti-CD38 agent therapy within the past approximately 2 months or within the past approximately 3 months. In certain embodiments, in step (a), the subject has been administered the immunomodulatory agent therapy within the past approximately 1 month, within the past approximately 2 months, or within the past approximately 3 months. In certain embodiments, in step (a), the subject has been administered the anti-SLAMF agent therapy within the past approximately 2 months. In certain embodiments, in step (b), the obtaining is performed within the past approximately 2 months or within the past approximately 3 months after the anti-CD38 therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within the past approximately 1 month, within the past approximately 2 months, or within the past approximately 3 months after the immunomodulatory agent therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within the past approximately 2 months after the anti-SLAMF agent therapy has been administered to the subject.

[0025] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the method comprising administering to the subject T cells produced from peripheral blood mononuclear cells (PBMCs) isolated from the patient, wherein the subject has been administered a prior therapy selected from an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy, and at the time the PBMCs are isolated, the subject last received the prior therapy from about 1 month to up to about 3 months prior to the time the PBMCs are isolated. In certain embodiments, the subject last received the anti-CD38 agent therapy about 2 months or up to about 3 months prior to the time the PBMCs are isolated. In certain embodiments, the subject last received the immunomodulatory agent therapy about 1 month, up to about 2 months, or up to about 3 months prior to the time the PBMCs are isolated. In certain embodiments, the subject last received the anti-SLAMF agent therapy about 2 months prior to the time the PBMCs are isolated.

[0026] In another aspect, provided herein is a method for treating a cancer caused by B cell maturation antigen (BCMA) - expressing cells in a subject in need thereof, the method comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from an anti-CD38 agent therapy, an immunomodulatory agent therapy, or an anti-SLAMF agent therapy, and the T cells are obtained from the subject from about 1 month to up to about 3 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (c) administering the manufactured BCMA CAR T cells to the subject for treating the cancer. In certain embodiments, step (a) is performed about 2 months or up to about 3 months after the subject has received the anti-CD38 agent therapy. In certain embodiments, step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received the immunomodulatory agent therapy. In certain embodiments, step (a) is performed about 2 months after the subject has received the anti-SLAMF agent therapy.

[0027] In another aspect, the present specification provides a method for treating cancer caused by B cell maturation antigen (BCMA) - expressing cells in a subject in need thereof, the method comprising: (a) administering to the subject an anti - CD38 agent therapy, an immunomodulatory agent therapy, and an anti - SLAMF agent therapy; (b) obtaining T cells from the subject about 1 month to up to about 3 months after step (a); (c) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (d) administering the manufactured BCMA CAR T cells to the subject to treat the cancer. In certain embodiments, in step (a), the anti - CD38 agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject about 2 months or up to about 3 months after step (a). In certain embodiments, in step (a), for the immunomodulatory agent therapy, in step (b), the T cells are obtained from the subject about 1 month, up to about 2 months, or up to about 3 months after step (a). In certain embodiments, in step (a), for the anti - SLAMF agent therapy, in step (b), the T cells are obtained from the subject about 2 months after step (a).

[0028] In another aspect, the present specification provides a method for treating cancer caused by B cell maturation antigen (BCMA) - expressing cells in a subject in need thereof, wherein the subject has been administered a prior therapy selected from anti - CD38 agent therapy, immunomodulatory agent therapy, and anti - SLAMF agent therapy, and the method comprises: (a) selecting a subject who has been administered the prior therapy within the past approximately 1 month to a maximum of within the past approximately 3 months; (b) obtaining T cells from the subject, wherein the obtaining is performed within the past approximately 1 month to a maximum of within the past approximately 3 months; (c) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (d) administering the manufactured BCMA CAR T cells to the subject for treating the cancer. In certain embodiments, in step (a), the subject has been administered anti - CD38 agent therapy within approximately 2 months or within approximately 3 months. In certain embodiments, in step (a), the subject has been administered immunomodulatory agent therapy within approximately 1 month, approximately 2 months, or approximately 3 months. In certain embodiments, in step (a), the subject has been administered anti - SLAMF agent therapy within approximately 2 months. In certain embodiments, in step (b), the obtaining is performed within approximately 2 months or within approximately 3 months after the anti - CD38 agent therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within approximately 1 month, approximately 2 months, or approximately 3 months after the immunomodulatory agent therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within approximately 2 months after the anti - SLAMF agent therapy has been administered to the subject.

[0029] In another aspect, the present specification provides a method for treating cancer caused by B cell maturation antigen (BCMA) - expressing cells in a subject in need thereof, the method comprising administering to the subject chimeric antigen receptor (CAR) T cells directed to BCMA produced from peripheral blood mononuclear cells (PBMCs) isolated from the patient (BCMA CAR T cells), wherein the subject has been administered a prior therapy selected from anti - CD38 agent therapy, immunomodulatory agent therapy, and anti - SLAMF agent therapy, and at the time the PBMCs are isolated, the subject last received the prior therapy from about 1 month to up to about 3 months before the time the PBMCs are isolated. In certain embodiments, the subject last received anti - CD38 agent therapy about 2 months or up to about 3 months before the time the PBMCs are isolated. In certain embodiments, the subject last received immunomodulatory agent therapy about 1 month, up to about 2 months, or up to about 3 months before the time the PBMCs are isolated. In certain embodiments, the subject last received anti - SLAMF agent therapy about 2 months before the time the PBMCs are isolated.

[0030] In another aspect, provided herein is a method of reducing the time to recovery from neutropenia following T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from a subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, or anti-SLAMF therapy, and the T cells are obtained from the subject from about 1 month to up to about 3 months after the subject has received the prior therapy; (b) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. In another aspect, provided herein is a method for reducing the time to recovery from thrombocytopenia following T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from a subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, or anti-SLAMF therapy, and the T cells are obtained from the subject from about 1 month to up to about 3 months after the subject has received the prior therapy; (b) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received anti-CD38 agent therapy. In certain embodiments, step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received immunomodulatory agent therapy. In certain embodiments, step (a) is performed about 2 months after the subject has received anti-SLAMF agent therapy.

[0031] In another aspect, the present specification provides a method for reducing the time until recovery from neutropenia after T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy, and the T cells are obtained from the subject about 1 month to at most about 3 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (c) administering the manufactured BCMA CAR T cells to the subject for treating cancer. In another aspect, the present specification provides a method for reducing the time until recovery from thrombocytopenia after T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy, and the T cells are obtained from the subject about 1 month to at most about 3 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (c) administering the manufactured BCMA CAR T cells to the subject for treating cancer. In certain embodiments, step (a) is performed about 2 months or at most about 3 months after the subject has received anti-CD38 agent therapy. In certain embodiments, step (a) is performed 1 month, at most about 2 months, or at most about 3 months after the subject has received immunomodulatory agent therapy. In certain embodiments, step (a) is performed about 2 months after the subject has received anti-SLAMF agent therapy.

[0032] In another aspect, the present specification provides a method for manufacturing T cells from a subject, the method comprising: (a) obtaining T cells from the subject, wherein the subject has previously received prior therapy for treating a tumor or cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, or anti-SLAMF agent therapy; and (b) manufacturing T cells comprising a recombinant receptor. In certain embodiments, step (a) is performed about 2 months or up to about 3 months after the subject has received anti-CD38 agent therapy. In certain embodiments, step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received immunomodulatory agent therapy. In certain embodiments, step (a) is performed about 2 months after the subject has received anti-SLAMF agent therapy.

[0033] In another aspect, the present specification provides a method for manufacturing T cells from a subject, the method comprising: (a) administering to the subject anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy as part of the treatment of a tumor or cancer; (b) obtaining T cells from the subject about 1 month to up to about 3 months after step (a); and (c) manufacturing T cells comprising a recombinant receptor. In certain embodiments, in step (a), anti-CD38 agent therapy is administered to the subject, and in step (b), T cells are obtained from the subject about 2 months or up to about 3 months after step (a). In certain embodiments, in step (a), immunomodulatory agent therapy is administered to the subject, and in step (b), T cells are obtained from the subject about 1 month, up to about 2 months, or up to about 3 months after step (a). In certain embodiments, in step (a), anti-SLAMF agent therapy is administered to the subject, and in step (b), T cells are obtained from the subject up to about 2 months after step (a).

[0034] In another aspect, provided herein is a method for manufacturing T cells from a subject in need thereof, where the subject has been administered a prior therapy selected from anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy, and the method includes: (a) selecting a subject who has been administered the prior therapy within the past approximately 1 month up to a maximum of within the past approximately 3 months; (b) obtaining T cells from the subject, where the obtaining is performed within the past approximately 1 month up to a maximum of within the past approximately 3 months; and (c) manufacturing T cells comprising a recombinant receptor. In certain embodiments, in step (a), the subject has been administered anti-CD38 agent therapy within the past approximately 2 months or within the past approximately 3 months. In certain embodiments, in step (a), the subject has been administered anti-immunomodulatory agent therapy within the past approximately 1 month, within the past approximately 2 months, or within the past approximately 3 months. In certain embodiments, in step (a), the subject has been administered anti-SLAMF agent therapy within the past approximately 2 months. In certain embodiments, in step (b), the obtaining is performed within the past approximately 2 months or within the past approximately 3 months after the anti-CD38 therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within the past approximately 1 month, within the past approximately 2 months, or within the past approximately 3 months after the immunomodulatory agent therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within the past approximately 2 months after the anti-SLAMF agent therapy has been administered to the subject.

[0035] In another aspect, provided herein is a method for manufacturing chimeric antigen receptor (CAR) T cells directed from a subject to BCMA (BCMA CAR T cells), the method comprising: (a) obtaining T cells from a subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, or anti-SLAMF agent therapy; and (b) being BCMA CAR T cells comprising a recombinant receptor. In certain embodiments, step (a) is performed about 2 months or up to about 3 months after the subject has received anti-CD38 agent therapy. In certain embodiments, step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received immunomodulatory agent therapy. In certain embodiments, step (a) is performed about 2 months after the subject has received anti-SLAMF agent therapy.

[0036] In another aspect, provided herein is a method for manufacturing chimeric antigen receptor (CAR) T cells directed from a subject to BCMA (BCMA CAR T cells), the method comprising: (a) administering to the subject an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy as part of the treatment of cancer; (b) obtaining T cells from the subject about 1 month to up to about 3 months after step (a); and (c) manufacturing BCMA CAR T cells comprising a recombinant receptor. In certain embodiments, in step (a), the anti-CD38 agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject about 2 months or up to about 3 months after step (a). In certain embodiments, in step (a), the immunomodulatory agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject about 1 month, up to about 2 months, or up to about 3 months after step (a). In certain embodiments, in step (a), the anti-SLAMF agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject about 2 months after step (a).

[0037] In another aspect, provided herein is a method for manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed from a subject in need thereof to BCMA, wherein the subject has been administered a prior therapy selected from anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy, and the method comprises: (a) selecting a subject who has been administered the prior therapy within the past approximately 1 month up to a maximum of within the past approximately 3 months; (b) obtaining T cells from the subject, wherein the obtaining is performed within the past approximately 1 month up to a maximum of within the past approximately 3 months; and (c) manufacturing BCMA CAR T cells comprising a recombinant receptor. In certain embodiments, in step (a), the subject has been administered anti-CD38 agent therapy within the past approximately 2 months or within the past approximately 3 months. In certain embodiments, in step (a), the subject has been administered immunomodulatory agent therapy within the past approximately 1 month, within the past approximately 2 months, or within the past approximately 3 months. In certain embodiments, in step (a), the subject has been administered anti-SLAMF agent therapy within the past approximately 2 months. In certain embodiments, in step (b), the obtaining is performed within the past approximately 2 months or within the past approximately 3 months after the anti-CD38 therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within the past approximately 1 month, within the past approximately 2 months, or within the past approximately 3 months after the immunomodulatory agent therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within the past approximately 2 months after the anti-SLAMF agent therapy has been administered to the subject.

[0038] In certain embodiments, the tumor or cancer is lymphoma, lung cancer, breast cancer, prostate cancer, liver cancer, bile duct cancer, glioma, colorectal adenocarcinoma, myelodysplasia, adrenocortical carcinoma, thyroid cancer, nasopharyngeal cancer, melanoma, skin cancer, colon cancer, desmoid tumor, fibromatosis, round cell tumor, endocrine tumor, Ewing's sarcoma, peripheral primitive neuroectodermal tumor, solid embryonal cell tumor, hepatoblastoma, neuroblastoma, non-rhabdomyosarcomatous soft tissue sarcoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, Wilms' tumor, glioblastoma, myxoma, fibroma, lipoma, chronic lymphocytic leukemia (small lymphocytic lymphoma), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytoma, plasmacytosis, extranodal marginal zone B-cell lymphoma, MALT lymphoma, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma, T-cell prolymphocytic leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), juvenile chronic myeloid leukemia (JCML), juvenile myelomonocytic leukemia (JMML), T-cell large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma, nasal type, enteropathy-type T-cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK cell lymphoma, mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (unspecified), anaplastic large cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or multiple myeloma. In certain embodiments, the cancer is multiple myeloma, chronic lymphocytic leukemia, or non-Hodgkin lymphoma.

[0039] In certain embodiments, the cancer is non-Hodgkin lymphoma, and the non-Hodgkin lymphoma is Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, or mantle cell lymphoma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the multiple myeloma is high-risk multiple myeloma. In certain embodiments, the multiple myeloma is relapsed and / or refractory multiple myeloma. In certain embodiments, the multiple myeloma is high-risk multiple myeloma, and the high-risk multiple myeloma is a disease characterized by R-ISS stage III disease and / or early relapse.

[0040] In certain embodiments, the engineered T cells are tumor-specific T cells, chimeric antigen receptor (CAR) T cells, engineered T cell receptor (TCR) T cells, or tumor-infiltrating lymphocytes (TIL). In certain embodiments, the engineered T cells are chimeric antigen receptor (CAR) T cells.

[0041] In certain embodiments, the production of T cells comprises (a) isolating PBMCs from a leukapheresis sample and (b) introducing a recombinant nucleic acid encoding a chimeric antigen receptor (CAR) into the isolated cells. In certain embodiments, the production of BCMA CAR T cells comprises (a) isolating T cells from a leukapheresis sample and (b) introducing a recombinant nucleic acid encoding a chimeric antigen receptor (CAR) into the isolated cells.

[0042] In certain embodiments, the introducing is by transduction using a viral vector comprising a recombinant nucleic acid encoding the CAR. In certain embodiments, the viral vector is a lentiviral vector. In certain embodiments, prior to the introducing, the production further comprises stimulating the isolated PBMCs or isolated T cells with an agent capable of activating the cells. In certain embodiments, the agent comprises an anti-CD3 antibody and / or an anti-CD28 antibody.

[0043] In certain embodiments, manufacturing further comprises expanding cells into which a recombinant nucleic acid encoding a chimeric antigen receptor (CAR) has been introduced. In certain embodiments, the CAR is an anti-BCMA CAR.

[0044] In certain embodiments, the BCMA CAR T cells comprise a CAR directed to BCMA, and the CAR directed to BCMA comprises an antibody or antibody fragment that targets BCMA. In certain embodiments, the BCMA CAR T cells comprise a CAR directed to BCMA, and the CAR directed to BCMA comprises a single-chain Fv antibody or antibody fragment (scFv).

[0045] In certain embodiments, the chimeric antigen receptor (CAR) comprises an extracellular antigen-binding domain that binds to BCMA, a transmembrane domain, and an intracellular signaling region. In certain embodiments, the intracellular signaling region further comprises a co-stimulatory signaling domain. In certain embodiments, the co-stimulatory signaling domain comprises the intracellular signaling domain of CD28, 4-1BB, or ICOS, or a signaling portion thereof. In certain embodiments, the co-stimulatory signaling domain is between the transmembrane domain and the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain. In certain embodiments, the transmembrane domain is or comprises a transmembrane domain derived from CD28 or CD8, optionally a transmembrane domain derived from human CD28 or CD8.

[0046] In certain embodiments, the CAR further comprises an extracellular spacer between the antigen-binding domain and the transmembrane domain. In certain embodiments, the spacer is derived from CD8, and optionally, the spacer is the CD8 alpha hinge. In certain embodiments, the transmembrane domain and the spacer are derived from CD8.

[0047] In certain embodiments, the BCMA CAR T cells comprise a CAR directed to BCMA, and the CAR directed to BCMA comprises SEQ ID NO: 38.

[0048] In certain embodiments, the BCMA CAR T cells are idecabtagene vicleucel cells.

[0049] In certain embodiments, the BCMA CAR T cells are cilta-cel cells.

[0050] In certain embodiments, the subject undergoes apheresis to collect PBMCs for manufacturing T cells prior to administration to the subject. In certain embodiments, the apheresis is leukapheresis.

[0051] In certain embodiments, the subject undergoes apheresis to collect PBMCs for manufacturing BCMA CAR T cells prior to administration to the subject. In certain embodiments, the apheresis is leukapheresis.

[0052] In certain embodiments, the T cells are administered by intravenous infusion.

[0053] In certain embodiments, the BCMA CAR T cells are administered by intravenous infusion.

[0054] In certain embodiments, the subject is human.

[0055] In certain embodiments, a subject having multiple myeloma is treated with BCMA CAR T cell therapy after the subject has received (i) a prior treatment having a negative effect on T cells, such as a proteasome inhibitor, a topoisomerase inhibitor, a stem cell transplant (e.g., ASCT), or an alkylating agent therapy, at least 6 months prior, at least 12 months prior, at least 18 months prior, or at least 24 months prior to obtaining T cells from the subject for manufacturing the BCMA CAR T cell therapy, and (ii) a prior treatment having a positive effect on T cells, such as an immunomodulatory agent, an anti-CD38 agent, or an anti-SLAMF agent, less than 1 month, less than 2 months, or less than 3 months prior to obtaining T cells from the subject for manufacturing the BCMA CAR T cell therapy. In some embodiments, a subject having multiple myeloma is treated with a proteasome inhibitor, a topoisomerase inhibitor, a stem cell transplant (e.g., ASCT), or an alkylating agent therapy and can then receive an immunomodulatory agent, an anti-CD38 agent, or an anti-SLAMF agent as a subsequent final line of treatment prior to BCMA CAR T therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0056]

Figure 1

Figure 2A

Figure 2B

Figure 3A

Figure 3B

Figure 4A

Figure 4B

Figure 5A

Figure 5B

Figure 6A

Figure 6B

Figure 7A

Figure 7B

Figure 7C

[0057] The disclosure presented herein generally presents improved methods for treating tumors or cancers (e.g., B cell-related diseases or cancers including multiple myeloma). The disclosure also presents herein methods for manufacturing T cells, e.g., chimeric antigen receptor (CAR) T cells (e.g., CAR T cells directed to BCMA (BCMA CAR T cells)). As used herein, the term “B cell-related condition” relates to conditions with inappropriate B cell activity and B cell malignancy.

[0058] Certain embodiments presented herein relate to improved adoptive cell therapies for diseases (e.g., tumors or cancers including multiple myeloma, or B cell-related diseases or cancers) using T cells (e.g., genetically modified immune effector cells, e.g., CAR T cells). Genetic approaches provide potential means to enhance the recognition and elimination of cancer cells by the immune system. One promising strategy is to genetically engineer immune effector cells to express a chimeric antigen receptor (CAR) that redirects cytotoxicity to cancer cells.

[0059] Before administering the T cell therapy disclosed herein, in a subject (e.g., a patient) who has received a prior therapy such as a topoisomerase inhibitor, a proteasome inhibitor, an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent therapy (e.g., in connection with a treatment by radiotherapy, chemotherapy, or both (e.g., the following)), an improved method for administering a T cell therapy (e.g., CAR T cell therapy) for use in the subject includes performing a step of isolating peripheral blood mononuclear cells (PBMCs) from the subject after a certain period (i.e., the "washout" period) after the prior therapy has been administered to the subject. Before administering the T cell therapy disclosed herein, in a subject who has received a prior therapy such as a topoisomerase inhibitor, a proteasome inhibitor, an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent therapy (e.g., in connection with a treatment by radiotherapy, chemotherapy, or both (e.g., the following)), an improved method for administering a T cell therapy (e.g., CAR T cell therapy) for use in the subject can be easily scaled up and can be used with genetically modified immune effector cells (e.g., CAR T cells) that show long-term persistence in vivo. Examples of genetically modified immune effector cells (e.g., CAR T cells) include cells that reduce humoral immune impairment by targeting B cells that express B cell maturation antigen (BCMA, CD269 or tumor necrosis factor receptor superfamily, member 17; also known as TNFRSF17). An improved method for manufacturing T cells, e.g., CAR T cells (e.g., BCMA CAR T cells), from PBMCs isolated from a patient who has received a topoisomerase inhibitor, a proteasome inhibitor, an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent therapy (e.g., in connection with a treatment by radiotherapy, chemotherapy, or both (e.g., the following)) is also disclosed herein.

[0060] BCMA is a member of the tumor necrosis factor receptor superfamily (see, e.g., Thompson et al., J. Exp. Medicine, 192(1): 129-135, 2000, and Mackay et al., Annu. Rev. Immunol, 21: 231-264, 2003). BCMA binds to B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) (see, e.g., Mackay et al., 2003 and Kalled et al., Immunological Reviews, 204: 43-54, 2005). Among non-malignant cells, BCMA has been reported to be expressed primarily in subsets of plasma cells and mature B cells (see, e.g., Laabi et al., EMBO J., 77(1): 3897-3904, 1992; Laabi et al., Nucleic Acids Res., 22(7): 1147-1154, 1994; Kalled et al., 2005; O'Connor et al., J. Exp. Medicine, 199(1): 91-97, 2004; and Ng et al., J. Immunol., 73(2): 807-817, 2004). BCMA-deficient mice are healthy and have normal numbers of B cells, but the survival of long-lived plasma cells is impaired (see, e.g., O'Connor et al., J. Exp. Medicine, 199(1): 91-97, 2004; Xu et al., Mol. Cell. Biol., 21(12): 4067-4074, 2001; and Schiemann et al., Science, 293(5537): 2111-2114, 2001).BCMA RNA is ubiquitously detected in multiple myeloma cells and other lymphomas, and BCMA protein has been detected on the surface of plasma cells from multiple myeloma patients by multiple researchers (see, e.g., Novak et al., Blood, 103(2): 689-694, 2004; Neri et al., Clinical Cancer Research, 73(19): 5903-5909, 2007; Bellucci et al., Blood, 105(10): 3945-3950, 2005; and Moreaux et al., Blood, 703(8): 3148-3157, 2004).

[0061] Cell therapies such as T cell-based therapies, e.g., adoptive T cell therapies (including therapies involving administration of cells expressing chimeric receptors specific for the cancer of interest, such as chimeric antigen receptors (CARs) and / or other recombinant antigen receptors, as well as other adoptive immune cells and adoptive T cell therapies), may be effective in treating diseases and disorders such as B cell malignancies. Engineered expression of recombinant receptors, such as chimeric antigen receptors (CARs), on the T cell surface enables redirection of T cell specificity. In clinical studies, CAR-T cells, e.g., anti-CD19 CAR-T cells, have resulted in durable complete responses in both leukemia and lymphoma patients (Porter et al. (2015) Sci Transl Med., 7:303ra139; Kochenderfer et al.,(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).

[0062] All publications, including patent documents, scientific papers, and databases, referred to in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were specifically and individually incorporated by reference. If the definitions set forth herein conflict with or are otherwise inconsistent with the definitions set forth in patents, applications, published applications, and other publications incorporated herein by reference, the definitions set forth herein shall control over the definitions incorporated herein by reference.

[0063] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0064] Methods for treating tumors or cancers using I.T cells and methods for producing T cells In one aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the method comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating the tumor or cancer selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, the prior therapy is a topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is a proteasome inhibitor therapy. In certain embodiments, step (a) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the subject has received the prior therapy.

[0065] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the method comprising: (a) administering to the subject a topoisomerase inhibitor therapy or a proteasome inhibitor therapy; (b) obtaining T cells from the subject at least about 6 months after the administration in step (a); (c) manufacturing T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (d) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, in step (a), a topoisomerase inhibitor therapy is administered to the subject. In certain embodiments, in step (a), a proteasome inhibitor therapy is administered to the subject. In certain embodiments, step (b) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the administration in step (a).

[0066] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the subject having been administered a prior therapy selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy, the method comprising: (a) selecting a subject who was administered the prior therapy at a time point more than 6 months ago; (b) obtaining T cells from the subject, wherein the obtaining is performed at least about 6 months after the prior therapy was administered to the subject; (c) manufacturing T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (d) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, the prior therapy is a topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is a proteasome inhibitor therapy. In certain embodiments, in step (a), the prior therapy is administered at a time point more than 7 months, more than 8 months, or more than 9 months ago. In certain embodiments, in step (b), the isolating is performed at least about 7 months, at least about 8 months, or at least about 9 months after the prior therapy was administered to the subject.

[0067] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the method comprising administering to the subject T cells produced from peripheral blood mononuclear cells (PBMCs) isolated from the patient, wherein the subject has been administered a prior therapy selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy, and at the time the PBMCs are isolated, the subject has received the prior therapy at least about 6 months prior to the time the PBMCs are isolated. In certain embodiments, the subject has been administered a topoisomerase inhibitor therapy. In certain embodiments, the subject has been administered a proteasome inhibitor therapy. In certain embodiments, the subject has received the prior therapy at least about 7 months, at least about 8 months, or at least about 9 months prior to the time the PBMCs are isolated.

[0068] In another aspect, provided herein is a method for treating a cancer caused by B cell maturation antigen (BCMA) - expressing cells in a subject in need thereof, the method comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a cancer selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (c) administering the manufactured BCMA CAR T cells to the subject for treating the cancer. In certain embodiments, the prior therapy is a topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is a proteasome inhibitor therapy, the method of claim 18. In certain embodiments, step (a) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the subject has received the prior therapy.

[0069] In another aspect, provided herein is a method for treating cancer caused by B cell maturation antigen (BCMA)-expressing cells in a subject in need thereof, the method comprising: (a) administering to the subject a topoisomerase inhibitor therapy or a proteasome inhibitor therapy; (b) obtaining T cells from the subject at least about 6 months after the administration in step (a); (c) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (d) administering to the subject the manufactured BCMA CAR T cells for treating the cancer. In certain embodiments, in step (a), the topoisomerase inhibitor therapy is administered to the subject. In certain embodiments, in step (a), the proteasome inhibitor therapy is administered to the subject. In certain embodiments, step (b) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the administration in step (a).

[0070] In another aspect, the present specification provides a method for treating cancer caused by B cell maturation antigen (BCMA) - expressing cells in a subject in need thereof, wherein the subject has been administered a prior therapy selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy as part of the treatment of cancer, and the method comprises: (a) selecting a subject who was administered the prior therapy more than 6 months ago; (b) obtaining T cells from the subject, wherein the obtaining is performed at least about 6 months after the prior therapy has been administered to the subject; (c) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured T cells comprise a recombinant receptor directed to cancer cells; and (d) administering the manufactured BCMA CAR T cells to the subject for treating cancer. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, in step (a), the prior therapy is administered more than 7 months, more than 8 months, or more than 9 months ago. In certain embodiments, in step (b), the obtaining is performed at least about 7 months, at least about 8 months, or at least about 9 months after the prior therapy has been administered to the subject.

[0071] In another aspect, the present specification provides a method for treating cancer caused by B cell maturation antigen (BCMA) - expressing cells in a subject in need thereof, the method comprising administering to the subject chimeric antigen receptor (CAR) T cells directed to BCMA produced from peripheral blood mononuclear cells (PBMCs) isolated from the patient (BCMA CAR T cells), wherein the subject has been administered a prior therapy selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and at the time the PBMCs are isolated, the subject had last received the prior therapy at least about 6 months before the time the PBMCs were isolated. In certain embodiments, the subject has been administered topoisomerase inhibitor therapy. In certain embodiments, the subject has been administered proteasome inhibitor therapy. In certain embodiments, the subject had last received the prior therapy at least about 7 months, at least about 8 months, or at least about 9 months before the time the PBMCs were isolated.

[0072] In another aspect, provided herein is a method of reducing the time for a subject to recover from neutropenia following T cell therapy, wherein the T cell therapy comprises: (a) obtaining T cells from a subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. In another aspect, provided herein is a method of reducing the time for a subject to recover from thrombocytopenia following T cell therapy, wherein the T cell therapy comprises: (a) obtaining T cells from a subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing the T cells for treating the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, step (a) is performed at least about 7 months before step (a), 8 months before step (a), or at least about 9 months after the subject has received the prior therapy.

[0073] In another aspect, provided herein is a method of reducing the time to recovery from neutropenia following T cell therapy in a subject, the T cell therapy comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured T cells comprise a recombinant receptor directed to cancer cells; and (c) administering the manufactured BCMA CAR T cells to the subject for treating the cancer. In another aspect, provided herein is a method of reducing the time to recovery from thrombocytopenia following T cell therapy in a subject, the T cell therapy comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (c) administering the manufactured BCMA CAR T cells to the subject for treating the cancer. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, step (a) is performed at least about 7 months before step (a), 8 months before step (a), or at least about 9 months after the subject has received the prior therapy.

[0074] In another aspect, provided herein is a method for manufacturing T cells from a subject, the method comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; and (b) manufacturing T cells comprising a recombinant receptor. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, step (a) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the subject has received the prior therapy.

