Methods for dosing and treatment with combined checkpoint inhibitor and CAR T cell therapy

Abstract

Provided herein are methods and uses of combination therapy involving T cell therapy, e.g., CAR T cell therapy, and checkpoint inhibitor therapy, e.g., anti-PD-1 antibodies and / or anti-LAG3 antibodies, for treating a subject with cancer, such as lymphoma, as well as related methods, uses, and articles of manufacture.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 167,596, filed March 29, 2021, entitled "Methods for Dosing and Treatment with a Combination of Checkpoint Inhibitor Therapy and CAR T-Cell Therapy," the entire contents of which are incorporated by reference for all purposes.

[0002] Incorporation by reference to sequence listing This application is being filed with an electronic Sequence Listing, which is provided as a file entitled 735042024940SeqList.txt, created on March 28, 2022, and which is 41,457 bytes in size. The information in the electronic Sequence Listing is incorporated by reference in its entirety.

[0003] Field The present disclosure relates, in some aspects, to methods and uses of combination therapy involving T cell therapy, e.g., CAR T cell therapy, and checkpoint inhibitor therapy, e.g., anti-PD-1 antibody and / or anti-LAG3 antibody, for treating a subject with cancer, such as lymphoma, as well as related methods, uses, and articles of manufacture. The T cell therapy includes cells expressing a recombinant receptor, such as a chimeric antigen receptor (CAR). [Background technology]

[0004] A variety of strategies are available for cell therapy to treat cancer, such as adoptive cell therapy, which involves administering cells that express chimeric receptors, such as chimeric antigen receptors (CARs) and / or other recombinant antigen receptors, specific to the disease or disorder of interest, as well as other adoptive immune cell and adoptive T cell therapies.In some cases, endogenous T cells, engineered T cells, or both may be exhausted, reducing their effectiveness.Therefore, improved methods are needed, for example, to overcome such exhaustion and increase the effectiveness of these methods.Methods and uses that meet such needs are provided. Summary of the Invention

[0005] Provided herein are methods of treating cancer, the methods comprising: (1) administering to a subject with a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of at least two doses, wherein (i) the first dose is administered between days 2 and 20, inclusive; and (ii) the doses are administered about every two weeks (Q2W) or about every four weeks (Q4W) in an amount of 140 or about 140 mg to 580 or about 580 mg, inclusive.

[0006] In some embodiments, the first dose is administered between days 8 and 15, inclusive. In some embodiments, the first dose is administered on day 8. In some embodiments, the first dose is administered on day 15.

[0007] In some embodiments, the amount of PD-1 inhibitor is at or about 160 mg to 560 mg or about 560 mg. In some embodiments, the amount of PD-1 inhibitor is at or about 240 mg or 480 mg or about 480 mg. In some embodiments, the amount of PD-1 inhibitor is 240 mg. In some embodiments, the amount of PD-1 inhibitor is 360 mg. In some embodiments, the amount of PD-1 inhibitor is 480 mg.

[0008] In some embodiments, the dose is administered about every two weeks (Q2W). In some embodiments, the dose is administered about every four weeks (Q4W). In some embodiments, the amount of PD-1 inhibitor is 240 mg and the dose is administered about Q2W, or the amount of PD-1 inhibitor is 480 mg and the dose is administered about Q4W. In some embodiments, the amount of PD-1 inhibitor is 240 mg and the dose is administered about Q2W. In some embodiments, the amount of PD-1 inhibitor is 360 mg and the dose is administered about Q3W. In some embodiments, the amount of PD-1 inhibitor is 480 mg and the dose is administered about Q4W.

[0009] In any of the provided embodiments, the method further comprises administering a dose of the LAG3 inhibitor to the subject about every two weeks (Q2W). In some embodiments, the method further comprises administering a dose of the LAG3 inhibitor to the subject about every three weeks (Q3W). In some embodiments, the method further comprises administering a dose of the LAG3 inhibitor to the subject about every four weeks (Q4W).

[0010] In any of the provided embodiments, the method further includes administering to the subject a LAG3 inhibitor in a dosing regimen comprising administering a dose of the LAG3 inhibitor on each of the same days as the dose of the PD-1 inhibitor is administered.

[0011] In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 60 or about 60 mg to 1040 or about 1040 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 120 or about 120 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 160 or about 160 mg to 1040 or about 1040 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 160 or about 160 mg to 320 or about 320 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 160 or about 160 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 240 or about 240 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 400 or about 400 mg to 560 or about 560 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 480 or about 480 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of at or about 880 mg to at or about 1040 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of at or about 960 mg.

[0012] In some embodiments, the amount of PD-1 inhibitor is 120 mg and the dose is administered about Q2W. In some embodiments, the amount of PD-1 inhibitor is 240 mg and the dose is administered about Q4W. In some embodiments, the amount of PD-1 inhibitor is 360 mg and the dose is administered about Q3W. In some embodiments, the amount of PD-1 inhibitor is 240 mg and the dose is administered about Q4W. In some embodiments, the amount of PD-1 inhibitor is 480 mg and the dose is administered about Q4W.

[0013] Also provided are methods of treating cancer, including: (1) administering to a subject having a CD19-expressing cancer on day 1 a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) (i) administering a first amount of a PD-1 inhibitor from at or about 140 mg to at or about 580 mg, inclusive, for a first cycle, wherein at least one dose of the first amount of the PD-1 inhibitor is administered in the first cycle. between days 2 and 20, inclusive; and (ii) for a second cycle, a second amount of the PD-1 inhibitor of at or about 380 mg to 580 or about 580 mg, inclusive, administered about once every four weeks (Q4W), wherein at least two doses of the second amount of the PD-1 inhibitor are administered in the second cycle, and the first dose of the second cycle is administered between days 50 and 65.

[0014] Also provided are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer on day 1 a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) (i) for a first cycle, a first amount of a PD-1 inhibitor of 140, or about 140 to 340, or about 340 mg, inclusive, administered once every two weeks (Q2W) or once every four weeks (Q4W), wherein at least two doses of the first amount of the PD-1 inhibitor are administered in the first cycle. and (ii) for a second cycle, a second amount of a PD-1 inhibitor from at or about 140 mg to 580 or about 580 mg, inclusive, administered about once every four weeks (Q4W), wherein at least two doses of the second amount are administered in the second cycle, and the first dose of the second cycle is administered between days 50 and 65.

[0015] Also provided are methods of treating cancer, including: (1) administering to a subject having a CD19-expressing cancer on day 1 a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) (i) administering a first amount of a PD-1 inhibitor from at or about 380 mg to 580 or about 580 mg, inclusive, in a first cycle, wherein at least one dose of the first amount of the PD-1 inhibitor is administered in the first cycle and the first and (ii) for a second cycle, a second amount of the PD-1 inhibitor of at or about 380 mg to 580 or about 580 mg, inclusive, administered about once every four weeks (Q4W), wherein at least two doses of the second amount are administered in the second cycle, and the first dose of the second cycle is administered between days 50 and 65.

[0016] In some embodiments, the first dose of the first cycle is administered between days 8 and 15, inclusive. In some embodiments, the first dose of the first cycle is administered on day 8. In some embodiments, the first cycle dose is administered on day 15.

[0017] In some embodiments, the first amount of the PD-1 inhibitor is from or about 160 mg to or about 320 mg, inclusive. In some embodiments, the first amount of the PD-1 inhibitor is from or about 200 mg to or about 200 mg, inclusive. In some embodiments, the first amount of the PD-1 inhibitor is from or about 280 mg to or about 280 mg, inclusive. In some embodiments, the first amount of the PD-1 inhibitor is from or about 240 mg to or about 240 mg. In some embodiments, the first amount of the PD-1 inhibitor is from 400 mg to or about 400 mg to or about 560 mg to or about 560 mg. In some embodiments, the first amount of the PD-1 inhibitor is from 440 mg to or about 440 mg to or about 520 mg to or about 520 mg. In some embodiments, the first amount of the PD-1 inhibitor is from 480 mg to or about 480 mg.

[0018] In some embodiments, the second amount of the PD-1 inhibitor is from or about 400 mg to or about 560 mg, inclusive. In some embodiments, the second amount of the PD-1 inhibitor is from or about 440 mg to or about 520 mg, inclusive. In some embodiments, the second amount of the PD-1 inhibitor is from or about 480 mg to or about 480 mg.

[0019] In some embodiments, the first cycle is at least about 4 weeks after administration of the first dose of the first cycle. In some embodiments, the first cycle is up to about 5 weeks after administration of the first dose of the first cycle. In some embodiments, the first cycle is up to about 6 weeks after administration of the first dose of the first cycle. In some embodiments, the first cycle is up to about 7 weeks after administration of the first dose of the first cycle. In some embodiments, the first cycle is up to about 8 weeks after administration of the dose of engineered T cells.

[0020] In some embodiments, a first amount of a dose of a PD-1 inhibitor is administered on days 8, 22, and 36. In some embodiments, a first amount of a dose of a PD-1 inhibitor is administered on days 8 and 36. In some embodiments, a first amount of a dose of a PD-1 inhibitor is administered on days 15, 29, and 43.

[0021] In some embodiments, the at least one dose of the first amount of the PD-1 inhibitor is a single dose administered on day 15.

[0022] In some embodiments, the second cycle is at least up to about 3 months after administration of the dose of engineered T cells. In some embodiments, the second cycle is up to about 3 months after administration of the dose of engineered T cells.

[0023] In some embodiments, the first and second doses of the second amount of the PD-1 inhibitor are administered on days 57 and 85, respectively.

[0024] In some embodiments, doses of a first amount of the PD-1 inhibitor are administered on days 8, 22, and 36, and the first and second doses of a second amount of the PD-1 inhibitor are administered on days 57 and 85, respectively. In some embodiments, doses of a first amount of the PD-1 inhibitor are administered on days 8 and 36, and the first and second doses of a second amount of the PD-1 inhibitor are administered on days 57 and 85, respectively. In some embodiments, doses of a first amount of the PD-1 inhibitor are administered on days 15, 29, and 43, and the first and second doses of a second amount of the PD-1 inhibitor are administered on days 57 and 85, respectively. In some embodiments, at least one dose of the first amount of the PD-1 inhibitor is a single dose administered on day 15, and the first and second doses of the second amount of the PD-1 inhibitor are administered on days 57 and 85, respectively.

[0025] In any of the provided embodiments, the method further comprises administering a dose of the LAG3 inhibitor to the subject about every two weeks (Q2W). In some embodiments, the method further comprises administering a dose of the LAG3 inhibitor to the subject about every three weeks (Q3W). In some embodiments, the method further comprises administering a dose of the LAG3 inhibitor to the subject about every four weeks (Q4W). In any of the provided embodiments, the method further comprises administering the LAG3 inhibitor to the subject in a dosing regimen comprising administration of a dose of the LAG3 inhibitor on each of the same days as the dose of the PD-1 inhibitor is administered.

[0026] In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 60 or about 60 mg to 1040 or about 1040 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 120 or about 120 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 160 or about 160 mg to 1040 or about 1040 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 160 or about 160 mg to 320 or about 320 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 160 or about 160 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 240 or about 240 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 400 or about 400 mg to 560 or about 560 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 480 or about 480 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of at or about 880 mg to at or about 1040 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of at or about 960 mg.

[0027] In some embodiments, each dose of the LAG3 inhibitor is administered in a first amount during a first cycle and a second amount during a second cycle.

[0028] In some embodiments, the first amount of the LAG3 inhibitor is from 60 or about 60 mg to 320 or about 320 mg. In some embodiments, the first amount of the LAG3 inhibitor is from 120 or about 120 mg. In some embodiments, the first amount of the LAG3 inhibitor is from 160 or about 160 mg to 320 or about 320 mg. In some embodiments, the first amount of the LAG3 inhibitor is from 160 or about 160 mg to 200 or about 200 mg to 280 or about 280 mg. In some embodiments, the first amount of the LAG3 inhibitor is from 240 or about 240 mg. In some embodiments, the first amount of the LAG3 inhibitor is from 400 or about 400 mg to 560 or about 560 mg. In some embodiments, the first amount of the LAG3 inhibitor is from 440 or about 440 mg to 520 or about 520 mg. In some embodiments, the first amount of the LAG3 inhibitor is 480 or about 480 mg. In some embodiments, the first amount of the LAG3 inhibitor is 880 or about 880 mg to 1040 or about 1040 mg. In some embodiments, the first amount of the LAG3 inhibitor is 920 or about 920 mg to 1000 or about 1000 mg. In some embodiments, the first amount of the LAG3 inhibitor is 960 or about 960 mg.

[0029] In some embodiments, the second amount of the LAG3 inhibitor is 400 or about 400 mg to 560 or about 560 mg. In some embodiments, the second amount of the LAG3 inhibitor is 440 or about 440 mg to 520 or about 520 mg. In some embodiments, the second amount of the LAG3 inhibitor is 480 or about 480 mg. In some embodiments, the second amount of the LAG3 inhibitor is 880 or about 880 mg to 1040 or about 1040 mg. In some embodiments, the second amount of the LAG3 inhibitor is 920 or about 920 mg to 1000 or about 1000 mg. In some embodiments, the second amount of the LAG3 inhibitor is 960 or about 960 mg.

[0030] In some embodiments, the first amount of the LAG3 inhibitor is 240 or about 240 mg, and the second amount of the LAG3 inhibitor is 480 or about 480 mg. In some embodiments, the first amount of the LAG3 inhibitor is 480 or about 480 mg, and the second amount of the LAG3 inhibitor is 480 or about 480 mg. In some embodiments, the first amount of the LAG3 inhibitor is 480 or about 480 mg, and the second amount of the LAG3 inhibitor is 960 or about 960 mg. In some embodiments, the first amount of the LAG3 inhibitor is 960 or about 960 mg, and the second amount of the LAG3 inhibitor is 960 or about 960 mg.

[0031] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19) on day 1; (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a PD-1 inhibitor that is 240 mg administered on days 8, 22, and 36; and (ii) administration of a second amount of the PD-1 inhibitor that is 480 mg administered on days 57 and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a LAG3 inhibitor that is 240 mg administered on days 8, 22, and 36; and (ii) administration of a second amount of the LAG3 inhibitor that is 480 mg administered on days 57 and 85.

[0032] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19) on day 1; (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a PD-1 inhibitor that is 240 mg administered on days 8, 22, and 36; and (ii) administration of a second amount of the PD-1 inhibitor that is 480 mg administered on days 57 and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a LAG3 inhibitor that is 480 mg administered on days 8, 22, and 36; and (ii) administration of a second amount of a LAG3 inhibitor that is 960 mg administered on days 57 and 85.

[0033] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19) on day 1; and (2) administering to the subject a PD-1 inhibitor in a dosing regimen including: (i) administration of a first amount of a PD-1 inhibitor, the first amount being 240 mg administered on days 8, 22, and 36; and (ii) administration of a second amount of a PD-1 inhibitor, the second amount being 480 mg administered on days 57 and 85.

[0034] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19) on day 1; (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor on days 8, 36, 57, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 480 mg of the LAG3 inhibitor on days 8, 36, 57, and 85.

[0035] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19) on day 1; (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor on days 8, 36, 57, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 960 mg of the LAG3 inhibitor on days 8, 36, 57, and 85.

[0036] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19) on day 1; and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor on days 8, 36, 57, and 85.

[0037] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19) on day 1; (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a PD-1 inhibitor that is 240 mg administered on days 15, 29, and 43; and (ii) administration of a second amount of the PD-1 inhibitor that is 480 mg administered on days 57 and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a LAG3 inhibitor that is 240 mg administered on days 15, 29, and 43; and (ii) administration of a second amount of the LAG3 inhibitor that is 480 mg administered on days 57 and 85.

[0038] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19) on day 1; (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a PD-1 inhibitor that is 240 mg administered on days 15, 29, and 43; and (ii) administration of a second amount of the PD-1 inhibitor that is 480 mg administered on days 57 and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a LAG3 inhibitor that is 480 mg administered on days 15, 29, and 43; and (ii) administration of a second amount of a LAG3 inhibitor that is 960 mg administered on days 57 and 85.

[0039] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19) on day 1; and (2) administering to the subject a PD-1 inhibitor in a dosing regimen including: (i) administration of a first amount of a PD-1 inhibitor, the first amount being 240 mg administered on days 15, 29, and 43; and (ii) administration of a second amount of a PD-1 inhibitor, the second amount being 480 mg administered on days 57 and 85.

[0040] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19) on day 1; (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor on days 15, 57, and 85; and (3) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of a LAG3 inhibitor on days 15, 57, and 85.

[0041] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19) on day 1; (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor on days 15, 57, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 960 mg of the LAG3 inhibitor on days 15, 57, and 85.

[0042] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy containing a dose of engineered cells containing T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19) on day 1; and (2) administering to the subject a PD-1 inhibitor on days 15, 57, and 85 in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor.