[0075] In another aspect, provided herein is a method for manufacturing T cells from a subject, the method comprising: (a) administering to the subject a topoisomerase inhibitor therapy or a proteasome inhibitor therapy as part of the treatment of a tumor or cancer; (b) obtaining T cells from the subject at least about 6 months after the administration in step (a); and (c) manufacturing T cells comprising a recombinant receptor. In certain embodiments, in step (a), a topoisomerase inhibitor therapy is administered to the subject. In certain embodiments, in step (a), a proteasome inhibitor therapy is administered to the subject. In certain embodiments, step (b) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the administration in step (a).

[0076] In another aspect, provided herein is a method for manufacturing T cells from a subject, where the subject has been administered a prior therapy selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy as part of the treatment of a tumor or cancer, the method comprising: (a) selecting a subject who was administered the prior therapy more than 6 months ago; (b) obtaining T cells from the subject, wherein the obtaining is performed at least about 6 months after the prior therapy has been administered to the subject; and (c) manufacturing T cells comprising a recombinant receptor. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, the prior therapy is administered more than 7 months, more than 8 months, or more than 9 months ago. In certain embodiments, in step (b), the obtaining is performed at least about 7 months, at least about 8 months, or at least about 9 months after the prior therapy has been administered to the subject.

[0077] In another aspect, provided herein is a method for manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells) from a subject, the method comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; and (b) manufacturing BCMA CAR T cells comprising a recombinant receptor. In certain embodiments, the prior therapy is topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is proteasome inhibitor therapy. In certain embodiments, step (a) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the subject has received the prior therapy.

[0078] In another aspect, provided herein is a method for manufacturing chimeric antigen receptor (CAR) T cells directed from a subject to BCMA (BCMA CAR T cells), the method comprising: (a) administering to the subject a topoisomerase inhibitor therapy or a proteasome inhibitor therapy as part of the treatment of cancer; (b) obtaining T cells from the subject at least about 6 months after the administration in step (a); and (c) manufacturing BCMA CAR T cells comprising a recombinant receptor. In certain embodiments, in step (a), a topoisomerase inhibitor therapy is administered to the subject. In certain embodiments, in step (a), a proteasome inhibitor therapy is administered to the subject. In certain embodiments, step (b) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the administration in step (a).

[0079] In another aspect, provided herein is a method for manufacturing chimeric antigen receptor (CAR) T cells directed from a subject to BCMA (BCMA CAR T cells), wherein the subject has been administered a prior therapy selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy, the method comprising: (a) selecting a subject who has been administered the prior therapy at a time point more than 6 months ago; (b) obtaining T cells from the subject, wherein the obtaining is performed at least about 6 months after the prior therapy has been administered to the subject; and (c) manufacturing BCMA CAR T cells comprising a recombinant receptor. In certain embodiments, the prior therapy is a topoisomerase inhibitor therapy. In certain embodiments, the prior therapy is a proteasome inhibitor therapy. In certain embodiments, in step (a), the prior therapy is administered at a time point more than 7 months, more than 8 months, or more than 9 months ago. In certain embodiments, in step (b), the obtaining is performed at least about 7 months, at least about 8 months, or at least about 9 months after the prior therapy has been administered to the subject.

[0080] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the method comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, or anti-SLAMF agent therapy, and the T cells are obtained from the subject from about 1 month to up to about 3 months after the subject has received the prior therapy; (b) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, step (a) is performed about 2 months or up to about 3 months after the subject has received anti-CD38 agent therapy. In certain embodiments, step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received immunomodulatory agent therapy. In certain embodiments, step (a) is performed about 2 months after the subject has received anti-SLAMF agent therapy.

[0081] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the method comprising: (a) administering to the subject anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy; (b) obtaining T cells from the subject from about 1 month to up to about 3 months after the administration in step (a); (c) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (d) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, in step (a), anti-CD38 agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject about 2 months or up to about 3 months after step (a). In certain embodiments, in step (a), immunomodulatory agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject about 1 month, up to about 2 months, or up to about 3 months after step (a). In certain embodiments, in step (a), anti-SLAMF agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject about 2 months after step (a).

[0082] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, wherein the subject has been administered a prior therapy selected from anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy, and the method comprises: (a) selecting a subject who has been administered the prior therapy within the most recent about 1 month to about 3 months; (b) obtaining T cells from the subject, wherein the obtaining is performed within the most recent about 1 month to about 3 months; (c) manufacturing T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (d) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, in step (a), the subject has been administered anti-CD38 agent therapy within the most recent about 2 months or about 3 months. In certain embodiments, in step (a), the subject has been administered immunomodulatory agent therapy within the most recent about 1 month, about 2 months, or about 3 months. In certain embodiments, in step (a), the subject has been administered anti-SLAMF agent therapy within the most recent about 2 months. In certain embodiments, in step (b), the obtaining is performed within the most recent about 2 months or about 3 months after the anti-CD38 therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within the most recent about 1 month, about 2 months, or about 3 months after the immunomodulatory agent therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within the most recent about 2 months after the anti-SLAMF agent therapy has been administered to the subject.

[0083] In another aspect, provided herein is a method for treating a tumor or cancer in a subject in need thereof, the method comprising administering to the subject T cells produced from peripheral blood mononuclear cells (PBMCs) isolated from the patient, wherein the subject has been administered a prior therapy selected from anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy, and at the time the PBMCs are isolated, the subject had last received the prior therapy from about 1 month to up to about 3 months before the time the PBMCs were isolated. In certain embodiments, the subject had last received anti-CD38 agent therapy about 2 months or up to about 3 months before the time the PBMCs were isolated. In certain embodiments, the subject had last received immunomodulatory agent therapy about 1 month, up to about 2 months, or up to about 3 months before the time the PBMCs were isolated. In certain embodiments, the subject had last received anti-SLAMF agent therapy about 2 months before the time the PBMCs were isolated.

[0084] In another aspect, provided herein is a method for treating cancer caused by B cell maturation antigen (BCMA)-expressing cells in a subject in need thereof, the method comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, or anti-SLAMF agent therapy, and the T cells are obtained from the subject from about 1 month to up to about 3 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (c) administering the manufactured BCMA CAR T cells to the subject for treating the cancer. In certain embodiments, step (a) is performed about 2 months or up to about 3 months after the subject has received anti-CD38 agent therapy. In certain embodiments, step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received immunomodulatory agent therapy. In certain embodiments, step (a) is performed about 2 months after the subject has received anti-SLAMF agent therapy.

[0085] In another aspect, the present specification provides a method for treating cancer caused by B cell maturation antigen (BCMA)-expressing cells in a subject in need thereof, the method comprising: (a) administering to the subject an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy; (b) obtaining T cells from the subject about 1 month to up to about 3 months after step (a); (c) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (d) administering the manufactured BCMA CAR T cells to the subject for treating the cancer. In certain embodiments, in step (a), the anti-CD38 agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject about 2 months or up to about 3 months after step (a). In certain embodiments, in step (a), the immunomodulatory agent therapy, and in step (b), the T cells are obtained from the subject about 1 month, up to about 2 months, or up to about 3 months after step (a). In certain embodiments, in step (a), the anti-SLAMF agent therapy, and in step (b), the T cells are obtained from the subject about 2 months after step (a).

[0086] In another aspect, provided herein is a method for treating cancer caused by B cell maturation antigen (BCMA) - expressing cells in a subject in need thereof, wherein the subject has been administered a prior therapy selected from anti - CD38 agent therapy, immunomodulatory agent therapy, and anti - SLAMF agent therapy, and the method comprises: (a) selecting a subject who has been administered the prior therapy within the past about 1 month to a maximum of within the past about 3 months; (b) obtaining T cells from the subject, wherein the obtaining is performed within the past about 1 month to a maximum of within the past about 3 months; (c) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (d) administering the manufactured BCMA CAR T cells to the subject for treating the cancer. In certain embodiments, in step (a), the subject has been administered anti - CD38 agent therapy within about 2 months or within about 3 months. In certain embodiments, in step (a), the subject has been administered immunomodulatory agent therapy within about 1 month, about 2 months, or about 3 months. In certain embodiments, in step (a), the subject has been administered anti - SLAMF agent therapy within about 2 months. In certain embodiments, in step (b), the obtaining is performed within about 2 months or within about 3 months after the anti - CD38 agent therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within about 1 month, about 2 months, or about 3 months after the immunomodulatory agent therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within about 2 months after the anti - SLAMF agent therapy has been administered to the subject.

[0087] In another aspect, provided herein is a method for treating cancer caused by B cell maturation antigen (BCMA)-expressing cells in a subject in need thereof, the method comprising administering to the subject chimeric antigen receptor (CAR) T cells directed to BCMA produced from peripheral blood mononuclear cells (PBMCs) isolated from the patient, wherein the subject has been administered a prior therapy selected from anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy, and at the time the PBMCs are isolated, the subject last received the prior therapy from about 1 month to up to about 3 months before the time the PBMCs are isolated. In certain embodiments, the subject last received anti-CD38 agent therapy from about 2 months or up to about 3 months before the time the PBMCs are isolated. In certain embodiments, the subject last received immunomodulatory agent therapy from about 1 month, up to about 2 months, or up to about 3 months before the time the PBMCs are isolated. In certain embodiments, the subject last received anti-SLAMF agent therapy about 2 months before the time the PBMCs are isolated.

[0088] In another aspect, provided herein is a method of reducing the time for a subject to recover from neutropenia after T cell therapy, the T cell therapy comprising: (a) obtaining T cells from a subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, or anti-SLAMF therapy, and the T cells are obtained from the subject about 1 month to up to about 3 months after the subject has received the prior therapy; (b) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. In another aspect, provided herein is a method for reducing the time for a subject to recover from thrombocytopenia after T cell therapy, the T cell therapy comprising: (a) obtaining T cells from a subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, or anti-SLAMF therapy, and the T cells are obtained from the subject about 1 month to up to about 3 months after the subject has received the prior therapy; (b) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. In certain embodiments, step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received anti-CD38 agent therapy. In certain embodiments, step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received immunomodulatory agent therapy. In certain embodiments, step (a) is performed about 2 months after the subject has received anti-SLAMF agent therapy.

[0089] In another aspect, provided herein is a method of reducing the time until recovery from neutropenia after T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from the subject, wherein the subject has previously received prior therapy for treating cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy, and the T cells are obtained from the subject from about 1 month to up to about 3 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (c) administering the manufactured BCMA CAR T cells to the subject for treating cancer. In another aspect, provided herein is a method of reducing the time until recovery from thrombocytopenia after T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from the subject, wherein the subject has previously received prior therapy for treating cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy, and the T cells are obtained from the subject from about 1 month to up to about 3 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (c) administering the manufactured BCMA CAR T cells to the subject for treating cancer. In certain embodiments, step (a) is performed about 2 months or up to about 3 months after the subject has received anti-CD38 agent therapy. In certain embodiments, step (a) is performed 1 month, up to about 2 months, or up to about 3 months after the subject has received immunomodulatory agent therapy. In certain embodiments, step (a) is performed about 2 months after the subject has received anti-SLAMF agent therapy.

[0090] In another aspect, provided herein is a method for manufacturing T cells from a subject, the method comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from an anti-CD38 agent therapy, an immunomodulatory agent therapy, or an anti-SLAMF agent therapy; and (b) manufacturing T cells comprising a recombinant receptor. In certain embodiments, step (a) is performed about 2 months or up to about 3 months after the subject has received the anti-CD38 agent therapy. In certain embodiments, step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received the immunomodulatory agent therapy. In certain embodiments, step (a) is performed about 2 months after the subject has received the anti-SLAMF agent therapy.

[0091] In another aspect, provided herein is a method for manufacturing T cells from a subject, the method comprising: (a) administering to the subject an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy as part of the treatment of a tumor or cancer; (b) obtaining T cells from the subject about 1 month to up to about 3 months after step (a); and (c) manufacturing T cells comprising a recombinant receptor. In certain embodiments, in step (a), the anti-CD38 agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject about 2 months or up to about 3 months after step (a). In certain embodiments, in step (a), the immunomodulatory agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject about 1 month, up to about 2 months, or up to about 3 months after step (a). In certain embodiments, in step (a), the anti-SLAMF agent therapy is administered to the subject, and in step (b), the T cells are obtained from the subject up to about 2 months after step (a).

[0092] In another aspect, the present specification provides a method for manufacturing T cells from a subject in need thereof, the subject having been administered a prior therapy selected from anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy, the method comprising: (a) selecting a subject who has been administered the prior therapy within the past approximately 1 month to a maximum of within the past approximately 3 months; (b) obtaining T cells from the subject, wherein the obtaining is performed within the past approximately 1 month to a maximum of within the past approximately 3 months; and (c) manufacturing T cells comprising a recombinant receptor. In certain embodiments, in step (a), the subject has been administered anti-CD38 agent therapy within the past approximately 2 months or within the past approximately 3 months. In certain embodiments, in step (a), the subject has been administered anti-immunomodulatory agent therapy within the past approximately 1 month, within the past approximately 2 months, or within the past approximately 3 months. In certain embodiments, in step (a), the subject has been administered anti-SLAMF agent therapy within the past approximately 2 months. In certain embodiments, in step (b), the obtaining is performed within the past approximately 2 months or within the past approximately 3 months after the anti-CD38 therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within the past approximately 1 month, within the past approximately 2 months, or within the past approximately 3 months after the immunomodulatory agent therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within the past approximately 2 months after the anti-SLAMF agent therapy has been administered to the subject.

[0093] In another aspect, provided herein is a method for manufacturing chimeric antigen receptor (CAR) T cells directed from a subject to BCMA (BCMA CAR T cells), the method comprising: (a) obtaining T cells from a subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, or anti-SLAMF agent therapy; and (b) being BCMA CAR T cells comprising a recombinant receptor. In certain embodiments, step (a) is performed about 2 months or up to about 3 months after the subject has received anti-CD38 agent therapy. In certain embodiments, step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received immunomodulatory agent therapy. In certain embodiments, step (a) is performed about 2 months after the subject has received anti-SLAMF agent therapy.

[0094] In another aspect, provided herein is a method for manufacturing chimeric antigen receptor (CAR) T cells directed from a subject to BCMA (BCMA CAR T cells), the method comprising: (a) administering to the subject anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy as part of the treatment of cancer; (b) obtaining T cells from the subject about 1 month to up to about 3 months after step (a); and (c) manufacturing BCMA CAR T cells comprising a recombinant receptor. In certain embodiments, in step (a), anti-CD38 agent therapy is administered to the subject, and in step (b), T cells are obtained from the subject about 2 months or up to about 3 months after step (a). In certain embodiments, in step (a), immunomodulatory agent therapy is administered to the subject, and in step (b), T cells are obtained from the subject about 1 month, up to about 2 months, or up to about 3 months after step (a). In certain embodiments, in step (a), anti-SLAMF agent therapy is administered to the subject, and in step (b), T cells are obtained from the subject about 2 months after step (a).

[0095] In another aspect, provided herein is a method for manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed from a subject in need thereof to BCMA, wherein the subject has been administered a prior therapy selected from anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy, and the method comprises: (a) selecting a subject who has been administered the prior therapy within the past about 1 month up to within the past about 3 months; (b) obtaining T cells from the subject, wherein the obtaining is performed within the past about 1 month up to within the past about 3 months; and (c) manufacturing BCMA CAR T cells comprising a recombinant receptor. In certain embodiments, in step (a), the subject has been administered anti-CD38 agent therapy within the past about 2 months or within the past about 3 months. In certain embodiments, in step (a), the subject has been administered immunomodulatory agent therapy within the past about 1 month, within the past about 2 months, or within the past about 3 months. In certain embodiments, in step (a), the subject has been administered anti-SLAMF agent therapy within the past about 2 months. In certain embodiments, in step (b), the obtaining is performed within the past about 2 months or within the past about 3 months after the anti-CD38 therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within the past about 1 month, within the past about 2 months, or within the past about 3 months after the immunomodulatory agent therapy has been administered to the subject. In certain embodiments, in step (b), the obtaining is performed within the past about 2 months after the anti-SLAMF agent therapy has been administered to the subject.

[0096] In certain embodiments of the methods presented herein, the method includes determining the functionality of T cells (e.g., prior to leukapheresis), such as the proportion of senescent T cells, the proportion of naive T cells, and / or the CD4:CD8 T cell ratio, for example, by determining the senescence of T cells. In some embodiments, the senescence marker is CD57. In some embodiments, the naive marker is CD28. In the methods presented herein, the determination can be made using standard techniques well known to those of ordinary skill in the relevant art. For example, in the methods presented herein, the determination step can be performed by utilizing techniques such as immunophenotyping of PBMCs, e.g., by multi-color flow cytometry, for markers related to T cell differentiation, memory, senescence, and / or exhaustion.

[0097] In certain embodiments, the proteasome inhibitor is bortezomib, carfilzomib, delanzomib, ixazomib, ixazomib citrate, oprozomib, or belinostat. In certain embodiments, the proteasome inhibitor is bortezomib, carfilzomib, ixazomib, oprozomib, or delanzomib. In some embodiments, the proteasome inhibitor is bortezomib. In some embodiments, the proteasome inhibitor is ixazomib. In some embodiments, the proteasome inhibitor is carfilzomib. The proteasome inhibitor can be any proteasome inhibitor that is used or can be used in the treatment of multiple myeloma.

[0098] In certain embodiments, the topoisomerase inhibitor is doxorubicin, doxorubicin hydrochloride, epirubicin, etoposide, liposomal doxorubicin hydrochloride, topotecan, t topotecan, pegylated liposomal doxorubicin hydrochloride, or doxorubicin hydrochloride. In certain embodiments, the topoisomerase inhibitor is etoposide, doxorubicin, doxorubicin hydrochloride, topotecan, or epirubicin. The topoisomerase inhibitor can be any topoisomerase inhibitor that is used or can be used in the treatment of multiple myeloma.

[0099] In certain embodiments, the anti-CD38 agent is an anti-CD38 antibody such as daratumumab or isatuximab. In some embodiments, the anti-CD38 antibody is daratumumab. The anti-CD38 agent can be any anti-CD38 agent that is used or can be used for the treatment of multiple myeloma.

[0100] In certain embodiments, the immunomodulatory agent is CC-122, CC-220, leflunomide, lenalidomide, thalidomide, or CELMoD®. In certain embodiments, the immunomodulatory agent is lenalidomide, pomalidomide, thalidomide, or CELMoD®. In some embodiments, the immunomodulatory agent is lenalidomide. In some embodiments, the immunomodulatory agent is pomalidomide. The immunomodulatory agent can be any immunomodulatory agent that is used or can be used for the treatment of multiple myeloma.

[0101] In certain embodiments, the anti-SLAMF agent is elotuzumab. The anti-SLAMF agent can be any anti-SLAMF agent that is used or can be used for the treatment of multiple myeloma.

[0102] In certain embodiments, the tumor or cancer is lymphoma, lung cancer, breast cancer, prostate cancer, liver cancer, bile duct cancer, glioma, colorectal adenocarcinoma, myelodysplasia, adrenocortical cancer, thyroid cancer, hypopharyngeal cancer, melanoma, skin cancer, colon cancer, desmoid tumor, fibromatosis, small round cell tumor, endocrine tumor, Ewing sarcoma, peripheral primitive neuroectodermal tumor, solid embryonal cell tumor, hepatoblastoma, neuroblastoma, non-rhabdomyosarcomatous soft tissue sarcoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, Wilms tumor, glioblastoma, myxoma, fibroma, lipoma, chronic lymphocytic leukemia (small lymphocytic lymphoma), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytoma, plasmacytosis, extranodal marginal zone B-cell lymphoma, MALT lymphoma, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma, T-cell prolymphocytic leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), juvenile chronic myeloid leukemia (JCML), juvenile myelomonocytic leukemia (JMML), T-cell large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma, nasal type, enteropathy-type T-cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK cell lymphoma, mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (unspecified), anaplastic large cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or multiple myeloma. In certain embodiments, the cancer is multiple myeloma, chronic lymphocytic leukemia, or non-Hodgkin lymphoma.

[0103] In certain embodiments, the cancer is non-Hodgkin lymphoma, and the non-Hodgkin lymphoma is Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, or mantle cell lymphoma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the multiple myeloma is high-risk multiple myeloma. In certain embodiments, the multiple myeloma is relapsed and / or refractory multiple myeloma. In certain embodiments, the multiple myeloma is high-risk multiple myeloma, and the high-risk multiple myeloma is a disease characterized by R-ISS stage III disease and / or early relapse.

[0104] In certain embodiments, the manufactured T cells are tumor-specific T cells, chimeric antigen receptor (CAR) T cells, engineered T cell receptor (TCR) T cells, or tumor-infiltrating lymphocytes (TILs). In certain embodiments, the manufactured T cells are chimeric antigen receptor (CAR) T cells. In certain embodiments, the manufactured T cells are one or more of tumor-specific T cells, chimeric antigen receptor (CAR) T cells, engineered T cell receptor (TCR) T cells, and tumor-infiltrating lymphocytes (TILs).

[0105] In certain embodiments, the subject is human.

[0106] In certain embodiments, the BCMA CAR T cells comprise a CAR directed to BCMA, and the CAR directed to BCMA comprises an antibody or antibody fragment that targets BCMA. In certain embodiments, the BCMA CAR T cells comprise a CAR directed to BCMA, and the CAR directed to BCMA comprises a single-chain Fv antibody or antibody fragment (scFv). In certain embodiments, the BCMA CAR T cells comprise a CAR directed to BCMA, and the CAR directed to BCMA comprises BCMA02 scFv, e.g., SEQ ID NO: 38. In certain embodiments, the BCMA CAR T cells are ABECMA® cells (cells used in the ABECMA® immunotherapy). In certain embodiments, the BCMA CAR T cells are siltuximab autologous cells. In certain embodiments, the BCMA CAR T cells are CARVYKTI™ cells (cells used in the CARVYKTI™ immunotherapy).

[0107] In certain embodiments, prior to administration to the subject, the subject undergoes an apheresis procedure, e.g., leukapheresis, to collect PBMCs for the manufacture of T cells or BCMA CAR T cells.

[0108] In certain embodiments, the T cells or BCMA CAR T cells are administered by intravenous infusion.

[0109] In certain embodiments, the CAR T cell therapy is BCMA02, JCARH125, JNJ-68284528 (LCAR-B38M; cilta-cel; CARVICTY™) (Janssen / Legend), P-BCMA-101 (Poseida), PBCAR269A (Poseida), P-BCMA-Allo1 (Poseida), Allo-715 (Pfizer / Allogene), CT053 (Carsgen), Descartes-08 (Cartesian), PHE885 (Novartis), ARI-002 (Hospital Clinic Barcelona, IDIBAPS), CTX120 (CRISPR Therapeutics); CD19 CAR T therapy, e.g., Yescarta, Kymriah, Tecartus, lisocabtagene maraleucel (liso-cel), or any other CAR T therapy that targets a cell surface marker.

[0110] In a specific aspect of any of the above embodiments, the cancer is brain cancer, glioblastoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma, lung cancer, uterine cancer, ovarian cancer, colorectal cancer, anal cancer, liver cancer, hepatocellular cancer, stomach cancer, testicular cancer, endometrial cancer, cervical cancer, Hodgkin's disease, non-Hodgkin lymphoma, esophageal cancer, intestinal cancer, thyroid cancer, adrenal cancer, bladder cancer, kidney cancer, breast cancer, multiple myeloma, sarcoma, anal cancer or squamous cell carcinoma.

[0111] In a specific embodiment, the number of T cells isolated from PBMC for use in the manufacture of chimeric antigen receptor (CAR) T cells (e.g., BCMA CAR T cells) is at least about 1×10 6 ~1×10 7 、1×10 7 ~1×10 8 、1×10 8 ~1×10 9 、or 1×10 9 ~1×10 10It is. In a specific embodiment, the number of T cells isolated from PBMCs for use in the production of chimeric antigen receptor (CAR) T cells (e.g., BCMA CAR T cells) is at least about 1×10 6 ~1×10 10 、1×10 7 ~1×10 10 、1×10 8 ~1×10 10 、or 1×10 9 ~1×10 10 It is. In a specific embodiment, the number of T cells isolated from PBMCs for use in the production of chimeric antigen receptor (CAR) T cells (e.g., BCMA CAR T cells) is at least about 1×10 6 ~1×10 7 、1×10 6 ~1×10 8 、1×10 6 ~1×10 9 、or 1×10 6 ~1×10 10 It is. In a specific embodiment, the number of T cells isolated from PBMCs for use in the production of chimeric antigen receptor (CAR) T cells (e.g., BCMA CAR T cells) is at least about 1×10 7 ~1×10 8 、1×10 7 ~1×10 9 、1×10 7 ~1×10 10 、or 1×10 8 ~1×10 10 It is.

[0112] The methods presented in this specification can utilize drug classes of topoisomerase inhibitors, proteasome inhibitors, anti-CD38 agents, immunomodulators, or anti-SLAMF agents. Non-limiting examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, oprozomib, or delanzomib. Non-limiting examples of topoisomerase inhibitors include etoposide, adriamycin, doxorubicin, topotecan, or epirubicin. Non-limiting examples of anti-CD38 agents include daratumumab or isatuximab. Non-limiting examples of immunomodulators include lenalidomide, pomalidomide, or thalidomide. Non-limiting examples of anti-SLAMF agents include elotuzumab.

[0113] In certain embodiments of any of the above aspects or embodiments, the subject is a human (e.g., a human patient). In certain embodiments of any of the above aspects or embodiments, the subject is a mammal. In certain embodiments, the mammal is a pet, a laboratory research animal, or a farm animal. In some embodiments, the pet, research animal, or farm animal is a dog, a cat, a horse, a monkey, a rabbit, a rat, a mouse, a guinea pig, a hamster, a pig, or a cow.

[0114] In certain specific embodiments of any of the above aspects or embodiments, the BCMA CAR T cells comprise a CAR directed to BCMA. In a specific embodiment, the CAR directed to BCMA comprises an antibody or antibody fragment that targets BCMA. In certain specific embodiments of any of the above aspects or embodiments, the BCMA CAR T cells comprise a CAR directed to BCMA, and the CAR directed to BCMA comprises a single-chain Fv antibody or antibody fragment (scFv). In certain specific embodiments of any of the above aspects or embodiments, the BCMA CAR T cells comprise a CAR directed to BCMA, and the CAR directed to BCMA comprises SEQ ID NO: 37. In certain specific embodiments of any of the above aspects or embodiments, the BCMA CAR T cells comprise a CAR directed to BCMA, and the CAR directed to BCMA comprises BCMA02 scFv, such as SEQ ID NO: 38. In certain specific embodiments, the CAR directed to BCMA is encoded by SEQ ID NO: 10. In certain specific embodiments, the BCMA CAR T cells comprise a nucleic acid, such as a vector, encoding a BCMA CAR T, such as the BCMA CAR T comprising amino acids 22-493 or 1-493 of SEQ ID NO: 9, SEQ ID NO: 37, or SEQ ID NO: 38, or a nucleic acid comprising SEQ ID NO: 10, such as a vector. In certain specific embodiments of any of the above aspects or embodiments, the BCMA CAR T cells are idecabtagene vicleucel cells. In certain specific embodiments, the BCMA CAR T cells are ABECMA® cells (cells used in the ABECMA® immunotherapy). In certain specific embodiments, the BCMA CAR T cells are silotacabtagene autoleucel cells. In certain specific embodiments, the BCMA CAR T cells are CARVYKTI™ cells (cells used in the CARVYKTI™ immunotherapy).

[0115] In a specific embodiment of any of the above aspects or embodiments, the immune cells are 150×10 6 cells to 450×10 6 cells, 300×10 6Cells ~ 600×10 6 Cells, 350×10 6 Cells ~ 600×10 6 Cells, 350×10 6 Cells ~ 550×10 6 Cells, 400×10 6 Cells ~ 600×10 6 Cells, 150×10 6 Cells ~ 300×10 6 Cells, or 400×10 6 Cells ~ 500×10 6 Administered at a dosage within the range of cells. In some embodiments, the immune cells are about 150×10 6 Cells, about 200×10 6 Cells, about 250×10 6 Cells, about 300×10 6 Cells, about 350×10 6 Cells, about 400×10 6 Cells, about 450×10 6 Cells, about 500×10 6 Cells, or about 550×10 6 Administered at a dosage of cells. In one embodiment, the immune cells are about 450×10 6 Administered at a dosage of cells. In some embodiments, the subject is administered a single infusion of immune cells expressing a chimeric antigen receptor (CAR). In some embodiments, the administration of immune cells expressing CAR is repeated (e.g., a second dose of immune cells is administered to the subject). In some embodiments, the subject is administered a single infusion of immune cells expressing a chimeric antigen receptor (CAR) directed to B cell maturation antigen (BCMA). In some embodiments, the administration of immune cells expressing CAR directed to BCMA is repeated (e.g., a second dose of immune cells is administered to the subject).

[0116] In any specific embodiment of any of the embodiments described herein, the immune cells (e.g., immune cells expressing CAR) are administered at a dosage of about 150×10 6 Cells to about 300×10 6 Cells. In any specific embodiment of any of the embodiments described herein, the immune cells (e.g., immune cells expressing CAR) are administered at a dosage of about 350×106 administered at a dosage of about 550×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 400×10 6 administered at a dosage of about 500×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 150×10 6 administered at a dosage of about 500×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 300×10 6 administered at a dosage of about 500×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 350×10 6 administered at a dosage of about 250×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 300×10 6 administered at a dosage of about 500×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 350×10 6 administered at a dosage of about 450×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 300×10 6 administered at a dosage of about 450×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 250×10 6 administered at a dosage of about 450×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 300×10 6 administered at a dosage of about 450×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 250×10 6 administered at a dosage of about 450×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 300×10 6 administered at a dosage of about 450×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 250×10 6 administered at a dosage of about 450×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 300×10 6 administered at a dosage of about 600×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 250×10 6 administered at a dosage of about 500×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 250×10 6 administered at a dosage of about 500×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 250×10 6 administered at a dosage of about 500×10 cells from the cells. In any specific embodiment of the embodiments described herein, the immune cells (e.g., immune cells expressing a CAR) are about 250×10 6It is administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells (e.g., immune cells expressing a CAR) are from about 350×10 6 cells to about 500×10 6 cells and are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells (e.g., immune cells expressing a CAR) are from about 400×10 6 cells to about 600×10 6 cells and are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells (e.g., immune cells expressing a CAR) are from about 400×10 6 cells to about 450×10 6 cells and are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells (e.g., immune cells expressing a CAR) are from about 200×10 6 cells to about 400×10 6 cells and are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells (e.g., immune cells expressing a CAR) are from about 200×10 6 cells to about 350×10 6 cells and are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells (e.g., immune cells expressing a CAR) are from about 200×10 6 cells to about 300×10 6 cells and are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells (e.g., immune cells expressing a CAR) are from about 450×10 6 cells to about 500×10 6 cells and are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells (e.g., immune cells expressing a CAR) are from about 250×10 6 cells to about 400×10 6 cells and are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells (e.g., immune cells expressing a CAR) are from about 250×10 6 cells to about 350×106 It is administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells (e.g., immune cells expressing a CAR) are about 450×10 6 It is administered at a dosage of cells. In any specific embodiment of the embodiments described herein, the immune cells are T cells (e.g., autologous T cells). In any specific embodiment of the embodiments described herein, the subject to be treated undergoes an apheresis method, such as leukapheresis, to collect autologous immune cells for the production of immune cells (e.g., immune cells expressing a CAR) prior to administration to the subject. In any specific embodiment of the embodiments described herein, immune cells (e.g., T cells) are administered by intravenous infusion.

[0117] In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 150×10 6 cells to about 300×10 6 It is administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 350×10 6 cells to about 550×10 6 It is administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 400×10 6 cells to about 500×10 6 It is administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 150×10 6 cells to about 250×10 6 It is administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 300×10 6 cells to about 500×10 6It is administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 350×10 6 cells to about 450×10 6 cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 300×10 6 cells to about 450×10 6 cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 250×10 6 cells to about 450×10 6 cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 300×10 6 cells to about 600×10 6 cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 250×10 6 cells to about 500×10 6 cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 350×10 6 cells to about 500×10 6 cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 400×10 6 cells to about 600×10 6 cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 400×10 6 cells to about 450×10 6 cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 200×10 6Cells ~ about 400×10 6 They are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 200×10 6 Cells ~ about 350×10 6 They are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 200×10 6 Cells ~ about 300×10 6 They are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 450×10 6 Cells ~ about 500×10 6 They are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 250×10 6 Cells ~ about 400×10 6 They are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 250×10 6 Cells ~ about 350×10 6 They are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 300×10 6 Cells ~ about 460×10 6 They are administered at a dosage of cells. In any specific embodiment of the embodiments described herein, immune cells expressing a CAR directed to BCMA are about 450×10 6It is administered at a dosage of cells. In any specific embodiment of the embodiments described herein, the immune cells are T cells (e.g., autologous T cells). In any specific embodiment of the embodiments described herein, the subject to be treated undergoes an apheresis method, e.g., leukapheresis, to collect autologous immune cells for the production of immune cells expressing a CAR directed to BCMA prior to administration to the subject. In any specific embodiment of the embodiments described herein, the immune cells (e.g., T cells) are administered by intravenous infusion.

[0118] In any specific embodiment of any aspect or embodiment disclosed herein, prior to administration of the immune cells (e.g., immune cells expressing a CAR), the subject to be treated is administered lymph node dissection (LD) chemotherapy. In a specific embodiment, the LD chemotherapy comprises fludarabine and / or cyclophosphamide. In a specific embodiment, the LD chemotherapy is for a period of 1, 2, 3, 4, 5, 6, or 7 days (e.g., 3 days), with fludarabine (e.g., about 30 mg / m 2 ) and cyclophosphamide (e.g., about 300 mg / m 2 ) by intravenous administration. In other specific embodiments, the LD chemotherapy comprises any of the chemotherapeutic agents described in Section X. In a specific embodiment, the subject is administered immune cells (e.g., immune cells expressing a CAR) 1, 2, 3, 4, 5, 6, or 7 days after administration of the LD chemotherapy (e.g., 2 or 3 days after administration of the LD chemotherapy). In a specific embodiment, the subject has not received any therapy prior to the start of the LD chemotherapy for at least 1 week or more, at least 2 weeks or more (at least 14 days or more), at least 3 weeks or more, at least 4 weeks or more, at least 5 weeks or more, or at least 6 weeks or more. In any specific embodiment of the embodiments disclosed herein, prior to administration of the immune cells (e.g., immune cells expressing a CAR), the subject to be treated has received only a single prior treatment regimen.

[0119] In certain embodiments of any of the aspects or embodiments disclosed herein, prior to administering immune cells expressing a CAR directed to BCMA, the subject to be treated is administered lymph node depletion (LD) chemotherapy. In certain embodiments, the LD chemotherapy comprises fludarabine and / or cyclophosphamide. In certain embodiments, the LD chemotherapy is for a period of 1, 2, 3, 4, 5, 6, or 7 days (e.g., 3 days), with fludarabine (e.g., about 30 mg / m 2 ) and cyclophosphamide (e.g., about 300 mg / m 2 ). In other certain embodiments, the LD chemotherapy comprises any of the chemotherapeutic agents described in Section X. In certain embodiments, the subject is administered immune cells expressing a chimeric antigen receptor (CAR) directed to B cell maturation antigen (BCMA) 1, 2, 3, 4, 5, 6, or 7 days after administration of the LD chemotherapy (e.g., 2 or 3 days after administration of the LD chemotherapy). In certain embodiments, the subject has not received any therapy prior to the start of the LD chemotherapy for at least 1 week or more, at least 2 weeks or more (at least 14 days or more), at least 3 weeks or more, at least 4 weeks or more, at least 5 weeks or more, or at least 6 weeks or more. In certain embodiments of any of the embodiments disclosed herein, prior to administering immune cells expressing a chimeric antigen receptor (CAR) directed to B cell maturation antigen (BCMA), the subject to be treated has received only a single prior treatment regimen.

[0120] In certain embodiments, the subject has received prior treatment having a negative effect on T cells, such as a proteasome inhibitor, a topoisomerase inhibitor, a stem cell transplant (e.g., ASCT), or an alkylating agent therapy, at least 6 months, 12 months, 18 months, or 24 months prior to obtaining T cells from the subject for manufacturing BCMA CAR T cell therapy. In certain embodiments, the subject has received prior treatment having a negative effect on T cells at least about 7 months, at least about 8 months, or at least about 9 months prior to obtaining T cells from the subject for manufacturing BCMA CAR T cell therapy. In certain embodiments, a subject having multiple myeloma is treated with BCMA CAR T cell therapy after receiving prior treatment having a negative effect on T cells, such as a proteasome inhibitor, a topoisomerase inhibitor, a stem cell transplant (e.g., ASCT), or an alkylating agent therapy, at least 6 months, 12 months, 18 months, or 24 months prior to obtaining T cells from the subject for manufacturing BCMA CAR T cell therapy. In certain embodiments, the subject has received prior treatment having a negative effect on T cells at least about 7 months, at least about 8 months, or at least about 9 months prior to obtaining T cells from the subject for manufacturing BCMA CAR T cell therapy. In certain embodiments, the subject has received prior treatment having a positive effect on T cells, such as an immunomodulatory agent, an anti-CD38 agent, or an anti-SLAMF agent, less than 1 month, less than 2 months, or less than 3 months prior to obtaining T cells from the subject for manufacturing BCMA CAR T cell therapy. In certain embodiments, a subject having multiple myeloma is treated with BCMA CAR T cell therapy after receiving prior treatment having a positive effect on T cells, such as an immunomodulatory agent, an anti-CD38 agent, or an anti-SLAMF agent, less than 1 month, less than 2 months, or less than 3 months prior to obtaining T cells from the subject for manufacturing BCMA CAR T cell therapy. In certain embodiments, a subject having multiple myeloma can be treated with an immunomodulatory agent, an anti-CD38 agent, or an anti-SLAMF agent as the subsequent final line of treatment after the prior treatment before BCMA CAR T therapy.Thus, in some embodiments, a subject having multiple myeloma is treated with a proteasome inhibitor, a topoisomerase inhibitor, a stem cell transplant (e.g., ASCT), or an alkylating agent therapy, and then, as a subsequent final line of treatment prior to BCMA CAR T therapy, can receive an immunomodulatory agent, an anti-CD38 agent, or an anti-SLAMF agent.

[0121] In certain embodiments, the subject has received a prior treatment that has a negative effect on T cells, such as a proteasome inhibitor, a topoisomerase inhibitor, a stem cell transplant (e.g., ASCT), or an alkylating agent therapy, at least 6 months, 12 months, 18 months, or 24 months before obtaining T cells from the subject for the manufacture of BCMA CAR T cell therapy, and (ii) a prior treatment that has a positive effect on T cells, such as an immunomodulatory agent, an anti-CD38 agent, or an anti-SLAMF agent, less than 1 month, less than 2 months, or less than 3 months before obtaining T cells from the subject for the manufacture of BCMA CAR T cell therapy. In certain embodiments, a subject having multiple myeloma has received a prior treatment that has a negative effect on T cells, such as a proteasome inhibitor, a topoisomerase inhibitor, a stem cell transplant (e.g., ASCT), or an alkylating agent therapy, at least 6 months, at least 12 months, at least 18 months, or at least 24 months before obtaining T cells from the subject for the manufacture of BCMA CAR T cell therapy, and (ii) a prior treatment that has a positive effect on T cells, such as an immunomodulatory agent, an anti-CD38 agent, or an anti-SLAMF agent, less than 1 month, less than 2 months, or less than 3 months before obtaining T cells from the subject for the manufacture of BCMA CAR T cell therapy, and is then treated with BCMA CAR T therapy. For example, a subject having multiple myeloma is treated with a proteasome inhibitor, a topoisomerase inhibitor, a stem cell transplant (e.g., ASCT), or an alkylating agent therapy, and then, as a subsequent final line of treatment prior to BCMA CAR T therapy, can receive an immunomodulatory agent, an anti-CD38 agent, or an anti-SLAMF agent.

[0122] In certain embodiments, a subject having multiple myeloma may be treated with an immunomodulatory agent, an anti-CD38 agent, or an anti-SLAMF agent as a subsequent final line of treatment after treatment prior to BCMA CAR T therapy.

[0123] For any of the above embodiments, the subject undergoes apheresis to collect and isolate the immune cells, e.g., T cells. In a specific embodiment of any of the above embodiments, the subject exhibits the following during the apheresis: M protein (serum protein electrophoresis [sPEP] or urine protein electrophoresis [uPEP]): sPEP ≥ 0.5 g / dL or uPEP ≥ 200 mg / 24 hours; no measurable disease in serum or urine, light chain type multiple myeloma with serum immunoglobulin free light chain ≥ 10 mg / dL and abnormal serum immunoglobulin kappa / lambda free light chain ratio; and / or Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. In a more specific embodiment, the subject during apheresis has received at least three prior treatment lines out of the prior treatment lines, including prior treatment with a proteasome inhibitor, an immunomodulatory agent (lenalidomide or pomalidomide), and an anti-CD38 antibody; for each of the at least three prior treatment lines, except when progressive disease was the best response to the prior treatment line, has received at least two cycles of continuous treatment; has evidence of progressive disease during or within 60 days of treatment in the most recent prior treatment line; and / or has achieved a response (above minimal response) to at least one of the prior treatment lines. In a specific embodiment of any of the above embodiments, the subject exhibits the following at the time of administration: M protein (serum protein electrophoresis [sPEP] or urine protein electrophoresis [uPEP]): sPEP ≥ 0.5 g / dL or uPEP ≥ 200 mg / 24 hours; no measurable disease in serum or urine, light chain type multiple myeloma with serum immunoglobulin free light chain ≥ 10 mg / dL and abnormal serum immunoglobulin kappa / lambda free light chain ratio; and / or Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.In another more specific embodiment, the subject has also previously received an anti-myeloma treatment regimen only once, has high-risk factors of R-ISS stage III and early relapse, and (i) if the subject has received induction therapy and stem cell transplantation, progressive disease (PD) less than 12 months from the first transplantation date, or (ii) if the subject has received only induction therapy, PD less than 12 months from the date of the last treatment regimen that should include at least a proteasome inhibitor, an immunomodulatory agent, and dexamethasone.

[0124] In a specific embodiment of any of the above aspects or embodiments, the CAR comprises an antibody or antibody fragment that targets BCMA. In a more specific embodiment, the CAR comprises a single-chain Fv antibody fragment (scFv). In a more specific embodiment, the CAR comprises BCMA02 scFv, for example, SEQ ID NO: 38. In a specific embodiment of any of the above aspects or embodiments, the immune cell is an idecabtagene vicleucel cell. In a particular embodiment, the BCMA CAR T cell is an ABECMA® cell (the cell used in the ABECMA® immunotherapy). In a particular embodiment, the BCMA CAR T cell is a cilta-cel autologous cell. In a particular embodiment, the BCMA CAR T cell is a CARVYKTI™ cell (the cell used in the CARVYKTI™ immunotherapy). In a particular embodiment, the BCMA CAR T cell is a cilta-cel autologous cell. In a particular embodiment, the BCMA CAR T cell is a CARVYKTI™ cell (the cell used in the CARVYKTI™ immunotherapy).

[0125] In one embodiment, the chimeric antigen receptor comprises BCMA, for example, a murine single-chain Fv antibody fragment that targets BCMA. In one embodiment, the chimeric antigen receptor comprises a murine anti-BCMA scFv that binds to a BCMA polypeptide, for example, a human BCMA polypeptide, a hinge domain comprising a CD8α polypeptide, a CD8α transmembrane domain, a CD137 (4-1BB) intracellular co-stimulatory signaling domain, and a CD3ζ primary signaling domain. In one embodiment, the chimeric antigen receptor comprises BCMA, for example, a murine scFv that targets BCMA, and the scFv is that of the anti-BCMA02 CAR of SEQ ID NO: 9. In one embodiment, the chimeric antigen receptor is or comprises SEQ ID NO: 9 or SEQ ID NO: 37. In one embodiment, the chimeric antigen receptor is or comprises SEQ ID NO: 9. In one embodiment, the chimeric antigen receptor is or comprises SEQ ID NO: 37. In a more specific embodiment of any of the embodiments herein, the immune cell is an ide-cel cell. In one embodiment, the immune cell comprises a chimeric antigen receptor that comprises BCMA, for example, a murine single-chain Fv antibody fragment that targets BCMA. In one embodiment, the immune cell comprises a chimeric antigen receptor that comprises a murine anti-BCMA scFv that binds to a BCMA polypeptide, for example, a hinge domain comprising a CD8α polypeptide, a CD8α transmembrane domain, a CD137 (4-1BB) intracellular co-stimulatory signaling domain, and a CD3ζ primary signaling domain. In one embodiment, the immune cell comprises a chimeric antigen receptor that is or comprises SEQ ID NO: 9 or SEQ ID NO: 37. In one embodiment, the immune cell comprises a chimeric antigen receptor that is or comprises SEQ ID NO: 9. In one embodiment, the immune cell comprises a chimeric antigen receptor that is or comprises SEQ ID NO: 37.

[0126] In other embodiments, the genetically modified immune effector cells contemplated herein are administered to a patient having a B cell-related disease, such as a B cell malignancy.

[0127] In certain specific embodiments of any of the above-described aspects or embodiments, the immune cells (e.g., CAR T cells) are 150×10 6 cells to 450×10 6 cells, 300×10 6 cells to 600×10 6 cells, 350×10 6 cells to 600×10 6 cells, 350×10 6 cells to 550×10 6 cells, 400×10 6 cells to 600×10 6 cells, 150×10 6 cells to 300×10 6 cells, or 400×10 6 cells to 500×10 6 cells and are administered at a dosage within this range. In some embodiments, the immune cells are about 150×10 6 cells, about 200×10 6 cells, about 250×10 6 cells, about 300×10 6 cells, about 350×10 6 cells, about 400×10 6 cells, about 450×10 6 cells, about 500×10 6 cells, or about 550×10 6 cells and are administered at a dosage within this range. In one embodiment, the immune cells are administered at a dosage of about 450×10 6 cells. In some embodiments, the subject is administered a single infusion of immune cells (e.g., immune cells expressing a chimeric antigen receptor (CAR)). In some embodiments, the administration of the immune cells (e.g., immune cells expressing a CAR) is repeated (e.g., a second dose of immune cells is administered to the subject). In some embodiments, the subject is administered a single infusion of immune cells (e.g., immune cells expressing a chimeric antigen receptor (CAR) directed to B cell maturation antigen (BCMA)). In some embodiments, the administration of the immune cells (e.g., immune cells expressing a CAR directed to BCMA) is repeated (e.g., a second dose of immune cells is administered to the subject).

[0128] In any specific embodiment of the embodiments described in this specification, the immune cells expressing CAR are administered at a dosage of about 150×10 6 cells to about 300×10 6 cells. In any specific embodiment of the embodiments described in this specification, the immune cells expressing CAR are administered at a dosage of about 350×10 6 cells to about 550×10 6 cells. In any specific embodiment of the embodiments described in this specification, the immune cells expressing CAR are administered at a dosage of about 400×10 6 cells to about 500×10 6 cells. In any specific embodiment of the embodiments described in this specification, the immune cells expressing CAR are administered at a dosage of about 150×10 6 cells to about 250×10 6 cells. In any specific embodiment of the embodiments described in this specification, the immune cells expressing CAR are administered at a dosage of about 300×10 6 cells to about 500×10 6 cells. In any specific embodiment of the embodiments described in this specification, the immune cells expressing CAR are administered at a dosage of about 350×10 6 cells to about 450×10 6 cells. In any specific embodiment of the embodiments described in this specification, the immune cells expressing CAR are administered at a dosage of about 300×10 6 cells to about 450×10 6 cells. In any specific embodiment of the embodiments described in this specification, the immune cells expressing CAR are administered at a dosage of about 250×10 6 cells to about 450×10 6 cells. In any specific embodiment of the embodiments described in this specification, the immune cells expressing CAR are administered at a dosage of about 300×10 6 cells to about 600×10 6 cells. In any specific embodiment of the embodiments described in this specification, the immune cells expressing CAR are administered at a dosage of about 250×10 6 cells to about 500×10 6administered at a dosage of cells. In any of the specific embodiments of the embodiments described herein, the immune cells expressing the CAR are about 350×10 6 cells to about 500×10 6 cells. In any of the specific embodiments of the embodiments described herein, the immune cells expressing the CAR are about 400×10 6 cells to about 600×10 6 cells. In any of the specific embodiments of the embodiments described herein, the immune cells expressing the CAR are about 400×10 6 cells to about 450×10 6 cells. In any of the specific embodiments of the embodiments described herein, the immune cells expressing the CAR are about 200×10 6 cells to about 400×10 6 cells. In any of the specific embodiments of the embodiments described herein, the immune cells expressing the CAR are about 200×10 6 cells to about 350×10 6 cells. In any of the specific embodiments of the embodiments described herein, the immune cells expressing the CAR are about 200×10 6 cells to about 300×10 6 cells. In any of the specific embodiments of the embodiments described herein, the immune cells expressing the CAR are about 450×10 6 cells to about 500×10 6 cells. In any of the specific embodiments of the embodiments described herein, the immune cells expressing the CAR are about 250×10 6 cells to about 400×10 6 cells. In any of the specific embodiments of the embodiments described herein, the immune cells expressing the CAR are about 250×10 6 cells to about 350×10 6 cells. In any of the specific embodiments of the embodiments described herein, the immune cells expressing the CAR are about 450×10 6It is administered at a dosage of cells. In any specific embodiment of the embodiments described herein, the immune cells are T cells (e.g., autologous T cells). In any specific embodiment of the embodiments described herein, the subject to be treated undergoes an apheresis method, such as leukapheresis, to collect autologous immune cells for the production of immune cells expressing CAR prior to administration to the subject. In any specific embodiment of the embodiments described herein, the immune cells (e.g., T cells) are administered by intravenous injection.

[0129] In any specific embodiment of the above-described aspect or embodiment, the CAR comprises an antibody or antibody fragment that targets a target antigen. The target antigen of interest can be any antigen of the target of interest, and can be, for example, an antigen on tumor cells. The tumor cells can be, for example, cells of solid tumors or cells of blood cancers. The antigen can be a cell of any tumor or cancer type, for example, lymphoma, leukemia, lung cancer, breast cancer, prostate cancer, liver cancer, bile duct cancer, glioma, colorectal adenocarcinoma, myelodysplasia, adrenocortical carcinoma, thyroid cancer, nasopharyngeal cancer, melanoma, for example, malignant melanoma, skin carcinoma, colorectal carcinoma, desmoid tumor, fibromatosis, small round cell tumor of fibroblastic origin, endocrine tumor, Ewing sarcoma, peripheral primitive neuroectodermal tumor, solid embryonal cell tumor, hepatoblastoma, neuroblastoma, non-rhabdomyosarcomatous soft tissue sarcoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, Wilms tumor, glioblastoma, myxoma, fibroma, lipoma, etc. Any antigen expressed on the cells. In a more specific embodiment, the lymphoma is chronic lymphocytic leukemia (small lymphocytic lymphoma), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytic myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, MALT lymphoma, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma, T-lymphoblastic prolymphocytic leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), juvenile chronic myeloid leukemia (JCML), juvenile myelomonocytic leukemia (JMML), T-lymphocytic large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T-lymphocytic leukemia / lymphoma, extranodal NK / T-lymphocytic lymphoma, nasal type, enteropathic type T-lymphocytic lymphoma, hepatosplenic T-lymphocytic lymphoma, blastic NK cell lymphoma, mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-lymphocyte lymphoma, peripheral T-lymphocyte lymphoma (specifically undetermined), anaplastic large cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or multiple myeloma.

[0130] In certain embodiments, the antigen is a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA). In various specific embodiments, but not limited to, tumor-associated antigens or tumor-specific antigens include Her2, prostate stem cell antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen-125 (CA-125), CA19-9, calretinin, MUC-1, epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen (MAGE), CD19, CD20, CD34, CD45, CD99, CD117, chromogranin, cytokeratin, desmin, glial fibrillary acidic protein (GFAP), gross cystic disease fluid protein (GCDFP-15), HMB-45 antigen, high molecular weight melanoma-associated antigen (HMW-MAA), protein melan-A (MART-1), myo-D1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase, synaptophysin, thyroglobulin, thyroid transcription factor-1, dimer of M2-type pyruvate kinase isozyme (tumor M2-PK), abnormal ras protein, or abnormal p53 protein.

[0131] In certain embodiments, the TAA or TSA is a cancer / testis (CT) antigen, such as BAGE, CAGE, CTAGE, FATE, GAGE, HCA661, HOM-TES-85, MAGEA, MAGEB, MAGEC, NA88, NY-ESO-1, NY-SAR-35, OY-TES-1, SPANXB1, SPA17, SSX, SYCP1, or TPTE.

[0132] In certain other embodiments, the TAA or TSA is a carbohydrate or ganglioside, such as fuc-GM1, GM2 (tumor fetal antigen immunogenicity-1; OFA-I-1), GD2 (OFA-I-2), GM3, GD3, etc.

[0133] In certain other embodiments, the TAA or TSA is alpha - actinin - 4, Bage - 1, BCR - ABL, Bcr - Abl fusion protein, beta - catenin, CA125, CA15 - 3 (CA27.29\BCAA), CA195, CA242, CA - 50, CAM43, Casp - 8, cdc27, cdk4, cdkn2a, CEA, coa - 1, dek - can fusion protein, EBNA, EF2, Epstein - Barr virus antigen, ETV6 - AML1 fusion protein, HLA - A2, HLA - A11, hsp70 - 2, KIAAO205, Mart2, Mum - 1, 2, and 3, neoPAP, myosin class I, OS - 9, pml - RARα fusion protein, PTPRK, K - ras, N - ras, triosephosphate isomerase, Gage3, 4, 5, 6, 7, GnTV, Herv - K - mel, Lage - 1, NA - 88, NY - Eso - 1 / Lage - 2, SP17, SSX - 2, TRP2 - Int2, gp100 (Pmel17), tyrosinase, TRP - 1, TRP - 2, MAGE - 1, MAGE - 3, RAGE, GAGE - 1, GAGE - 2, p15(58), RAGE, SCP - 1, Hom / Mel - 40, PRAME, p53, H - Ras, HER - 2 / neu, E2A - PRL, H4 - RET, IGH - IGK, MYL - RAR, human papillomavirus (HPV) antigens E6 and E7, TSP - 180, MAGE - 4, MAGE - 5, MAGE - 6, p185erbB2, p180erbB - 3, c - met, nm - 23H1, PSA, TAG - 72 - 4, CA19 - 9, CA72 - 4, CAM17.1. NuMa, K-ras, β-catenin, Mum-1, p16, TAGE, PSMA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, 13HCG, BCA225, BTAA, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\70K, NY-CO-1, RCAS1, SDCCAG16, TA-90, TAAL6, TAG72, TLP, TPS, CD19, CD22, CD27, CD30, CD70, GD2 (ganglioside G2), EGFRvIII (epidermal growth factor variant III), sperm protein 17 (Sp17), mesothelin, PAP (prostatic acid phosphatase), prostain, TARP (T cell receptor gamma alternate reading frame protein), Trp-p8, STEAP1 (prostate transmembrane epithelial antigen 1 with six transmembrane domains), an abnormal ras protein, or an abnormal p53 protein. In another specific embodiment, the tumor-associated antigen or tumor-specific antigen is integrin αvβ3 (CD61), galectin, K-Ras (V-Ki-ras2 Kirsten rat sarcoma virus oncogene), or Ral-B.

[0134] In a specific embodiment, the TAA or TSA is CD20, CD123, CLL-1, CD38, CS-1, CD138, ROR1, FAP, MUC1, PSCA, EGFRvIII, EPHA2, or GD2. In a more specific embodiment, the TAA or TSA is CD123, CLL-1, CD38, or CS-1. In a specific embodiment, the extracellular domain of the CAR binds to CS-1. In a further specific embodiment, the extracellular domain comprises a single-chain version of elotuzumab and / or an antigen-binding fragment of elotuzumab. In a specific embodiment, the extracellular domain of the CAR binds to CD20. In a more specific embodiment, the extracellular domain of the CAR is an scFv that binds to CD20 or an antigen-binding fragment thereof.

[0135] Other tumor-associated antigens and tumor-specific antigens are known to those skilled in the art.

[0136] Antibodies and scFvs that bind to TSA and TAA are known in the art, and the nucleotide sequences encoding them are also known.

[0137] In certain specific embodiments, the antigen is not considered to be TSA or TAA, but rather an antigen associated with tumor cells or damage resulting from tumors. In a specific embodiment, the antigen is a tumor microenvironment-associated antigen (TMAA). In certain embodiments, for example, TMAA is a growth factor, cytokine or interleukin, such as a growth factor, cytokine or interleukin associated with angiogenesis or vasculogenesis. Such growth factors, cytokines, or interleukins may include, for example, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), or interleukin-8 (IL-8). Tumors can also create a locally hypoxic environment in the tumor. As such, in other specific embodiments, TMAA is a hypoxia-related factor, such as HIF-1α, HIF-1β, HIF-2α, HIF-2β, HIF-3α, or HIF-3β. Tumors can also cause local damage to normal tissues and cause the release of molecules known as damage-associated molecular pattern molecules (DAMPs; also known as alarmins). Thus, in other specific embodiments, TMAA is a DAMP, such as a heat shock protein, chromatin-related protein high mobility group box 1 (HMGB1), S100A8 (MRP8, calgranulin A), S100A9 (MRP14, calgranulin B), serum amyloid A (SAA), or can be deoxyribonucleic acid, adenosine triphosphate, uric acid, or heparan sulfate. In a specific embodiment, TMAA is VEGF-A, EGF, PDGF, IGF, or bFGF.

[0138] In a specific embodiment of any of the above-described aspects or embodiments, the CAR comprises an antibody or antibody fragment that targets a target antigen. In a more specific embodiment, the CAR comprises a single-chain Fv antibody fragment (scFv). In one embodiment, the chimeric antigen receptor comprises an scFv that binds to a target antigen, such as an antigen on a tumor cell, a hinge domain comprising a CD8α polypeptide, a CD8α transmembrane domain, a CD137 (4-1BB) intracellular co-stimulatory signaling domain, and a CD3ζ primary signaling domain. The tumor cells can be, for example, cells of a solid tumor or cells of a blood cancer. The antigen can be any antigen expressed on the cells of any tumor or cancer type. In one embodiment, the immune cell comprises a chimeric antigen receptor comprising a single-chain Fv antibody fragment that targets a target antigen. In one embodiment, the immune cell comprises a chimeric antigen receptor comprising an scFv that binds to a target antigen, a hinge domain comprising a CD8α polypeptide, a CD8α transmembrane domain, a CD137 (4-1BB) intracellular co-stimulatory signaling domain, and a CD3ζ primary signaling domain.