[0043] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor; and (3) administering to the subject a LAG3 inhibitor. In some embodiments, a first dose of the PD-1 inhibitor and a first dose of the LAG3 inhibitor are each administered independently between days 2 and 20, inclusive.

[0044] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer on day 1 a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against the cancer; (2) administering to the subject a PD-1 inhibitor; and (3) administering to the subject a LAG3 inhibitor.

[0045] In some embodiments, the first dose of the PD-1 inhibitor and the first dose of the LAG3 inhibitor are administered on the same day.

[0046] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); and (2) administering a PD-1 inhibitor to the subject in a dosing regimen comprising administration of at least two doses, wherein (i) administration of a first dose of the PD-1 inhibitor occurs between day 2 and day 20, inclusive; and (ii) each dose of the PD-1 inhibitor is between at or about 140 mg and 580 mg, inclusive.

[0047] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against the cancer; and (2) administering a PD-1 inhibitor to the subject in a dosing regimen comprising the administration of at least two doses, wherein (i) the administration of a first dose of the PD-1 inhibitor is between day 2 and day 20, inclusive; and (ii) each dose of the PD-1 inhibitor is between at or about 140 mg and 580 mg, inclusive.

[0048] In some embodiments, each subsequent dose of the PD-1 inhibitor is administered about 2 weeks, about 3 weeks, or about 4 weeks after the previous dose of the PD-1 inhibitor. In some embodiments, the dose of the PD-1 inhibitor is administered about 2 weeks after the previous dose of the PD-1 inhibitor. In some embodiments, the dose of the PD-1 inhibitor is administered about 3 weeks after the previous dose of the PD-1 inhibitor. In some embodiments, the dose of the PD-1 inhibitor is administered about 4 weeks after the previous dose of the PD-1 inhibitor.

[0049] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of at least two doses, wherein: (i) administration of a first dose of the PD-1 inhibitor is between days 2 and 20, inclusive; and (ii) administration of each subsequent dose of the PD-1 inhibitor about 2 weeks, about 3 weeks, or about 4 weeks after the previous dose of the PD-1 inhibitor.

[0050] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against the cancer; and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising the administration of at least two doses, wherein: (i) the administration of a first dose of the PD-1 inhibitor is between day 2 and day 20, inclusive; and (ii) each subsequent dose of the PD-1 inhibitor is administered about 2 weeks, about 3 weeks, or about 4 weeks after the previous dose of the PD-1 inhibitor.

[0051] In some embodiments, each dose of the PD-1 inhibitor is from at or about 140 mg to at or about 580 mg, inclusive. In some embodiments, the first dose of the PD-1 inhibitor is administered between days 8 and 15, inclusive. In some embodiments, the first dose of the PD-1 inhibitor is administered on day 8. In some embodiments, the first dose of the PD-1 inhibitor is administered on day 15.

[0052] In some embodiments, the PD-1 inhibitor is administered for a period not exceeding about 3 months. In some embodiments, the final dose of the PD-1 inhibitor is administered between about day 80 and about day 90. In some embodiments, the final dose of the PD-1 inhibitor is administered at about day 85.

[0053] In some embodiments, each dose of the PD-1 inhibitor is at or about 160 mg to at or about 560 mg. In some embodiments, each dose of the PD-1 inhibitor is at or about 240 mg or at or about 240 mg or 480 mg or about 480 mg. In some embodiments, each dose of the PD-1 inhibitor is 240 mg. In some embodiments, each dose of the PD-1 inhibitor is 480 mg. In some embodiments, at least one dose of the PD-1 inhibitor is 240 mg and at least one dose of the PD-1 inhibitor is 480 mg.

[0054] In some embodiments, at least four doses of the PD-1 inhibitor are administered. In some embodiments, four doses, five doses, or six doses of the PD-1 inhibitor are administered. In some embodiments, four doses of the PD-1 inhibitor are administered. In some embodiments, five doses of the PD-1 inhibitor are administered. In some embodiments, six doses of the PD-1 inhibitor are administered.

[0055] In some embodiments, the first three doses of the PD-1 inhibitor are administered every two weeks (Q2W). In some embodiments, each dose of the PD-1 inhibitor is administered every two weeks (Q2W).

[0056] In some embodiments, the fourth dose of the PD-1 inhibitor is administered about three weeks or about four weeks after the previous dose of the PD-1 inhibitor. In some embodiments, the fourth dose of the PD-1 inhibitor is administered about three weeks after the previous dose of the PD-1 inhibitor. In some embodiments, the fourth dose of the PD-1 inhibitor is administered about four weeks after the previous dose of the PD-1 inhibitor.

[0057] In some embodiments, five doses of the PD-1 inhibitor are administered, hi some embodiments, the fifth dose of the PD-1 inhibitor is administered about four weeks after the fourth dose of the PD-1 inhibitor.

[0058] In some embodiments, about 240 mg of the PD-1 inhibitor is administered on each of days 8, 22, and 36. In some embodiments, about 240 mg of the PD-1 inhibitor is administered on each of days 15, 29, and 43. In some embodiments, about 480 mg of the PD-1 inhibitor is administered on each of days 8, 36, 64, and 85. In some embodiments, about 480 mg of the PD-1 inhibitor is administered on each of days 15, 43, 64, and 85.

[0059] In some embodiments, the method further comprises administering a LAG3 inhibitor to the subject. In some embodiments, the first dose of the LAG3 inhibitor is administered between days 2 and 20, inclusive. In some embodiments, the first dose of the LAG3 inhibitor is administered between days 8 and 15, inclusive. In some embodiments, the first dose of the LAG3 inhibitor is administered on day 8. In some embodiments, the first dose of the LAG3 inhibitor is administered on day 15.

[0060] In some embodiments, each dose of the LAG3 inhibitor is about 60 mg to about 540 mg, inclusive. In some embodiments, each dose of the LAG3 inhibitor is about 120 mg to about 480 mg. In some embodiments, each dose of the LAG3 inhibitor is about 120 mg. In some embodiments, each dose of the LAG3 inhibitor is about 240 mg. In some embodiments, each dose of the LAG3 inhibitor is about 480 mg.

[0061] In some embodiments, at least three doses of the LAG3 inhibitor are administered. In some embodiments, three doses, four doses, or six doses of the LAG3 inhibitor are administered. In some embodiments, three doses of the LAG3 inhibitor are administered. In some embodiments, four doses of the LAG3 inhibitor are administered. In some embodiments, six doses of the LAG3 inhibitor are administered.

[0062] In some embodiments, the first three doses of the LAG3 inhibitor are administered every two weeks (Q2W). In some embodiments, each dose of the LAG3 inhibitor is administered every two weeks (Q2W).

[0063] In some embodiments, the second dose of the LAG3 inhibitor is administered about 4 weeks after the first dose of the LAG3 inhibitor.

[0064] In some embodiments, the dose of the PD-1 inhibitor and the dose of the LAG3 inhibitor are administered at the same frequency. In some embodiments, (i) each dose of the PD-1 inhibitor is administered on the same day as the dose of the LAG3 inhibitor, and / or (ii) each dose of the LAG3 inhibitor is administered on the same day as the dose of the PD-1 inhibitor. In some embodiments, (i) each dose of the PD-1 inhibitor is administered on the same day as the dose of the LAG3 inhibitor, or (ii) each dose of the LAG3 inhibitor is administered on the same day as the dose of the PD-1 inhibitor. In some embodiments, each dose of the PD-1 inhibitor is administered on the same day as the dose of the LAG3 inhibitor. In some embodiments, each dose of the LAG3 inhibitor is administered on the same day as the dose of the PD-1 inhibitor. In some embodiments, (i) each dose of the PD-1 inhibitor is administered on the same day as the dose of the LAG3 inhibitor, and (ii) each dose of the LAG3 inhibitor is administered on the same day as the dose of the PD-1 inhibitor.

[0065] In some embodiments, the dose of the LAG3 inhibitor is administered half as frequently as the dose of the PD-1 inhibitor.

[0066] In some embodiments, each dose of the PD-1 inhibitor is twice the dose of the LAG3 inhibitor. In some embodiments, each dose of the PD-1 inhibitor is the same as the dose of the LAG3 inhibitor.

[0067] In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are formulated in a single composition. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are formulated in a single composition for intravenous administration.

[0068] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 240 mg of the PD-1 inhibitor on days 8, 22, 36, 57, 71, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 240 mg of the LAG3 inhibitor on days 8, 36, and 71.

[0069] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 240 mg of the PD-1 inhibitor on days 15, 29, 43, 57, 71, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 240 mg on days 15, 43, and 71.

[0070] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 240 mg of the PD-1 inhibitor on days 8, 22, 36, 57, 71, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 240 mg of the LAG3 inhibitor on days 8, 22, 36, 57, 71, and 85.

[0071] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 240 mg of the PD-1 inhibitor on days 15, 29, 43, 57, 71, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 240 mg of the LAG3 inhibitor on days 8, 15, 29, 43, 57, 71, and 85.

[0072] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a PD-1 inhibitor, the first amount being 240 mg administered on days 8, 22, and 36; and (ii) administration of a second amount of a PD-1 inhibitor, the second amount being 480 mg administered on days 57 and 85.

[0073] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a PD-1 inhibitor, the first amount being 240 mg administered on days 15, 29, and 43; and (ii) administration of a second amount of a PD-1 inhibitor, the second amount being 480 mg administered on days 57 and 85.

[0074] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administering 240 mg of the PD-1 inhibitor on days 8, 22, 36, 57, 71, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administering 120 mg of the LAG3 inhibitor on days 8, 22, 36, 57, 71, and 85.

[0075] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 240 mg of the PD-1 inhibitor on days 15, 29, 43, 57, 71, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 120 mg of the LAG3 inhibitor on days 15, 29, 43, 57, 71, and 85.

[0076] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor on days 8, 36, 64, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 240 mg of the LAG3 inhibitor on days 8, 36, 64, and 85.

[0077] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor on days 15, 43, 64, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 240 mg of the LAG3 inhibitor on days 15, 43, 64, and 85.

[0078] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor on days 8, 36, 64, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 480 mg of the LAG3 inhibitor on days 8, 36, 64, and 85.

[0079] Also provided herein are methods of treating cancer, comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor on days 15, 43, 64, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 480 mg of the LAG3 inhibitor on days 15, 43, 64, and 85.

[0080] Also provided herein is the use of a PD-1 inhibitor and a LAG3 inhibitor in the manufacture of a medicament for treating a subject having a CD19-expressing cancer, wherein the subject has been pre-administered, on day 1, a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19).

[0081] Also provided herein is the use of a PD-1 inhibitor and a LAG3 inhibitor in the manufacture of a medicament for treating a subject having a CD19-expressing cancer, wherein the subject has previously been administered, on day 1, a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against the cancer.

[0082] In some embodiments, the medicament is administered to the subject between days 2 and 20.

[0083] Also provided herein is the use of a PD-1 inhibitor in the manufacture of a medicament for treating a subject with a CD19-expressing cancer, wherein: (1) at least two doses of the medicament are administered to the subject; (2) a first dose of the medicament is administered to the subject between day 2 and day 20, inclusive; (3) each dose of the medicament comprises between at or about 140 mg and 580 or about 580 mg of the PD-1 inhibitor, inclusive; and (4) the subject has previously been administered, on day 1, a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19).

[0084] Also provided herein is the use of a PD-1 inhibitor in the manufacture of a medicament for treating a subject having a CD19-expressing cancer, wherein (1) at least two doses of the medicament are administered to the subject; (2) a first dose of the medicament is administered to the subject between day 2 and day 20, inclusive; (3) each dose of the medicament comprises between at or about 140 mg and 580 or about 580 mg of the PD-1 inhibitor, inclusive; and (4) the subject has previously been administered, on day 1, a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against the cancer.

[0085] In some embodiments, each subsequent dose of the medication is administered about 2 weeks, about 3 weeks, or about 4 weeks after the previous dose of the medication.

[0086] Also provided herein is the use of a PD-1 inhibitor in the manufacture of a medicament for treating a CD19-expressing cancer, wherein: (1) at least two doses of the medicament are administered to the subject; (2) a first dose of the medicament is administered to the subject between days 2 and 20, inclusive; (3) each subsequent dose of the medicament is administered about 2 weeks, about 3 weeks, or about 4 weeks after the previous dose of the medicament; and (4) the subject has previously been administered, on day 1, a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19).

[0087] Also provided herein is the use of a PD-1 inhibitor in the manufacture of a medicament for treating a CD19-expressing cancer, wherein: (1) at least two doses of the medicament are administered to the subject; (2) a first dose of the medicament is administered to the subject between day 2 and day 20, inclusive; (3) each subsequent dose of the medicament is administered about 2 weeks, about 3 weeks, or about 4 weeks after the previous dose of the medicament; and (4) the subject has previously been administered, on day 1, a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against the cancer.

[0088] In some embodiments, each dose of the medicament comprises from at or about 140 mg to at or about 580 mg of the PD-1 inhibitor, inclusive. In some embodiments, the subject is administered a LAG3 inhibitor following administration of the cell therapy.

[0089] Also provided herein is a combination of a PD-1 inhibitor and a LAG3 inhibitor for use in a method of treating cancer, the method comprising: (1) administering to a subject having a CD19-expressing cancer on day 1 a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor; and (3) administering to the subject a LAG3 inhibitor.

[0090] Also provided herein is a combination of a PD-1 inhibitor and a LAG3 inhibitor for use in a method of treating cancer, the method comprising: (1) administering to a subject having a CD19-expressing cancer on day 1 a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against the cancer; (2) administering to the subject a PD-1 inhibitor; and (3) administering to the subject a LAG3 inhibitor.

[0091] In some embodiments, the first dose of the PD-1 inhibitor and the first dose of the LAG3 inhibitor are each administered independently between days 2 and 20. In some embodiments, the first dose of the PD-1 inhibitor and the first dose of the LAG3 inhibitor are administered on the same day.

[0092] Also provided herein is a PD-1 inhibitor for use in a method of treating cancer, the method comprising: (1) administering to a subject having a CD19-expressing cancer on day 1 a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) administering a PD-1 inhibitor to the subject in a dosing regimen comprising administration of at least two doses, wherein (i) administration of a first dose of the PD-1 inhibitor occurs between day 2 and day 20, inclusive; and (ii) each dose of the PD-1 inhibitor is from at or about 140 mg to 580 or about 580 mg, inclusive.

[0093] Also provided herein is a PD-1 inhibitor for use in a method of treating cancer, the method comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against the cancer; and (2) administering a PD-1 inhibitor to the subject in a dosing regimen comprising the administration of at least two doses, wherein (i) the administration of a first dose of the PD-1 inhibitor is between day 2 and day 20, inclusive; and (ii) each dose of the PD-1 inhibitor is between at or about 140 mg and 580 mg, inclusive.

[0094] In some embodiments, each subsequent dose of the PD-1 inhibitor is administered about 2 weeks, about 3 weeks, or about 4 weeks after the previous dose of the PD-1 inhibitor.

[0095] Also provided herein is a PD-1 inhibitor for use in a method of treating cancer, the method comprising: (1) administering to a subject having a CD19-expressing cancer on day 1 a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) administering a PD-1 inhibitor to the subject in a dosing regimen comprising administration of at least two doses, wherein: (i) a first dose of the PD-1 inhibitor is administered between days 2 and 20, inclusive; and (ii) each subsequent dose of the PD-1 inhibitor is administered about 2 weeks, about 3 weeks, or about 4 weeks after the previous dose of the PD-1 inhibitor.

[0096] Also provided herein is a PD-1 inhibitor for use in a method of treating cancer, the method comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against the cancer; and (2) administering a PD-1 inhibitor to the subject in a dosing regimen comprising administration of at least two doses, wherein: (i) a first dose of the PD-1 inhibitor is administered between days 2 and 20, inclusive; and (ii) each subsequent dose of the PD-1 inhibitor is administered about 2 weeks, about 3 weeks, or about 4 weeks after the previous dose of the PD-1 inhibitor.

[0097] In some embodiments, each dose of the PD-1 inhibitor is from at or about 140 mg to at or about 580 mg, inclusive. In some embodiments, the method further includes administering a LAG3 inhibitor to the subject.

[0098] In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody contains a heavy chain variable (VH) region having CDR1, CDR2, and CDR3 containing the amino acid sequences set forth in SEQ ID NOs: 60, 61, and 62, respectively, and a light chain variable (VL) region having CDR1, CDR2, and CDR3 containing the amino acid sequences set forth in SEQ ID NOs: 63, 64, and 65, respectively. In some embodiments, the VH region contains the amino acid sequence set forth in SEQ ID NO: 66, and the VL region contains the amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the anti-PD-1 antibody is nivolumab.