[0139] In a specific embodiment of any of the above aspects or embodiments, the CAR comprises an antibody or antibody fragment targeting BCMA. In a more specific embodiment, the CAR comprises a single-chain Fv antibody fragment (scFv). In a more specific embodiment, the CAR comprises BCMA02 scFv, for example, SEQ ID NO: 38. In a specific embodiment of any of the above aspects or embodiments, the immune cell is an idecabtagene vicleucel cell. In a particular embodiment, the BCMA CAR T cell is an ABECMA® cell (the cell used in the ABECMA® immunotherapy). In one embodiment, the chimeric antigen receptor comprises BCMA, for example, a mouse single-chain Fv antibody fragment targeting BCMA. In one embodiment, the chimeric antigen receptor comprises a mouse anti-BCMA scFv that binds to a BCMA polypeptide, for example, a human BCMA polypeptide, a hinge domain comprising a CD8α polypeptide, a CD8α transmembrane domain, a CD137 (4-1BB) intracellular co-stimulatory signaling domain, and a CD3ζ primary signaling domain. In one embodiment, the chimeric antigen receptor comprises BCMA, for example, a mouse scFv targeting BCMA, and the scFv is that of the anti-BCMA02 CAR of SEQ ID NO: 9 or SEQ ID NO: 37. In one embodiment, the chimeric antigen receptor is SEQ ID NO: 9 or comprises SEQ ID NO: 9. In one embodiment, the chimeric antigen receptor is SEQ ID NO: 37 or comprises SEQ ID NO: 37. In a more specific embodiment of any of the embodiments herein, the immune cell is an idecabtagene vicleucel (ide-cel) cell. In one embodiment, the immune cell comprises a chimeric antigen receptor comprising BCMA, for example, a mouse single-chain Fv antibody fragment targeting BCMA. In one embodiment, the immune cell comprises a chimeric antigen receptor comprising a mouse anti-BCMA scFv that binds to a BCMA polypeptide, for example, a hinge domain comprising a CD8α polypeptide, a CD8α transmembrane domain, a CD137 (4-1BB) intracellular co-stimulatory signaling domain, and a CD3ζ primary signaling domain. In one embodiment, the immune cell comprises a chimeric antigen receptor that is SEQ ID NO: 9 or comprises SEQ ID NO: 9.In one embodiment, the immune cell comprises a chimeric antigen receptor that is or comprises SEQ ID NO: 37.

[0140] In other embodiments, the genetically modified immune effector cells contemplated herein are administered to patients having a B cell-related condition, such as an autoimmune disease associated with B cells or a B cell malignancy.

[0141] In another specific embodiment of any of the above aspects or embodiments, the subject has received one or more lines of prior therapy. In a more specific embodiment, the one or more lines of prior therapy include a proteasome inhibitor, lenalidomide, pomalidomide, thalidomide, bortezomib, dexamethasone, cyclophosphamide, doxorubicin, carfilzomib, ixazomib, cisplatin, doxorubicin, etoposide, the anti-CD38 antibody panobinostat, or elotuzumab.In a more specific embodiment, prior to said administration, the subject has received one or more lines of prior therapy including: daratumumab, pomalidomide, and dexamethasone (DPd); daratumumab, bortezomib, and dexamethasone (DVd); ixazomib, lenalidomide, and dexamethasone (IRd); daratumumab, lenalidomide, and dexamethasone; bortezomib, lenalidomide, and dexamethasone (RVd); bortezomib, cyclophosphamide, and dexamethasone (BCd); bortezomib, doxorubicin, and dexamethasone; carfilzomib, lenalidomide, and dexamethasone (CRd); bortezomib and dexamethasone; bortezomib, thalidomide, and dexamethasone; lenalidomide and dexamethasone; dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide, and bortezomib (VTD-PACE); lenalidomide and low-dose dexamethasone; bortezomib, cyclophosphamide and dexamethasone; carfilzomib and dexamethasone; lenalidomide alone; bortezomib alone; daratumumab alone; elotuzumab, lenalidomide, and dexamethasone; elotuzumab, pomalidomide, and dexamethasone; bendamustine, bortezomib, and dexamethasone; bendamustine, lenalidomide, and dexamethasone; pomalidomide and dexamethasone; pomalidomide, bortezomib, and dexamethasone; pomalidomide, carfilzomib, and dexamethasone; bortezomib and liposomal doxorubicin; cyclophosphamide, lenalidomide, and dexamethasone; elotuzumab, bortezomib, and dexamethasone; ixazomib and dexamethasone; panobinostat, bortezomib and dexamethasone; panobinostat and carfilzomib; or pomalidomide, cyclophosphamide and dexamethasone.

[0142] The practice of the subject matter presented in this specification employs, unless otherwise indicated, conventional methods of chemistry, biochemistry, organic chemistry, molecular biology, microbiology, recombinant DNA technology, genetics, immunology, and cell biology within the skill of the art, many of which are described below for illustrative purposes. Such techniques are well explained in the literature. For example, Sambrook, et al., Molecular Cloning: A Laboratory Manual (3rd Edition, 2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Maniatis et al., Molecular Cloning: A Laboratory Manual (1982); Ausubel et al., Current Protocols in Molecular Biology (John Wiley and Sons, updated July 2008); Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience; Glover, DNA Cloning: A Practical Approach, vol. I & II (IRL Press, Oxford, 1985); Anand, Techniques for the Analysis of Complex Genomes, (Academic Press, New York, 1992); Transcription and Translation (B. Hames & S. Higgins, Eds., 1984); Perbal, A Practical Guide to Molecular Cloning (1984); Harlow and Lane, Antibodies, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1998) Current Protocols in Immunology Q. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach and W. Strober, eds., 1991); Annual Review of Immunology; and research papers in journals such as Advances in Immunology.

[0143] A. Prior therapy Disclosed herein are methods for treating a subject having cancer, including administration of a T cell therapy (e.g., CAR T cells or TCE), wherein the subject has relapsed after treatment with a prior therapy for treating cancer or is refractory to a prior therapy for treating cancer. In some embodiments, the method further comprises administering to the subject a subsequent therapy for treating cancer after administration of the T cell therapy, and there is a washout period between the prior therapy and the subsequent therapy. In some embodiments, the class of therapies is topoisomerase inhibitors, proteasome inhibitors, anti-CD38 agents, immunomodulatory agents, and anti-SLAMF agents. In some embodiments, the class of treatment is topoisomerase inhibitors. In some embodiments, the class of therapies is proteasome inhibitors. In some embodiments, the class of therapies is anti-CD38 agents. In some embodiments, the class of therapies is immunomodulatory agents. In some embodiments, the class of therapies is anti-SLAMF agents.

[0144] 1. Less recent exposure to prior treatment (longer washout period) In some embodiments, but not limited to, for prior therapies such as topoisomerase inhibitors, proteasome inhibitors, stem cell transplantation (e.g., ASCT), or alkylating agent therapy, a longer washout period between the prior therapy and the subsequent CAR T cell therapy is desirable. In some embodiments, but not limited to, for prior therapies such as topoisomerase inhibitors or proteasome inhibitors, a longer washout period between the prior therapy and the subsequent CAR T cell therapy is desirable.

[0145] In certain embodiments, a subject with multiple myeloma is treated with BCMA CAR T cell therapy at least 6 months, at least 7 months, at least 8 months, or at least 9 months after the subject has received a prior treatment that has a negative effect on T cells, such as a proteasome inhibitor or a topoisomerase inhibitor, prior to obtaining T cells from the subject for manufacturing the BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from the subject within 24 months, within 18 months, within 12 months, or within 9 months for manufacturing the BCMA CAR T cell therapy after the subject has received a prior treatment that has a negative effect on T cells, such as a proteasome inhibitor or a topoisomerase inhibitor. In certain embodiments, the T cells are obtained from the subject within 24 months for manufacturing the BCMA CAR T cell therapy after the subject has received a prior treatment that has a negative effect on T cells, such as a proteasome inhibitor or a topoisomerase inhibitor. In certain embodiments, the T cells are obtained from the subject within 9 months for manufacturing the BCMA CAR T cell therapy after the subject has received a prior treatment that has a negative effect on T cells, such as a proteasome inhibitor or a topoisomerase inhibitor.

[0146] In certain embodiments, T cells are obtained from a subject at a time between 6 months and 24 months, between 6 months and 18 months, between 6 months and 12 months, or between 6 months and 9 months after the subject has received a prior treatment that has a negative effect on the T cells, such as a proteasome inhibitor or a topoisomerase inhibitor, for manufacturing BCMA CAR T cell therapy. In certain embodiments, T cells are obtained from a subject at a time between 6 months and 24 months after the subject has received a prior treatment that has a negative effect on the T cells, such as a proteasome inhibitor or a topoisomerase inhibitor, for manufacturing BCMA CAR T cell therapy. In certain embodiments, T cells are obtained from a subject at a time between 6 months and 9 months after the subject has received a prior treatment that has a negative effect on the T cells, such as a proteasome inhibitor or a topoisomerase inhibitor, for manufacturing BCMA CAR T cell therapy.

[0147] a. Topoisomerase inhibitors In some embodiments, the prior therapy for treating cancer is a topoisomerase inhibitor.

[0148] In some embodiments, the topoisomerase inhibitor inhibits the activity of DNA topoisomerase. In some embodiments, the topoisomerase inhibitor can be a type I topoisomerase. In some embodiments, the topoisomerase inhibitor can be a type II topoisomerase. In some embodiments, the topoisomerase inhibitor prevents topoisomerase from performing DNA strand cleavage. In some embodiments, the topoisomerase inhibitor associates with the topoisomerase-DNA complex and prevents the religation step of the topoisomerase mechanism.

[0149] In some embodiments, the topoisomerase inhibitor is selected from the group consisting of doxorubicin, doxicycline hydrochloride, epirubicin, etoposide, liposomal doxorubicin-HCL, topotecan, t topotecan, pegylated liposomal doxorubicin hydrochloride, and doxicycline hydrochloride.

[0150] In some embodiments, the topoisomerase inhibitor is a type I topoisomerase. In some embodiments, the topoisomerase inhibitor is also known as Hycamtin® and is (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione monohydrochloride. In some embodiments, the proteasome is topotecan. In some embodiments, the topoisomerase inhibitor has the following structure:

Chemical formula

[0151] Compositions of topotecan include, but are not limited to, those described in U.S. Pat. Nos. 5,004,758, 5,674,872, 5,734,056, 7,754,733, 7,754,785 and 8,158,645, and International Publications WO2005 / 002546 and WO2005 / 046608 (each incorporated herein by reference in its entirety).

[0152] In some embodiments, a composition comprising topotecan is a "ready-to-use" formulation containing etoposide in a dissolved or solubilized form and is intended to be used as is or further diluted with an intravenous diluent. In some embodiments, the composition comprising topotecan should be injected intravenously or orally ingested as a capsule.

[0153] In some embodiments, the topoisomerase inhibitor is type II topoisomerase. In some embodiments, the topoisomerase inhibitor is also known as VePesid®, Etopophos®, Toposar®, or VP-16, which is 4'-demethyl-epipodophyllotoxin 9-[4,6-O-(R)-ethylidene-β-D-glucopyranoside], 4'-(dihydrogen phosphate). In some embodiments, the topoisomerase inhibitor is etoposide. In some embodiments, the topoisomerase inhibitor has the following structure:

Chemical formula

[0154] Compositions of etoposide include, but are not limited to, those described in U.S. Patent Nos. 4,701,327, 4,772,589, 4,734,284, 5,609,882, and 8,828,925 (each incorporated herein by reference in its entirety).

[0155] In some embodiments, a composition comprising etoposide is a "ready-to-use" formulation containing etoposide in a dissolved or solubilized form, and is intended to be used as is or further diluted with an intravenous diluent. In some embodiments, a composition comprising etoposide should be injected intravenously.

[0156] In some embodiments, the topoisomerase inhibitor is topoisomerase II. In some embodiments, the topoisomerase inhibitor is also known as Adriamycin®, Doxil®, or Myocet® and is (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione. In some embodiments, the topoisomerase inhibitor is doxorubicin. In some embodiments, the topoisomerase inhibitor has the following structure:

Chemical formula

[0157] Compositions of doxorubicin include, but are not limited to, those described in U.S. Patent Nos. 3,524,844; 4,211,864; 4,898,735; 5,013,556; 5,698,529; 5,817,321; 6,060,518; 6,227,410; 6,387,406; and 8,148,338 (each incorporated herein by reference in its entirety).

[0158] In some embodiments, the composition comprising doxorubicin is a "ready-to-use" formulation containing doxorubicin in a dissolved or solubilized form, intended to be used as such or further diluted with an intravenous diluent. In some embodiments, the composition comprising doxorubicin is to be injected intravenously or intravesically.

[0159] In some embodiments, the topoisomerase inhibitor is a type II topoisomerase. In some embodiments, the topoisomerase inhibitor is also known as Ellence® or Pharmarubicin PFS® and is (8S,10S)-10-{[(2R,4S,5R,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy}-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-5,7,8,9,10,12-hexahydrotetracene-5,12-dione. In some embodiments, the proteasome is epirubicin. In some embodiments, the topoisomerase inhibitor has the following structure:

Chemical formula

[0160] Compositions of epirubicin include, but are not limited to, those described in U.S. Patent No. 8,802,830 and International Publication No. WO2007 / 075092, each of which is incorporated herein by reference in its entirety.

[0161] In some embodiments, a composition comprising epirubicin is a "ready-to-use" formulation containing epirubicin in a dissolved or solubilized form and is intended to be used as is or further diluted with an intravenous diluent. In some embodiments, the composition comprising epirubicin should be injected intravenously, intravesically, or intraarterially.

[0162] It should be noted that if there is a discrepancy between the structure shown and the name given to that structure, the structure shown is given more weight. Further, if the stereochemistry of a structure or a part of a structure is not indicated, for example, by a bold or dashed line, that structure or part of the structure is to be interpreted as encompassing all stereoisomers of that structure.

[0163] In certain embodiments, a subject with multiple myeloma is treated with BCMA CAR T cell therapy at least 6 months, at least 7 months, at least 8 months, or at least 9 months after the subject received a prior topoisomerase inhibitor therapy to obtain T cells from the subject for manufacturing the BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from the subject within 24 months, within 18 months, within 12 months, or within 9 months after the subject received a prior topoisomerase inhibitor therapy to manufacture the BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from the subject within 24 months after the subject received a prior topoisomerase inhibitor therapy to manufacture the BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from the subject within 9 months after the subject received a prior topoisomerase inhibitor therapy to manufacture the BCMA CAR T cell therapy.

[0164] In certain embodiments, the T cells are obtained from a subject at a time between 6 months and 24 months, between 6 months and 18 months, between 6 months and 12 months, or between 6 months and 9 months after the subject has received topoisomerase inhibitor therapy in the past for the manufacture of BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from a subject at a time between 6 months and 24 months after the subject has received topoisomerase inhibitor therapy in the past for the manufacture of BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from a subject at a time between 6 months and 9 months after the subject has received topoisomerase inhibitor therapy in the past for the manufacture of BCMA CAR T cell therapy.

[0165] b. Proteasome inhibitors In some embodiments, the prior therapy for treating cancer is a proteasome inhibitor.

[0166] In some embodiments, the proteasome inhibitor inhibits the 26S proteasome. In some embodiments, inhibition of the 26S proteasome inhibits or blocks proteasome-mediated targeted proteolysis, thereby disrupting cell signaling pathways and resulting in cell cycle arrest, apoptosis, and inhibition of angiogenesis. In some embodiments, the proteasome inhibitor inhibits nuclear factor kappa B (NFkB).

[0167] In some embodiments, the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, delanzomib, ixazomib, ixazomib citrate, oprozomib, and velcade. In some embodiments, the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib. In some embodiments, the proteasome inhibitor is bortezomib. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the proteasome inhibitor is ixazomib.

[0168] In some embodiments, the proteasome inhibitor reversibly inhibits the 26S proteasome. In some embodiments, the proteasome inhibitor is also known as bortezomib or Velcade® [(1R)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid. In some embodiments, the proteasome inhibitor is bortezomib. In some embodiments, the prior therapy is bortezomib. In some embodiments, the proteasome inhibitor has the following structure: [Chemical Formula] and includes its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers or racemic mixtures, and compositions thereof. In some embodiments, the proteasome inhibitor is a pharmaceutically acceptable salt of bortezomib. In some embodiments, the proteasome inhibitor is a solvate of bortezomib. In some embodiments, the proteasome inhibitor is a hydrate of bortezomib. In some embodiments, the proteasome inhibitor is a stereoisomer of bortezomib. In some embodiments, the proteasome inhibitor is a tautomer of bortezomib. In some embodiments, the proteasome inhibitor is a racemic mixture of bortezomib. In some embodiments, the proteasome inhibitor is bortezomib. In some embodiments, the prior therapy is bortezomib.

[0169] Compositions of bortezomib include, but are not limited to, those described in U.S. Patent Nos. 6,083,903, 6,713,446, 6,958,319, 8,962,572, and 10,314,880, and International Publications WO2006 / 052733 and WO2016 / 166653 (each incorporated herein by reference in its entirety).

[0170] In some embodiments, a composition comprising bortezomib is a "ready-to-use" formulation containing bortezomib in a dissolved or solubilized form, and is intended to be used as is or further diluted with an intravenous diluent. In preferred embodiments, the pharmaceutical composition comprising bortezomib is formulated for parenteral administration, such as by injection or infusion.

[0171] Suitable solvents can be selected from aqueous and non-aqueous solvents, such as, but not limited to, glycerin, ethanol, n-propanol, n-butanol, isopropanol, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, cyclohexane, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI), acetone, tetrahydrofuran (THF), dimethylformamide (DMF), propylene carbonate (PC), dimethyl isosorbide, water and mixtures thereof. Preferred solvents are ethanol, glycerin and water.

[0172] The bortezomib formulation may contain stabilizers such as sugars and amino acids. Suitable stabilizers may include glucose, trehalose, sucrose, mannitol, sorbitol, arginine, glycine, proline, methionine, lysine and the like.

[0173] The bortezomib formulation may contain a chelating agent. Suitable chelating agents include DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), EDTA (ethylenediaminetetraacetic acid), ODDA (1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7), TTTA (1,7,13-triaza-4,10,16-trioxacyclooctadecane-N,N’,N’’-triacetic acid), DOTRP (tetraethylene glycol-1,5,9-triazacyclododecane-N,N’,N’’,-tris(methylenephosphonic acid)), EGTA (ethylene glycol-bis(P-aminoethyl ether)-tetraacetic acid), and the like.

[0174] The bortezomib formulation can also contain one or more antioxidants. Suitable antioxidants include, but are not limited to, monothioglycerol, ascorbic acid, sodium bisulfite, sodium metabisulfite, L-cysteine, thioglycolic acid, citric acid, tartaric acid, phosphoric acid, gluconic acid, thiodipropionic acid, and the like. The most preferred antioxidant is monothioglycerol.

[0175] The bortezomib formulation for use in the present invention can optionally contain other pharmaceutically acceptable adjuvants such as buffers, pH adjusters, preservatives, tonicity modifiers, and the like. The above lists of solvents, stabilizers, chelating agents, and antioxidants can also be used in pharmaceutical compositions containing other cytotoxic agents described herein, unless otherwise specified.

[0176] In some embodiments, the proteasome inhibitor is a selective proteasome inhibitor. In some embodiments, the proteasome inhibitor is an irreversible proteasome inhibitor. In some embodiments, the proteasome inhibitor is irreversible and a selective proteasome inhibitor. In some embodiments, the proteasome inhibitor is an analog of epoxomicin. In some embodiments, the proteasome inhibitor irreversibly and selectively binds to the N-terminal threonine-containing active site of the 20S proteasome. In some embodiments, the proteasome inhibitor is (2S)-4-methyl-N-[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxirane-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]-4-phenylbutanoyl]amino]pentanamide, also known as carfilzomib or Kyprolis®. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the prior therapy is carfilzomib. In some embodiments, the proteasome inhibitor has the following structure: [Chemical formula] or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixture thereof, and compositions thereof. In some embodiments, the proteasome inhibitor is a pharmaceutically acceptable salt of carfilzomib. In some embodiments, the proteasome inhibitor is a solvate of carfilzomib. In some embodiments, the proteasome inhibitor is a hydrate of carfilzomib. In some embodiments, the proteasome inhibitor is a stereoisomer of carfilzomib. In some embodiments, the proteasome inhibitor is a tautomer of carfilzomib. In some embodiments, the proteasome inhibitor is a racemic mixture of carfilzomib. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the prior therapy is carfilzomib.

[0177] Compositions of carfilzomib include, but are not limited to, those described in U.S. Patent Nos. 7,232,818, 7,417,042, 7,491,704, 7,737,112, 8,129,346, 8,207,127, 8,207,125, 8,207,126, 8,207,297, 9,493,582, 9,511,109, and 10,098,890, and International Publication No. WO2015 / 198257 (each incorporated herein by reference in its entirety).

[0178] In some embodiments, the proteasome inhibitor reversibly inhibits the CT-L proteolytic (β5) site of the 20S proteasome. In some embodiments, the proteasome inhibitor is [(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]boronic acid, also known as ixazomib or Ninlaro®. In some embodiments, the proteasome inhibitor is ixazomib. In some embodiments, the prior therapy is ixazomib. In some embodiments, the proteasome inhibitor has the following structure:

Chemical formula

[0179] Examples of carfilzomib compositions include, but are not limited to, those described in U.S. Patent Nos. 8,871,745; 8,530,694; 7,442,830; 9,175,017; 8,003,819; 9,233,115; 8,546,608; 7,687,662; and 8,859,504, and International Publications WO2016 / 165677; WO2017 / 174064; and WO2017 / 046815 (each incorporated herein by reference in its entirety).

[0180] In some embodiments, the proteasome inhibitor selectively inhibits the chymotrypsin-like activity of both constitutive proteasome (PSMB5) and immunoproteasome (LMP7). In some embodiments, the proteasome inhibitor is O-methyl-N-(2-methyl-1,3-thiazole-5-carbonyl)-L-seryl-O-methyl-N-{ (2S)-1-[(2R)-2-methyloxiran-2-yl]-1-oxo-3-phenylpropan-2-yl}-L-serinamide, also known as oprozomib. In some embodiments, the proteasome inhibitor is oprozomib. In some embodiments, the prior therapy is oprozomib. In some embodiments, the proteasome inhibitor has the following structure:

Chemical formula

[0181] Compositions of oprozomib include, but are not limited to, those described in U.S. Patent No. 8,853,147 and International Publication No. WO2014 / 066681 (each incorporated herein by reference in its entirety).

[0182] In some embodiments, the proteasome inhibitor inhibits the chymotrypsin-like activity of the proteasome. In some embodiments, the proteasome inhibitor is also known as delanzomib [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]butanoyl]amino]-3-methylbutyl]boronic acid. In some embodiments, the prior therapy is delanzomib. In some embodiments, the prior therapy is delanzomib. In some embodiments, the proteasome inhibitor has the following structure:

Chemical formula

[0183] Compositions of delanzomib include, but are not limited to, those described in International Publication No. WO2019 / 223723, which is hereby incorporated by reference in its entirety.

[0184] It should be noted that if there is a discrepancy between the structure shown and the name given to that structure, the structure shown is to be given more weight. Further, if the stereochemistry of a structure or a part of a structure is not indicated, for example, by a bold or broken line, that structure or part of the structure is to be interpreted as encompassing all stereoisomers of that structure.

[0185] In certain embodiments, a subject with multiple myeloma is treated with BCMA CAR T cell therapy at least 6 months, at least 7 months, at least 8 months, or at least 9 months after obtaining T cells from the subject for manufacturing the BCMA CAR T cell therapy, after the subject has previously received proteasome inhibitor therapy. In certain embodiments, the T cells are obtained from the subject for manufacturing BCMA CAR T cell therapy within 24 months, within 18 months, within 12 months, or within 12 months after the subject has previously received proteasome inhibitor therapy. In certain embodiments, the T cells are obtained from the subject for manufacturing BCMA CAR T cell therapy within 24 months after the subject has previously received proteasome inhibitor therapy. In certain embodiments, the T cells are obtained from the subject for manufacturing BCMA CAR T cell therapy within 9 months after the subject has previously received proteasome inhibitor therapy.

[0186] In certain embodiments, the T cells are obtained from the subject for manufacturing BCMA CAR T cell therapy at a time between 6 months and 24 months, between 6 months and 18 months, between 6 months and 12 months, or between 6 months and 9 months after the subject has previously received proteasome inhibitor therapy. In certain embodiments, the T cells are obtained from the subject for manufacturing BCMA CAR T cell therapy at a time between 6 months and 24 months after the subject has previously received proteasome inhibitor therapy. In certain embodiments, the T cells are obtained from the subject for manufacturing BCMA CAR T cell therapy at a time between 6 months and 9 months after the subject has previously received proteasome inhibitor therapy.

[0187] 2. More recent exposure to prior therapy (shorter washout period) In some embodiments, but not limited to, for prior therapies such as anti-CD38 agents, immunomodulatory agents, and anti-SLAMF agents, it is desirable to shorten the washout period between the prior therapy and the subsequent CAR T cell therapy.

[0188] In certain embodiments, a subject having multiple myeloma is treated with BCMA CAR T cell therapy after receiving an immunomodulatory agent, an anti-CD38 agent, or an anti-SLAMF agent less than 1 month, less than 2 months, less than 3 months, or less than 4 months prior to obtaining T cells from the subject for use in a prior treatment that has a positive effect on T cells, such as BCMA CAR T cell therapy. In certain embodiments, T cells are obtained from the subject within 4 months, within 3 months, within 2 months, within 1 month, or within 15 days for use in manufacturing BCMA CAR T cell therapy after the subject has received a prior treatment that has a positive effect on T cells, such as an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent. In certain embodiments, T cells are obtained from the subject within 4 months for use in manufacturing BCMA CAR T cell therapy after the subject has received a prior treatment that has a positive effect on T cells, such as an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent. In certain embodiments, T cells are obtained from the subject within 3 months for use in manufacturing BCMA CAR T cell therapy after the subject has received a prior treatment that has a positive effect on T cells, such as an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent.

[0189] In certain embodiments, the T cells are obtained from a subject for manufacturing BCMA CAR T cell therapy at a time between 15 days and 4 months, between 15 days and 3 months, between 15 days and 2 months, or between 15 days and 1 month after the subject has received a prior treatment that has a positive effect on the T cells, such as an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent. In certain embodiments, the T cells are obtained from a subject for manufacturing BCMA CAR T cell therapy at a time between 15 days and 4 months after the subject has received a prior treatment that has a positive effect on the T cells, such as an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent. In certain embodiments, the T cells are obtained from a subject for manufacturing BCMA CAR T cell therapy at a time between 15 days and 3 months after the subject has received a prior treatment that has a positive effect on the T cells, such as an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent. In certain embodiments, the T cells are obtained from a subject for manufacturing BCMA CAR T cell therapy at a time between 15 days and 2 months after the subject has received a prior treatment that has a positive effect on the T cells, such as an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent. In certain embodiments, the T cells are obtained from a subject for manufacturing BCMA CAR T cell therapy at a time between 15 days and 1 month after the subject has received a prior treatment that has a positive effect on the T cells, such as an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent. In certain embodiments, the T cells are obtained from a subject for manufacturing BCMA CAR T cell therapy at a time between 1 month and 4 months, between 1 month and 3 months, or between 1 month and 2 months after the subject has received a prior treatment that has a positive effect on the T cells, such as an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent. In certain embodiments, the T cells are obtained from a subject for manufacturing BCMA CAR T cell therapy at a time between 1 month and 4 months after the subject has received a prior treatment that has a positive effect on the T cells, such as an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent.In certain embodiments, the T cells are obtained from a subject at some time between 1 month and 3 months after the subject has received a prior treatment that has a positive effect on the T cells, such as an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent, for the manufacture of BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from a subject at some time between 1 month and 2 months after the subject has received a prior treatment that has a positive effect on the T cells, such as an anti-CD38 agent, an immunomodulatory agent, or an anti-SLAMF agent, for the manufacture of BCMA CAR T cell therapy.

[0190] a. Anti-CD38 agents In some embodiments, the prior therapy for treating cancer is an anti-CD38 agent. In some embodiments, the prior therapy for treating cancer is an anti-CD38 antibody. In some embodiments, the anti-CD38 antibody is a monoclonal antibody. In some embodiments, the anti-CD38 antibody is a fully human antibody or a chimeric antibody.

[0191] In some embodiments, the anti-CD38 antibody is a fully human antibody. In some embodiments, the anti-CD38 antibody is selected from the group consisting of daratumumab, MOR202, and TAK-079. In some embodiments, the anti-CD38 antibody comprises CDRH-1, CDRH-2, and CDR-H3, each comprising the amino acid sequences of SEQ ID NOs: 275-277. In some embodiments, the anti-CD38 antibody comprises CDRL-1, CDRL-2, and CDR-L3, each comprising the amino acid sequences of SEQ ID NOs: 278-280. In some embodiments, the anti-CD38 antibody comprises CDRH-1, CDRH-2, and CDR-H3, each comprising the amino acid sequences of SEQ ID NOs: 275-277, and CDRL-1, CDRL-2, and CDR-L3, each comprising the amino acid sequences of SEQ ID NOs: 278-280. In some embodiments, the anti-CD38 antibody comprises the VH region set forth in SEQ ID NO: 281. In some embodiments, the anti-CD38 antibody comprises the VL region set forth in SEQ ID NO: 282. In some embodiments, the anti-CD38 antibody comprises the VH region set forth in SEQ ID NO: 281 and the VL region set forth in SEQ ID NO: 282. In some embodiments, the anti-CD38 antibody is daratumumab. In some embodiments, the prior therapy is daratumumab.

[0192] In some embodiments, the antibody is a chimeric antibody. In some embodiments, the anti-CD38 antibody comprises CDRH-1, CDRH-2, and CDR-H3, each comprising the amino acid sequence of SEQ ID NOs: 283-285. In some embodiments, the anti-CD38 antibody comprises CDRL-1, CDRL-2, and CDR-L3, each comprising the amino acid sequence of SEQ ID NOs: 286-288. In some embodiments, the anti-CD38 antibody comprises CDRH-1, CDRH-2, and CDR-H3, each comprising the amino acid sequence of SEQ ID NOs: 283-285, and CDRL-1, CDRL-2, and CDR-L3, each comprising the amino acid sequence of SEQ ID NOs: 286-288. In some embodiments, the anti-CD38 antibody comprises the VH region set forth in SEQ ID NO: 289. In some embodiments, the anti-CD38 antibody comprises the VL region set forth in SEQ ID NO: 290. In some embodiments, the anti-CD38 antibody comprises the VH region set forth in SEQ ID NO: 289 and the VL region set forth in SEQ ID NO: 290. In some embodiments, the anti-CD38 antibody is isatuximab. In some embodiments, the prior therapy is isatuximab.

[0193] In certain embodiments, a subject having multiple myeloma is treated with BCMA CAR T cell therapy after the subject has previously received anti-CD38 agent therapy less than 1 month, less than 2 months, or less than 3 months prior to obtaining T cells from the subject for manufacturing the BCMA CAR T cell therapy. In certain embodiments, a subject having multiple myeloma is treated with BCMA CAR T cell therapy after the subject has previously received anti-CD38 agent therapy less than 2 months prior to obtaining T cells from the subject for manufacturing the BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from the subject within 4 months, within 3 months, or within 2 months for manufacturing the BCMA CAR T cell therapy after the subject has previously received anti-CD38 agent therapy. In certain embodiments, the T cells are obtained from the subject within 3 months for manufacturing the BCMA CAR T cell therapy after the subject has previously received anti-CD38 agent therapy.

[0194] In certain embodiments, the T cells are obtained from a subject at a time between 1 month and 4 months, between 1 month and 3 months, or between 1 month and 2 months after the subject has received anti-CD38 agent therapy in the past for manufacturing BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from a subject at a time between 2 months and 4 months, or between 2 months and 3 months after the subject has received anti-CD38 agent therapy for manufacturing BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from a subject at a time between 2 months and 3 months after the subject has received anti-CD38 agent therapy in the past for manufacturing BCMA CAR T cell therapy.

[0195] In some embodiments, the anti-CD38 agent therapy is the final line of treatment subsequent to the treatment before the subject receives BCMA CAR T cell therapy.

[0196] b. Immunomodulatory agents In some embodiments, the prior therapy for treating cancer is an immunomodulatory agent. In some embodiments, the immunomodulatory agent is a cereblon-modulating compound. In some embodiments, the immunomodulatory agent is a cereblon-binding compound. Cereblon functions as a substrate receptor for the CRL4 ubiquitin E3 ligase, and the binding of a cereblon-modulating compound can induce the recruitment, ubiquitination, and destruction of certain target substrates such as Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3, also known as Ikaros and Aiolos, respectively). In some embodiments, the administration of the immunomodulatory agent induces the ubiquitination of Aiolos and / or Ikaros. In some embodiments, the administration of the immunomodulatory agent induces the degradation of Aiolos and / or Ikaros. In some aspects, the degree of degradation induced by the immunomodulatory agent is related to its antitumor effect. For example, an increase in degradation is related to a greater antitumor effect by the immunomodulatory agent. In some embodiments, the immunomodulatory agent is an IMiD® or a CELMoD®.

[0197] Exemplary immunomodulators include substituted 2-(2,6-dioxopiperidin-3-yl)phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoindoles described in U.S. Patent Nos. 6,281,230 and 6,316,471. Further exemplary immunomodulators belong to a group of isoindoleimides disclosed in U.S. Patent Nos. 6,395,754, 6,555,554, 7,091,353, U.S. Patent Application Publication No. 2004 / 0029832, and International Publication No. WO98 / 54170.

[0198] In some embodiments, the immunomodulator is selected from the group consisting of thalidomide, lenalidomide, pomalidomide, iberdelomide (CC-220), CC-92480, CC-99282, CC-91633, and CC-90009, their enantiomers or mixtures of enantiomers, or their pharmaceutically acceptable salts, solvates, hydrates, co-crystals, inclusion compounds, or polymorphs. In some embodiments, the immunomodulator is selected from the group consisting of thalidomide, lenalidomide, pomalidomide, iberdelomide (CC-220), CC-92480, CC-99282, CC-91633, and CC-90009, or their pharmaceutically acceptable salts. In some embodiments, the immunomodulator is selected from the group consisting of thalidomide, lenalidomide, pomalidomide, iberdelomide (CC-220), CC-92480, CC-99282, and CC-90009, or their pharmaceutically acceptable salts. In some embodiments, the immunomodulator is lenalidomide. In some embodiments, the immunomodulator is pomalidomide.

[0199] In some embodiments, the immunomodulatory agent is administered at a dosage of (about) 0.1 mg to 100 mg, (about) 0.1 mg to 75 mg, (about) 0.1 mg to 50 mg, (about) 0.1 mg to 25 mg, (about) 0.1 mg to 10 mg, (about) 0.1 mg to 5 mg, (about) 0.1 mg to 1 mg, (about) 1 mg to 100 mg, (about) 1 mg to 75 mg, (about) 1 mg to 50 mg, (about) 1 mg to 25 mg, (about) 1 mg to 10 mg, (about) 1 mg to 5 mg, (about) 5 mg to 100 mg, (about) 5 mg to 75 mg, (about) 5 mg to 50 mg, (about) 5 mg to 25 mg, (about) 5 mg to 10 mg, (about) 10 mg to 100 mg, (about) 10 mg to 75 mg, (about) 10 mg to 50 mg, (about) 10 mg to 25 mg, (about) 25 mg to 100 mg, (about) 25 mg to 75 mg, (about) 25 mg to 50 mg, (about) 50 mg to 100 mg, (about) 50 mg to 75 mg, or (about) 75 mg to 100 mg (each inclusive). In some embodiments, the dosage is a daily dosage. In some embodiments, the dosage is a once-daily dosage. In some embodiments, the dosage is the amount of immunomodulatory agent administered each day on which the immunomodulatory agent is administered.

[0200] In some embodiments, the immunomodulatory agent is administered at a dose of (about) 0.1 mg to about 1.0 mg, (about) 0.1 mg to 0.9 mg, (about) 0.1 mg to 0.8 mg, (about) 0.1 mg to 0.7 mg, (about) 0.1 mg to 0.6 mg, (about) 0.1 mg to 0.5 mg, (about) 0.1 mg to 0.4 mg, (about) 0.1 mg to 0.3 mg, (about) 0.1 mg to 0.2 mg, (about) 0.2 mg to 1.0 mg, (about) 0.2 mg to 0.9 mg, (about) 0.2 mg to 0.8 mg, (about) 0.2 mg to 0.7 mg, (about) 0.2 mg to 0.6 mg, (about) 0.2 mg to 0.5 mg, (about) 0.2 mg to 0.4 mg, (about) 0.2 mg to 0.3 mg, (about) 0.3 mg to 1.0 mg, (about) 0.3 mg to 0.9 mg, (about) 0.3 mg to 0.8 mg, (about) 0.3 mg to 0.7 mg, (about) 0.3 mg to 0.6 mg, (about) 0.3 mg to 0.5 mg, (about) 0.3 mg to 0.4 mg, (about) 0.4 mg to 1.0 mg, (about) 0.4 mg to 0.9 mg, (about) 0.4 mg to 0.8 mg, (about) 0.4 mg to 0.7 mg, (about) 0.4 mg to 0.6 mg, (about) 0.4 mg to 0.5 mg, (about) 0.5 mg to 1.0 mg, (about) 0.5 mg to 0.9 mg, (about) 0.5 mg to 0.8 mg, (about) 0.5 mg to 0.7 mg, (about) 0.5 mg to 0.6 mg, (about) 0.6 mg to 1.0 mg, (about) 0.6 mg to 0.9 mg, (about) 0.6 mg to 0.8 mg, (about) 0.6 mg to 0.7 mg, (about) 0.7 mg to 1.0 mg, (about) 0.7 mg to 0.9 mg, (about) 0.7 mg to 0.8 mg, (about) 0.8 mg to 1.0 mg, (about) 0.8 mg to 0.9 mg, or (about) 0.9 mg to 1.0 mg (each inclusive). In some embodiments, the dose is a daily dose. In some embodiments, the dose is a once-daily dose. In some embodiments, the dose is the amount of the immunomodulatory agent administered each day on which the immunomodulatory agent is administered.

[0201] In some embodiments, the immunomodulatory agent is administered several times a day, twice a day, daily, every other day, three times a week, twice a week, or once a week. In some embodiments, the immunomodulatory agent is administered daily. In some embodiments, the immunomodulatory agent is administered daily for several consecutive days. In some embodiments, the immunomodulatory agent is administered daily for up to about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more than 30 consecutive days.

[0202] In some embodiments, the immunomodulatory agent is administered in one cycle. In some embodiments, a cycle includes a dosing period during which the immunomodulatory agent is administered and a rest period during which the immunomodulatory agent is not administered thereafter. In some embodiments, the rest period is about 1 day or more, about 3 days or more continuously, about 5 days or more continuously, about 7 days or more continuously, about 8 days or more continuously, about 9 days or more continuously, about 10 days or more continuously, about 11 days or more continuously, about 12 days or more continuously, about 13 days or more continuously, about 14 days or more continuously, about 15 days or more continuously, about 16 days or more continuously, about 17 days or more continuously, about 18 days or more continuously, about 19 days or more continuously, about 20 days or more continuously, about 21 days or more continuously, or about 28 days or more continuously. In some embodiments, the immunomodulatory agent is administered once a day for 14 days over a 21-day treatment cycle. In some embodiments, the immunomodulatory agent is administered once a day for 21 days over a 28-day treatment cycle.

[0203] In some embodiments, the immunomodulatory agent is administered in at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles, at least 9 cycles, at least 10 cycles, at least 11 cycles, or at least 12 cycles. In some embodiments, the immunomodulatory agent is administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 cycles.

[0204] In some embodiments, the immunomodulatory agent is administered orally. In some embodiments, the immunomodulatory agent is administered as a tablet or capsule. In some embodiments, the immunomodulatory agent is administered intravenously.

[0205] In some embodiments, the immunomodulatory agent is thalidomide ((RS)-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione), also known as Thalomid®. In some embodiments, the immunomodulatory agent has the following structure:

Chemical formula

[0206] In some embodiments, the immunomodulatory agent is lenalidomide (3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione), also known as Revlimid®. In some embodiments, the immunomodulatory agent has the following structure:

Chemical formula

[0207] In some embodiments, the immunomodulatory agent is pomalidomide (4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione), also known as Pomalyst®. In some embodiments, the immunomodulatory agent has the following structure:

Chemical formula

[0208] In some embodiments, the immunomodulatory agent has the structure:

Chemical formula

[0209] In some embodiments, the immunomodulatory agent has the structure:

Chemical formula

[0210] In some embodiments, the immunomodulatory agent has the structure:

Chemical formula

[0211] In some embodiments, the immunomodulatory agent is CC-91633 or an enantiomer or mixture of enantiomers of CC-91633, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound or polymorph thereof. In some embodiments, the immunomodulatory agent is a pharmaceutically acceptable salt of CC-91633. In some embodiments, the immunomodulatory agent is a solvate of CC-91633. In some embodiments, the immunomodulatory agent is a hydrate of CC-91633. In some embodiments, the immunomodulatory agent is a cocrystal of CC-91633. In some embodiments, the immunomodulatory agent is an inclusion compound of CC-91633. In some embodiments, the immunomodulatory agent is a polymorph of CC-91633. In some embodiments, the immunomodulatory agent is CC-91633. In some embodiments, the prior therapy is CC-91633.

[0212] In some embodiments, the immunomodulatory agent has the structure:

Chemical formula

[0213] In some embodiments, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic and organic acids and bases. Suitable pharmaceutically acceptable base addition salts include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine), and procaine. Suitable non-toxic acids include inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, fulminic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Others are well known to those skilled in the art. See, for example, Remington’s Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton PA (1995).

[0214] In some embodiments, the term "stereoisomer" or "stereoisomerically pure" means one stereoisomer of a drug that is substantially free of other stereoisomers of that drug. For example, a stereoisomerically pure drug having one chiral center is substantially free of the enantiomer on the opposite side of that drug. A stereoisomerically pure drug having two chiral centers is substantially free of other diastereomers of that drug. Typical stereoisomerically pure drugs include more than about 80% by weight of one stereoisomer of the drug and less than about 20% by weight of the other stereoisomer of the drug, more than about 90% by weight of one stereoisomer of the drug and less than about 10% by weight of the other stereoisomer of the drug, more than about 95% by weight of one stereoisomer of the drug and less than about 5% by weight of the other stereoisomer of the drug, or more than about 97% by weight of one stereoisomer of the drug and less than about 3% by weight of the other stereoisomer of the drug. Drugs can have chiral centers and can exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. Methods that include administration of such isomers of the immunomodulatory agent, including administration of mixtures thereof, are included in the embodiments provided herein.

[0215] In some embodiments, the immunomodulatory agent contains one chiral center and may exist as a mixture of enantiomers, e.g., a racemic mixture. The present disclosure encompasses the use of such agents in stereoisomerically pure form, as well as the use of mixtures of those forms. For example, in the methods and compositions disclosed herein, mixtures containing equal or unequal amounts of the enantiomers of the immunomodulatory agent can be used. These isomers can be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al, Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al, Tetrahedron 33 :2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0216] It should be understood that the chiral center of the immunomodulatory agent may undergo epimerization in vivo. Thus, one of ordinary skill in the art will recognize that if epimerization occurs in vivo, administration of the (R)-form of the immunomodulatory agent may be equivalent to administration of the (S)-form of the immunomodulatory agent.

[0217] The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography on a chiral stationary phase.

[0218] In some embodiments, the term "solvate" means a physical association of a drug with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain embodiments, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. In some embodiments, "solvate" includes both the solution phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0219] Irrespective of the stereoisomer or isotopic composition, it is understood that the immunomodulatory agent can be administered in any form of the pharmaceutically acceptable salts described herein. Similarly, it is understood that the isotopic composition can vary independently of the stereoisomeric composition of the immunomodulatory agent. Further, the isotopic composition is limited to the elements present in the immunomodulatory agent or its salts and can vary independently of the choice of pharmaceutically acceptable salts of the immunomodulatory agent.

[0220] It should be noted that if there is a discrepancy between the structure shown and the name given to that structure, the structure shown is given more weight. Further, if the stereochemistry of a structure or a part of a structure is not indicated, for example, by a bold or dashed line, that structure or part of the structure is to be interpreted as encompassing all of its stereoisomers.

[0221] In certain embodiments, a subject having multiple myeloma is treated with BCMA CAR T cell therapy less than 1 month, less than 2 months, less than 3 months, or less than 4 months before T cells are obtained from the subject to produce the BCMA CAR T cell therapy, after having previously received immunomodulatory agent therapy. In certain embodiments, the T cells are obtained from the subject within 4 months, within 3 months, within 2 months, within 1 month, or within 15 days to produce the BCMA CAR T cell therapy after the subject has previously received immunomodulatory agent therapy. In certain embodiments, the T cells are obtained from the subject within 3 months to produce the BCMA CAR T cell therapy after the subject has previously received immunomodulatory agent therapy.

[0222] In certain embodiments, the T cells are obtained from the subject at some time between 15 days and 4 months or between 15 days and 3 months after the subject has previously received immunomodulatory agent therapy to produce the BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from the subject at some time between 15 days and 3 months after the subject has previously received immunomodulatory agent therapy to produce the BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from the subject at some time between 1 month and 4 months, between 1 month and 3 months, or between 1 month and 2 months after the subject has previously received immunomodulatory agent therapy to produce the BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from the subject at some time between 1 month and 3 months after the subject has previously received immunomodulatory agent therapy to produce the BCMA CAR T cell therapy.

[0223] In some embodiments, the immunomodulatory agent therapy is the final line of treatment subsequent to the treatment before the subject receives BCMA CAR T cell therapy.

[0224] c. Anti-SLAMF agents In some embodiments, the prior therapy for treating cancer is an anti-signaling lymphocytic activation molecule F7 (SLAMF) agent. In some embodiments, SLAMF is also known as CS1 (CD2 subset 1), CRACC (CD2-like receptor-activated cytotoxic cell), and CD319. In some embodiments, the prior therapy for treating cancer is an anti-SLAMF antibody. In some embodiments, the anti-SLAMF antibody is a monoclonal antibody. In some embodiments, the anti-SLAMF antibody is a fully human antibody or a chimeric antibody.

[0225] In some embodiments, the anti-SLAMF antibody is a fully human antibody. In some embodiments, the anti-SLAMF antibody comprises CDRH-1, CDRH-2, and CDR-H3, each comprising the amino acid sequences of SEQ ID NOs: 291-293. In some embodiments, the anti-SLAMF antibody comprises CDRL-1, CDRL-2, and CDR-L3, each comprising the amino acid sequences of SEQ ID NOs: 294-296. In some embodiments, the anti-SLAMF antibody comprises CDRH-1, CDRH-2, and CDR-H3, each comprising the amino acid sequences of SEQ ID NOs: 291-293; and CDRL-1, CDRL-2, and CDR-L3, each comprising the amino acid sequences of SEQ ID NOs: 294-296. In some embodiments, the anti-SLAMF antibody comprises the VH region set forth in SEQ ID NO: 297. In some embodiments, the anti-SLAMF antibody comprises the VL region set forth in SEQ ID NO: 298. In some embodiments, the anti-SLAMF antibody comprises the VH region set forth in SEQ ID NO: 297 and the VL region set forth in SEQ ID NO: 298. In some embodiments, the anti-SLAMF antibody is elotuzumab. In some embodiments, the anti-SLAMF antibody is Empliciti®. In some embodiments, the prior therapy is elotuzumab. In some embodiments, the prior therapy is Empliciti®.

[0226] In certain embodiments, a subject having multiple myeloma is treated with BCMA CAR T cell therapy after the subject has received anti-SLAMF agent therapy less than 3 months or less than 2 months prior to obtaining T cells from the subject for manufacturing the BCMA CAR T cell therapy. In certain embodiments, a subject having multiple myeloma is treated with BCMA CAR T cell therapy after the subject has received anti-SLAMF agent therapy less than 2 months prior to obtaining T cells from the subject for manufacturing the BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from the subject within 2 months or within 1 month to manufacture BCMA CAR T cell therapy after the subject has been previously administered an anti-SLAMF agent. In certain embodiments, the T cells are obtained from the subject within 2 months to manufacture BCMA CAR T cell therapy after the subject has received anti-SLAMF agent therapy in the past.

[0227] In certain embodiments, the T cells are obtained from the subject at some time between 15 days and 2 months after the subject has received anti-SLAMF agent therapy in the past to manufacture BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from the subject at some time between 1 month and 2 months after the subject has received anti-SLAMF agent therapy in the past to manufacture BCMA CAR T cell therapy. In certain embodiments, the T cells are obtained from the subject at some time between 2 months and 3 months after the subject has received anti-SLAMF agent therapy in the past to manufacture BCMA CAR T cell therapy.

[0228] In some embodiments, the anti-SLAMF agent therapy is the final line of treatment subsequent to the treatment before the subject receives BCMA CAR T cell therapy.

[0229] The prior therapy described in "A. Prior Therapy" above can be any therapy used for the treatment of multiple myeloma and can be administered at the dosages and regimens used for the treatment of multiple myeloma.

[0230] II. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred embodiments of the compositions, methods, and materials are described herein. For the purposes of the present disclosure, the following terms are defined below.

[0231] As used herein, the articles “a,” “an,” and “the” are used to refer to one or more of the grammatical objects of the articles (i.e., at least one, or one or more). By way of example, “an element” means one element or one or more elements.

[0232] The use of alternatives (e.g., “or”) should be understood to mean either one of the alternatives, both, or a combination thereof.

[0233] The term “and / or” should be understood to mean either one of the alternatives or both.

[0234] As used herein, the terms “about” or “approximately” refer to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% relative to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length. In one embodiment, the terms “about” or “approximately” refer to a range of quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that is ±15%, ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% with respect to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length.

[0235] Throughout this specification, unless the context requires otherwise, the words "comprise", "comprises" and "comprising" are to be interpreted as including the stated step or element or group of steps or elements but not excluding any other step or element or group of steps or elements. "Consisting of" means, without limitation, including what follows the phrase "consisting of". Thus, the phrase "consisting of" indicates that the recited elements are required or essential and that no other elements may be present. "Consisting essentially of" means including the elements recited after the phrase, limited to other elements that do not interfere with or contribute to the activity or action specified in this disclosure for the recited elements. Thus, the phrase "consisting essentially of" indicates that the recited elements are required or essential, but that no other elements that materially affect the activity or action of the recited elements are present.

[0236] References throughout this specification to "one embodiment", "an embodiment", "a particular embodiment", "related embodiments", "a particular embodiment", "additional embodiments", "further embodiments" or combinations thereof mean that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure presented herein. Thus, although the foregoing phrases appear in various places throughout this specification, they are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, it is understood that a positive recitation of a feature in one embodiment is not a basis for excluding the feature in a particular embodiment.

[0237] "Human BCMA" refers to BCMA found in a human subject and having, for example, SEQ ID NO: 11.

[0238] III. Chimeric antigen receptor In some embodiments, genetically engineered receptors that redirect the cytotoxicity of immune effector cells to B cells are provided. These genetically engineered receptors are referred to herein as chimeric antigen receptors (CARs). A CAR is a molecule that combines antibody-based specificity for a desired antigen (e.g., BCMA) with a T cell receptor activation intracellular domain to produce a chimeric protein that exhibits specific anti-BCMA cellular immune activity. As used herein, the term "chimeric" describes being composed of different proteins or portions of DNA of different origins.

[0239] In some embodiments of the provided methods and uses, engineered cells, such as T cells, express a chimeric receptor, such as a chimeric antigen receptor (CAR), containing one or more domains that combine a ligand-binding domain (e.g., an antibody or antibody fragment) that provides specificity for a desired antigen (e.g., a tumor antigen) with an intracellular signaling domain. In some embodiments, the intracellular signaling domain is an activating intracellular domain portion, such as a T cell activation domain, that provides a primary activation signal. In some embodiments, the intracellular signaling domain contains or additionally contains a co-stimulatory signaling domain to facilitate effector function. When a molecule, e.g., an antigen, binds specifically to the receptor, the receptor generally delivers an immune-stimulatory signal, such as a signal transduced by ITAM, intracellularly, thereby promoting an immune response targeting a disease or condition. In some embodiments, genetically engineering immune cells with a chimeric receptor can regulate the activity of T cells and, in some cases, can regulate the differentiation or homeostasis of T cells, thereby obtaining genetically engineered cells with improved in vivo lifespan, survival, and / or persistence, such as for use in adoptive cell therapy.

[0240] The terms "complementary determining region" and "CDR" are synonymous with "hypervariable region" or "HVR" and are known in the art to refer to discontinuous sequences of amino acids within the antibody variable regions that confer antigen specificity and / or binding affinity. Generally, each heavy chain variable region has three CDRs (CDR-H1, CDR-H2, CDR-H3), and each light chain variable region has three CDRs (CDR-L1, CDR-L2, CDR-L3). The terms "framework region" and "FR" are known in the art to refer to the non-CDR portions of the variable regions of the heavy and light chains. Generally, each full-length heavy chain variable region has four FRs (FR-H1, FR-H2, FR-H3, and FR-H4), and each full-length light chain variable region has four FRs (FR-L1, FR-L2, FR-L3, and FR-L4).

[0241] The exact amino acid sequence boundaries of a given CDR or FR can be readily determined using any of several well-known schemes, such as Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme); Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme); MacCallum et al., J. Mol. Biol. 262:732-745 (1996), “Antibody-antigen interactions: Contact analysis and binding site topography,” J. Mol. Biol. 262, 732-745.” (“Contact” numbering scheme); Lefranc MP et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev Comp Immunol, 2003 Jan;27(1):55-77 (“IMGT” numbering scheme); Honegger A and Plueckthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol, 2001 Jun 8;309(3):657-70, (“Aho” numbering scheme); and Martin et al., including those described in “Modeling antibody hypervariable loops: a combined algorithm,” PNAS, 1989, 86(23):9268-9272, (the “AbM” numbering scheme).

[0242] The boundaries of the given CDRs or FRs may vary depending on the scheme used for identification. For example, the Kabat scheme is based on a structural alignment, while the Chothia scheme is based on structural information. The numbering of both the Kabat and Chothia schemes is based on the sequence lengths of the most common antibody regions, with insertions being accommodated by insertion letters such as “30a” and deletions being present in some antibodies. In these two schemes, differences in numbering occur because certain insertions and deletions (“indels”) are placed at different positions. The Contact scheme is based on the analysis of complex crystal structures and is similar to the Chothia numbering scheme in many respects. The AbM scheme is a compromise between Kabat and Chothia definitions based on those used in Oxford Molecular's AbM antibody modeling software.

[0243] Table 1 below lists exemplary position boundaries of CDR-L1, CDR-L2, CDR-L3 and CDR-H1, CDR-H2, CDR-H3 identified by the Kabat, Chothia, AbM and Contact schemes, respectively. For CDR-H1, residue numbers are described using both the Kabat and Chothia numbering schemes. The FRs are located between the CDRs. For example, FR-L1 is located before CDR-L1, FR-L2 is located between CDR-L1 and CDR-L2, and FR-L3 is located between CDR-L2 and CDR-L3, etc. It should be noted that the Kabat numbering scheme shown places the insertions at H35A and H35B, so the end of the Chothia CDR-H1 loop varies between H32 and H34 depending on the loop length when numbered according to the shown Kabat numbering rules.

[0244]

Table 1

[0245] Thus, unless otherwise specified, a given antibody or region thereof, e.g., the “CDR” or “complementary determining region” of its variable region, or an individually specified CDR (e.g., CDR-H1, CDR-H2, CDR-H3), is to be understood to encompass the complementary determining region defined (or specified) by any of the foregoing schemes or by other known schemes. For example, if a particular CDR (e.g., CDR-H3) is described as including the amino acid sequence of the corresponding CDR in a given V H or V L region amino acid sequence, such CDR is understood to have the sequence of the corresponding CDR (e.g., CDR-H3) within the variable region as defined by any of the foregoing schemes or by other known schemes. In some embodiments, a particular CDR sequence is specified. Exemplary CDR sequences of the provided antibodies are described using various numbering schemes, but it is understood that the provided antibodies may include CDRs described according to any of the other numbering schemes described above or other numbering schemes known to those of skill in the art.

[0246] Similarly, unless otherwise specified, a given antibody or region thereof, e.g., the FR of its variable region or an individually specified FR(s) (e.g., FR-H1, FR-H2, FR-H3, FR-H4), should be understood to encompass a framework region defined (or specified) by any of the known schemes. In some cases, a scheme for identifying specific CDRs, FRs, or multiple FRs or CDRs, such as those defined by the Kabat, Chothia, AbM, IMGT or Contact methods, or other known schemes, is specified. In other cases, the specific amino acid sequences of the CDRs or FRs are indicated. Antibody fragments can be made by a variety of techniques including, but not limited to, proteolytic digestion of intact antibodies, as well as production by recombinant host cells. In some embodiments, the antibody is a recombinantly produced fragment, e.g., a fragment that includes non-naturally occurring arrangements such as those having two or more antibody regions or chains connected by a synthetic linker, e.g., a peptide linker, and / or a fragment that may not be produced by enzymatic digestion of a naturally occurring intact antibody. In some aspects, the antibody fragment is a scFv.

[0247] The CAR T cell therapies to which the embodiments described in this specification are applicable include any CAR T cell therapy, for example, BCMA02, JCARH125, JNJ-68284528 (LCAR-B38M; cilta-cel; CARVICTY (trademark)) (Janssen / Legend), P-BCMA-101 (Poseida), PBCAR269A (Poseida), P-BCMA-Allo1 (Poseida), Allo-715 (Pfizer / Allogene), CT053 (Carsgen), Descartes-08 (Cartesian), PHE885 (Novartis), ARI-002 (Hospital Clinic Barcelona, IDIBAPS), CTX120 (CRISPR Therapeutics); CD19 CAR T therapies, for example, Yescarta, Kymriah, Tecartus, lisocabtagene maraleucel (liso-cel), and CAR T therapies targeting any other cell surface marker.