[0099] In some embodiments, the LAG3 inhibitor is an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody contains a heavy chain variable (VH) region having CDR1, CDR2, and CDR3 containing the amino acid sequences set forth in SEQ ID NOs: 68, 69, and 70, respectively, and a light chain variable (VL) region having CDR1, CDR2, and CDR3 containing the amino acid sequences set forth in SEQ ID NOs: 71, 72, and 73, respectively. In some embodiments, the VH region contains the amino acid sequence set forth in SEQ ID NO: 74, and the VL region contains the amino acid sequence set forth in SEQ ID NO: 75. In some embodiments, the anti-LAG3 antibody is leratolimab.

[0100] In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered simultaneously. In some embodiments, the simultaneous administration of the PD-1 inhibitor and the LAG3 inhibitor to a subject comprises administration of a single composition comprising the PD-1 inhibitor and the LAG3 inhibitor. In some embodiments, the single composition comprises about 480 mg of the PD-1 inhibitor and about 160 mg of the LAG3 inhibitor. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered together as a single composition over a period of 15 or about 15 minutes, 30 or about 30 minutes, 45 or about 45 minutes, 60 or about 60 minutes, 75 or about 75 minutes, or 90 or about 90 minutes. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered together as a single composition over a period of 15 or about 15 minutes. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered as a single composition over a period of 30 or about 30 minutes. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered as a single composition over a period of 45 or about 45 minutes. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered as a single composition over a period of at or about 60 minutes. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered as a single composition over a period of at or about 75 minutes. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered as a single composition over a period of at or about 90 minutes.

[0101] In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered sequentially as separate compositions. In some embodiments, the separate administration of the PD-1 inhibitor and the LAG3 inhibitor comprises a first composition comprising one of the PD-1 inhibitor and the LAG3 inhibitor and a second composition comprising the other of the PD-1 inhibitor and the LAG3 inhibitor. In some embodiments, administration of the second composition begins 5 or about 5 minutes, 10 or about 10 minutes, 15 or about 15 minutes, 20 or about 20 minutes, 25 or about 25 minutes, 30 or about 30 minutes, 35 or about 35 minutes, 40 or about 40 minutes, or 45 or about 45 minutes after administration of the first composition is complete. In some embodiments, administration of the second composition begins 15 or about 15 minutes after administration of the first composition is complete. In some embodiments, administration of the second composition begins 30 or about 30 minutes after administration of the first composition is complete. In some embodiments, the first composition comprises a PD-1 inhibitor. In some embodiments, the second composition comprises 960 mg or about 960 mg of a LAG3 inhibitor and is administered 30 minutes or about 30 minutes after administration of the first composition comprising the PD-1 inhibitor.

[0102] In some embodiments, the composition comprising the PD-1 inhibitor is administered over a period of 15 or about 15 minutes, 30 or about 30 minutes, 45 or about 45 minutes, or 60 or about 60 minutes. In some embodiments, the composition comprising the PD-1 inhibitor is administered over a period of 15 or about 15 minutes. In some embodiments, the composition comprising the PD-1 inhibitor is administered over a period of 30 or about 30 minutes. In some embodiments, the composition comprising the PD-1 inhibitor is administered over a period of 45 or about 45 minutes.

[0103] In some embodiments, the composition comprising a LAG3 inhibitor is administered over a period of 45 or about 45 minutes, 60 or about 60 minutes, or 75 or about 75 minutes. In some embodiments, the composition comprising a LAG3 inhibitor is administered over a period of 45 or about 45 minutes. In some embodiments, the composition comprising a LAG3 inhibitor is administered over a period of 60 or about 60 minutes. In some embodiments, the composition comprising a LAG3 inhibitor is administered over a period of 75 or about 75 minutes.

[0104] In some embodiments, the method further comprises administering lymphodepletion therapy to the subject prior to administration of the dose of engineered T cells. In some embodiments, the lymphodepletion therapy is completed within about 7 days prior to initiation of administration of the dose of engineered T cells. In some embodiments, the administration of lymphodepletion therapy is completed within about 2-7 days prior to initiation of administration of the dose of engineered T cells. In some embodiments, the lymphodepletion therapy comprises administration of fludarabine and / or cyclophosphamide. In some embodiments, the lymphodepletion therapy comprises administration of at or about 200 mg / m 2 ~400 or approximately 400 mg / m 2 , 300 or about 300 mg / m 2 (inclusive) cyclophosphamide, and / or 20 or about 20 mg / m 2 ~40 or approximately 40 mg / m 2 , 30mg / m as appropriate 2 In some embodiments, lymphodepletion therapy comprises administration of fludarabine at or about 300 mg / m daily for 2-4 days, optionally 3 days. 2 In some embodiments, the lymphodepletion therapy comprises administration of cyclophosphamide at or about 30 mg / m (inclusive) for three days. 2 In some embodiments, the lymphodepletion therapy comprises administration of at or about 300 mg / m fludarabine daily for three days. 2 of cyclophosphamide and 30 or about 30 mg / m 2 This includes the concomitant administration of fludarabine daily for 3 days.

[0105] In some embodiments, the CD19 is human CD19.

[0106] In some embodiments, the chimeric antigen receptor (CAR) contains an scFv containing the variable heavy and variable light regions of the antibody FMC63, a spacer that is 15 amino acids or less and contains an immunoglobulin hinge region or a modified version thereof, a transmembrane domain, and an intracellular signaling domain that contains the signaling domain of the CD3-zeta (CD3ζ) chain and a costimulatory signaling region that is the signaling domain of 4-1BB.

[0107] In some embodiments, the immunoglobulin hinge region or modified version thereof contains the formula X1PPX2P (where X1 is glycine, cysteine, or arginine and X2 is cysteine ​​or threonine) (SEQ ID NO:58). In some embodiments, the immunoglobulin hinge region or modified version thereof is an IgG1 hinge or modified version thereof. In some embodiments, the immunoglobulin hinge region or modified version thereof is an IgG4 hinge or modified version thereof. In some embodiments, the spacer contains a sequence set forth in SEQ ID NO:1, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34, or a variant of any of the foregoing having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the sequence set forth in SEQ ID NO:1, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34. In some embodiments, the spacer consists of a sequence set forth in SEQ ID NO:1, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34, or a variant of any of the foregoing having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the sequence set forth in SEQ ID NO:1, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

[0108] In some embodiments, the spacer is 12 or about 12 amino acids in length. In some embodiments, the spacer contains the sequence set forth in SEQ ID NO: 1. In some embodiments, the spacer consists of the sequence set forth in SEQ ID NO: 1.

[0109] In some embodiments, the transmembrane domain is the transmembrane domain of CD28. In some embodiments, the transmembrane domain contains a sequence of amino acids set forth in SEQ ID NO: 8, or a sequence of amino acids with at least or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 8. In some embodiments, the transmembrane domain contains a sequence of amino acids set forth in SEQ ID NO: 8. In some embodiments, the transmembrane domain contains a sequence of amino acids with at least or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 8.

[0110] In some embodiments, the costimulatory domain contains the sequence set forth in SEQ ID NO: 12, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the sequence set forth in SEQ ID NO: 12. In some embodiments, the costimulatory domain contains the sequence set forth in SEQ ID NO: 12. In some embodiments, the costimulatory domain contains a sequence of amino acids that exhibits at least or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 12.

[0111] In some embodiments, the signaling domain of the CD3-zeta (CD3ζ) chain comprises the sequence set forth in SEQ ID NO: 13, 14, or 15, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the sequence set forth in SEQ ID NO: 13, 14, or 15. In some embodiments, the signaling domain of the CD3-zeta (CD3ζ) chain comprises the sequence set forth in SEQ ID NO: 13, 14, or 15. In some embodiments, the signaling domain of the CD3-zeta (CD3ζ) chain contains a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the sequence set forth in SEQ ID NO: 13, 14, or 15. In some embodiments, the signaling domain of the CD3-zeta (CD3ζ) chain contains a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the sequence set forth in SEQ ID NO: 13.

[0112] In some embodiments, the scFv contains the CDRL1 sequence of SEQ ID NO: 35, the CDRL2 sequence of SEQ ID NO: 55, and the CDRL3 sequence of SEQ ID NO: 56, as well as the CDRH1 sequence of SEQ ID NO: 38, the CDRH2 sequence of SEQ ID NO: 39, and the CDRH3 sequence of SEQ ID NO: 54. In some embodiments, the scFv contains the CDRL1 sequence of SEQ ID NO: 35, the CDRL2 sequence of SEQ ID NO: 36, and the CDRL3 sequence of SEQ ID NO: 37, as well as the CDRH1 sequence of SEQ ID NO: 38, the CDRH2 sequence of SEQ ID NO: 39, and the CDRH3 sequence of SEQ ID NO: 40. In some embodiments, the scFv contains a VFV containing, in order from N-terminus to C-terminus, the sequences set forth in SEQ ID NO: 42. L and V containing the sequence set forth in SEQ ID NO: 41 HIn some embodiments, the scFv comprises the sequence set forth in SEQ ID NO:43.

[0113] In some embodiments, the CAR contains, in order from N-terminus to C-terminus, an extracellular antigen-binding domain that is an scFv set forth in SEQ ID NO: 43, a spacer set forth in SEQ ID NO: 1, a transmembrane domain set forth in SEQ ID NO: 8, a 4-1BB costimulatory signaling domain set forth in SEQ ID NO: 12, and a signaling domain of the CD3-zeta (CD3ζ) chain set forth in SEQ ID NO: 13.

[0114] In some embodiments, the dose of engineered T cells contains CD4+ T CAR-expressing cells and CD8+ CAR-expressing T cells. In some embodiments, the dose of engineered T cells is about 5×10 7 CAR-expressing T cells ~ approximately 1.1 x 10 8 In some embodiments, the dose of engineered T cells contains about 5 x 10 CAR-expressing T cells (inclusive). 7 In some embodiments, the dose of engineered T cells contains about 1 x 10 CAR-expressing T cells. 8 Contains CAR-expressing T cells.

[0115] In some embodiments, administering a dose of engineered T cells comprises administering multiple separate compositions, the multiple separate compositions comprising a first composition containing CD8+ CAR-expressing T cells and a second composition containing CD4+ CAR-expressing T cells. In some embodiments, the first composition and the second composition are administered 0 to 12 hours apart, 0 to 6 hours apart, or 0 to 2 hours apart, or the administration of the first composition and the administration of the second composition are performed on the same day, about 0 to about 12 hours apart, about 0 to about 6 hours apart, or about 0 to about 2 hours apart. In some embodiments, the initiation of administration of the first composition and the initiation of administration of the second composition are performed about 1 minute to about 1 hour apart, or about 5 minutes to about 30 minutes apart. In some embodiments, the first composition and the second composition are administered 2 hours or less, 1 hour or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less apart. In some embodiments, the first composition and the second composition are administered less than 2 hours apart. In some embodiments, a first composition containing CD8+ CAR-expressing T cells is administered before a second composition containing CD4+ CAR-expressing T cells. In some embodiments, the dose of engineered T cells is administered intravenously.

[0116] In some embodiments, the T cells are primary T cells obtained from a sample from a subject, where the sample is optionally a whole blood sample, an apheresis sample, or a leukapheresis sample. In some embodiments, the sample is an apheresis sample. In some embodiments, the sample is a leukapheresis sample. In some embodiments, the sample is obtained from the subject prior to administering lymphodepletion therapy to the subject. In some embodiments, the T cells are autologous to the subject. In some embodiments, the subject is human.

[0117] In some embodiments, the CD19-expressing cancer is a B-cell malignancy. In some embodiments, the CD19-expressing cancer is myeloma, leukemia, or lymphoma. In some embodiments, the CD19-expressing cancer is acute lymphocytic leukemia (ALL), adult ALL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), non-Hodgkin's lymphoma (NHL), or large B-cell lymphoma. In some embodiments, the CD19-expressing cancer is non-Hodgkin's lymphoma (NHL). In some embodiments, the NHL is selected from the group consisting of transformed indolent NHL, follicular lymphoma grade 3B (FL3B), T-cell / histiocytic large B-cell lymphoma, Epstein-Barr virus (EBV)-positive DLBCL NOS, primary mediastinal (thymic) large B-cell lymphoma, and diffuse large B-cell lymphoma not otherwise specified (DLBCL), including high-grade B-cell lymphomas with MYC and BCL2 and / or BCL6 rearrangements with DLBCL histology (double / triple hit lymphomas). In some embodiments, the NHL is selected from the group consisting of transformed indolent NHL, follicular lymphoma grade 3B (FL3B), T-cell / histiocytic-rich large B-cell lymphoma, Epstein-Barr virus (EBV)-positive DLBCL NOS, primary mediastinal (thymic) large B-cell lymphoma, Richter transformation, and diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), including high-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements with DLBCL histology (double / triple hit lymphomas).

[0118] In some embodiments, the NHL is relapsed / refractory (R / R) NHL. In some embodiments, the subject has relapsed or is refractory to at least two previous lines of systemic therapy for CD19-expressing cancer. In some embodiments, at least one of the at least two previous lines of systemic therapy comprises a CD20 targeting agent and an anthracycline.

[0119] In some embodiments, the subject has an ECOG performance status of 0 or 1. In some embodiments, the subject has an ECOG performance status of 0. In some embodiments, the subject has an ECOG performance status of 1. In some embodiments, the subject's ECOG performance status is determined at the time of administration of the dose of engineered T cells. In some embodiments, the subject's ECOG performance status is determined at screening. In some embodiments, screening occurs about 1 week to about 2 weeks prior to administration of the dose of engineered T cells.

[0120] In some embodiments, the subject has positron emission tomography (PET) positive disease. In some embodiments, the PET positive disease is determined at the time of administration of the dose of engineered T cells. In some embodiments, the PET positive disease is determined at screening. In some embodiments, the subject has computed tomography (CT) measurable disease. In some embodiments, the CT measurable disease is determined at the time of administration of the dose of engineered T cells. In some embodiments, the CT measurable disease is determined at screening. In some embodiments, the subject has PET positive and CT measurable disease. In some embodiments, screening occurs about 1 week to about 2 weeks prior to administration of the dose of engineered T cells.

[0121] In some embodiments, the subject is 2 In some embodiments, the subject has a sum of the products of perpendicular diameters (SPD) of up to six index lesions. In some embodiments, the SPD is measured by CT scan. In some embodiments, the subject has a 25 cm 2 The sum of the products of perpendicular diameters (SPD) of up to six index lesions or more. In some embodiments, the SPD is determined at the time of administration of the dose of engineered T cells. In some embodiments, the SPD is determined at the time of screening. In some embodiments, screening occurs about 1 week to about 2 weeks before administration of the dose of engineered T cells. [Brief explanation of the drawings]

[0122] [Figure 1] FIG. 1 shows the expression, as indicated by mean fluorescence intensity (MFI), of LAG3 by endogenous CD3+ cells in subjects showing either complete response (CR) or progressive disease (PD) 3 months after treatment. [Figure 2A] Figure 2A shows the correlation between LAG3 gene expression by CAR T cells and the maximum concentration (Cmax) of CD3+ CAR T cells (cells / μL). Pearson correlation: -0.70, p=1.3×10-7; Spearman correlation: -0.71, p=3.2×10-7. [Figure 2B] FIG. 2B shows LAG3 gene expression among subjects with short (<90 days) or long (>180 days) progression-free survival (PFS) (p=0.012). [Figure 3] FIG. 3 shows PD-1 gene expression by endogenous T cells 2 months after treatment for subjects who showed either a complete response (CR) or progressive disease (PD) 9 months after treatment. [Figure 4A] Figure 4A shows PD-1 expression by CD3+CAR+ cells 3 months after treatment for subjects showing either a complete response (CR) or progressive disease (PD) at 3 months post-treatment, as analyzed by the mean fluorescence intensity (MFI) of PD-1 expression. [Figure 4B] Figure 4B shows PD-1 expression by CD4+CAR+ cells 3 months after treatment for subjects showing either a complete response (CR) or progressive disease (PD) at 3 months post-treatment, as analyzed by the mean fluorescence intensity (MFI) of PD-1 expression. [Figure 4C] Figure 4C shows PD-1 expression by CD8+CAR+ cells after 3 months of treatment for subjects showing either a complete response (CR) or progressive disease (PD) at 3 months post-treatment, analyzed by or as the mean fluorescence intensity (MFI) of PD-1 expression. [Figure 5A] Figures 5A and 5B show PD-1 gene expression by CD3+CAR+ cells at various time points after treatment for subjects showing either a complete response (CR) or progressive disease (PD) 3 months after treatment. [Figure 5B] Figures 5A and 5B show PD-1 gene expression by CD3+CAR+ cells at various time points after treatment for subjects showing either a complete response (CR) or progressive disease (PD) 3 months after treatment. [Figure 6] Figure 6 shows an exemplary dosing regimen for treating non-Hodgkin's lymphoma (NHL) with combination therapy of CAR-expressing T cells, an exemplary anti-PD-1 antibody, and, optionally, an exemplary anti-LAG3 antibody (D: day; R: leratolimab; N: nivolumab; LDC: lymphodepleting chemotherapy). [Figure 7A] FIG. 7A shows peripheral LAG3 receptor occupancy (RO) at various doses of leratolimab and nivolumab dosed every 4 weeks (Q4W). [Figure 7B] FIG. 7B shows predicted tumor LAG3 receptor occupancy (RO) at various doses of leratolimab dosed every four weeks (Q4W). [Figure 7C] FIG. 7C shows predicted free soluble LAG3 (sLAG3) over time with a dose of 800 mg leratolimab. [Figure 8A] 8A-8C show exemplary dosing regimens for treating non-Hodgkin's lymphoma (NHL) with a combination of CAR-expressing T cells, an exemplary anti-PD-1 antibody, and, where appropriate, an exemplary anti-LAG3 antibody (D: day; R: leratolimab; N: nivolumab; LDC: lymphodepleting chemotherapy). For each cohort, leukapheresis, LDC, and CAR T-cell infusion are performed on the indicated days. [Figure 8B] 8A-8C show exemplary dosing regimens for treating non-Hodgkin's lymphoma (NHL) with a combination of CAR-expressing T cells, an exemplary anti-PD-1 antibody, and, where appropriate, an exemplary anti-LAG3 antibody (D: day; R: leratolimab; N: nivolumab; LDC: lymphodepleting chemotherapy). For each cohort, leukapheresis, LDC, and CAR T-cell infusion are performed on the indicated days. [Figure 8C]8A-8C show exemplary dosing regimens for treating non-Hodgkin's lymphoma (NHL) with a combination of CAR-expressing T cells, an exemplary anti-PD-1 antibody, and, where appropriate, an exemplary anti-LAG3 antibody (D: day; R: leratolimab; N: nivolumab; LDC: lymphodepleting chemotherapy). For each cohort, leukapheresis, LDC, and CAR T-cell infusion are performed on the indicated days. DETAILED DESCRIPTION OF THE INVENTION

[0123] All references cited herein are incorporated by reference in their entirety.

[0124] Provided herein are combination therapies for treating a subject with cancer, the combination therapies involving administration of T cell therapy (e.g., CAR-T cells) and checkpoint inhibitor therapy (e.g., anti-PD-1 antibodies and / or anti-LAG3 antibodies) to treat cancers or tumors, such as lymphomas, particularly non-Hodgkin's lymphoma (NHL). In some embodiments, the T cell therapy includes any such therapy that specifically binds to an antigen associated with, expressed by, or present on cells of the cancer. In certain embodiments, the T cell therapy is or involves T cells expressing a chimeric antigen receptor (CAR) that binds CD19. In certain embodiments, the T cell therapy is or involves T cells expressing a chimeric antigen receptor (CAR) that binds CD20. In certain embodiments, the T cell therapy is or involves T cells expressing a chimeric antigen receptor (CAR) that binds CD22. In some embodiments, the checkpoint inhibitor therapy includes one or more antibodies targeting a checkpoint inhibitor, such as PD-1 and / or LAG3. Some provided embodiments include combination therapy involving administration of T cell therapy (e.g., CAR-expressing T cells) and checkpoint inhibitor therapy (e.g., anti-PD-1 antibody and / or anti-LAG3 antibody). Thus, in some embodiments, methods and uses include administering to a subject in adoptive cell therapy T cells expressing an engineered (recombinant) cell surface receptor in combination with an anti-PD-1 antibody, and optionally an anti-LAG3 antibody, where the engineered (recombinant) cell surface receptor is typically a chimeric receptor, such as a chimeric antigen receptor (CAR), that recognizes an antigen expressed by, associated with, and / or specific to the cell type from which it was derived.

[0125] In some embodiments, the combination of T cell therapy and checkpoint inhibitor therapy is administered to a subject having a particular disease or condition to be treated, e.g., by adoptive cell therapy, such as adoptive T cell therapy. In some embodiments, the method involves treating a subject having a CD19-expressing cancer, e.g., a B-cell malignancy (e.g., NHL), with a dose of antigen receptor-expressing cells (e.g., CAR-expressing cells).

[0126] In some embodiments, provided methods involve treating a specific group or subset of subjects, e.g., subjects identified as having high-risk disease. In some aspects, the methods treat subjects with poor-prognosis NHL, such as NHL that has relapsed or is refractory (R / R) to standard therapy and / or has a poor prognosis. In some cases, the overall response rate (ORR) to available therapy, standard therapy, or reference therapy for the disease and / or patient population for which the therapy is indicated is less than 40%, and / or the complete response (CR) is less than 20%. In some embodiments, in chemotherapy-resistant DLBCL, the ORR with reference or available treatment or standard therapy is about 26%, and the CR is about 8% (Crump et al. Outomes in refractory aggressive diffuse large B-cell lymphoma (DLBCL): Results from the international SCHOLAR study. ASCO 2016 [Abstract 7516]). In some aspects, the methods, compositions, uses and articles of manufacture provided achieve improved and superior response to available therapies.

[0127] CD19 is a 95-kDa glycoprotein present on B cells from early development through differentiation into plasma cells (Stamenkovic et al., J Exp Med. 1988; 168(3):1205-10). It is a member of the immunoglobulin superfamily and functions as a positive regulator of the B cell receptor by lowering the signaling threshold for B cell activation (Brentjens et al., Blood. 2011; 118(18):4817-28; LeBien et al., Blood. 2008; 112(5):1570-80). CD19 is an attractive therapeutic target because it is expressed by most B cell malignancies, including B cell NHL (Davila et al., Oncoimmunology. 2012;(9):1577-83). Importantly, CD19 is not expressed on hematopoietic stem cells or on any normal tissues except those of the B cell lineage. Furthermore, CD19 is not shed into the circulation, thereby limiting off-target adverse effects (Shank et al., Pharmacotherapy. 2017;37(3):334-45).

[0128] In certain embodiments, the methods provided herein are based on administering a CD19-directed CAR T cell therapy in combination with checkpoint inhibitor therapy, in which the CAR contains a CD19-directed scFv antigen-binding domain (e.g., from FMC63). The CAR further contains an intracellular signaling domain containing a signaling domain from CD3 zeta and also contains a 4-1BB costimulatory domain, which has been associated with a lower incidence of cytokine release syndrome (CRS) and neurotoxicity (NT; e.g., neurological events (NE)) compared to CD28-containing constructs (Lu et al. J Clin Oncol. 2018;36:3041). In some embodiments, the methods provided herein involve CD8+ and CD4+ T cell subsets, which are separately transduced and expanded in vitro and administered at equal (approximately 1:1) target doses. In some embodiments, there is less variability in the total dose of CD4+ CAR+ T cells and CD8+ CAR+ T cells administered, two parameters that have been associated with increased toxicity in previous studies (Neelapu et al., N Engl Med. 2017. 377;2531-44; Turtle et al., Sci Transl Med. 2016;8:355ra116; Hay et al., Blood. 2017;130:2295-306).

[0129] In certain embodiments, the methods provided herein are based on administering a CD19-directed CAR T-cell therapy, in which the CAR contains a CD19-directed scFv antigen-binding domain (e.g., from FMC63), in combination with a checkpoint inhibitor therapy, including an anti-PD-1 antibody, and optionally, an anti-LAG3 antibody.

[0130] In some embodiments, the methods involve administering a combination therapy to selected subjects or subjects identified as having a particular prognosis or at risk for a B-cell malignancy, such as NHL. Lymphomas, such as NHL, are variable diseases. Some subjects with NHL can survive without treatment, while others may require immediate intervention. In some embodiments, the methods, uses, and articles of manufacture involve or are used to treat subjects by selecting or identifying a particular group or subset of subjects based on a particular type of disease, diagnostic criteria, previous treatment, and / or response to previous treatment, such as any of the groups of subjects described. In some embodiments, the methods involve treating subjects who have relapsed or become refractory following remission after treatment with one or more previous therapies; or subjects who have relapsed or are refractory (R / R) to one or more previous therapies, e.g., first-line or higher-line standard therapy. In some embodiments, at least one of the one or more previous lines of therapy included an anti-CD20 agent and an anthracycline. In some embodiments, the methods involve treating a subject who has relapsed after remission following treatment with two or more prior therapies, or who has become refractory to two or more prior therapies; or who has relapsed or is refractory (R / R) to two or more prior therapies, e.g., two or more lines of standard therapy. In some embodiments, at least one of the two or more prior lines of therapy included an anti-CD20 agent and an anthracycline.

[0131] In certain embodiments, the provided combination therapies and methods improve the response to T cell therapy due to the activity of the checkpoint inhibitor therapy reducing or preventing exhaustion of endogenous T cells, T cell therapy cells (e.g., CAR T cells), or both. In some embodiments, the endogenous T cells, T cell therapy cells (e.g., CAR T cells), or both thereby exhibit improved efficacy, such as effector-mediated killing of antigen-expressing cells, when provided with checkpoint inhibitor therapy.

[0132] In some embodiments, the provided combination therapies and methods improve the response to T cell therapy due to the activity of the checkpoint inhibitor therapy increasing the expansion and / or persistence of the administered cells (e.g., CAR T cells) of the T cell therapy. Thus, in some embodiments, the cells (e.g., CAR T cells) of the T cell therapy exhibit improved expansion and / or persistence when provided with checkpoint inhibitor therapy.

[0133] In some aspects, the provided methods, compositions, uses, and articles of manufacture achieve improved and superior response to available therapies, including T cell therapy alone or checkpoint inhibitor therapy alone, hi some embodiments, the improved or superior response is compared to the current standard of care (SOC).

[0134] Also provided herein are combinations and articles of manufacture, e.g., kits, containing compositions constituting T cell therapy and / or compositions constituting checkpoint inhibitor therapy, e.g., anti-PD-1 antibodies and / or anti-LAG3 antibodies, and the use of such compositions and combinations to treat or prevent CD19-expressing cancers, such as B cell malignancies (e.g., non-Hodgkin's lymphoma).

[0135] Cellular therapies, e.g., T cell-based therapies, e.g., adoptive T cell therapies (including therapies involving the administration of cells expressing chimeric receptors specific for a cancer of interest, such as chimeric antigen receptors (CARs) and / or other recombinant antigen receptors, as well as other adoptive immune cell and adoptive T cell therapies), can be effective in treating diseases and disorders, such as B cell malignancies. The engineered expression of recombinant receptors, such as chimeric antigen receptors (CARs), on the surface of T cells allows for the redirection of T cell specificity. In clinical studies, CAR-T cells, such as anti-CD19 CAR-T cells, have produced durable complete responses in both leukemia and lymphoma patients (Porter et al. (2015) Sci Transl Med., 7:303ra139; Kochenderfer (2015) J. Clin. Oncol., 33: 540-9; Lee et al. (2015) Lancet, 385:517-28; Maude et al. (2014) N Engl J Med, 371:1507-17).

[0136] In certain circumstances, the approach available for adoptive cell therapy may not always be completely satisfactory.In some circumstances, optimal efficacy may depend on the ability of administered cells to recognize and bind to targets, such as target antigens, and the ability of administered cells to perform various effector functions, including cytotoxic killing of cancer cells and secretion of various factors such as cytokines.However, in some cases, administered cells may become exhausted, which may reduce the effectiveness of performing various effector functions, including killing of cancer cells and secretion of cytokines.In particular, the results herein demonstrate that checkpoint inhibitor therapy can reduce or prevent the exhaustion of cells in T cell therapy.

[0137] In some aspects, the provided combination methods and uses provide or achieve improved or more durable responses or efficacy compared to alternative methods, such as alternative methods that involve administration of T cell therapy alone but not in combination with checkpoint inhibitor therapy (e.g., anti-PD-1 antibody and, optionally, anti-LAG3 antibody). In some embodiments, the methods are advantageous by virtue of preventing or reducing exhaustion of the administered cells of the T cell therapy by administering the checkpoint inhibitor therapy (e.g., anti-PD-1 antibody and, optionally, anti-LAG3 antibody) after (within 8 or 15 days of) administration of the T cell therapy (e.g., CAR-T cells). In some embodiments of the provided methods, the T cell therapy is a CAR-expressing T cell (CAR T cell), and it has further been found that this advantageous effect of preventing or reducing exhaustion of the administered cells can be achieved by initiating administration of the checkpoint inhibitor therapy (e.g., anti-PD-1 antibody and, optionally, anti-LAG3 antibody) within a certain time frame after the start of administration of the T cell therapy to minimize or avoid deleterious effects of the checkpoint inhibitor therapy on the cells of the T cell therapy. In particular, administration of checkpoint inhibitor therapy can exacerbate activation-induced cell death (AICD) of T cell therapy cells. However, delaying administration of checkpoint inhibitor therapy (e.g., anti-PD-1 antibody and, optionally, anti-LAG3 antibody) until AICD is near or has peaked can avoid deleterious effects on T cell therapy cells and can substantially improve, e.g., synergistically increase, T cell-mediated killing of tumors by T cell therapy cells (e.g., CAR-T cells).

[0138] The provided methods are based on the observation that blockade of PD-1 can improve the anti-tumor activity of CAR-expressing T cells, such as by blocking inhibitory signals and preventing T cell exhaustion or restoring T cells, and that such improvement can be further increased by adding LAG3 blockade. In some embodiments, the combination of PD-1 and LAG3 blockade exhibits synergistic effects.

[0139] LAG3 is a checkpoint receptor protein expressed on chronically exhausted T cells and is often co-expressed with another checkpoint protein, PD-1, on tolerized tumor-infiltrating lymphocytes (TILs) across many tumor types (Chauvin et al., (2015) 125(5):2046-58; Speiser et al., Nat Rev Immunol (2014) 14(11):768-74; Sharma et al., Cell (2017) 168(4):707-723). Notably, it is observed herein that in subjects treated with CAR T cells, exhaustion markers, including PD-1 and LAG3, are upregulated on both CAR T cells and non-transduced T cells in subjects who do not or poorly respond to therapy (see Example 1). These results demonstrate that administration of checkpoint inhibitor therapy can improve response to T cell therapy, such as CAR T cells. In particular, dual checkpoint blockade, such as with anti-PD-1 and anti-LAG3 antibodies, can result in enhanced T cell effector function greater than the effect of either antibody alone.

[0140] Programmed cell death-1 (PD-1) cluster of differentiation 279 (CD279) is a cell surface membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and B lymphocytes. Binding of PD-1 to its ligands, programmed death-ligand 1 (PD-L1) and 2 (PD-L2), results in downregulation of lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes immune responses and antigen-specific T cell responses to both foreign antigens and self-antigens.

[0141] Following activation, T cells express PD-1 on their surface and secrete interferons, which in turn induce the expression of checkpoint inhibitors such as PD-L1 and PD-L2 on tumor cells and bystander cells (Hoekstra et al., Nat Cancer (2020) 1(3):291-301) (Garcia Diaz et al., Cell Rep (2017) 19(6):1189-1201). Binding of PD-L1 and / or PD-L2 on tumor cells (including lymphomas) and the tumor microenvironment to PD-1 on T cells (including CAR T cells) results in inhibitory checkpoint signaling, thereby reducing cytotoxicity and exhausting the T cells (Andorsky, Clin Cancer Res (2011) 17(13):4232-44).

[0142] Various strategies exist for blocking the PD-1 / PD-L1 pathway. In some embodiments, the PD-1 / PD-L1 pathway is targeted with PD-1 blockade, including PD-1 pathway inhibitors such as anti-PD-1 antibodies. PD-1 pathway inhibitors have been shown to be safe and effective in subjects with various cancers and may be useful in reversing PD-L1-mediated immune suppression in subjects treated with CAR T cells.

[0143] PD-1 pathway inhibitors for use in the methods of the present disclosure include, but are not limited to, PD-1 inhibitors and / or PD-L1 inhibitors.

[0144] In some embodiments, the PD-1 inhibitor and / or the PD-L1 inhibitor is a small molecule.

[0145] In some embodiments, the PD-1 inhibitor and / or the PD-L1 inhibitor is a millamolecule.

[0146] In some embodiments, the PD-1 inhibitor and / or the PD-L1 inhibitor is a macrocyclic peptide.

[0147] In certain embodiments, the PD-1 inhibitor and / or PD-L1 inhibitor is BMS-986189.

[0148] In some embodiments, the PD-1 inhibitor is an inhibitor disclosed in International Publication No. WO2014 / 151634, the entirety of which is incorporated herein by reference.

[0149] In some embodiments, the PD-1 inhibitor is INCMGA00012 (Insight Pharmaceuticals).