[0248] The extracellular domain of the polypeptide (also referred to as the binding domain or antigen-specific binding domain) binds to the antigen of interest. In certain embodiments, the extracellular domain comprises a receptor that binds to the antigen, or a portion of the receptor. The extracellular domain can be, for example, a receptor that binds to the antigen, or a portion of the receptor. In certain embodiments, the extracellular domain comprises an antibody or an antigen-binding portion thereof, or is an antibody or an antigen-binding portion thereof. In a specific embodiment, the extracellular domain comprises a single-chain Fv domain or is a single-chain Fv domain. The single-chain Fv domain can comprise, for example, V H linked to V L by a flexible linker, and the V L and V H are derived from an antibody that binds to the antigen.

[0249] The antigen to which the extracellular domain of the polypeptide binds can be any antigen of interest, for example, an antigen on a tumor cell. The tumor cell can be, for example, a cell of a solid tumor or a cell of a blood cancer. The antigen can be a cell of any tumor or cancer type, for example, lymphoma, leukemia, lung cancer, breast cancer, prostate cancer, liver cancer, bile duct cancer, glioma, colorectal adenocarcinoma, myelodysplasia, adrenocortical cancer, thyroid cancer, nasopharyngeal cancer, melanoma, such as malignant melanoma, skin carcinoma, colorectal carcinoma, desmoid tumor, fibromatosis, fibrous histiocytoma, endocrine tumor, Ewing sarcoma, peripheral primitive neuroectodermal tumor, solid embryonal tumor, hepatoblastoma, neuroblastoma, non-rhabdomyosarcomatous soft tissue sarcoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, Wilms tumor, glioblastoma, myxoma, fibroma, lipoma, etc. Any antigen expressed on the cells. In a more specific embodiment, the lymphoma is chronic lymphocytic leukemia (small lymphocytic lymphoma), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytoma, plasmacytosis, extranodal marginal zone B-cell lymphoma, MALT lymphoma, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma, T-lymphoblastic prolymphocytic leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), juvenile chronic myeloid leukemia (JCML), juvenile myelomonocytic leukemia (JMML), T-lymphocytic large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T-lymphocytic leukemia / lymphoma, extranodal NK / T-lymphocytic lymphoma, nasal type, enteropathic T-lymphocytic lymphoma, hepatosplenic T-lymphocyte lymphoma, blastic NK cell lymphoma, mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-lymphocyte lymphoma, peripheral T-lymphocyte lymphoma (specifically not determined), anaplastic large cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or multiple myeloma.

[0250] In certain embodiments, the antigen is a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA). In various specific embodiments, but not limited to, the tumor-associated antigen or tumor-specific antigen is Her2, prostate stem cell antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen-125 (CA-125), CA19-9, calretinin, MUC-1, epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen (MAGE), CD19, CD20, CD34, CD45, CD99, CD117, chromogranin, cytokeratin, desmin, glial fibrillary acidic protein (GFAP), gross cystic disease fluid protein (GCDFP-15), HMB-45 antigen, high molecular weight melanoma-associated antigen (HMW-MAA), protein melan-A (MART-1), myo-D1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase, synaptophysin, thyroglobulin, thyroid transcription factor-1, dimer of M2-type pyruvate kinase isozyme (tumor M2-PK), abnormal ras protein, or abnormal p53 protein.

[0251] In certain embodiments, the TAA or TSA is a cancer / testis (CT) antigen, such as, for example, BAGE, CAGE, CTAGE, FATE, GAGE, HCA661, HOM-TES-85, MAGEA, MAGEB, MAGEC, NA88, NY-ESO-1, NY-SAR-35, OY-TES-1, SPANXB1, SPA17, SSX, SYCP1, or TPTE.

[0252] In certain other embodiments, the TAA or TSA is a carbohydrate or ganglioside, such as, for example, fuc-GM1, GM2 (tumor fetal antigen immunogenicity-1; OFA-I-1), GD2 (OFA-I-2), GM3, GD3, and the like.

[0253] In certain other embodiments, the TAA or TSA is alpha - actinin - 4, Bage - 1, BCR - ABL, Bcr - Abl fusion protein, beta - catenin, CA125, CA15 - 3 (CA27.29\BCAA), CA195, CA242, CA - 50, CAM43, Casp - 8, cdc27, cdk4, cdkn2a, CEA, coa - 1, dek - can fusion protein, EBNA, EF2, Epstein - Barr virus antigen, ETV6 - AML1 fusion protein, HLA - A2, HLA - A11, hsp70 - 2, KIAAO205, Mart2, Mum - 1, 2, and 3, neoPAP, myosin class I, OS - 9, pml - RARα fusion protein, PTPRK, K - ras, N - ras, triosephosphate isomerase, Gage3, 4, 5, 6, 7, GnTV, Herv - K - mel, Lage - 1, NA - 88, NY - Eso - 1 / Lage - 2, SP17, SSX - 2, TRP2 - Int2, gp100 (Pmel17), tyrosinase, TRP - 1, TRP - 2, MAGE - 1, MAGE - 3, RAGE, GAGE - 1, GAGE - 2, p15(58), RAGE, SCP - 1, Hom / Mel - 40, PRAME, p53, H - Ras, HER - 2 / neu, E2A - PRL, H4 - RET, IGH - IGK, MYL - RAR, human papillomavirus (HPV) antigens E6 and E7, TSP - 180, MAGE - 4, MAGE - 5, MAGE - 6, p185erbB2, p180erbB - 3, c - met, nm - 23H1, PSA, TAG - 72 - 4, CA19 - 9, CA72 - 4, CAM17.1. NuMa, K-ras, β-catenin, Mum-1, p16, TAGE, PSMA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, 13HCG, BCA225, BTAA, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\70K, NY-CO-1, RCAS1, SDCCAG16, TA-90, TAAL6, TAG72, TLP, TPS, CD19, CD22, CD27, CD30, CD70, GD2 (ganglioside G2), EGFRvIII (epidermal growth factor variant III), sperm protein 17 (Sp17), mesothelin, PAP (prostatic acid phosphatase), prostain, TARP (T cell receptor gamma alternate reading frame protein), Trp-p8, STEAP1 (prostate transmembrane epithelial antigen 1 with six transmembrane domains), an abnormal ras protein, or an abnormal p53 protein. In another specific embodiment, the tumor-associated antigen or tumor-specific antigen is integrin αvβ3 (CD61), galectin, K-Ras (V-Ki-ras2 Kirsten rat sarcoma virus oncogene), or Ral-B.

[0254] In a specific embodiment, the TAA or TSA is CD20, CD123, CLL-1, CD38, CS-1, CD138, ROR1, FAP, MUC1, PSCA, EGFRvIII, EPHA2, or GD2. In a more specific embodiment, the TAA or TSA is CD123, CLL-1, CD38, or CS-1. In a specific embodiment, the extracellular domain of the CAR binds to CS-1. In a further specific embodiment, the extracellular domain comprises a single-chain version of elotuzumab and / or an antigen-binding fragment of elotuzumab. In a specific embodiment, the extracellular domain of the CAR binds to CD20. In a more specific embodiment, the extracellular domain of the CAR is an scFv that binds to CD20 or an antigen-binding fragment thereof.

[0255] Other tumor-associated antigens and tumor-specific antigens are known to those skilled in the art.

[0256] Antibodies and scFvs that bind to TSA and TAA are known in the art, and the nucleotide sequences encoding them are also known.

[0257] In certain specific embodiments, the antigen is not considered to be TSA or TAA, but rather an antigen associated with tumor cells or damage caused by tumors. In a specific embodiment, the antigen is a tumor microenvironment-associated antigen (TMAA). In certain embodiments, for example, TMAA is a growth factor, cytokine or interleukin, such as a growth factor, cytokine or interleukin associated with angiogenesis or vasculogenesis. Such growth factors, cytokines, or interleukins can include, for example, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), or interleukin-8 (IL-8). Tumors can also create a locally hypoxic environment in the tumor. As such, in other specific embodiments, TMAA is a hypoxia-related factor, such as HIF-1α, HIF-1β, HIF-2α, HIF-2β, HIF-3α, or HIF-3β. Tumors can also cause local damage to normal tissue and cause the release of molecules known as damage-associated molecular pattern molecules (DAMPs; also known as alarmins). Thus, in other specific embodiments, TMAA is a DAMP, such as a heat shock protein, chromatin-related protein high mobility group box 1 (HMGB1), S100A8 (MRP8, calgranulin A), S100A9 (MRP14, calgranulin B), serum amyloid A (SAA), or can be deoxyribonucleic acid, adenosine triphosphate, uric acid, or heparan sulfate. In a specific embodiment, TMAA is VEGF-A, EGF, PDGF, IGF, or bFGF.

[0258] In certain embodiments, the extracellular domain is connected to the transmembrane domain by a linker, spacer or hinge polypeptide sequence, such as a sequence derived from CD28.

[0259] In certain embodiments, the CAR contemplated herein includes an extracellular domain that binds to BCMA, a transmembrane domain, and an intracellular signaling domain. Binding of the anti-BCMA antigen-binding domain of the CAR to BCMA on the target cell surface results in clustering of the CAR and delivers an activation stimulus to the cell containing the CAR. The main feature of the CAR is to utilize the cell-specific targeting ability of monoclonal antibodies, soluble ligands, or cell-specific coreceptors to redirect the specificity of immune effector cells in a major histocompatibility (MHC)-independent manner, thereby inducing the ability to mediate proliferation, cytokine production, phagocytosis, or the production of molecules that induce cell death of target antigen-expressing cells.

[0260] In various embodiments, the CAR includes an extracellular binding domain that includes a murine anti-BCMA (e.g., human BCMA)-specific binding domain; a transmembrane domain; one or more intracellular co-stimulatory signaling domains; and a primary signaling domain.

[0261] In certain embodiments, the CAR includes an extracellular binding domain that includes a murine anti-BCMA (e.g., human BCMA) antibody or an antigen-binding fragment thereof; one or more hinge domains or spacer domains; a transmembrane domain; one or more intracellular co-stimulatory signaling domains; and a primary signaling domain.

[0262] A. Binding domain In certain embodiments, the CAR contemplated herein includes an extracellular binding domain that includes a murine anti-BCMA antibody or an antigen-binding fragment thereof that specifically binds to a human BCMA polypeptide expressed on B cells. As used herein, the terms "binding domain," "extracellular domain," "extracellular binding domain," "antigen-specific binding domain," and "extracellular antigen-specific binding domain" are used interchangeably and provide a CAR that has the ability to specifically bind to a target antigen of interest, e.g., BCMA. The binding domain can be derived from any of natural, synthetic, semi-synthetic, or recombinant sources.

[0263] As used herein, the terms "specific binding affinity", "specifically binds", "specifically bound", "specifically binding", or "specifically targets" refer to the binding of an anti-BCMA antibody or an antigen-binding fragment thereof (or a CAR containing the same) to BCMA with a binding affinity higher than the background binding. The binding domain (or a CAR containing the binding domain or a fusion protein containing the binding domain) binds or associates with BCMA "specifically" if it binds at an affinity of, for example, about 10 5 M -1 or higher or a K a (i.e., the equilibrium binding constant of a particular binding interaction in units of 1 / M). In certain embodiments, the binding domain (or its fusion protein) binds to the target at a K of about 10 6 M -1 , 10 7 M -1 , 10 8 M -1 , 10 9 M -1 , 10 10 M -1 , 10 11 M -1 , 10 12 M -1 , or 10 13 M -1 or higher. A "high affinity" binding domain (or its single-chain fusion protein) binds to the target with a K of at least 10 a M 7 , at least 10 -1 M 8 , at least 10 -1 M 9 , at least 10 -1 M 10 , at least 10 -1 M 11 , at least 10 -1 M 12 , at least 10 -1 M 13 , at least 10 -1 M arefers to a binding domain having the same. In some embodiments, the BCMA-Fc fusion polypeptide comprises the sequence set forth in SEQ ID NO: 205.

[0264] Alternatively, affinity can be defined as the equilibrium dissociation constant (K -5 for a particular binding interaction in units of M (e.g., 10 -13 M to 10 d M or less). The affinity of the binding domain polypeptides and CAR proteins according to the present disclosure can be readily determined by conventional techniques such as competitive ELISA (enzyme-linked immunosorbent assay), binding association or displacement assays using a labeled ligand, or using a surface plasmon resonance apparatus such as a Biacore T100 available from Biacore, Inc., Piscataway, NJ, or optical biosensor technologies such as an EPIC system or EnSpire available from Corning and Perkin Elmer, respectively (see also, e.g., Scatchard et al. (1949) Ann. N.Y. Acad. Sci. 51:660; and U.S. Patent Nos. 5,283,173; 5,468,614, or equivalents).

[0265] In one embodiment, the affinity of specific binding is about 2-fold, about 5-fold, about 10-fold, about 20-fold, about 50-fold, about 100-fold, or about 1000-fold or more of the background binding.

[0266] Various assays are known for evaluating binding affinity and / or determining whether a binding molecule (e.g., an antibody or fragment thereof) specifically binds to a particular ligand (e.g., an antigen such as the BCMA protein). Determining the binding affinity of a binding molecule, e.g., an antibody, for an antigen, e.g., BCMA, is within the skill of the art. For example, in some embodiments, surface plasmon resonance (SPR) analysis (e.g., see Scatchard et al., Ann. N.Y. Acad. Sci. 51:660, 1949; Wilson, Science 295:2103, 2002; Wolff et al., Cancer Res. 53:2560, 1993; and U.S. Patent Nos. 5,283,173, 5,468,614, or equivalents) using a BIAcore® device can be used to determine the binding kinetics and binding constants of complexes between two proteins (e.g., an antibody or fragment thereof, and an antigen, e.g., BCMA cell surface protein, soluble BCMA protein).

[0267] SPR measures changes in the concentration of molecules at the sensor surface as they bind to or dissociate from the sensor surface. Changes in the SPR signal are proportional to changes in the mass concentration near the surface, thereby allowing the binding kinetics between two molecules to be measured. The dissociation constant of a complex can be determined by monitoring the change in refractive index over time as buffer passes over the chip. Other suitable assays for measuring the binding of one protein to another include, for example, immunoassays such as enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA), or determination of binding by monitoring changes in the spectroscopic or optical properties of the protein through fluorescence, UV absorption, circular dichroism, or nuclear magnetic resonance (NMR). Other exemplary assays include, but are not limited to, Western blot, ELISA, analytical ultracentrifugation, spectroscopy, flow cytometry, sequencing, and detection of expressed polynucleotides or other methods for protein binding.

[0268] In certain embodiments, the extracellular binding domain of the CAR comprises an antibody or an antigen-binding fragment thereof. An "antibody" refers to a binder that specifically recognizes and binds to an epitope of an antigen, such as a peptide, lipid, polysaccharide, or nucleic acid containing an antigenic determinant, such as one recognized by an immune cell, and comprises at least the immunoglobulin variable region of the light or heavy chain of a polypeptide.

[0269] "Antigen (Ag)" refers to a compound, composition, or substance that can stimulate an animal's antibody production or T cell response, including compositions (e.g., those containing cancer-specific proteins) that are injected or absorbed by an animal. Antigens react with products of specific humoral or cellular immunity, including those induced by heterologous antigens such as the disclosed antigens. In certain embodiments, the target antigen is an epitope of the BCMA polypeptide.

[0270] "Epitope" or "antigenic determinant" refers to the region of an antigen to which a binder binds. Epitopes can be formed from contiguous amino acids or from non-contiguous amino acids juxtaposed by the tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained even when exposed to denaturing solvents, while epitopes formed by tertiary folding typically disappear when treated with a denaturing solvent. Epitopes typically contain at least 3, more usually at least 5, about 9, or about 8 - 10 amino acids in a unique spatial conformation.

[0271] Antibodies include camelid Ig, Ig NAR, Fab fragments, Fab' fragments, F(ab)'2 fragments, F(ab)'3 fragments, Fv, single-chain Fv proteins ("scFv"), bis-scFv, (scFv) 2Antigen-binding fragments of antibodies are included, such as minibodies, diabodies, triabodies, tetra-bodies, disulfide-stabilized Fv proteins ("dsFv"), and single domain antibodies (sdAb, nanobodies), as well as portions of full-length antibodies that are responsible for antigen binding. This term also includes genetically engineered forms such as chimeric antibodies (e.g., humanized mouse antibodies), heteroconjugate antibodies (e.g., bispecific antibodies), and their antigen-binding fragments. See Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, IL); Kuby, J., Immunology, 3rd Ed., W. H. Freeman & Co., New York, 1997.

[0272] As will be understood by those skilled in the art, as described elsewhere herein, a complete antibody includes two heavy chains and two light chains. Each heavy chain consists of a variable region and first, second, and third constant regions, and each light chain consists of a variable region and a constant region. Mammalian heavy chains are classified as α, δ, ε, γ, and μ. Mammalian light chains are classified as λ or κ. Immunoglobulins containing heavy chains α, δ, ε, γ, and μ are classified as immunoglobulin (Ig) A, IgD, IgE, IgG, and IgM. A complete antibody forms a "Y" shape. The axis of the "Y" consists of the second and third constant regions (fourth constant region for IgE and IgM) of the two heavy chains bound together, and a disulfide bond (interchain) is formed in the hinge. Heavy chains γ, α, and δ have a constant region composed of three tandem (in a row) Ig domains and a hinge region to add flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The second and third constant regions are called the "CH2 domain" and the "CH3 domain", respectively. Each arm of the "Y" includes the variable region of a single light chain and the variable region and first constant region of a single heavy chain bound to the constant region. The variable regions of the light and heavy chains are involved in antigen binding.

[0273] The variable regions of the light and heavy chains contain "framework" regions interrupted by three hypervariable regions, also called "complementary determining regions" or "CDRs". The CDRs can be defined or identified by conventional methods, for example, by the sequences according to Kabat et al (Wu, TT and Kabat, E. A., J Exp Med. 132(2):211-50, (1970); Borden, P. and Kabat E. A., PNAS, 84: 2440-2443 (1987); see Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1991, incorporated herein by reference), or by the structures according to Chothia et al (Chothia, C. and Lesk, A.M., J Mol. Biol., 196(4): 901-917 (1987), Chothia, C. et al, Nature, 342: 877 - 883 (1989)).

[0274] The sequences of the framework regions of different light or heavy chains are relatively conserved within a species such as humans. The framework region of an antibody is the combination of the framework regions of the constituent light and heavy chains, and plays a role in arranging and aligning the CDRs in three-dimensional space. CDRs are mainly involved in binding to the epitopes of antigens. The CDRs of each chain are typically called CDR1, CDR2, and CDR3, are numbered consecutively starting from the N-terminus, and are typically identified by the chain on which a particular CDR is located. Thus, the CDRs located in the variable domain of the heavy chain of an antibody are called CDRH1, CDRH2, and CDRH3, and the CDRs located in the variable domain of the light chain of an antibody are called CDRL1, CDRL2, and CDRL3. Antibodies with different specificities (i.e., different binding sites for different antigens) have different CDRs. Although it is the CDRs that differ among antibodies, only a limited number of amino acid positions within the CDRs are directly involved in antigen binding. These positions within the CDRs are called specificity-determining residues (SDRs). Exemplary examples of light chain CDRs suitable for constructing the humanized BCMA CAR contemplated herein include, but are not limited to, the CDR sequences set forth in SEQ ID NOs: 1-3. Exemplary examples of heavy chain CDRs suitable for constructing the humanized BCMA CAR contemplated herein include, but are not limited to, the CDR sequences set forth in SEQ ID NOs: 4-6.

[0275] References to "V H " or "VH" refer to the variable region of an immunoglobulin heavy chain and include the variable regions of the antibodies, Fvs, scFvs, dsFvs, Fabs, or other antibody fragments disclosed herein. References to "V L " or "VL" refer to the variable region of an immunoglobulin light chain and include the variable regions of the antibodies, Fvs, scFvs, dsFvs, Fabs, or other antibody fragments disclosed herein.

[0276] A "monoclonal antibody" is an antibody produced by a single clone of B lymphocytes or an antibody produced by a cell into which the light and heavy chain genes of a single antibody have been introduced. Monoclonal antibodies are produced by methods known to those skilled in the art, for example, by creating cells that form hybrid antibodies from the fusion of myeloma cells and immune spleen cells. Monoclonal antibodies include humanized monoclonal antibodies.

[0277] A "chimeric antibody" has framework residues from one species, such as a human, and CDRs (generally conferring antigen-binding properties) from another species, such as a mouse. In certain embodiments, the CAR contemplated herein includes an antigen-specific binding domain that is a chimeric antibody or an antigen-binding fragment thereof.

[0278] A "humanized" antibody is an immunoglobulin that includes a human framework region and one or more CDRs from a non-human (e.g., mouse, rat, or synthetic) immunoglobulin. The non-human immunoglobulin that provides the CDRs is referred to as the "donor," and the human immunoglobulin that provides the framework is referred to as the "acceptor."

[0279] Also, among the anti-BCMA antibodies included in the provided CARs are human antibodies. A "human antibody" is an antibody having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human or human cell that utilizes a human antibody repertoire or other human antibody coding sequences, including a human antibody library, or an antibody produced by a non-human source. This term excludes humanized forms of non-human antibodies that include non-human antigen-binding regions, e.g., those in which all or substantially all of the CDRs are non-human. The term includes antigen-binding fragments of human antibodies.

[0280] Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies having human variable regions in response to an antigen challenge. Such animals typically contain all or part of the human immunoglobulin locus in place of the endogenous immunoglobulin locus, or are present extrachromosomally or randomly integrated into the chromosomes of the animal. In such transgenic animals, the endogenous immunoglobulin locus is generally inactivated. Human antibodies can also be derived from human antibody libraries, including phage display and cell-free libraries, that contain sequences encoding antibodies derived from the human repertoire.

[0281] In certain embodiments, mouse anti-BCMA (e.g., human BCMA) antibodies or antigen-binding fragments thereof include, but are not limited to, camelid Ig (camelized antibodies (VHH)), Ig NAR, Fab fragments, Fab’ fragments, F(ab)’ 2 fragments, F(ab)’ 3 fragments, Fv, single-chain Fv antibodies (“scFv”), bis-scFv, (scFv) 2 , minibodies, diabodies, triabodies, tetra-bodies, disulfide-stabilized Fv proteins (“dsFv”), and single domain antibodies (sdAb, nanobodies).

[0282] As used herein, “camelid Ig” or “camelid VHH” refers to the smallest known antigen-binding unit of a heavy chain antibody (Koch-Nolte, et al, FASEB J., 21: 3490-3498 (2007)). “Heavy chain antibody” or “camelid antibody” refers to an antibody that contains two VH domains and no light chain (Riechmann L. et al, J. Immunol. Methods 231:25-38 (1999), International Publication Nos. WO94 / 04678 and WO94 / 25591, U.S. Patent No. 6,005,079).

[0283] The "IgNAR" of "immunoglobulin new antigen receptor" refers to a kind of antibody derived from the shark immune repertoire, which consists of a homodimer of one variable new antigen receptor (VNAR) domain and five constant new antigen receptor (CNAR) domains. IgNAR represents part of the scaffold of the smallest known immunoglobulin-based protein, is very stable, and has efficient binding properties. This unique stability is due to both (i) the underlying Ig scaffold that exhibits a significant number of charged hydrophilic surface-exposed residues compared to the conventional antibody VH and VL domains found in mouse antibodies, and (ii) the structural features stabilized in the complementarity-determining region (CDR) loops, including inter-loop disulfide bridges and intra-loop hydrogen bonds.

[0284] Papain digestion of an antibody generates two identical antigen-binding fragments called "Fab" fragments, each having one antigen-binding site, and the remaining "Fc" fragment reflects the ability to crystallize easily from its name. Pepsin treatment yields an F(ab’)2 fragment that has two antigen-binding sites and can still cross-link antigens.

[0285] "Fv" is the smallest antibody fragment that contains a complete antigen-binding site. In one embodiment, the double-stranded Fv species consists of a dimer in which one heavy-chain variable domain and one light-chain variable domain are tightly non-covalently bound. In the single-chain Fv (scFv) species, one heavy-chain and one light-chain variable domain can be covalently linked by a flexible peptide linker such that the light and heavy chains can associate in a "dimer" structure similar to that in the double-stranded Fv species. It is in such a structure that the three hypervariable regions (HVRs) of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Overall, six HVRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of the Fv containing only the three HVRs specific for the antigen), although with a lower affinity than the entire binding site, has the ability to recognize and bind the antigen.

[0286] The Fab fragment contains the variable domains of the heavy and light chains, and further contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. The Fab' fragment differs from the Fab fragment by the addition of several residues at the carboxy terminus of the heavy chain CH1 domain that includes one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for a Fab' in which the cysteine residue(s) of the constant domain have a free thiol group. The F(ab')2 antibody fragment was originally generated as a pair of Fab' fragments with a hinge cysteine in between. Other chemical linkages of antibody fragments are also known.

[0287] The term "diabody" refers to an antibody fragment having two antigen-binding sites, the fragment comprising a heavy chain variable domain (VH) linked to a light chain variable domain (VL) within the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains on the other chain, forming two antigen-binding sites. The diabody can be bivalent or bispecific. Diabodies are described in more detail, for example, in European Patent Application Publication No. 404,097, International Publication No. WO1993 / 01161, Hudson et al., Nat. Med. 9:129-134 (2003); Hollinger et al., PNAS USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

[0288] "Single domain antibody" or "sdAb" or "nanobody" refers to an antibody fragment consisting of the variable region of an antibody heavy chain (VH domain) or the variable region of an antibody light chain (VL domain) (Holt, L., et al, 2003, Trends in Biotechnology, 21(11): 484-490).

[0289] The "single-chain Fv" or "scFv" antibody fragment contains the VH and VL domains of the antibody, and these domains are present in a single polypeptide chain in either orientation (e.g., VL-VH or VH-VL). Generally, the scFv polypeptide further includes a polypeptide linker between the VH domain and the VL domain such that the scFv can form the desired structure for antigen binding. For a review of scFv, see, for example, Pluckthuen in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York, 1994), pp. 269-315.

[0290] In certain embodiments, the CARs contemplated herein include an antigen-specific binding domain that is a murine scFv. Single-chain antibodies can be cloned from the V-region genes of hybridomas specific for a desired target. The generation of such hybridomas is routine. Techniques that can be used to clone the variable region heavy chain (VH) and variable region light chain (VL) are described, for example, in Orlandi et al., PNAS, 1989; 86: 3833-3837.

[0291] In some embodiments, the CAR comprises the variable heavy (V H ) region and / or variable light (V L)It includes the BCMA-binding portion or portion of an antibody molecule such as a domain, for example, an scFv antibody fragment. Chimeric receptors such as CARs generally include a portion of an antibody molecule, generally the variable heavy (VH) chain region and / or variable light (VL) chain region of the antibody, for example, an extracellular antigen-binding domain such as an scFv antibody fragment. In some embodiments, the provided BCMA-binding CAR contains an antibody that confers the BCMA-binding properties of the provided CAR, for example, an anti-BCMA antibody, or an antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding domain can be any anti-BCMA antibody described or derived from any anti-BCMA antibody described. For example, see Carpenter et al., Clin. Cancer Res., 2013, 19(8):2048-2060; Feng et al., Scand. J. Immunol. (2020) 92:e12910; U.S. Patent No. 9,034,324, U.S. Patent No. 9,765,342, U.S. Patent Application Publication No. 2016 / 0046724, No. 2017 / 0183418, and International Publication Nos. WO2016 / 090320, WO2016 / 090327, WO2016 / 094304, WO2016 / 014565, WO2016 / 014789, WO2010 / 104949, WO2017 / 025038, WO2017 / 173256, WO2018 / 085690, or WO2021 / 091978. Any of such anti-BCMA antibodies or antigen-binding fragments can be used in the provided CAR. In some embodiments, the anti-BCMA CAR contains one or more single-domain anti-BCMA antibodies. In some embodiments, the one or more single-domain anti-BCMA antibodies are derived from the antibodies described in International Publication No. WO2017025038 or WO2018028647. In some embodiments, the anti-BCMA CAR includes the single-domain antibody sequence described in SEQ ID NO: 111. In some embodiments, the anti-BCMA CAR contains two single-domain anti-BCMA antibodies. In some embodiments, the two single-domain anti-BCMA antibodies are derived from one or more antibodies described in International Publication No. WO2017025038 or WO2018028647.In some embodiments, the BCMA binding domain is described in International Publication No. WO2017025038 or WO2018028647, and includes or consists of, with or without a signal peptide, A37353-G4S-A37917 (where G4S is a linker between two binding domains), provided, for example, in SEQ ID NOs: 300, 301, and 302 of International Publication No. WO2017025038 or WO2018028647. In some embodiments, the anti-BCMA CAR contains an antigen-binding domain that is a scFv containing a variable heavy chain (V H ) and / or variable light chain (V L ) region. In some embodiments, the scFv containing a variable heavy chain (V H ) and / or variable light chain (V L ) region is derived from an antibody described in International Publication No. WO2016 / 090320 or WO2016 / 090327. In some embodiments, the scFv containing a variable heavy chain (V H ) and / or variable light chain (V L ) region is derived from an antibody described in International Publication No. WO2019 / 090003. In some embodiments, the scFv containing a variable heavy chain (V H ) and / or variable light chain (V L ) region is derived from an antibody described in International Publication No. WO2016 / 094304 or WO2021 / 091978. In some embodiments, the scFv containing a variable heavy chain (V H ) and / or variable light chain (V L ) region is derived from an antibody described in International Publication No. WO2018 / 133877. In some embodiments, the scFv containing a variable heavy chain (V H ) and / or variable light chain (V L) The scFv containing the [[area]] is derived from the antibody described in International Publication No. WO2019 / 149269. In some embodiments, the anti-BCMA CAR is any one described in International Publication No. WO2019 / 173636 or WO2020 / 051374A. In some embodiments, the anti-BCMA CAR is any one described in International Publication No. WO2018 / 102752. In some embodiments, the anti-BCMA CAR is any one described in International Publication No. WO2020 / 112796 or WO2021 / 173630.