[0150] In some embodiments, the PD-1 inhibitor comprises a combination of an anti-PD-1 antibody disclosed herein and a PD-1 small molecule inhibitor.

[0151] In some embodiments, the PD-L1 inhibitor is a miramolecule having the formula shown in Formula (I):

[0152] [ka] wherein R 1 ~R 13 is the amino acid side chain, and R a ~R n is hydrogen, methyl, or forms a ring together with the adjacent R group, and R 14 is -C(O)NHR 15 where R 15is hydrogen or a glycine residue optionally substituted with additional glycine residues and / or tails that may improve pharmacokinetic properties. In some embodiments, PD-L1 inhibitors include compounds disclosed in International Publication No. WO2014 / 151634, which is incorporated herein by reference in its entirety. In some embodiments, the PD-L1 inhibitor comprises a compound disclosed in International Publication Nos. WO2016 / 039749, WO2016 / 149351, WO2016 / 077518, WO2016 / 100285, WO2016 / 100608, WO2016 / 126646, WO2016 / 057624, WO2017 / 151830, WO2017 / 176608, WO2018 / 085750, WO2018 / 237153, or WO2019 / 070643, each of which is incorporated by reference herein in its entirety.

[0153] In some embodiments, the PD-L1 inhibitor comprises a small molecule PD-L1 inhibitor disclosed in International Publication Nos. WO2015 / 034820, WO2015 / 160641, WO2018 / 044963, WO2017 / 066227, WO2018 / 009505, WO2018 / 183171, WO2018 / 118848, WO2019 / 147662, or WO2019 / 169123, each of which is incorporated by reference in its entirety.

[0154] In some embodiments, the PD-1 pathway inhibitor is a soluble PD-L2 polypeptide. In some embodiments, the soluble PD-L2 polypeptide is a fusion polypeptide. In some embodiments, the soluble PD-L2 polypeptide comprises a ligand-binding fragment of the PD-L2 extracellular domain. In some embodiments, the soluble PD-L2 polypeptide further comprises a half-life extending moiety. In some embodiments, the half-life extending moiety comprises an immunoglobulin constant region or portion thereof, an immunoglobulin-binding polypeptide, immunoglobulin G (IgG), an albumin-binding polypeptide (ABP), a PAS-modified moiety, a HES-modified moiety, XTEN, a PEGylated moiety, an Fc region, or any combination thereof. In some embodiments, the soluble PD-L2 polypeptide is AMP-224 (see, e.g., U.S. Patent Application Publication No. 2013 / 0017199).

[0155] In some embodiments, the PD-1 pathway inhibitor is an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

[0156] In some embodiments, the PD-1 pathway inhibitor is formulated for intravenous administration.

[0157] In some embodiments, the PD-1 pathway inhibitor is administered in a fixed dose.

[0158] In some embodiments, the PD-1 pathway inhibitor is at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about 5 ... mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

[0159] In some embodiments, the PD-1 pathway inhibitor is about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, or about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 35 0mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 5 20mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 6 90mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 1080m g, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0160] In some embodiments, the PD-1 pathway inhibitor is administered in a weight-based dose.

[0161] In some embodiments, the PD-1 pathway inhibitor is at least about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, about 0.003 mg / kg to about 1 ... About 0.8mg / kg, about 0.003mg / kg~about 0.7mg / kg, about 0.003mg / kg~about 0.6mg / kg, about 0.003mg / kg~about 0.5mg / kg, about 0.003mg / kg~about 0. 4mg / kg, about 0.003mg / kg to about 0.3mg / kg, about 0.003mg / kg to about 0.2mg / kg, about 0.003mg / kg to about 0.1mg / kg, about 0.1mg / kg to about 25mg / kg, Approximately 0.1mg / kg to approximately 20mg / kg, approximately 0.1mg / kg to approximately 15mg / kg, approximately 0.1mg / kg to approximately 10mg / kg, approximately 0.1mg / kg to approximately 5mg / kg, approximately 0.1mg / kg to approximately 1mg / k g, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about 5 mg / kg The dose is administered at a range of about 5 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

[0162] In some embodiments, the PD-1 pathway inhibitor is at about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0. 9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

[0163] In some embodiments, the dose of the PD-1 pathway inhibitor is administered in a constant amount.

[0164] In some embodiments, the dose of the PD-1 pathway inhibitor is administered in varying amounts. For example, in some embodiments, the maintenance (or continuing) dose of the PD-1 pathway inhibitor may be higher than or the same as the initially administered loading dose. In some embodiments, the maintenance dose of the PD-1 pathway inhibitor may be lower than or the same as the loading dose.

[0165] In some embodiments, the dose of the PD-1 pathway inhibitor is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

[0166] Anti-PD-1 antibody Anti-PD-1 antibodies known in the art can be used in the methods of the present disclosure. Various human monoclonal antibodies that specifically bind to PD-1 with high affinity are disclosed in U.S. Patent No. 8,008,449. The anti-PD-1 human antibodies disclosed in U.S. Patent No. 8,008,449 have been demonstrated to exhibit one or more of the following characteristics: (a) a specific binding affinity of 1×10 as determined by surface plasmon resonance using a Biacore biosensor system; -7 (b) binds to human PD-1 with a KD of 1M or less; (b) does not substantially bind to human CD28, CTLA-4, or ICOS; (c) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay; (d) increases interferon-γ production in an MLR assay; (e) increases IL-2 secretion in an MLR assay; (f) binds to human PD-1 and cynomolgus PD-1; (g) inhibits the binding of PD-L1 and / or PD-L2 to PD-1; (h) stimulates an antigen-specific memory response; (i) stimulates an antibody response; and (j) inhibits tumor cell growth in vivo. Anti-PD-1 antibodies that can be used in the present disclosure include monoclonal antibodies that specifically bind to human PD-1 and exhibit at least one, and in some embodiments at least five, of the foregoing characteristics.

[0167] Other anti-PD-1 monoclonal antibodies that can be used in the methods of the disclosure are described in, for example, U.S. Patent Nos. 6,808,710, 7,488,802, 8,168,757, and 8,354,509, U.S. Patent Application Publication No. 2016 / 0272708, and PCT Publication Nos. WO2012 / 145493, WO2008 / 156712, WO2015 / 112900, WO2012 / 145493, WO2015 / 112800, WO2014 / 206107, WO2015 / 35606, WO2015 / 085847, WO2014 / 179664, WO2017 / 020291, WO2017 / 02085 8, WO2016 / 197367, WO2017 / 024515, WO2017 / 025051, WO2017 / 123557, WO2016 / 106159 , WO2014 / 194302, WO2017 / 040790, WO2017 / 133540, WO2017 / 132827, WO2017 / 024465, and WO2017 / 106061, WO2017 / 19846, WO2017 / 024465, WO2017 / 025016, WO2017 / 132825, and WO2017 / 133540, each of which is incorporated herein by reference in its entirety.

[0168] Anti-PD-1 antibodies that can be used in the methods of the disclosure include nivolumab (also known as OPDIVO®, 5C4, BMS-936558, MDX-1106, and ONO-4538), pembrolizumab (Merck; also known as KEYTRUDA®, lambrolizumab, and MK3475; see WO2008 / 156712), PDR001 (Novartis; also known as spartalizumab; see WO2015 / 112900 and U.S. Patent No. 9,683,048), MEDI-0680 (AstraZeneca; also known as AMP-514; see WO2012 / 145493), TSR-042 (Tesaro Biopharmaceutical; also known as ANB011 or dostallimab; see WO2014 / 179664), cemiplimab (Regeneron; also known as LIBTAYO® or REGN2810; see WO2015 / 112800 and U.S. Patent No. 9,987,500), JS001 (TAIZHOU JUNSHI PHARMA; also known as toripalimab; Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), PF-06801591 (Pfizer; also known as sasanlimab; see U.S. Patent Application Publication No. 2016 / 0159905), BGB-A317 (Beigene; also known as tislelizumab; see WO2015 / 35606 and U.S. Patent Application Publication No. 2015 / 0079109), BI 754091 (Boehringer Ingelheim; see Zettl M et al., Cancer. Res. (2018);78(13 Suppl):Abstract 4558), INCSHR1210 (Jiangsu Hengrui Medicine; also known as SHR-1210 or camrelizumab; WO2015 / 085847; Si-Yang Liu et al., J. Hematol. Oncol.10:136 (2017)), GLS-010 (Wuxi / Harbin Gloria Pharmaceuticals; also known as WBP3055; see Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), AM-0001 (Armo), STI-1110 (Sorrento Therapeutics; see WO2014 / 194302), AGEN2034 (Agenus; see WO2017 / 040790), MGA012 (Macrogenics; see WO2017 / 19846), BCD-100 (Biocad; Kaplon et al., mAbs 10(2):183-203 (2018)), IBI308 (Innovent; also known as sintilimab; see WO2017 / 024465, WO2017 / 025016, WO2017 / 132825, and WO2017 / 133540), and SSI-361 (Lyvgen Biopharma Holdings Limited, U.S. Patent Application Publication No. 2018 / 0346569).

[0169] Anti-PD-1 antibodies that can be used in the methods of the present disclosure also include isolated antibodies that specifically bind to human PD-1 and cross-compete for binding to human PD-1 with any of the anti-PD-1 antibodies disclosed herein, e.g., nivolumab (see, e.g., U.S. Patent Nos. 8,008,449 and 8,779,105; WO2013 / 173223). In some embodiments, the anti-PD-1 antibody binds to the same epitope as any of the anti-PD-1 antibodies described herein, e.g., nivolumab.

[0170] In some embodiments, an antibody that cross-competes with any of the anti-PD-1 antibodies disclosed herein, such as nivolumab, for binding to human PD-1 or binds to the same epitope region is a monoclonal antibody. These cross-competing antibodies for administration to human subjects are chimeric, engineered, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0171] Anti-PD-1 antibodies that can be used in the methods of the disclosure also include antigen-binding portions of any of the above full-length antibodies.

[0172] Anti-PD-1 antibodies that can be used in the methods of the present disclosure are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and / or PD-L2, and inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-1 "antibody" includes an antigen-binding portion or fragment that binds to the PD-1 receptor and exhibits functional properties similar to those of a whole antibody in inhibiting ligand binding and upregulating the immune system. In certain embodiments, the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1.

[0173] In some embodiments, the anti-PD-1 antibody is a full-length antibody. In some aspects, the anti-PD-1 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. In some aspects, the multispecific antibody is a DART, DVD-Ig, or bispecific antibody.

[0174] In some embodiments, the anti-PD-1 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0175] In some embodiments, the anti-PD-1 antibody is, or comprises an antigen-binding portion of, nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, cemiplimab, JS001, PF-06801591, BGB-A317, BI 754091, INCSHR1210, GLS-010, AM-001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, or SSI-361.

[0176] In some embodiments, the anti-PD-1 antibody is nivolumab. Nivolumab is a human monoclonal antibody that targets PD-1. Nivolumab (Opdivo®) has been approved for the treatment of several types of cancer in multiple regions, including the United States (US, December 2014), the European Union (EU, June 2015), and Japan (JP, July 2014). Nivolumab is a fully human IgG4(S228P)PD-1 immune checkpoint inhibitor antibody that blocks downregulation of anti-tumor T cell function by selectively preventing interaction with PD-1 ligands (PD-L1 and PD-L2) (U.S. Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9):846-56).

[0177] In some embodiments, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 (S228P) antibody directed against the human cell surface receptor PD-1. Pembrolizumab is described, for example, in U.S. Patent Nos. 8,354,509 and 8,900,587.

[0178] In some embodiments, pembrolizumab is administered at a fixed dose of about 200 mg about once every two weeks. In some embodiments, pembrolizumab is administered at a fixed dose of about 200 mg about once every three weeks. In some embodiments, pembrolizumab is administered at a fixed dose of about 400 mg about once every four weeks. In some embodiments, pembrolizumab is administered at a fixed dose of about 400 mg about once every six weeks. In some embodiments, pembrolizumab is administered at a fixed dose of about 300 mg about once every four to five weeks.

[0179] In some embodiments, pembrolizumab is administered intravenously at a dose of about 200 mg on day 1, then about once every three weeks. In some embodiments, pembrolizumab is administered for a maximum of 35 cycles. In some embodiments, pembrolizumab is administered intravenously at a dose of about 200 mg for about 30 minutes on day 1 of a three-week cycle for a maximum of 35 cycles.

[0180] In some embodiments, the anti-PD-1 antibody is cemiplimab (REGN2810), which is described, for example, in WO2015 / 112800 and U.S. Patent No. 9,987,500.

[0181] In some embodiments, cemiplimab is administered intravenously at a dose of about 3 mg / kg or about 350 mg about once every three weeks.

[0182] In some embodiments, the anti-PD-1 antibody is spartalizumab (PDR001), which is described, for example, in WO2015 / 112900 and U.S. Patent No. 9,683,048.

[0183] In some embodiments, spartalizumab is administered intravenously at a dose of about 300 mg about once every three weeks or at a dose of 400 mg about once every four weeks.

[0184] Anti-PD-L1 antibody In some embodiments, the PD-1 / PD-L1 pathway is targeted by PD-1 blockade, including by anti-PD-L1 antibodies. Anti-PD-L1 antibodies known in the art can be used in the methods of the disclosure. Examples of anti-PD-L1 antibodies useful in the compositions and methods of the disclosure include the antibodies disclosed in U.S. Patent No. 9,580,507. The anti-PD-L1 human monoclonal antibody disclosed in U.S. Patent No. 9,580,507 has been demonstrated to exhibit one or more of the following characteristics: (a) a PD-1 / PD-L1 activity of 1×10 6 as determined by surface plasmon resonance using a Biacore biosensor system; -7 (b) binds to human PD-L1 with a KD of less than or equal to M; (b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay; (c) increases interferon-γ production in an MLR assay; (d) increases IL-2 secretion in an MLR assay; (e) stimulates antibody responses; and (f) reverses the effects of T regulatory cells on T-cell effector cells and / or dendritic cells. Anti-PD-L1 antibodies that can be used in the present disclosure include monoclonal antibodies that specifically bind to human PD-L1 and exhibit at least one, and in some embodiments at least five, of the foregoing characteristics.

[0185] Anti-PD-L1 antibodies that can be used in the methods of the disclosure include BMS-936559 (12A4, also known as MDX-1105; see, e.g., U.S. Patent No. 7,943,743 and WO2013 / 173223), atezolizumab (Roche; TECENTRIQ®; MPDL3280A, also known as RG7446; see U.S. Patent No. 8,217,149; Herbst et al. (2013) J Clin Oncol 31(suppl):3000), durvalumab (AstraZeneca; IMFINZI™, also known as MEDI-4736; see WO2011 / 066389), avelumab (Pfizer; BAVENCIO®, also known as MSB-0010718C; see WO2013 / 079174), STI-1014 (Sorrento; see WO2013 / 181634), CX-072 (Cytomx; see WO2016 / 149201), KN035 (3D Med / Alphamab; see Zhang et al., Cell Discov. 7:3 (March 2017)), LY3300054 (Eli Lilly Co.; see, e.g., WO2017 / 034916), BGB-A333 (BeiGene; see Desai et al., JCO 36 (15suppl):TPS3113 (2018)), ICO 36, FAZ053 (Novartis), and CK-301 (Checkpoint Therapeutics; see Gorelik et al., AACR:Abstract 4606 (Apr 2016)).

[0186] Anti-PD-L1 antibodies that can be used in the methods of the disclosure also include isolated antibodies that specifically bind to human PD-L1 and cross-compete for binding to human PD-L1 with any of the anti-PD-L1 antibodies disclosed herein, e.g., atezolizumab, durvalumab, and / or avelumab. In some embodiments, the anti-PD-L1 antibody binds to the same epitope as any of the anti-PD-L1 antibodies described herein, e.g., atezolizumab, durvalumab, and / or avelumab. In certain embodiments, the antibody that cross-competes for binding to human PD-L1 or binds to the same epitope region as any of the anti-PD-L1 antibodies disclosed herein, e.g., atezolizumab, durvalumab, and / or avelumab, is a monoclonal antibody. These cross-competing antibodies for administration to human subjects are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0187] Anti-PD-L1 antibodies that can be used in the methods of the disclosure also include antigen-binding portions of any of the above full-length antibodies.

[0188] Anti-PD-L1 antibodies that can be used in the methods of the disclosure are antibodies that bind to PD-L1 with high specificity and affinity, block PD-1 binding, and inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-L1 "antibody" includes an antigen-binding portion or fragment that binds to PD-L1 and exhibits functional properties similar to those of a whole antibody in inhibiting receptor binding and upregulating the immune system. In certain embodiments, the anti-PD-L1 antibody or antigen-binding portion thereof cross-competes with atezolizumab, durvalumab, and / or avelumab for binding to human PD-L1.

[0189] In some embodiments, an anti-PD-L1 antibody is used in place of an anti-PD-1 antibody in any of the methods disclosed herein.

[0190] In some embodiments, the anti-PD-L1 antibody is a full-length antibody.

[0191] In some embodiments, the anti-PD-L1 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is a DART, DVD-Ig, or bispecific antibody.

[0192] In some embodiments, the anti-PD-L1 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0193] In some embodiments, the anti-PD-L1 antibody is, or comprises an antigen-binding portion of, BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, or CK-301.

[0194] In some embodiments, the PD-L1 antibody is atezolizumab. Atezolizumab is a fully humanized IgG1 monoclonal anti-PD-L1 antibody. In some embodiments, atezolizumab is administered at a fixed dose of about 800 mg about once every two weeks. In some embodiments, atezolizumab is administered at a fixed dose of about 840 mg about once every two weeks.

[0195] In some embodiments, atezolizumab is administered intravenously on day 1 of a 3-week cycle at a dose of about 1,200 mg.

[0196] In some embodiments, atezolizumab is administered intravenously at a dose of about 1,200 mg on day 1 of a 3-week cycle, and bevacizumab is administered at a dose of about 15 mg / kg on day 1 of each cycle.

[0197] In some embodiments, the PD-L1 antibody is durvalumab. Durvalumab is a human IgG1 kappa monoclonal anti-PD-L1 antibody. In some embodiments, durvalumab is administered at a dose of about 10 mg / kg about once every two weeks. In some embodiments, durvalumab is administered at a dose of about 10 mg / kg about once every two weeks for up to 12 months. In some embodiments, durvalumab is administered at a flat dose of about 800 mg / kg about once every two weeks. In some embodiments, durvalumab is administered at a flat dose of about 1200 mg / kg about once every three weeks.

[0198] In some embodiments, the PD-L1 antibody is avelumab. Avelumab is a human IgG1 lambda monoclonal anti-PD-L1 antibody. In some embodiments, avelumab is administered at a fixed dose of about 800 mg about once every two weeks.

[0199] Phase 1 studies using antibodies against PD-1 or PD-L1 in combination with CD19-directed CAR T therapy have demonstrated an acceptable safety profile and potentially beneficial effects on CAR T pharmacokinetics, thus indicating that further evaluation of this approach is warranted (Siddiqi et al., Blood (2017) 129(8):1039-41; Tholouli et al., Ann Oncol (2020) 31 Suppl 4; S651). However, some patients become resistant to therapy targeting PD-1 and / or PD-L1. The precise mechanisms of such resistance are largely unknown, but it is hypothesized that anti-PD-1 and / or anti-PD-L1 therapy may cause T cells to upregulate other inhibitory receptors, such as TIM3, LAG3, and / or CTLA4.

[0200] Adding LAG3 blockade to PD-1 blockade in combination with T cell therapy, such as CAR T cells, can further improve antitumor activity, such as in aggressive NHL, by blocking inhibitory signals and preventing T cell exhaustion or restoring T cells. Lymphocyte activation gene 3 (LAG3; also known as cluster of differentiation 223 (CD223)) is a checkpoint receptor expressed on several immune cell types, including activated CD4+ and CD8+ T cells, memory T cells, Treg cells, and natural killer cells (Andrews et al., Immunol Rev (2017) 276(1): 80-96). Activation of the LAG3 pathway occurs when LAG3 interacts with its ligands, such as MHC class II or other emerging ligands (e.g., FGL1), thereby inducing inhibitory activity that reduces effector T cell function (Andrews et al., Immunol Rev (2017) 276(1): 80-96; Wang et al., Cell (2019) 176(1-1): 334-347). Increased expression of LAG3 on TILs, particularly in association with PD-1 expression, further promotes T cell exhaustion, thereby impairing their ability to attack tumor cells and increasing the likelihood of tumor growth (Andrews et al., (2017) 276(1): 80-96; Woo et al., Cancer Res (2012) 72(4):917-27). Inhibition of the LAG3 pathway can restore the effector function of exhausted T cells, thus promoting pro-inflammatory cytokine signaling and ultimately anti-tumor responses.

[0201] There are various anti-LAG3 strategies for blocking LAG3, including LAG3 inhibitors such as anti-LAG3 antibodies. LAG3 inhibitors for use in the methods of the present disclosure include, but are not limited to, LAG3 antibodies and soluble LAG3 polypeptides. Anti-LAG3 antibodies include antibodies that specifically bind to LAG3 (i.e., "anti-LAG3 antibodies").

[0202] In some embodiments, the LAG3 inhibitor is an anti-LAG3 antibody.

[0203] Antibodies that bind to LAG3 are disclosed, for example, in International Publication No. WO / 2015 / 042246 and U.S. Patent Application Publication Nos. 2014 / 0093511 and 2011 / 0150892, each of which is incorporated by reference in its entirety.

[0204] An exemplary LAG3 antibody useful in the present disclosure is 25F7 (described in U.S. Patent Application Publication No. 2011 / 0150892). An additional exemplary LAG3 antibody useful in the present disclosure is BMS-986016 (relatolimab). In some embodiments, an anti-LAG3 antibody useful in the present disclosure cross-competes with 25F7 or BMS-986016. In some embodiments, an anti-LAG3 antibody useful in the present disclosure binds to the same epitope as 25F7 or BMS-986016. In some embodiments, an anti-LAG3 antibody comprises the six CDRs of 25F7 or BMS-986016.

[0205] Other art-recognized anti-LAG3 antibodies that can be used in the methods of the present disclosure include IMP731 (H5L7BW), described in U.S. Patent Application Publication No. 2011 / 007023, MK-4280 (28G-10, favezelimab), described in WO2016028672 and U.S. Patent Application Publication No. 2020 / 0055938, Burova E, et al., J. Immunother. Cancer (2016); 4(Supp. 1): P195 and REGN3767 (fianlimab), described in U.S. Pat. No. 10,358,495; humanized BAP050, described in WO2017 / 019894; GSK2831781; IMP-701 (LAG-525; ieramilimab), described in U.S. Pat. No. 10,711,060 and U.S. Patent Application Publication No. 2020 / 0172617; aLAG3(0414); aLAG3(0416); Sym022; TSR-033; TSR-075; XmAb841 (formerly known as XmAb22841); MGD013 (tebotelimab); BI754111; FS118; P These include 13B02-30, AVA-017, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, and ABL501.These and other anti-LAG3 antibodies useful in the claimed invention are described in, e.g., U.S. Pat. No. 10,188,730, WO2016 / 028672, WO2017 / 106129, WO2017 / 062888, WO2009 / 044273, WO2018 / 069500, WO2016 / 126858 , WO2014 / 179664, WO2016 / 200782, WO2015 / 200119, WO2017 / 019846, WO2017 / 1987 41, WO2017 / 220555, WO2017 / 220569, WO2018 / 071500, WO2017 / 015560, WO2017 / 02 5498, WO2017 / 087589, WO2017 / 087901, WO2018 / 083087, WO2017 / 149143, WO2017 / 219995, US2017 / 0260271, WO2017 / 086367, WO2017 / 086419, WO2018 / 034227, WO20 18 / 185046, WO2018 / 185043, WO2018 / 217940, WO19 / 011306, WO2018 / 208868, WO2014 / 140180, WO2018 / 201096, WO2018 / 204374, and WO2019 / 018730, the contents of each of which are incorporated herein by reference in their entirety.

[0206] Anti-LAG3 antibodies that can be used in the methods of the present disclosure also include isolated antibodies that specifically bind to human LAG3 and cross-compete with any of the anti-LAG3 antibodies disclosed herein, such as leratolimab, for binding to human LAG3. In some embodiments, the anti-LAG3 antibody binds to the same epitope as any of the anti-LAG3 antibodies described herein, such as leratolimab.

[0207] In some embodiments, any of the anti-LAG3 antibodies disclosed herein, such as relatolimab, that cross-compete for binding to human LAG3 or bind to the same epitope region are monoclonal antibodies. These cross-competing antibodies for administration to human subjects are chimeric, engineered, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0208] The ability of an antibody to cross-compete for binding to an antigen indicates that the antibody binds to the same epitope region of the antigen and sterically blocks the binding of other cross-competing antibodies to that specific epitope region. These cross-competing antibodies are expected to have functional properties very similar to those of a reference antibody, such as leratolimab, because they bind to the same epitope region. Cross-competing antibodies can be easily identified based on their cross-competing ability in standard binding assays, such as Biacore analysis, ELISA assays, or flow cytometry (see, for example, WO2013 / 173223).

[0209] Anti-LAG3 antibodies that can be used in the methods of the present disclosure also include antigen-binding portions of any of the above full-length antibodies. It is well established that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0210] In some embodiments, the anti-LAG3 antibody is a full-length antibody.

[0211] In some embodiments, the anti-LAG3 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is a dual affinity retargeting antibody (DART), DVD-Ig, or bispecific antibody.

[0212] In some embodiments, the anti-LAG3 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0213] In some embodiments, the anti-LAG3 antibody is selected from the group consisting of BMS-986016 (leratolimab), IMP731 (H5L7BW), MK4280 (28G-10, favezelimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, yeramilimab), aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P 13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, or ABL501, or comprises an antigen-binding portion thereof.

[0214] In some embodiments, the anti-LAG3 antibody is MGD013 (tebotelimab), a bispecific PD-1 x LAG3 DART. In some embodiments, tebotelimab is administered intravenously at a dose of about 300 mg or about 600 mg about once every two or three weeks. In some embodiments, tebotelimab is administered intravenously at a dose of about 300 mg about once every two weeks. In some embodiments, tebotelimab is administered intravenously at a dose of about 600 mg about once every three weeks.

[0215] In some embodiments, the anti-LAG3 antibody is REGN3767 (fianlimab). In some embodiments, fianlimab is administered intravenously at a dose of about 1 mg / kg, about 3 mg / kg, about 10 mg / kg, or about 20 mg / kg approximately once every three weeks. In some embodiments, fianlimab is administered intravenously at a dose of about 1600 mg approximately once every three weeks.

[0216] In some embodiments, the anti-LAG3 antibody is LAG525 (Ielamirimab). In some embodiments, Ielamirimab is administered intravenously at a dose of about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, or about 1300 mg about once every 2, 3, or 4 weeks.

[0217] In some embodiments, the anti-LAG3 antibody is MK4280 (fabezelimab). In some embodiments, favezelimab is administered intravenously at a dose of about 7 mg, about 21 mg, about 70 mg, about 210 mg, about 700 mg, or about 800 mg about once every three weeks or about once every six weeks. In some embodiments, favezelimab is administered intravenously at a dose of about 200 mg about once every three weeks. In some embodiments, favezelimab is administered intravenously at a dose of about 800 mg about once every six weeks. In some embodiments, favezelimab is administered intravenously at a dose of about 800 mg on day 1, then about once every three weeks. In some embodiments, favezelimab is administered for a maximum of 35 cycles. In some embodiments, favezelimab is administered intravenously at a dose of about 800 mg over about 30 minutes on day 1 of a 3-week cycle for up to 35 cycles.

[0218] In some embodiments, the LAG3 inhibitor is a soluble LAG3 polypeptide. In some embodiments, the soluble LAG3 polypeptide is a fusion polypeptide, for example, a fusion protein comprising the extracellular portion of LAG3. In some embodiments, the soluble LAG3 polypeptide is a LAG3-Fc fusion polypeptide that can bind to MHC class II. In some embodiments, the soluble LAG3 polypeptide comprises a ligand-binding fragment of the LAG3 extracellular domain.

[0219] In some embodiments, the LAG3 inhibitor is formulated for intravenous administration.

[0220] In some embodiments, the LAG3 inhibitor is administered in a fixed dose.

[0221] In some embodiments, the LAG3 inhibitor is at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg The dose may be about 100 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

[0222] In some embodiments, the LAG3 inhibitor is about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, or about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 35 0mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 5 20mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 6 90mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 1080m g, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0223] In some embodiments, the LAG3 inhibitor is administered in a weight-based dose.

[0224] In some embodiments, the LAG3 inhibitor is at least about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, about 0.003 mg / kg to about 0 .8mg / kg, about 0.003mg / kg to about 0.7mg / kg, about 0.003mg / kg to about 0.6mg / kg, about 0.003mg / kg to about 0.5mg / kg, about 0.003mg / kg to about 0.4m g / kg, about 0.003mg / kg to about 0.3mg / kg, about 0.003mg / kg to about 0.2mg / kg, about 0.003mg / kg to about 0.1mg / kg, about 0.1mg / kg to about 25mg / kg, about 0.1mg / kg to about 20mg / kg, about 0.1mg / kg to about 15mg / kg, about 0.1mg / kg to about 10mg / kg, about 0.1mg / kg to about 5mg / kg, about 0.1mg / kg to about 1mg / kg , about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about 5 mg / k The dose is administered at a range of about 10 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

[0225] In some embodiments, the LAG3 inhibitor is about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

[0226] In some embodiments, the dose of the LAG3 inhibitor is administered in a constant amount.

[0227] In some embodiments, the dose of LAG3 inhibitor is administered in various amounts.For example, in some embodiments, the maintenance (or continuing) dose of LAG3 inhibitor can be higher than or the same as the loading dose that is initially administered.In some embodiments, the maintenance dose of LAG3 inhibitor can be lower than or the same as the loading dose.

[0228] In some embodiments, the dose of the LAG3 inhibitor is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

[0229] In some embodiments, the anti-LAG3 antibody is leratolimab. Lelatolimab (BMS-986016) is a fully human lymphocyte activation gene 3 (LAG3)-specific antibody isolated after immunization of transgenic mice expressing human immunoglobulin (Ig) genes. Lelatolimab binds with high affinity to the LAG3 receptor expressed on T cells and prevents the receptor from binding to cells bearing its ligand, major histocompatibility complex (MHC) class II and fibrinogen-like protein 1 (FGL-1) (Andrews, Immunol Rev. 2017 March; 276(1): 80-96; Wang, Cell. 2019 Jan 10; 176(1-1): 334-347). Lelatolimab binding inhibits the negative regulatory function of LAG3, mediated by its interaction with its ligand in vitro.

[0230] It is observed herein that resistance to immunotherapy, such as treatment with anti-PD-1 antibodies, can be overcome by additional blockade of LAG3. In particular, the results herein demonstrate that near or complete engagement of the LAG3 receptor—both in its soluble form and its membrane-bound form—can result in improved responses, including improved responses in patients who do not respond to anti-PD-1 therapy alone. For example, Opdualag™ is a fixed-dose dual immunotherapy combination treatment of nivolumab and leratolimab approved by the FDA for the treatment of adult patients and pediatric patients aged 12 years and older with unresectable or metastatic melanoma.

[0231] Combining T cell therapy with checkpoint inhibitor therapy, including both anti-PD-1 and anti-LAG3 antibodies, can improve responses compared to combining T cell therapy with anti-PD-1 antibodies alone.

[0232] Observations herein indicate that combining T cell therapy, e.g., CAR-T cell therapy, with both a PD-1 inhibitor and a LAG3 inhibitor is advantageous. Results herein indicate that a relatively high dose of an anti-LAG3 antibody (e.g., 480 mg or 960 mg, such as 480 mg every two weeks (Q2W) or 960 mg every four weeks (Q4W)) increases LAG3 receptor occupancy in both the peripheral blood and the tumor microenvironment. In particular, it is observed herein that a high dose of the anti-LAG3 antibody leratolimab (e.g., 960 mg Q4W) minimizes the amount of soluble free LAG3 receptor protein in the peripheral blood (see Example 2). In some embodiments, maximized LAG3 receptor occupancy and / or minimized soluble free LAG3 can improve response to T cell therapy, e.g., CAR T cells. In some embodiments, both maximizing LAG3 receptor occupancy and minimizing soluble free LAG3 receptors will improve response to T cell therapy. In some embodiments, near or complete engagement of LAG3 in the tumor microenvironment and periphery improves clinical outcomes by reducing or eliminating the likelihood of LAG3 expression by T cells.

[0233] In some aspects, such effects are observed despite subjects exhibiting resistance to PD-1 inhibitors or high PD-1 levels. In particular, it is observed herein that there is a synergistic effect of combining a PD-1 inhibitor (e.g., an anti-PD-1 antibody such as nivolumab) with a LAG3 inhibitor (e.g., an anti-LAG3 antibody). In some embodiments, treatment with an anti-PD-1 antibody and an anti-LAG3 antibody is more effective than treatment with either antibody alone, including in subjects who do not respond to treatment with an anti-PD-1 antibody. Thus, in some embodiments, the provided combination therapy achieves synergistic effects and activity compared to therapy involving administration of a PD-1 inhibitor without administration of a LAG3 inhibitor.