[0292] In some embodiments, an antibody, such as an anti-BCMA antibody or antigen-binding fragment, comprises a heavy chain and / or light chain variable (V H or V L ) region sequence as described, or a sufficient antigen-binding portion thereof. In some embodiments, the anti-BCMA antibody, such as an antigen-binding fragment, comprises a V H region sequence containing CDR-H1, CDR-H2 and / or CDR-H3 as described or a sufficient antigen-binding portion thereof. In some embodiments, the anti-BCMA antibody, such as an antigen-binding fragment, comprises a V L region sequence containing CDR-L1, CDR-L2 and / or CDR-L3 as described or a sufficient antigen-binding portion. In some embodiments, the anti-BCMA antibody, such as an antigen-binding fragment, contains a V H region sequence containing CDR-H1, CDR-H2 and / or CDR-H3 as described and a V L region sequence containing CDR-L1, CDR-L2 and / or CDR-L3 as described. Also, among the antibodies, there are those having at least (about) 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical sequences to such sequences.

[0293] In some embodiments, the antibody is a single-domain antibody (sdAb) comprising only a V H region sequence or a sufficient antigen-binding portion thereof, such as the above-mentioned V HIt is any of the arrays (e.g., CDR-H1, CDR-H2, CDR-H3 and / or CDR-H4).

[0294] In some embodiments, the antibodies provided herein (e.g., anti-BCMA antibodies) or antigen-binding fragments thereof that contain a V H region further comprise a light chain or a sufficient antigen-binding portion thereof. For example, in some embodiments, the antibody or antigen-binding fragment thereof comprises a V H region and a V L region, or a sufficient antigen-binding portion of a V H region and a V L region. In such embodiments, the sequence of the V H region can be any of the sequences of V H described above. In some such embodiments, the antibody is an antigen-binding fragment such as a Fab or scFv. In some such embodiments, the antibody is a full-length antibody that also contains a constant region.

[0295] In some embodiments, the CAR is an anti-BCMA CAR that is specific for BCMA, e.g., human BCMA. Chimeric antigen receptors comprising anti-BCMA antibodies, including murine anti-human BCMA antibodies and human anti-human BCMA antibodies, and cells expressing such chimeric receptors have been previously reported. See Carpenter et al., Clin Cancer Res., 2013, 19(8):2048-2060, U.S. Patent No. 9,765,342, International Publication Nos. WO2016 / 090320, WO2016090327, WO2010104949A2, WO2016 / 0046724, WO2016 / 014789, WO2016 / 094304, WO2017 / 025038, and WO2017173256.

[0296] In some embodiments, the anti-BCMA CAR comprises a variable heavy chain (V H ) and / or a variable light chain (V L) contains an antigen-binding domain such as an scFv containing the [[]] region. In some embodiments, the antigen-binding domain is an antibody fragment containing variable heavy (VH) and variable light (VL) regions. In some embodiments, the anti-BCMA CAR is derived from an antibody described in International Publication No. WO2016 / 090320 or WO2016 / 090327, the variable heavy chain (V H ) and / or variable light chain (V L ) regions, and contains an antigen-binding domain such as an scFv.

[0297] In some embodiments, the antigen-binding domain is an antibody fragment containing variable heavy chain (V H ) and variable light chain (V L ) regions. In some aspects, the V H region has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the V H region amino acid sequence described in any of SEQ ID NOs: 8, 56, 58, 60, 66, 68, 70, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 178, 180, 182 and 184, or includes it; and / or the V L region has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the V L region amino acid sequence described in any of SEQ ID NOs: 7, 57, 59, 61, 67, 69, 71, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 179, 181, 183 and 185, or includes it.

[0298] In some embodiments, the antigen-binding domain such as an scFv contains the V H described in SEQ ID NO: 8 and the V L described in SEQ ID NO: 7. In some embodiments, the antigen-binding domain such as an scFv contains the V H described in SEQ ID NO: 56 and the V described in SEQ ID NO: 57L contains. In some embodiments, an antigen-binding domain such as scFv comprises the V set forth in SEQ ID NO: 58 H and the V set forth in SEQ ID NO: 59 L contains. In some embodiments, an antigen-binding domain such as scFv comprises the V set forth in SEQ ID NO: 60 H and the V set forth in SEQ ID NO: 61 L contains. In some embodiments, an antigen-binding domain such as scFv comprises the V set forth in SEQ ID NO: 66 H and the V set forth in SEQ ID NO: 67 L contains. In some embodiments, an antigen-binding domain such as scFv comprises the V set forth in SEQ ID NO: 68 H and the V set forth in SEQ ID NO: 69 L contains. In some embodiments, an antigen-binding domain such as scFv comprises the V set forth in SEQ ID NO: 70 H and the V set forth in SEQ ID NO: 71 L contains. In some embodiments, an antigen-binding domain such as scFv comprises the V set forth in SEQ ID NO: 75 H and the V set forth in SEQ ID NO: 76 L contains. In some embodiments, an antigen-binding domain such as scFv comprises the V set forth in SEQ ID NO: 77 H and the V set forth in SEQ ID NO: 78 L contains. In some embodiments, an antigen-binding domain such as scFv comprises the V set forth in SEQ ID NO: 79 H and the V set forth in SEQ ID NO: 80 L contains. In some embodiments, an antigen-binding domain such as scFv comprises the V set forth in SEQ ID NO: 81 H and the V set forth in SEQ ID NO: 82 L contains. In some embodiments, an antigen-binding domain such as scFv comprises the V set forth in SEQ ID NO: 83 H and the V set forth in SEQ ID NO: 84 L contains. In some embodiments, an antigen-binding domain such as scFv comprises the V set forth in SEQ ID NO: 85 H and the V set forth in SEQ ID NO: 86 L contains. In some embodiments, an antigen-binding domain such as scFv comprises the V set forth in SEQ ID NO: 87 Hand V set forth in SEQ ID NO: 88 L and contains. In some embodiments, an antigen-binding domain such as an scFv is V set forth in SEQ ID NO: 89 H and V set forth in SEQ ID NO: 90 L and contains. In some embodiments, an antigen-binding domain such as an scFv is V set forth in SEQ ID NO: 91 H and V set forth in SEQ ID NO: 92 L and contains. In some embodiments, an antigen-binding domain such as an scFv is V set forth in SEQ ID NO: 93 H and V set forth in SEQ ID NO: 94 L and contains. In some embodiments, an antigen-binding domain such as an scFv is V set forth in SEQ ID NO: 95 H and V set forth in SEQ ID NO: 96 L and contains. In some embodiments, an antigen-binding domain such as an scFv is V set forth in SEQ ID NO: 97 H and V set forth in SEQ ID NO: 98 L and contains. In some embodiments, an antigen-binding domain such as an scFv is V set forth in SEQ ID NO: 99 H and V set forth in SEQ ID NO: 100 L and contains. In some embodiments, an antigen-binding domain such as an scFv is V set forth in SEQ ID NO: 101 H and V set forth in SEQ ID NO: 102 L and contains. In some embodiments, an antigen-binding domain such as an scFv is V set forth in SEQ ID NO: 103 H and V set forth in SEQ ID NO: 104 L and contains. In some embodiments, an antigen-binding domain such as an scFv is V set forth in SEQ ID NO: 105 H and V set forth in SEQ ID NO: 106 L and contains. In some embodiments, an antigen-binding domain such as an scFv is V set forth in SEQ ID NO: 107 H and V set forth in SEQ ID NO: 108 L and contains. In some embodiments, an antigen-binding domain such as an scFv is V set forth in SEQ ID NO: 109 H and V set forth in SEQ ID NO: 110 LIt contains. In some embodiments, an antigen-binding domain such as an scFv comprises the V set forth in SEQ ID NO: 178 H and the V set forth in SEQ ID NO: 179 L It contains. In some embodiments, an antigen-binding domain such as an scFv comprises the V set forth in SEQ ID NO: 180 H and the V set forth in SEQ ID NO: 181 L It contains. In some embodiments, an antigen-binding domain such as an scFv comprises the V set forth in SEQ ID NO: 182 H and the V set forth in SEQ ID NO: 183 L It contains. In some embodiments, an antigen-binding domain such as an scFv comprises the V set forth in SEQ ID NO: 184 H and the V set forth in SEQ ID NO: 185 L It contains. In some embodiments, V H or V L exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity with any of the aforementioned V H or V L sequences and has an amino acid sequence that retains binding to BCMA. In some embodiments, the V H region is the amino terminus of the V L region. In some embodiments, the V H region is the carboxy terminus of the V L region. In some embodiments, the variable heavy chain and the variable light chain are connected by a linker. In some embodiments, the linker is as set forth in SEQ ID NO: 63, 22, 64, or 72. In some embodiments, the linker is as set forth in SEQ ID NO: 54 or 55.

[0299] Among the anti-BCMA CARs provided, an antibody or antigen-binding fragment comprises a V having an amino acid sequence that is the sequence set forth in SEQ ID NO: 8, or has at least (about) 90%, (about) 91%, (about) 92%, (about) 93%, (about) 94%, (about) 95%, (about) 96%, (about) 97%, (about) 98%, or (about) 99% identity with SEQ ID NO: 8 HContains a domain: V comprising the amino acid sequence set forth in SEQ ID NO: 7, or an amino acid sequence having at least (about) 90%, (about) 91%, (about) 92%, (about) 93%, (about) 94%, (about) 95%, (about) 96%, (about) 97%, (about) 98%, or (about) 99% identity to SEQ ID NO: 7 L There is a CAR containing the domain. In some embodiments, the antibody or antigen-binding fragment of the provided CAR has a V domain having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively H domain, and a V domain having CDRL1, CDRL2, and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively L domain. In some embodiments, the antibody or antigen-binding fragment of the provided CAR has a V domain having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 222, 223, and 224, respectively H domain, and a V domain having CDRL1, CDRL2, and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 225, 226, and 227, respectively L domain. In some embodiments, the antibody or antigen-binding fragment of the provided CAR has a V domain having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 228, 229, and 230, respectively H domain, and a V domain having CDRL1, CDRL2, and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 231, 232, and 233, respectively L domain. In some embodiments, the antibody or antigen-binding fragment of the provided CAR has a V domain having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 234, 235, and 236, respectively H domain, and a V domain having CDRL1, CDRL2, and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 237, 238, and 239, respectively L domain. In some embodiments, the V H domain comprises the sequence set forth in SEQ ID NO: 8, and the V LThe region includes the sequence set forth in SEQ ID NO: 7. In some embodiments, the antibody or antigen-binding fragment is a single-chain antibody fragment such as an scFv. In some embodiments, the scFv includes the amino acid sequence set forth in SEQ ID NO: 38, or an amino acid sequence having at least (about) 90%, (about) 91%, (about) 92%, (about) 93%, (about) 94%, (about) 95%, (about) 96%, (about) 97%, (about) 98%, or (about) 99% identity to SEQ ID NO: 38. In some embodiments, the anti-BCMA CAR has the amino acid sequence set forth in SEQ ID NO: 37, or an amino acid sequence having at least (about) 90%, (about) 91%, (about) 92%, (about) 93%, (about) 94%, (about) 95%, (about) 96%, (about) 97%, (about) 98%, or (about) 99% identity to SEQ ID NO: 37. In some embodiments, the anti-BCMA CAR is encoded by the polynucleotide sequence set forth in SEQ ID NO: 240, or a polynucleotide sequence having at least (about) 90%, (about) 91%, (about) 92%, (about) 93%, (about) 94%, (about) 95%, (about) 96%, (about) 97%, (about) 98%, or (about) 99% identity to SEQ ID NO: 240.

[0300] Among the anti-BCMA CARs provided, there are those in which the antibody or antigen-binding fragment contains a V H region that includes the sequence set forth in SEQ ID NO: 60, or an amino acid sequence having at least (about) 90%, (about) 91%, (about) 92%, (about) 93%, (about) 94%, (about) 95%, (about) 96%, (about) 97%, (about) 98%, or (about) 99% identity to SEQ ID NO: 60; and a V L region that includes the sequence set forth in SEQ ID NO: 61, or an amino acid sequence having at least (about) 90%, (about) 91%, (about) 92%, (about) 93%, (about) 94%, (about) 95%, (about) 96%, (about) 97%, (about) 98%, or (about) 99% identity to SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment of the CAR provided has CDRH1, CDRH2, and CDRH3 that include the amino acid sequences of SEQ ID NOs: 206, 207, and 208, respectively, in the V HA V region having CDRL1, CDRL2, and CDRL3, which contain the amino acid sequences of SEQ ID NOs: 216, 217, and 218, respectively L A provided antibody or antigen-binding fragment of a CAR contains a V region having CDRH1, CDRH2, and CDRH3, which contain the amino acid sequences of SEQ ID NOs: 209, 210, and 215, respectively H A V region having CDRL1, CDRL2, and CDRL3, which contain the amino acid sequences of SEQ ID NOs: 216, 217, and 218, respectively L A provided antibody or antigen-binding fragment of a CAR contains a V region having CDRH1, CDRH2, and CDRH3, which contain the amino acid sequences of SEQ ID NOs: 211, 212, and 215, respectively H A V region having CDRL1, CDRL2, and CDRL3, which contain the amino acid sequences of SEQ ID NOs: 216, 217, and 218, respectively L A provided antibody or antigen-binding fragment of a CAR contains a V region having CDRH1, CDRH2, and CDRH3, which contain the amino acid sequences of SEQ ID NOs: 213, 214, and 215, respectively H A provided antibody or antigen-binding fragment of a CAR contains a V region having CDRH1, CDRH2, and CDRH3, which contain the amino acid sequences of SEQ ID NOs: 213, 214, and 215, respectively H A V region having CDRL1, CDRL2, and CDRL3, which contain the amino acid sequences of SEQ ID NOs: 219, 220, and 218, respectively L A provided antibody or antigen-binding fragment of a CAR contains a V region having CDRH1, CDRH2, and CDRH3, which contain the amino acid sequences of SEQ ID NOs: 213, 214, and 215, respectively H The V region contains the sequence set forth in SEQ ID NO: 60, and the V LThe region includes the sequence set forth in SEQ ID NO: 61. In some embodiments, the antibody or antigen-binding fragment is a single-chain antibody fragment such as an scFv. In some embodiments, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 221, or an amino acid sequence having at least (about) 90%, (about) 91%, (about) 92%, (about) 93%, (about) 94%, (about) 95%, (about) 96%, (about) 97%, (about) 98%, or (about) 99% identity to SEQ ID NO: 221. In some embodiments, the anti-BCMA CAR has the amino acid sequence set forth in SEQ ID NO: 157, or an amino acid sequence having at least (about) 90%, (about) 91%, (about) 92%, (about) 93%, (about) 94%, (about) 95%, (about) 96%, (about) 97%, (about) 98%, or (about) 99% identity to SEQ ID NO: 157. In some embodiments, the anti-BCMA CAR has the amino acid sequence set forth in SEQ ID NO: 158, or an amino acid sequence having at least (about) 90%, (about) 91%, (about) 92%, (about) 93%, (about) 94%, (about) 95%, (about) 96%, (about) 97%, (about) 98%, or (about) 99% identity to SEQ ID NO: 158.

[0301] In some embodiments, the scFv comprises the amino acid sequence set forth in any one of SEQ ID NOs: 241-272, or an amino acid sequence having at least 90, 95, 96, 97, 98, 99, or 100% sequence identity to the sequence set forth in any one of SEQ ID NOs: 241-272.

[0302] In some embodiments, the antigen-binding domain comprises an sdAb. In some embodiments, the antigen-binding domain contains the sequence set forth in SEQ ID NO: 77. In some embodiments, the antigen-binding domain comprises a sequence that is at least (about) 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, or 100% identical to the sequence set forth in SEQ ID NO: 77.

[0303] In some embodiments, the CAR comprises an amino acid sequence set forth in any one of SEQ ID NO: 37 and SEQ ID NOs: 124-174, or an amino acid sequence having at least 90%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence set forth in any one of SEQ ID NO: 37 and SEQ ID NOs: 124-174.

[0304] In certain embodiments, an antigen-specific binding domain that is a murine scFv that binds to a human BCMA polypeptide. Exemplary examples of variable heavy chains suitable for constructing a BCMA CAR contemplated herein include, but are not limited to, the amino acid sequence set forth in SEQ ID NO: 8. Exemplary examples of variable light chains suitable for constructing a BCMA CAR contemplated herein include, but are not limited to, the amino acid sequence set forth in SEQ ID NO: 7.

[0305] The BCMA-specific binding domains provided herein also include one, two, three, four, five, or six CDRs. Such CDRs can be non-human CDRs or modified non-human CDRs selected from CDRL1, CDRL2, and CDRL3 of the light chain and CDRH1, CDRH2, and CDRH3 of the heavy chain. In certain embodiments, the BCMA-specific binding domain comprises (a) a light chain variable region comprising light chain CDRL1, light chain CDRL2, and light chain CDRL3, and (b) a heavy chain variable region comprising heavy chain CDRH1, heavy chain CDRH2, and heavy chain CDRH3.

[0306] B. Linker In certain embodiments, the CARs contemplated herein can include linker residues between various domains, added, for example, for proper spacing and conformation of the molecule. In certain embodiments, the linker is a variable region linker sequence. "Variable region linker sequence" means V H and V LA linker is an amino acid sequence that connects the domains and provides a spacer function that accommodates the interaction of the two sub-binding domains such that the resulting polypeptide retains the same specific binding affinity for the same target molecule as an antibody containing the same light and heavy chain variable regions. The CARs contemplated herein may contain one, two, three, four, or five or more linkers. In certain embodiments, the linker is about 1 to about 25 amino acids, about 5 to about 20 amino acids, or about 10 to about 20 amino acids, or any intervening amino acids in length. In some embodiments, the linker is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more amino acids in length.

[0307] Illustrative examples of linkers include glycine polymers (G) n ; glycine-serine polymer (G 1-5 S 1-5 ) n (n is an integer of at least 1, 2, 3, 4, or 5); glycine-alanine polymers; alanine-serine polymers; and other flexible linkers known in the art. Glycine and glycine-serine polymers are relatively unstructured and therefore can function as neutral tethers between domains of fusion proteins such as CARs described herein. Glycine has access to much more phi-psi space than alanine and is much less restricted than residues with longer side chains (see Scheraga, Rev. Computational Chem. 11173-142 (1992)). Those skilled in the art will recognize that the design of CARs in certain embodiments can include linkers that are fully or partially flexible, such that the linker can include one or more moieties that confer a less flexible structure, as well as flexible linkers, to provide the desired CAR structure.

[0308] Other exemplary linkers include, but are not limited to, the following amino acid sequences: GGG; DGGGS (SEQ ID NO: 12); TGEKP (SEQ ID NO: 13) (see, e.g., Liu et al., PNAS 5525-5530 (1997)); GGRR (SEQ ID NO: 14) (Pomerantz et al. 1995, supra); (GGGGS) n (where n = 1, 2, 3, 4 or 5 and GGGGS is identified as SEQ ID NO: 15) (Kim et al., PNAS 93, 1156-1160 (1996)); EGKSSGSGSESKVD (SEQ ID NO: 16) (Chaudhary et al., 1990, Proc. Natl. Acad. Sci. U.S.A. 87:1066-1070); KESGSVSSEQLAQFRSLD (SEQ ID NO: 17) (Bird et al., 1988, Science 242:423-426); GGRRGGGS (SEQ ID NO: 18); LRQRDGERP (SEQ ID NO: 19); LRQKDGGGSERP (SEQ ID NO: 20); LRQKd(GGGS) 2 ERP (SEQ ID NO: 21). Alternatively, the flexible linker can be designed rationally using a computer program (Desjarlais & Berg, PNAS 90:2256-2260 (1993), PNAS 91:11099-11103 (1994)) that can model both the DNA binding site and the peptide itself, or by phage display methods. In one embodiment, the linker comprises the following amino acid sequence: GSTSGSGKPGSGEGSTKG (SEQ ID NO: 22) (Cooper et al., Blood, 101(4): 1637-1644 (2003)).

[0309] In some embodiments, the antibody is an antigen-binding fragment such as scFv, with a heavy chain variable region (V H ) and a light chain variable region (V LIt includes one or more linkers that connect two antibody domains or regions such as these. The linker is typically a peptide linker, for example, a flexible and / or soluble peptide linker. Some linkers are rich in glycine and serine and / or optionally threonine. In some embodiments, the linker further includes charged residues such as lysine and / or glutamic acid, and the solubility can be improved. In some embodiments, the linker further includes one or more prolines. In some aspects, linkers rich in glycine and serine (and / or threonine) contain at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of such amino acid(s). In some embodiments, they contain at least (about) 50%, 55%, 60%, 70%, or 75% glycine, serine, and / or threonine. In some embodiments, the linker is substantially composed entirely of glycine, serine, and / or threonine. The linker generally has a length of about 5 to about 50 amino acids, typically (about) 10 to (about) 30, for example, between 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, and in some examples, has a length of 10 to 25 amino acids. Exemplary linkers include linkers having various repeat numbers of the sequence GGGGS (4GS; SEQ ID NO: 15) or GGGS (3GS; SEQ ID NO: 62), for example, repeats between 2, 3, 4, and 5 of such sequences. Exemplary linkers include those having or consisting of the sequences set forth in SEQ ID NO: 63 (GGGGSGGGGSGGGGS), SEQ ID NO: 22 (GSTSGSGKPGSGEGSTKG), SEQ ID NO: 64 (SRGGGGSGGGGSGGGGSLEMA), or SEQ ID NO: 72 (ASGGGGSGGRASGGGGS). In some embodiments, the linker is the sequence set forth in SEQ ID NO: 22 or includes it. In some embodiments, the linker is the sequence set forth in SEQ ID NO: 274 or includes it.

[0310] C. Spacer domain In certain embodiments, one or more "spacer domains" follow the binding domain of the CAR, which refers to a region that moves the antigen-binding domain away from the effector cell surface to enable proper cell / cell contact, antigen binding, and activation (Patel et al., Gene Therapy, 1999; 6: 412-419). Spacer domains can be derived from any of natural, synthetic, semi-synthetic, or recombinant sources. In certain embodiments, the spacer domain is part of an immunoglobulin and includes, but is not limited to, one or more heavy chain constant regions, such as CH2 and CH3. The spacer domain can include the amino acid sequence of a naturally occurring immunoglobulin hinge region or a modified immunoglobulin hinge region.

[0311] In some embodiments, the antibody portion of the recombinant receptor, e.g., the CAR, f...

Claims

**Claim 1** A method for treating a tumor or cancer in a subject in need thereof, comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. A method as described above. **Claim 2** The method according to claim 1, wherein the prior therapy is a topoisomerase inhibitor therapy. **Claim 3** The method according to claim 1, wherein the prior therapy is a proteasome inhibitor therapy. **Claim 4** The method according to any one of claims 1 to 3, wherein step (a) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the subject has received the prior therapy. **Claim 5** A method for treating a tumor or cancer in a subject in need thereof, comprising: (a) administering to the subject a topoisomerase inhibitor therapy or a proteasome inhibitor therapy; (b) obtaining T cells from the subject at least about 6 months after the administration in step (a); (c) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (d) administering the manufactured T cells to the subject for treating the tumor or cancer. A method as described above. **Claim 6** The method according to claim 5, wherein in step (a), a topoisomerase inhibitor therapy is administered to the subject. **Claim 7** The method according to claim 5, wherein in step (a), a proteasome inhibitor therapy is administered to the subject. **Claim 8** The method according to any one of claims 5 to 7, wherein step (b) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the administration in step (a). **Claim 9** A method for treating a tumor or cancer in a subject in need thereof, wherein the subject has been administered a prior therapy selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy, and the method comprises: (a) selecting a subject who has received the prior therapy at a time point more than 6 months ago. (b) Obtaining T cells from a subject, wherein the obtaining is performed at least about 6 months after the administration of the prior therapy to the subject; (c) Manufacturing T cells, wherein the manufactured T cells contain a recombinant receptor directed towards tumor or cancer cells; (d) Administering the manufactured T cells to the subject for treating the tumor or cancer A method comprising the above. [

10. ] The method according to claim 9, wherein the prior therapy is a topoisomerase inhibitor therapy. [

11. ] The method according to claim 9, wherein the prior therapy is a proteasome inhibitor therapy. [

12. ] The method according to any one of claims 9 to 11, wherein in step (a), the prior therapy is administered at a time point before 7 months, 8 months, or 9 months ago. [

13. ] The method according to any one of claims 9 to 12, wherein in step (b), the isolation is performed at least about 7 months, at least about 8 months, or at least about 9 months after the administration of the prior therapy to the subject. [

14. ] A method for treating a tumor or cancer in a subject in need thereof, comprising administering to the subject T cells manufactured from peripheral blood mononuclear cells (PBMCs) isolated from the patient, wherein the subject has been administered a prior therapy selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy, and at the time when the PBMCs are isolated, the subject has received the prior therapy last at least about 6 months before the time when the PBMCs are isolated. [

15. ] The method according to claim 14, wherein the subject has been administered a topoisomerase inhibitor therapy. [

16. ] The method according to claim 14, wherein the subject has been administered a proteasome inhibitor therapy. [

17. ] The method according to any one of claims 14 to 16, wherein the subject has received the prior therapy last at least about 7 months, at least about 8 months, or at least about 9 months before the time when the PBMCs are isolated. [

18. ] A method for treating cancer caused by B cell maturation antigen (BCMA) - expressing cells in a subject in need thereof, comprising: (a) Obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating cancer selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy. T cells are obtained from a subject at least about 6 months after the subject has received a prior therapy, and (b) manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed to BCMA, wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells, and (c) administering the manufactured BCMA CAR T cells to a subject to treat cancer A method comprising.

19. The method according to claim 18, wherein the prior therapy is a topoisomerase inhibitor therapy.

20. The method according to claim 18, wherein the prior therapy is a proteasome inhibitor therapy.

21. The method according to any one of claims 18 to 20, wherein step (a) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the subject has received the prior therapy.

22. A method for treating cancer caused by B cell maturation antigen (BCMA) -expressing cells in a subject in need thereof, the method comprising: (a) administering to the subject a topoisomerase inhibitor therapy or a proteasome inhibitor therapy; and (b) obtaining T cells from the subject at least about 6 months after the administration in step (a); and (c) manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed to BCMA, wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (d) administering the manufactured BCMA CAR T cells to the subject to treat cancer A method comprising.

23. The method according to claim 22, wherein in step (a), a topoisomerase inhibitor therapy is administered to the subject.

24. The method according to claim 22, wherein in step (a), a proteasome inhibitor therapy is administered to the subject.

25. The method according to any one of claims 22 to 24, wherein step (b) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the administration in step (a).

26. A method for treating cancer caused by B cell maturation antigen (BCMA) -expressing cells in a subject in need thereof, wherein the subject has received a prior therapy selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy as part of the treatment of the cancer, and the method comprises: (a) selecting a subject who has been administered a prior therapy at a time more than six months ago; (b) obtaining T cells from the subject, wherein the obtaining is performed at least about six months after the prior therapy has been administered to the subject; (c) manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed to BCMA, wherein the manufactured T cells comprise a recombinant receptor directed to cancer cells; (d) administering the manufactured BCMA CAR T cells to the subject for treating cancer A method comprising the steps above. **Claim 27** The method according to claim 26, wherein the prior therapy is a topoisomerase inhibitor therapy. **Claim 28** The method according to claim 26, wherein the prior therapy is a proteasome inhibitor therapy. **Claim 29** The method according to any one of claims 26 to 28, wherein in step (a), the prior therapy is administered at a time more than seven months, more than eight months, or more than nine months ago. **Claim 30** The method according to any one of claims 26 to 29, wherein in step (b), the obtaining is performed at least about seven months, at least about eight months, or at least about nine months after the prior therapy has been administered to the subject. **Claim 31** A method for treating cancer caused by B cell maturation antigen (BCMA) - expressing cells in a subject in need thereof, comprising administering to the subject chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed to BCMA, which are manufactured from peripheral blood mononuclear cells (PBMCs) isolated from the patient, wherein the subject has been administered a prior therapy selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy, and at the time when the PBMCs are isolated, the subject has received the prior therapy last at least about six months before the time when the PBMCs are isolated. **Claim 32** The method according to claim 31, wherein the subject has been administered a topoisomerase inhibitor therapy. **Claim 33** The method according to claim 31, wherein the subject has been administered a proteasome inhibitor therapy. **Claim 34** The method according to any one of claims 31 to 33, wherein the subject has received the prior therapy last at least about seven months, at least about eight months, or at least about nine months before the time when the PBMCs are isolated. **Claim 35** A method for reducing the time until recovery from neutropenia after T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing the T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. A method comprising the above steps.

36. A method for reducing the time until recovery from thrombocytopenia after T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing T cells for treating the tumor or cancer; and (c) administering the manufactured T cells to the subject for treating the tumor or cancer. A method comprising the above steps.