[0234] Among provided embodiments, the methods involve combination therapy with a therapy targeted or directed at killing cancer cells, e.g., T cell therapy, such as CAR T cell therapy, and checkpoint inhibitor therapy. In some aspects, the checkpoint inhibitor therapy inhibits one or more checkpoints, e.g., immune checkpoints. In some embodiments, the immune checkpoint is PD-1. In some embodiments, the checkpoint inhibitor therapy comprises or consists of an anti-PD-1 antibody. In some embodiments, the immune checkpoint is LAG3. In some embodiments, the immune checkpoint is PD-1. In some embodiments, the checkpoint inhibitor therapy comprises an anti-LAG3 antibody. In some embodiments, the checkpoint inhibitor therapy targets PD-1 and / or LAG3. In some embodiments, the checkpoint inhibitor therapy targets PD-1 and LAG3. In some embodiments, the checkpoint inhibitor comprises or consists of an anti-PD-1 antibody and an anti-LAG3 antibody. Thus, in some embodiments, the methods involve combination therapy with CAR T cell therapy and checkpoint inhibitor therapy comprising an anti-PD-1 antibody and an anti-LAG3 antibody. In some cases, the combination therapy is a CD19-targeted CAR T-cell therapy, an anti-PD-1 antibody (e.g., nivolumab), and an anti-LAG3 antibody (e.g., leratolimab).

[0235] In some aspects, improved response to combination therapy is observed despite the tumor or disease or target cells themselves being insensitive, resistant, and / or otherwise poorly responsive to T cell therapy (e.g., CAR T cells) or checkpoint inhibitor therapy when each is administered alone. In some embodiments, the T cell therapy cells (e.g., CAR T cells) have reduced effector function and / or exhibit exhaustion. In some aspects, such exhaustion and / or reduced effector function of T cell therapy is due to increased expression of one or more immune checkpoints by the T cells. For example, it is observed herein that CAR T cells of subjects exhibiting poorer clinical responses have higher PD-1 and LAG3 expression. Thus, checkpoint inhibitor therapy can reduce expression of one or more immune checkpoints by the T cell therapy cells, thereby increasing the effector function of the cells. In some embodiments, the provided combination therapy achieves synergistic effects and activity compared to therapy involving administration of only T cell therapy or only checkpoint inhibitor therapy administered at the same dosing regimen, e.g., dose and frequency.

[0236] Furthermore, in some aspects, the subject's endogenous T cells have reduced effector function and / or exhibit exhaustion. In some aspects, such exhaustion and / or reduced effector function of endogenous T cells is due to increased expression of one or more immune checkpoints by the endogenous T cells. For example, it is observed herein that endogenous (i.e., CAR-negative) T cells of subjects exhibiting poorer clinical responses have higher PD-1 and LAG3 expression. Thus, checkpoint inhibitor therapy can reduce the expression of one or more immune checkpoints by endogenous T cells, thereby increasing the effector function of the cells. In some embodiments, the provided combination therapy achieves synergistic effects and activity compared to therapy involving the administration of only T cell therapy or only checkpoint inhibitor therapy administered at the same dosage regimen, e.g., dose and frequency.

[0237] In some embodiments, provided embodiments involve initiating administration of checkpoint inhibitor therapy, e.g., an anti-PD-1 antibody and, optionally, an anti-LAG3 antibody, after administration of T cell therapy (e.g., CAR T cell therapy) in a dosing regimen. In some embodiments, initiation of administration of checkpoint inhibitor therapy occurs after administration of T cell therapy, such as between about one and two weeks after administration of T cell therapy to treat cancer. In some embodiments, administration of checkpoint inhibitor therapy begins after activation-induced cell death (AICD) of T cell therapy cells has peaked. In some embodiments, administration of checkpoint inhibitor therapy, such as an anti-PD-1 antibody, and, optionally, an anti-LAG3 antibody, occurs about one week after administration of T cell therapy. In some cases, administration of T cell therapy (e.g., CAR T cell therapy) occurs on day 1, and administration of checkpoint inhibitor therapy begins on day 8. In some embodiments, administration of checkpoint inhibitor therapy, such as an anti-PD-1 antibody, and, optionally, an anti-LAG3 antibody, occurs about two weeks after administration of T cell therapy. In some cases, administration of T cell therapy (e.g., CAR T cell therapy) occurs on day 1 and administration of checkpoint inhibitor therapy begins on day 15.

[0238] In some embodiments, the method includes administering to the subject a PD-1 inhibitor (e.g., an anti-PD-1 antibody such as nivolumab) and a LAG3 inhibitor (e.g., an anti-LAG3 antibody such as leratolimab) after administration of T cell therapy (e.g., anti-CD19 CAR T cells). In some embodiments, the first dose of the PD-1 inhibitor is administered between days 2 and 20, inclusive. In some embodiments, the first dose of the LAG3 inhibitor is administered between days 2 and 20, inclusive. In some embodiments, the first dose of the PD-1 inhibitor and the first dose of the LAG3 inhibitor are each administered independently between days 2 and 20, inclusive. In some embodiments, the first dose of the PD-1 inhibitor and the first dose of the LAG3 inhibitor are administered on the same day.

[0239] In some embodiments, the method includes administering a PD-1 inhibitor (e.g., an anti-PD-1 antibody such as nivolumab) to the subject after administration of T cell therapy (e.g., anti-CD19 CAR T cells). In some embodiments, the method includes administering at least two doses of the PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is administered in a dosing regimen including administration of the PD-1 inhibitor about every two weeks (Q2W) or about every four weeks (Q4W). In some embodiments, the PD-1 inhibitor is administered in a dosing regimen including at least two doses, with the first dose administered between days 2 and 20, inclusive, and the T cell therapy being administered on day 1. In some embodiments, the first dose of the PD-1 inhibitor is administered between days 2 and 20, inclusive, and the T cell therapy being administered on day 1. In some embodiments, each subsequent dose of the PD-1 inhibitor is administered about 2 weeks, about 3 weeks, or about 4 weeks after the previous dose of the PD-1 inhibitor. In some embodiments, between about 140 mg and 580 mg of a PD-1 inhibitor (eg, an anti-PD-1 antibody such as nivolumab) is administered in each dose.

[0240] In some embodiments, the first dose of the PD-1 inhibitor is administered on day 8. In some embodiments, the first dose of the PD-1 inhibitor is administered on day 15. In some embodiments, about 240 mg of the PD-1 inhibitor (e.g., an anti-PD-1 antibody such as nivolumab) is administered in each dose. In some embodiments, about 480 mg of the PD-1 inhibitor (e.g., an anti-PD-1 antibody such as nivolumab) is administered in each dose.

[0241] In some embodiments, the method comprises administering four doses of the PD-1 inhibitor. In some embodiments, each of the four doses of the PD-1 inhibitor is about 480 mg. In some embodiments, the second dose of the PD-1 inhibitor is administered about four weeks after the first dose of the PD-1 inhibitor. In some embodiments, the third dose of the PD-1 inhibitor is administered about three weeks or about four weeks after the second dose of the PD-1 inhibitor. In some embodiments, the third dose of the PD-1 inhibitor is administered about three weeks after the second dose of the PD-1 inhibitor. In some embodiments, the third dose of the PD-1 inhibitor is administered about four weeks after the second dose of the PD-1 inhibitor. In some embodiments, the fourth dose of the PD-1 inhibitor is administered about three weeks after the third dose of the PD-1 inhibitor.

[0242] In some embodiments, the method comprises administering five doses of the PD-1 inhibitor. In some embodiments, at least one dose of the PD-1 inhibitor is about 240 mg and at least one dose of the PD-1 inhibitor is about 480 mg. In some embodiments, three doses of the PD-1 inhibitor are 240 mg and the subsequent two doses of the PD-1 inhibitor are 480 mg. In some embodiments, the second and third doses of the PD-1 inhibitor are each administered about two weeks after the previous dose of the PD-1 inhibitor. In some embodiments, the fourth dose of the PD-1 inhibitor is administered about three weeks after the third dose of the PD-1 inhibitor. In some embodiments, each of the first four doses of the PD-1 inhibitor are administered about two weeks after the previous dose of the PD-1 inhibitor. In some embodiments, the fifth dose of the PD-1 inhibitor is administered about four weeks after the fourth dose of the PD-1 inhibitor.

[0243] In some embodiments, the method comprises administering six doses of the PD-1 inhibitor. In some embodiments, the first and second doses of the PD-1 inhibitor are each administered about two weeks after the previous dose of the PD-1 inhibitor. In some embodiments, the second, third, fifth, and sixth doses of the PD-1 inhibitor are each administered about two weeks after the previous dose of the PD-1 inhibitor. In some embodiments, the fifth dose of the PD-1 inhibitor is administered about three weeks after the fourth dose of the PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is administered about every two weeks (Q2W).

[0244] In some embodiments, the PD-1 inhibitor is administered for a period not exceeding about 3 months. In some embodiments, the dosing regimen lasts about 3 weeks. In some embodiments, the final dose of the PD-1 inhibitor is administered between about day 80 and about day 90. In some embodiments, the final dose of the PD-1 inhibitor is administered on about day 85.

[0245] In some embodiments, the methods include administering a T cell therapy (e.g., anti-CD19 CAR T cells) to a subject on day 1, followed by administration of a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is administered in a dosing regimen comprising a first cycle and a second cycle.

[0246] In some embodiments, the first dose of a PD-1 inhibitor (e.g., an anti-PD-1 antibody such as nivolumab) of the first cycle is administered to a subject between about days 2 and 20. In some embodiments, between about 140 mg and about 580 mg of nivolumab is administered in each dose of the first cycle. In some embodiments, about 240 mg of nivolumab is administered in each dose of the first cycle. In some embodiments, about 480 mg of nivolumab is administered in each dose of the first cycle. In some embodiments, at least one dose or at least two doses of a PD-1 inhibitor are administered in the first cycle. In some embodiments, one dose of a PD-1 inhibitor is administered in the first cycle. In some embodiments, two doses of a PD-1 inhibitor are administered in the first cycle. In some embodiments, three doses of a PD-1 inhibitor are administered in the first cycle.

[0247] In some embodiments, the first dose of a PD-1 inhibitor (e.g., an anti-PD-1 antibody such as nivolumab) of the second cycle is administered to the subject between about days 50 and 65. In some embodiments, between about 140 mg and about 580 mg of nivolumab is administered in each dose of the second cycle. In some embodiments, about 240 mg of nivolumab is administered in each dose of the second cycle. In some embodiments, about 480 mg of nivolumab is administered in each dose of the second cycle. In some embodiments, at least two doses of the PD-1 inhibitor are administered during the first cycle. In some embodiments, two doses of the PD-1 inhibitor are administered during the first cycle.

[0248] In some embodiments, the method further includes administering a LAG3 inhibitor (e.g., an anti-LAG3 antibody such as leratolimab) to the subject. In some embodiments, the dose of the LAG3 inhibitor is administered about every two weeks (Q2W). In some embodiments, the dose of the LAG3 inhibitor is administered about every four weeks (Q4W). In some embodiments, the first dose of the LAG3 inhibitor is administered between days 2 and 20, inclusive, and the T cell therapy is administered on day 1. In some embodiments, the first dose of the LAG3 inhibitor is administered between days 8 and 15, inclusive, and the T cell therapy is administered on day 1. In some embodiments, the first dose of the LAG3 inhibitor is administered on day 8. In some embodiments, the first dose of the LAG3 inhibitor is administered on day 15. In some embodiments, each subsequent dose of the LAG3 inhibitor is administered about 2 weeks, about 3 weeks, about 4 weeks, or about 5 weeks after the previous dose of the LAG3 inhibitor. In some embodiments, a dose of a LAG3 inhibitor (e.g., an anti-LAG3 antibody such as leratolimab) is administered on each of the same days that a dose of a PD-1 inhibitor (e.g., an anti-PD-1 antibody such as nivolumab) is administered.

[0249] In some embodiments, between about 60 mg and 1040 mg of a LAG3 inhibitor (e.g., an anti-LAG3 antibody such as leratolimab) is administered in each dose. In some embodiments, 120 mg of leratolimab is administered in each dose. In some embodiments, between about 160 mg and 1040 mg of a LAG3 inhibitor (e.g., an anti-LAG3 antibody such as leratolimab) is administered in each dose. In some embodiments, 160 mg of leratolimab is administered in each dose. In some embodiments, 240 mg of leratolimab is administered in each dose. In some embodiments, 480 mg of leratolimab is administered in each dose. In some embodiments, 960 mg of leratolimab is administered in each dose.

[0250] In some embodiments, the method comprises administering three doses of the LAG3 inhibitor. In some embodiments, the second dose is administered about 4 weeks after the first dose. In some embodiments, the third dose is administered about 4 weeks or about 5 weeks after the second dose. In some embodiments, the third dose is administered about 4 weeks after the second dose. In some embodiments, the third dose is administered about 5 weeks after the second dose. In some embodiments, each dose of the LAG3 inhibitor is about 240 mg.

[0251] In some embodiments, the method comprises administering four doses of the LAG3 inhibitor. In some embodiments, the second dose is administered about four weeks after the first dose. In some embodiments, the third dose is administered about three weeks or about four weeks after the second dose. In some embodiments, the third dose is administered about three weeks after the second dose. In some embodiments, the third dose is administered about four weeks after the second dose. In some embodiments, the fourth dose is administered about three weeks after the third dose. In some embodiments, each dose of the LAG3 inhibitor is about 240 mg. In some embodiments, each dose of the LAG3 inhibitor is about 480 mg.

[0252] In some embodiments, the method comprises administering six doses of the LAG3 inhibitor. In some embodiments, the second and third doses of the LAG3 inhibitor are each administered about two weeks after the previous dose of the LAG3 inhibitor. In some embodiments, the second, third, fifth, and sixth doses are each administered about two weeks after the previous dose. In some embodiments, the fourth dose of the LAG3 inhibitor is administered about three weeks after the third dose of the LAG3 inhibitor. In some embodiments, the doses of the LAG3 inhibitor are administered about every two weeks (Q2W).

[0253] In some embodiments, the LAG3 inhibitor (e.g., an anti-LAG3 antibody such as leratolimab) is administered in a dosing regimen comprising a first cycle and a second cycle. In some embodiments, between about 160 mg and about 1040 mg of leratolimab is administered in each dose of the first cycle. In some embodiments, about 240 mg of leratolimab is administered in each dose of the first cycle. In some embodiments, about 480 mg of nivolumab is administered in each dose of the first cycle. In some embodiments, about 960 mg of nivolumab is administered in each dose of the first cycle. In some embodiments, at least one dose or at least two doses of the LAG3 inhibitor are administered in the first cycle. In some embodiments, one dose of the LAG3 inhibitor is administered in the first cycle. In some embodiments, two doses of the LAG3 inhibitor are administered in the first cycle. In some embodiments, three doses of the LAG3 inhibitor are administered in the first cycle.

[0254] In some embodiments, between about 400 mg and about 1040 mg of leratolimab is administered in each dose of the second cycle. In some embodiments, about 480 mg of nivolumab is administered in each dose of the second cycle. In some embodiments, about 960 mg of nivolumab is administered in each dose of the second cycle. In some embodiments, at least two doses of the LAG3 inhibitor are administered in the first cycle. In some embodiments, two doses of the LAG3 inhibitor are administered in the first cycle.

[0255] In some embodiments, about 480 mg nivolumab and about 160 mg leratolimab are administered Q4W.

[0256] In some embodiments, the provided methods can enhance CAR-T cell therapy and, in some aspects, improve the treatment outcome of subjects with cancers that are resistant or refractory to other therapies, have aggressive or high-risk cancers, and / or would or are likely to show a relatively low response rate to CAR-T cell therapy when administered without checkpoint inhibitor therapy. In some aspects, administration of checkpoint inhibitor therapy, e.g., an anti-PD-1 antibody and, optionally, an anti-LAG3 antibody, according to the provided methods can increase the activity of CAR-expressing cells for treating cancer, e.g., a B-cell malignancy such as NHL, by reducing or preventing exhaustion of CAR T cells. In some aspects, administration of checkpoint inhibitor therapy, e.g., an anti-PD-1 antibody and, optionally, an anti-LAG3 antibody, according to the provided methods can increase the activity of endogenous T cells for treating cancer, e.g., a B-cell malignancy such as NHL, by reducing or preventing exhaustion of endogenous T cells. In some aspects, the anti-tumor activity of administered CAR+ T cells against CD19-expressing cancers (e.g., B-cell malignancies, e.g., NHL) is improved. In some aspects, the anti-tumor activity of endogenous T cells against CD19-expressing cancers (e.g., B-cell malignancies such as NHL) is improved.