37. The method according to claim 35 or claim 36, wherein the prior therapy is topoisomerase inhibitor therapy.

38. The method according to claim 35 or claim 36, wherein the prior therapy is proteasome inhibitor therapy.

39. The method according to any one of claims 35 to 38, wherein step (a) is performed at least about 7 months before step (a), 8 months before step (a), or at least about 9 months after the subject has received the prior therapy.

40. A method for reducing the time until recovery from neutropenia after T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed to BCMA, wherein the manufactured T cells comprise a recombinant receptor directed to cancer cells; (c) administering the manufactured BCMA CAR T cells to a subject for treating cancer A method comprising the steps of: **Claim 41** A method for reducing the time until recovery from thrombocytopenia after T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from a subject, the subject having previously received a prior therapy for treating cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells being obtained from the subject at least about 6 months after the subject received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed to BCMA, wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; (c) administering the manufactured BCMA CAR T cells to a subject for treating cancer A method comprising the steps of: **Claim 42** The method according to claim 40 or claim 41, wherein the prior therapy is topoisomerase inhibitor therapy. **Claim 43** The method according to claim 40 or claim 41, wherein the prior therapy is proteasome inhibitor therapy. **Claim 44** The method according to any one of claims 40 to 43, wherein step (a) is performed at least about 7 months before step (a), about 8 months before step (a), or at least about 9 months after the subject received the prior therapy. **Claim 45** A method for manufacturing T cells from a subject, comprising: (a) obtaining T cells from a subject, the subject having previously received a prior therapy for treating a tumor or cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells being obtained from the subject at least about 6 months after the subject received the prior therapy; (b) manufacturing T cells comprising a recombinant receptor A method comprising the steps of: **Claim 46** The method according to claim 45, wherein the prior therapy is topoisomerase inhibitor therapy. **Claim 47** The method according to claim 45, wherein the prior therapy is proteasome inhibitor therapy. **Claim 48** The method according to any one of claims 45 to 47, wherein step (a) is performed at least about 7 months, at least about 8 months, and at least about 9 months after the subject has received prior therapy. **Claim 49** A method for manufacturing T cells from a subject, comprising: (a) administering to the subject a topoisomerase inhibitor therapy or a proteasome inhibitor therapy as part of the treatment of a tumor or cancer; (b) obtaining T cells from the subject at least about 6 months after the administration in step (a); and (c) manufacturing T cells comprising a recombinant receptor. **Claim 50** The method according to claim 49, wherein in step (a), a topoisomerase inhibitor therapy is administered to the subject. **Claim 51** The method according to claim 49, wherein in step (a), a proteasome inhibitor therapy is administered to the subject. **Claim 52** The method according to any one of claims 49 to 51, wherein step (b) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the administration in step (a). **Claim 53** A method for manufacturing T cells from a subject, wherein the subject has received a prior therapy selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy as part of the treatment of a tumor or cancer, and the method comprises: (a) selecting a subject who has received the prior therapy at a time point more than 6 months ago; (b) obtaining T cells from the subject, wherein the obtaining is performed at least about 6 months after the prior therapy has been administered to the subject; and (c) manufacturing T cells comprising a recombinant receptor. **Claim 54** The method according to claim 53, wherein the prior therapy is a topoisomerase inhibitor therapy. **Claim 55** The method according to claim 53, wherein the prior therapy is a proteasome inhibitor therapy. **Claim 56** The method according to any one of claims 53 to 55, wherein in step (a), the prior therapy is administered at a time point more than 7 months, more than 8 months, or more than 9 months ago. **Claim 57** The method according to any one of claims 53 to 56, wherein in step (b), the obtaining is performed at least about 7 months, at least about 8 months, or at least about 9 months after the prior therapy has been administered to the subject. **Claim 58** A method for manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells) from a subject, comprising: ​ ​ (a) Obtaining T cells from a subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the T cells are obtained from the subject at least about 6 months after the subject has received the prior therapy, and (b) manufacturing BCMA CAR T cells comprising a recombinant receptor A method comprising:

59. The method according to claim 58, wherein the prior therapy is topoisomerase inhibitor therapy.

60. The method according to claim 58, wherein the prior therapy is proteasome inhibitor therapy.

61. The method according to any one of claims 58 to 60, wherein step (a) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the subject has received the prior therapy.

62. A method for manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed from a subject to BCMA, comprising: administering to the subject a topoisomerase inhibitor therapy or a proteasome inhibitor therapy as part of the treatment of cancer; obtaining T cells from the subject at least about 6 months after the administration in step (a); and manufacturing BCMA CAR T cells comprising a recombinant receptor A method comprising:

63. The method according to claim 62, wherein in step (a), a topoisomerase inhibitor therapy is administered to the subject.

64. The method according to claim 62, wherein in step (a), a proteasome inhibitor therapy is administered to the subject.

65. The method according to any one of claims 62 to 64, wherein step (b) is performed at least about 7 months, at least about 8 months, or at least about 9 months after the administration in step (a).

66. A method for manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed from a subject to BCMA, wherein the subject has been administered a prior therapy selected from topoisomerase inhibitor therapy or proteasome inhibitor therapy, and the method comprises: selecting a subject who has received the prior therapy at a time point more than 6 months ago; obtaining T cells from the subject, wherein the obtaining is performed at least about 6 months after the prior therapy has been administered to the subject; and manufacturing BCMA CAR T cells comprising a recombinant receptor A method comprising

67. The method according to claim 66, wherein the prior therapy is a topoisomerase inhibitor therapy.

68. The method according to claim 66, wherein the prior therapy is a proteasome inhibitor therapy.

69. The method according to any one of claims 66 to 68, wherein in step (a), the prior therapy is administered at a time point more than 7 months, 8 months, or 9 months ago.

70. The method according to claim 67 or claim 68, wherein in step (b), the obtaining is performed at least about 7 months, at least about 8 months, or at least about 9 months after the prior therapy is administered to the subject.

71. A method for treating a tumor or cancer in a subject in need thereof, comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from an anti-CD38 agent therapy, an immunomodulatory agent therapy, or an anti-SLAMF agent therapy, and the T cells are obtained from the subject about 1 month to at most about 3 months after the subject has received the prior therapy; (b) manufacturing T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; (c) administering the manufactured T cells to the subject for treating the tumor or cancer A method comprising

72. The method according to claim 71, wherein step (a) is performed about 2 months or at most about 3 months after the subject has received the anti-CD38 agent therapy.

73. The method according to claim 71, wherein step (a) is performed about 1 month, at most about 2 months, or at most about 3 months after the subject has received the immunomodulatory agent therapy.

74. The method according to claim 71, wherein step (a) is performed about 2 months after the subject has received the anti-SLAMF agent therapy.

75. A method for treating a tumor or cancer in a subject in need thereof, comprising: (a) administering an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy to the subject; (b) obtaining T cells from the subject about 1 month to at most about 3 months after the administration in step (a); (c) manufacturing T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer; (d) administering the manufactured T cells to the subject for treating the tumor or cancer A method comprising

76. The method according to claim 75, wherein in step (a), an anti-CD38 agent therapy is administered to a subject, and in step (b), T cells are obtained from the subject about 2 months or up to about 3 months after step (a).

77. The method according to claim 75, wherein in step (a), an immunomodulatory agent therapy is administered to a subject, and in step (b), T cells are obtained from the subject about 1 month, up to about 2 months, or up to about 3 months after step (a).

78. The method according to claim 75, wherein in step (a), an anti-SLAMF agent therapy is administered to a subject, and in step (b), T cells are obtained from the subject about 2 months after step (a).

79. A method for treating a tumor or cancer in a subject in need thereof, wherein the subject has been administered a prior therapy selected from an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy, and the method comprises: (a) selecting a subject who has been administered the prior therapy within the past about 1 month to within the past about 3 months; (b) obtaining T cells from the subject, wherein the obtaining is performed within the past about 1 month to within the past about 3 months; (c) manufacturing T cells, wherein the manufactured T cells comprise a recombinant receptor directed to tumor or cancer cells; (d) administering the manufactured T cells to the subject for treating the tumor or cancer. A method comprising the above steps.

80. The method according to claim 79, wherein in step (a), the subject has been administered an anti-CD38 agent therapy within the past about 2 months or within the past about 3 months.

81. The method according to claim 79, wherein in step (a), the subject has been administered an immunomodulatory agent therapy within the past about 1 month, within the past about 2 months, or within the past about 3 months.

82. The method according to claim 79, wherein in step (a), the subject has been administered an anti-SLAMF agent therapy within the past about 2 months.

83. The method according to claim 79, wherein in step (b), the obtaining is performed within the past about 2 months or within the past about 3 months after the anti-CD38 therapy is administered to the subject.

84. The method according to claim 79, wherein in step (b), the obtaining is performed within the past about 1 month, within the past about 2 months, or within the past about 3 months after the immunomodulatory agent therapy is administered to the subject.

85. The method according to claim 79, wherein, in step (b), the obtaining is performed within about 2 months in the past after the anti-SLAMF agent therapy has been administered to the subject.

86. A method for treating a tumor or cancer in a subject in need thereof, comprising administering to the subject T cells produced from peripheral blood mononuclear cells (PBMCs) isolated from the patient, wherein the subject has been administered a prior therapy selected from an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy, and wherein, at the time when the PBMCs are isolated, the subject has received the prior therapy most recently about 1 month to at most about 3 months before the time when the PBMCs are isolated.

87. The method according to claim 86, wherein the subject has received the anti-CD38 agent therapy most recently about 2 months or at most about 3 months before the time when the PBMCs are isolated.

88. The method according to claim 86, wherein the subject has received the immunomodulatory agent therapy most recently about 1 month, at most about 2 months, or at most about 3 months before the time when the PBMCs are isolated.

89. The method according to claim 86, wherein the subject has received the anti-SLAMF agent therapy most recently about 2 months before the time when the PBMCs are isolated.

90. A method for treating cancer caused by B cell maturation antigen (BCMA) expressing cells in a subject in need thereof, comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from an anti-CD38 agent therapy, an immunomodulatory agent therapy, or an anti-SLAMF agent therapy, and the T cells are obtained from the subject about 1 month to at most about 3 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed to BCMA, wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; and (c) administering the manufactured BCMA CAR T cells to the subject for treating the cancer.

91. The method according to claim 90, wherein step (a) is performed about 2 months or at most about 3 months after the subject has received the anti-CD38 agent therapy.

92. The method according to claim 90, wherein step (a) is performed about 1 month, at most about 2 months, or at most about 3 months after the subject has received the immunomodulatory agent therapy.

93. The method according to claim 90, wherein step (a) is performed about 2 months after the subject has received anti-SLAMF agent therapy.

94. A method for treating cancer caused by B cell maturation antigen (BCMA) -expressing cells in a subject in need thereof, comprising: (a) administering to the subject an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy; (b) obtaining T cells from the subject about 1 month to up to about 3 months after step (a); (c) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; (d) administering the manufactured BCMA CAR T cells to the subject to treat the cancer. A method comprising the steps of:

95. The method according to claim 94, wherein in step (a), an anti-CD38 agent therapy is administered to the subject, and in step (b), T cells are obtained from the subject about 2 months or up to about 3 months after step (a).

96. The method according to claim 94, wherein in step (a), an immunomodulatory agent therapy is administered, and in step (b), T cells are obtained from the subject about 1 month, up to about 2 months, or up to about 3 months after step (a).

97. The method according to claim 94, wherein in step (a), an anti-SLAMF agent therapy is administered, and in step (b), T cells are obtained from the subject about 2 months after step (a).

98. A method for treating cancer caused by B cell maturation antigen (BCMA) -expressing cells in a subject in need thereof, wherein the subject has received a prior therapy selected from an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy, and the method comprises: (a) selecting a subject who has received the prior therapy within the past about 1 month to within the past about 3 months; (b) obtaining T cells from the subject, wherein the obtaining is performed within the past about 1 month to within the past about 3 months; (c) manufacturing chimeric antigen receptor (CAR) T cells directed to BCMA (BCMA CAR T cells), wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; (d) administering the manufactured BCMA CAR T cells to the subject to treat the cancer. A method comprising the steps of:

99. The method according to claim 98, wherein in step (a), the subject has been administered an anti-CD38 agent therapy within about 2 months or within about 3 months.

100. The method according to claim 98, wherein in step (a), the subject has been administered an immunomodulatory agent therapy within about 1 month, within about 2 months, or within about 3 months.

101. The method according to claim 98, wherein in step (a), the subject has been administered an anti-SLAMF agent therapy within about 2 months.

102. The method according to claim 98, wherein in step (b), the obtaining is performed within about 2 months or within about 3 months after the anti-CD38 agent therapy has been administered to the subject.

103. The method according to claim 98, wherein in step (b), the obtaining is performed within about 1 month, within about 2 months, or within about 3 months after the immunomodulatory agent therapy has been administered to the subject.

104. The method according to claim 98, wherein in step (b), the obtaining is performed within about 2 months after the anti-SLAMF agent therapy has been administered to the subject.

105. A method for treating cancer caused by B cell maturation antigen (BCMA) -expressing cells in a subject in need thereof, comprising administering to the subject chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed to BCMA produced from peripheral blood mononuclear cells (PBMCs) isolated from the patient, wherein the subject has been administered a prior therapy selected from an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy, and at the time when the PBMCs are isolated, the subject has received the prior therapy at most about 3 months and about 1 month before the time when the PBMCs are isolated.

106. The method according to claim 105, wherein the subject has received the anti-CD38 agent therapy at most about 3 months and about 2 months before the time when the PBMCs are isolated.

107. The method according to claim 105, wherein the subject has received the immunomodulatory agent therapy at most about 3 months, at most about 2 months, or at most about 1 month before the time when the PBMCs are isolated.

108. The method according to claim 105, wherein the subject has received the anti-SLAMF agent therapy at most about 2 months before the time when the PBMCs are isolated.

109. A method for reducing the time until recovery from neutropenia after T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from the subject, The subject has previously received a prior therapy for treating a tumor or cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, or anti-SLAMF therapy, and the T cells are obtained from the subject about 1 month to up to about 3 months after the subject has received the prior therapy, and (b) manufacturing T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer, and (c) administering the manufactured T cells to the subject for treating the tumor or cancer comprising a method.

110. A method for reducing the time until recovery from thrombocytopenia after T cell therapy in a subject, wherein the T cell therapy is (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, or anti-SLAMF therapy, and the T cells are obtained from the subject about 1 month to up to about 3 months after the subject has received the prior therapy, and (b) manufacturing T cells, wherein the manufactured T cells comprise a recombinant receptor directed to cells of the tumor or cancer, and (c) administering the manufactured T cells to the subject for treating the tumor or cancer comprising a method.

111. The method according to claim 109 or claim 110, wherein step (a) is performed about 2 months or up to about 3 months after the subject has received anti-CD38 agent therapy.

112. The method according to claim 109 or claim 110, wherein step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received immunomodulatory agent therapy.

113. The method according to claim 109 or claim 110, wherein step (a) is performed about 2 months after the subject has received anti-SLAMF agent therapy.

114. A method for reducing the time until recovery from neutropenia after T cell therapy in a subject, wherein the T cell therapy is (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy, and the T cells are obtained from the subject about 1 month to up to about 3 months after the subject has received the prior therapy, and (b) manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed to BCMA, wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; (c) administering the manufactured BCMA CAR T cells to a subject for treating cancer A method comprising the steps of: **Claim 115** A method for reducing the time until recovery from thrombocytopenia after T cell therapy in a subject, wherein the T cell therapy comprises: (a) obtaining T cells from the subject, wherein the subject has previously received prior therapy for treating cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy, and the T cells are obtained from the subject about 1 month to at most about 3 months after the subject has received the prior therapy; (b) manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed to BCMA, wherein the manufactured CAR T cells comprise a recombinant receptor directed to cancer cells; (c) administering the manufactured BCMA CAR T cells to a subject for treating cancer A method comprising the steps of: **Claim 116** The method according to claim 114 or claim 115, wherein step (a) is performed about 2 months or at most about 3 months after the subject has received anti-CD38 agent therapy. **Claim 117** The method according to claim 114 or claim 115, wherein step (a) is performed 1 month, at most about 2 months, or at most about 3 months after the subject has received immunomodulatory agent therapy. **Claim 118** The method according to claim 114 or claim 115, wherein step (a) is performed about 2 months after the subject has received anti-SLAMF agent therapy. **Claim 119** A method for manufacturing T cells from a subject, comprising: (a) obtaining T cells from the subject, wherein the subject has previously received prior therapy for treating a tumor or cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, or anti-SLAMF agent therapy; (b) manufacturing T cells comprising a recombinant receptor A method comprising the steps of: **Claim 120** The method according to claim 119, wherein step (a) is performed about 2 months or at most about 3 months after the subject has received anti-CD38 agent therapy. **Claim 121** The method according to claim 119, wherein step (a) is performed about 1 month, at most about 2 months, or at most about 3 months after the subject has received immunomodulatory agent therapy. Claim 122 The method according to claim 119, wherein step (a) is performed approximately 2 months after the subject has received anti-SLAMF agent therapy. Claim 123 A method for producing T cells from a subject, comprising: (a) administering to the subject an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy as part of the treatment of a tumor or cancer; (b) obtaining T cells from the subject approximately 1 month to a maximum of approximately 3 months after step (a); (c) producing T cells comprising a recombinant receptor and the method includes. Claim 124 The method according to claim 123, wherein in step (a), an anti-CD38 agent therapy is administered to the subject, and in step (b), T cells are obtained from the subject approximately 2 months or a maximum of approximately 3 months after step (a). Claim 125 The method according to claim 123, wherein in step (a), an immunomodulatory agent therapy is administered to the subject, and in step (b), T cells are obtained from the subject approximately 1 month, a maximum of approximately 2 months, or a maximum of approximately 3 months after step (a). Claim 126 The method according to claim 123, wherein in step (a), an anti-SLAMF agent therapy is administered to the subject, and in step (b), T cells are obtained from the subject a maximum of approximately 2 months after step (a). Claim 127 A method for producing T cells from a subject in need thereof, wherein the subject has been administered a prior therapy selected from an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy, and the method comprises: (a) selecting a subject who has been administered the prior therapy within the past approximately 1 month to a maximum of within the past approximately 3 months; (b) obtaining T cells from the subject, wherein the obtaining is performed within the past approximately 1 month to a maximum of within the past approximately 3 months; (c) producing T cells comprising a recombinant receptor and the method includes. Claim 128 The method according to claim 127, wherein in step (a), the subject has been administered an anti-CD38 agent therapy within the past approximately 2 months or within the past approximately 3 months. Claim 129 The method according to claim 127, wherein in step (a), the subject has been administered an anti-immunomodulatory agent therapy within the past approximately 1 month, within the past approximately 2 months, or within the past approximately 3 months. Claim 130 The method according to claim 127, wherein in step (a), the subject has been administered an anti-SLAMF agent therapy within the past approximately 2 months. Claim 131 The method according to claim 127, wherein, in step (b), the obtaining is performed within about 2 months or within about 3 months in the past after the anti-CD38 therapy has been administered to the subject.

132. The method according to claim 127, wherein, in step (b), the obtaining is performed within about 1 month, within about 2 months, or within about 3 months in the past after the immunomodulatory agent therapy has been administered to the subject.

133. The method according to claim 127, wherein, in step (b), the obtaining is performed within about 2 months in the past after the anti-SLAMF agent therapy has been administered to the subject.

134. A method for manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed from a subject to BCMA, comprising: (a) obtaining T cells from the subject, wherein the subject has previously received a prior therapy for treating a tumor or cancer selected from anti-CD38 agent therapy, immunomodulatory agent therapy, or anti-SLAMF agent therapy; (b) manufacturing BCMA CAR T cells comprising a recombinant receptor.

135. The method according to claim 134, wherein step (a) is performed about 2 months or up to about 3 months after the subject has received anti-CD38 agent therapy.

136. The method according to claim 134, wherein step (a) is performed about 1 month, up to about 2 months, or up to about 3 months after the subject has received immunomodulatory agent therapy.

137. The method according to claim 134, wherein step (a) is performed about 2 months after the subject has received anti-SLAMF agent therapy.

138. A method for manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed from a subject to BCMA, comprising: (a) administering anti-CD38 agent therapy, immunomodulatory agent therapy, and anti-SLAMF agent therapy to the subject as part of the treatment of cancer; (b) obtaining T cells from the subject about 1 month to up to about 3 months after step (a); (c) manufacturing BCMA CAR T cells comprising a recombinant receptor.

139. The method according to claim 138, wherein in step (a), anti-CD38 agent therapy is administered to the subject, and in step (b), T cells are obtained from the subject about 2 months or up to about 3 months after step (a).

140. The method according to claim 138, wherein in step (a), an immunomodulatory agent therapy is administered to a subject, and in step (b), T cells are obtained from the subject about 1 month, at most about 2 months, or at most about 3 months after step (a).

141. The method according to claim 138, wherein in step (a), an anti-SLAMF agent therapy is administered to a subject, and in step (b), T cells are obtained from the subject about 2 months after step (a).

142. A method for manufacturing chimeric antigen receptor (CAR) T cells (BCMA CAR T cells) directed from a subject in need thereof to BCMA, wherein the subject has been administered a prior therapy selected from an anti-CD38 agent therapy, an immunomodulatory agent therapy, and an anti-SLAMF agent therapy, and the method comprises: (a) selecting a subject who has been administered a prior therapy within about 1 month to at most within about 3 months in the past; (b) obtaining T cells from the subject, wherein the obtaining is performed within about 1 month to at most within about 3 months in the past; (c) manufacturing BCMA CAR T cells comprising a recombinant receptor The method comprising the steps of.

143. The method according to claim 142, wherein in step (a), the subject has been administered an anti-CD38 agent therapy within about 2 months or within about 3 months in the past.

144. The method according to claim 142, wherein in step (a), the subject has been administered an immunomodulatory agent therapy within about 1 month, within about 2 months, or within about 3 months in the past.

145. The method according to claim 142, wherein in step (a), the subject has been administered an anti-SLAMF agent therapy within about 2 months in the past.

146. The method according to claim 142, wherein in step (b), the obtaining is performed within about 2 months or within about 3 months in the past after the anti-CD38 therapy has been administered to the subject.

147. The method according to claim 142, wherein in step (b), the obtaining is performed within about 1 month, within about 2 months, or within about 3 months in the past after the immunomodulatory agent therapy has been administered to the subject.

148. The method according to claim 142, wherein in step (b), the obtaining is performed within about 2 months in the past after the anti-SLAMF agent therapy has been administered to the subject.

149. The tumor or cancer is lymphoma, lung cancer, breast cancer, prostate cancer, liver cancer, bile duct cancer, glioma, colorectal adenocarcinoma, myelodysplasia, adrenocortical cancer, thyroid cancer, nasopharyngeal cancer, melanoma, skin cancer, colon cancer, desmoid tumor, fibromatosis, small round cell tumor, endocrine tumor, Ewing sarcoma, peripheral primitive neuroectodermal tumor, solid embryonal cell tumor, hepatoblastoma, neuroblastoma, non-rhabdomyosarcomatous soft tissue sarcoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, Wilms tumor, glioblastoma, myxoma, fibroma, lipoma, chronic lymphocytic leukemia (small lymphocytic lymphoma), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, MALT lymphoma, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma, T-cell prolymphocytic leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), juvenile chronic myeloid leukemia (JCML), juvenile myelomonocytic leukemia (JMML), T-cell large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma, nasal type, enteropathy-type T-cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK cell lymphoma, mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (not otherwise specified), anaplastic large cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or multiple myeloma, the method according to any one of claims 1 to 148.

150. The cancer is multiple myeloma, chronic lymphocytic leukemia, or non-Hodgkin lymphoma, the method according to any one of claims 1 to 149.

151. The cancer is non-Hodgkin lymphoma, and the non-Hodgkin lymphoma is Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, or mantle cell lymphoma, the method according to claim 150.

152. The method according to claim 150, wherein the cancer is multiple myeloma.

153. The method according to claim 152, wherein the multiple myeloma is high-risk multiple myeloma.

154. The method according to claim 152 or claim 153, wherein the multiple myeloma is relapsed and / or refractory multiple myeloma.

155. The method according to any one of claims 152 to 154, wherein the multiple myeloma is high-risk multiple myeloma, and the high-risk multiple myeloma is a disease characterized by R-ISS stage III disease and / or early relapse.

156. The method according to any one of claims 1 to 155, wherein the produced T cells are tumor-specific T cells, chimeric antigen receptor (CAR) T cells, engineered T cell receptor (TCR) T cells, or tumor-infiltrating lymphocytes (TIL).

157. The method according to any one of claims 1 to 156, wherein the produced T cells are chimeric antigen receptor (CAR) T cells.

158. The production of T cells comprises (a) isolating PBMC from a leukapheresis sample, and (b) introducing a recombinant nucleic acid encoding a chimeric antigen receptor (CAR) into the isolated cells The method according to any one of claims 1 to 17, 35 to 39, 45 to 57, 71 to 89, 109 to 113, 119 to 133, or 149 to 157.

159. The production of BCMA CAR T cells comprises (a) isolating T cells from a leukapheresis sample, and (b) introducing a recombinant nucleic acid encoding a chimeric antigen receptor (CAR) into the isolated cells The method according to any one of claims 18 to 34, 40 to 44, 58 to 70, 90 to 108, 114 to 118, or 134 to 157.

160. The method according to claim 158 or claim 159, wherein the introducing is by transduction using a viral vector comprising a recombinant nucleic acid encoding a CAR.

161. The method according to claim 160, wherein the viral vector is a lentiviral vector.

162. Before the introducing, the production further comprises stimulating the isolated PBMC or isolated T cells with an agent capable of activating the cells. The method according to any one of claims 158 to 161.

163. The method according to claim 162, wherein the agent comprises an anti-CD3 antibody and / or an anti-CD28 antibody.

164. The method according to any one of claims 158 to 163, wherein the manufacturing further comprises expanding cells into which a recombinant nucleic acid encoding a chimeric antigen receptor (CAR) has been introduced.

165. The method according to claim 164, wherein the CAR is an anti-BCMA CAR.

166. The method according to any one of claims 18 to 34, 40 to 44, 58 to 70, 90 to 108, 114 to 118, or 134 to 157, or 159 to 165, wherein the BCMA CAR T cells comprise a CAR directed to BCMA, and the CAR directed to BCMA comprises an antibody or antibody fragment that targets BCMA.

167. The method according to any one of claims 18 to 34, 40 to 44, 58 to 70, 90 to 108, 114 to 118, or 134 to 157, or 159 to 166, wherein the BCMA CAR T cells comprise a CAR directed to BCMA, and the CAR directed to BCMA comprises a single-chain Fv antibody or antibody fragment (scFv).

168. The method according to any one of claims 18 to 34, 40 to 44, 58 to 70, 90 to 108, 114 to 118, or 134 to 157, or 159 to 167, wherein the chimeric antigen receptor (CAR) comprises an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling region that binds to BCMA.

169. The method according to claim 168, wherein the intracellular signaling region further comprises a co-stimulatory signaling domain.

170. The method according to claim 169, wherein the co-stimulatory signaling domain comprises the intracellular signaling domain of CD28, 4-1BB, or ICOS, or a signaling portion thereof.

171. The method according to claim 169 or claim 170, wherein the co-stimulatory signaling domain is between the transmembrane domain and the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain.

172. The method according to any one of claims 168 to 171, wherein the transmembrane domain is a transmembrane domain derived from CD28 or CD8, optionally a transmembrane domain derived from human CD28 or CD8, or comprises the same.

173. The method according to any one of claims 18-34, 40-44, 58-70, 90-108, 114-118, or 134-157, or 159-172, wherein the CAR further comprises an extracellular spacer between the antigen-binding domain and the transmembrane domain.

174. The method according to claim 173, wherein the spacer is derived from CD8, and optionally, the spacer is the CD8 alpha hinge.

175. The method according to claim 173 or claim 174, wherein the transmembrane domain and the spacer are derived from CD8.

176. The method according to any one of claims 18-34, 40-44, 58-70, 90-108, 114-118, or 134-157, or 159-175, wherein the BCMA CAR T cell comprises a CAR directed to BCMA, and the CAR directed to BCMA comprises SEQ ID NO:

38.

177. The method according to any one of claims 18-34, 40-44, 58-70, 90-108, 114-118, or 134-157, or 159-176, wherein the BCMA CAR T cell is an idecabtagene vicleucel cell.

178. The method according to any one of claims 18-34, 40-44, 58-70, 90-108, 114-118, or 134-157, or 159-175, wherein the BCMA CAR T cell is a siltuximab autoleucel cell.

179. The method according to any one of claims 14-17 or 86-89, wherein the subject undergoes an apheresis procedure to collect PBMCs for the production of T cells prior to administration to the subject.

180. The method according to claim 179, wherein the apheresis procedure is a leukapheresis procedure.

181. The method according to any one of claims 31-34 or 105-108, wherein the subject undergoes an apheresis procedure to collect PBMCs for the production of BCMA CAR T cells prior to administration to the subject.

182. The method according to claim 181, wherein the apheresis procedure is a leukapheresis procedure.

183. The method according to any one of claims 1-17, 35-39, 45-57, 71-89, 109-113, 119-133, 149-158, 160-165, or 179-180, wherein the T cells are administered by intravenous infusion.

184. The method according to any one of claims 18-34, 40-44, 58-70, 90-108, 114-118, or 134-157, 159-178, or 181-182, wherein the BCMA CAR T cells are administered by intravenous injection.

185. The method according to any one of claims 1-184, wherein the subject is a human.

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