[0257] I. Combination Therapy Provided herein are methods of treatment involving administering a T cell therapy, such as an engineered cell or a composition containing the engineered cells (e.g., CAR T cells), in combination with a checkpoint inhibitor therapy (e.g., an anti-PD-1 antibody and, optionally, an anti-LAG3 antibody). In some embodiments, the T cell therapy (e.g., CAR T cells) specifically recognizes and / or specifically binds to an antigen associated with, expressed by, or present on a cancer cell. In some embodiments, the antigen is CD19.

[0258] Also provided are methods and uses of combination therapy of T cell therapy, such as engineered cells (e.g., CAR T cells), and checkpoint inhibitor therapy (e.g., anti-PD-1 antibodies and optionally anti-LAG3 antibodies), and / or compositions thereof, including methods for treating a subject having a disease or condition. In some embodiments, the use of combination therapy of T cell therapy, such as engineered cells (CAR T cells), and checkpoint inhibitor therapy (e.g., anti-PD-1 antibodies and optionally anti-LAG3 antibodies) for the treatment of a disease or condition is also provided. In some embodiments, the use of combination therapy of T cell therapy, such as engineered cells or compositions containing engineered cells (e.g., CAR T cells), and checkpoint inhibitor therapy (e.g., anti-PD-1 antibodies and optionally anti-LAG3 antibodies) is in accordance with any of the methods described herein.

[0259] Also provided are combinations and articles of manufacture, e.g., kits, containing compositions that constitute T cell therapy and / or compositions that constitute checkpoint inhibitor therapy (e.g., anti-PD-1 antibodies and, optionally, anti-LAG3 antibodies), as well as uses of such compositions and combinations to treat or prevent conditions such as CD19-expressing cancers (e.g., B-cell malignancies, e.g., NHL).

[0260] In some aspects, T cell therapy (e.g., CD19-targeted CAR T cells) is administered on day 1. In some embodiments, the method can include administering a checkpoint inhibitor therapy (e.g., an anti-PD-1 antibody, such as nivolumab, and optionally an anti-LAG3 antibody, such as relatolimab) subsequent to administration of the T cell therapy on day 1 (2-20 days after initiation of administration), where the T cell therapy specifically binds to an antigen associated with, expressed by, or present on cells of a CD19-expressing cancer (e.g., a B-cell malignancy such as NHL). In some embodiments, the checkpoint inhibitor therapy (e.g., an anti-PD-1 antibody, such as nivolumab, and optionally an anti-LAG3 antibody, such as relatolimab) is administered between about days 2 and 20, such as day 8 or day 15.

[0261] In some embodiments, the method involves administering checkpoint inhibitor therapy (e.g., an anti-PD-1 antibody, such as nivolumab, and optionally an anti-LAG3 antibody, such as relatolimab) in a dosing regimen comprising administering checkpoint inhibitor therapy every two weeks (Q2W) or every four weeks (Q4W). In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of at or between about 140 mg and 580 mg. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of about 240 mg. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of about 480 mg.

[0262] In some embodiments, the method comprises administering checkpoint inhibitor therapy (e.g., an anti-PD-1 antibody, such as nivolumab, and optionally an anti-LAG3 antibody, such as relatolimab) in a dosing regimen comprising administering checkpoint inhibitor therapy every two weeks (Q2W). In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of 60 mg, or between about 60 mg and 320 mg, or about 320 mg, about every two weeks. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of 120 mg, or between about 120 mg, about every two weeks. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of 140 mg, or between about 140 mg and 320 mg, or about 320 mg, about every two weeks. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of 240 mg, or about 240 mg, about every two weeks.

[0263] In some embodiments, the method comprises administering checkpoint inhibitor therapy (e.g., an anti-PD-1 antibody, such as nivolumab, and optionally an anti-LAG3 antibody, such as relatolimab) in a dosing regimen comprising administration of checkpoint inhibitor therapy every four weeks (Q4W). In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of 380 mg, or between about 380 mg and 580 mg, or about 580 mg, about every four weeks. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of 480 mg, or about 480 mg, about every four weeks.

[0264] In some embodiments, the method includes administering checkpoint inhibitor therapy (e.g., an anti-PD-1 antibody, such as nivolumab, and an anti-LAG3 antibody, such as leratolimab) in a dosing regimen comprising administering the checkpoint inhibitor therapy every two weeks (Q2W) or every four weeks (Q4W). In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of between at or about 60 mg and 1040 mg or about 1040 mg. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of between at or about 140 mg and 1040 mg or about 1040 mg.

[0265] In some embodiments, the method includes administering checkpoint inhibitor therapy (e.g., an anti-PD-1 antibody, such as nivolumab, and an anti-LAG3 antibody, such as leratolimab) in a dosing regimen comprising administering checkpoint inhibitor therapy every two weeks (Q2W). In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 60 mg, or between about 60 mg and 540 mg, or about 540 mg, about every two weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 120 mg, or between about 120 mg, and 540 mg, or about 540 mg, about every two weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 140 mg, or between about 140 mg and 540 mg, or about 540 mg, about every two weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 160 mg, or about 160 mg, about every two weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 240 mg or about 240 mg about every two weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 360 mg or about 360 mg about every two weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 480 mg or about 480 mg about every two weeks.

[0266] In some embodiments, the method comprises administering checkpoint inhibitor therapy (e.g., an anti-PD-1 antibody, such as nivolumab, and optionally an anti-LAG3 antibody, such as leratolimab) in a dosing regimen comprising administration of checkpoint inhibitor therapy every four weeks (Q4W). In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 60 mg, or between about 60 mg and 1040 mg, or about 1040 mg, about every four weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 880 mg, or between about 880 mg and 1040 mg, or about 1040 mg, about every four weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 120 mg, or about 120 mg, about every four weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 160 mg, or about 160 mg, about every four weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 240 mg or about 240 mg about every four weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 360 mg or about 360 mg about every four weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 480 mg or about 480 mg about every four weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 960 mg or about 960 mg about every four weeks.

[0267] In some embodiments, the method comprises administering checkpoint inhibitor therapy (e.g., an anti-PD-1 antibody, such as nivolumab, and an anti-LAG3 antibody, such as leratolimab) in a dosing regimen comprising administering checkpoint inhibitor therapy every three weeks (Q3W). In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 60 mg, or between about 60 mg and 1040 mg, or about 1040 mg, about every three weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 880 mg, or between about 880 mg and 1040 mg, or about 1040 mg, about every three weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 120 mg, or about 120 mg, about every three weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 160 mg, or about 160 mg, about every three weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 240 mg or about 240 mg about every three weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 360 mg or about 360 mg about every three weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 480 mg or about 480 mg about every three weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 960 mg or about 960 mg about every three weeks.

[0268] In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) and the anti-LAG3 antibody (e.g., leratolimab) are administered on the same day. In some embodiments, about 240 mg of the anti-PD-1 antibody (e.g., nivolumab) and about 120 mg of the anti-LAG3 antibody (e.g., leratolimab) are administered on the same day. In some embodiments, about 240 mg of the anti-PD-1 antibody (e.g., nivolumab) and about 240 mg of the anti-LAG3 antibody (e.g., leratolimab) are administered on the same day. In some embodiments, about 480 mg of the anti-PD-1 antibody (e.g., nivolumab) and about 160 mg of the anti-LAG3 antibody (e.g., leratolimab) are administered on the same day. In some embodiments, about 480 mg of the anti-PD-1 antibody (e.g., nivolumab) and about 240 mg of the anti-LAG3 antibody (e.g., leratolimab) are administered on the same day. In some embodiments, about 480 mg of an anti-PD-1 antibody (e.g., nivolumab) and about 480 mg of an anti-LAG3 antibody (e.g., leratolimab) are administered on the same day.

[0269] In some embodiments, a PD-1 inhibitor (e.g., an anti-PD-1 antibody such as nivolumab) is administered to a subject as a monotherapy (e.g., monotherapy) in combination with a T cell therapy (e.g., a CAR T cell). In some embodiments, administration as monotherapy consists of only one type of treatment for treating a disease or condition, unless otherwise provided. In some embodiments, a PD-1 inhibitor (e.g., an anti-PD-1 antibody) is provided as monotherapy with a T cell therapy; thus, besides the provision of (1) a PD-1 inhibitor and (2) an immunotherapy or cell therapy, no other treatment is provided to treat the disease or condition.

[0270] In some embodiments, the method includes administering a checkpoint inhibitor therapy (e.g., an anti-PD-1 antibody such as nivolumab) in a first cycle and a second cycle. In some embodiments, the first dose of the first cycle is administered between about days 2 and 20. In some embodiments, the first dose of the first cycle is administered on about day 8. In some embodiments, the first dose of the first cycle is administered on about day 15. In some embodiments, at least one dose of the PD-1 inhibitor is administered in the first cycle. In some embodiments, one dose of the PD-1 inhibitor is administered in the first cycle. In some embodiments, the PD-1 inhibitor is administered on day 15 of the first cycle. In some embodiments, two doses of the PD-1 inhibitor are administered in the first cycle. In some embodiments, the PD-1 inhibitor is administered on days 8 and 36 of the first cycle. In some embodiments, three doses of the PD-1 inhibitor are administered in the first cycle. In some embodiments, the PD-1 inhibitor is administered on days 8, 22, and 36 of the first cycle. In some embodiments, the PD-1 inhibitor is administered on days 15, 29, and 43 of the first cycle. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of between at or about 140 mg and 580 mg or about 580 mg. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of between at or about 140 mg and 320 mg or about 320 mg. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of at or about 240 mg. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of between at or about 380 mg and 580 mg or about 580 mg. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of 480 mg or about 480 mg. In some embodiments, 240 mg or about 240 mg of the PD-1 inhibitor is administered on days 8, 22, and 36 of the first cycle. In some embodiments, 480 mg or about 480 mg of the PD-1 inhibitor is administered on days 8 and 36 of the first cycle.In some embodiments, 240 mg, or about 240 mg, of the PD-1 inhibitor is administered on days 15, 29, and 43 of the first cycle. In some embodiments, 480 mg, or about 480 mg, of the PD-1 inhibitor is administered on day 15 of the first cycle.

[0271] In some embodiments, the first dose of the second cycle is administered between about days 50 and 65. In some embodiments, the first dose of the second cycle is administered on about day 57. In some embodiments, at least two doses of the PD-1 inhibitor are administered in the second cycle. In some embodiments, two doses of the PD-1 inhibitor are administered in the second cycle. In some embodiments, the PD-1 inhibitor is administered on days 57 and 85 of the second cycle. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of 140 mg or between about 140 mg and 580 mg or about 580 mg. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of 380 mg or between about 380 mg and 580 mg or about 580 mg. In some embodiments, the anti-PD-1 antibody (e.g., nivolumab) is administered in an amount of 480 mg or about 480 mg. In some embodiments, 480 mg or about 480 mg of the PD-1 inhibitor is administered on days 57 and 85 of the second cycle.

[0272] In some embodiments, a PD-1 inhibitor (e.g., an anti-PD-1 antibody such as nivolumab) and a LAG3 inhibitor (e.g., an anti-LAG3 antibody such as relatolimab) are administered to a subject as a combination therapy in combination with T cell therapy (e.g., CAR T cells). In some embodiments, a PD-1 inhibitor (e.g., an anti-PD-1 antibody such as nivolumab) and a LAG3 inhibitor (e.g., an anti-LAG3 antibody such as relatolimab) are provided as a combination therapy along with T cell therapy; thus, besides providing (1) the PD-1 and LAG3 inhibitors and (2) the T cell therapy, no other treatments are provided to treat the disease or condition.

[0273] In some embodiments, the method includes administering checkpoint inhibitor therapy (e.g., an anti-PD-1 antibody, such as nivolumab, and an anti-LAG3 antibody, such as leratolimab) in a first cycle and a second cycle. In some embodiments, the first dose of the first cycle is administered between about days 2 and 20. In some embodiments, the first dose of the first cycle is administered on about day 8. In some embodiments, the first dose of the first cycle is administered on about day 15.

[0274] In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of between 140 mg or about 140 mg and 1040 mg or about 1040 mg. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of between 140 mg or about 140 mg and 540 mg or about 540 mg about every two weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 240 mg or about 240 mg about every two weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 480 mg or about 480 mg about every two weeks. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of between 880 mg or about 880 mg and 1040 mg or about 1040 mg about every four weeks.

[0275] In some embodiments, the LAG3 inhibitor is administered on the same day as the PD-1 inhibitor is administered. In some embodiments, at least one dose of the LAG3 inhibitor is administered in the first cycle. In some embodiments, one dose of the LAG3 inhibitor is administered in the first cycle. In some embodiments, the LAG3 inhibitor is administered on day 15 of the first cycle. In some embodiments, two doses of the LAG3 inhibitor are administered in the first cycle. In some embodiments, the LAG3 inhibitor is administered on days 8 and 36 of the first cycle. In some embodiments, three doses of the LAG3 inhibitor are administered in the first cycle. In some embodiments, the LAG3 inhibitor is administered on days 8, 22, and 36 of the first cycle. In some embodiments, the LAG3 inhibitor is administered on days 15, 29, and 43 of the first cycle. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 140 mg or about 140 mg to 1040 mg or about 1040 mg. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 140 mg or about 140 mg to 320 mg or about 320 mg. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 240 mg or about 240 mg. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 380 mg or about 380 mg to 580 mg or about 580 mg. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 480 mg or about 480 mg. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount between 880 mg or about 880 mg and 1040 mg or about 1040 mg. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 960 mg or about 960 mg. In some embodiments, 240 mg or about 240 mg of the LAG3 inhibitor is administered on days 8, 22, and 36 of the first cycle. In some embodiments, 480 mg or about 480 mg of the LAG3 inhibitor is administered on days 8, 22, and 36 of the first cycle.In some embodiments, 480 mg or about 480 mg of the LAG3 inhibitor is administered on days 8 and 36 of the first cycle. In some embodiments, 960 mg or about 960 mg of the LAG3 inhibitor is administered on days 8 and 36 of the first cycle. In some embodiments, 240 mg or about 240 mg of the LAG3 inhibitor is administered on days 15, 29, and 43 of the first cycle. In some embodiments, 480 mg or about 480 mg of the LAG3 inhibitor is administered on days 15, 29, and 43 of the first cycle. In some embodiments, 480 mg or about 480 mg of the LAG3 inhibitor is administered on day 15 of the first cycle. In some embodiments, 960 mg or about 960 mg of the LAG3 inhibitor is administered on day 15 of the first cycle.

[0276] In some embodiments, the first dose of the second cycle is administered between about days 50 and 65. In some embodiments, the first dose of the second cycle is administered on about day 57. In some embodiments, at least two doses of the LAG3 inhibitor are administered in the second cycle. In some embodiments, two doses of the LAG3 inhibitor are administered in the second cycle. In some embodiments, the LAG3 inhibitor is administered on days 57 and 85 of the second cycle. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 400 mg or between about 400 mg and 1040 mg or about 1040 mg. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 380 mg or between about 380 mg and 580 mg or about 580 mg. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 480 mg or about 480 mg. In some embodiments, 480 mg or about 480 mg of the LAG3 inhibitor is administered on days 57 and 85 of the second cycle. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount between 880 mg or about 880 mg and 1040 mg or about 1040 mg. In some embodiments, the anti-LAG3 antibody (e.g., leratolimab) is administered in an amount of 960 mg or about 960 mg. In some embodiments, 960 mg or about 960 mg of the LAG3 inhibitor is administered on days 57 and 85 of the second cycle.

[0277] In some embodiments, the T cell therapy is adoptive cell therapy. In some embodiments, the T cell therapy is or includes transgenic TCR therapy or recombinant receptor-expressing cell therapy, which may be chimeric antigen receptor (CAR)-expressing T cell therapy. In some embodiments, the therapy targets CD19. In some cases, the T cell therapy includes T cells expressing a chimeric antigen receptor (CAR), where the antigen-binding domain of the CAR binds to CD19. In some embodiments, the adoptive cell therapy includes cells that are autologous to the subject. In some embodiments, the cells that are autologous to the subject are engineered to express a chimeric antigen receptor (CAR). In some embodiments, CAR-expressing autologous T cells are provided to the subject. In some embodiments, the cells and dosage regimens for administering the cells may include any described in Section II.

[0278] In some embodiments, checkpoint inhibitor therapy reduces or prevents cell exhaustion of cell therapy. In some embodiments, checkpoint inhibitor therapy reduces or prevents exhaustion of endogenous T cells. In some ways, checkpoint inhibitor therapy reduces resistance of cancer cells to T cell therapy.

[0279] In some embodiments, the T cell therapy (e.g., CAR-expressing T cells) and checkpoint inhibitor therapy are provided as pharmaceutical compositions for administration to a subject. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of one or both of the agents for the described combination therapy, e.g., T cells for adoptive cell therapy, and checkpoint inhibitor therapy (e.g., anti-PD-1 antibody and, optionally, anti-LAG3 antibody). In some embodiments, the pharmaceutical composition contains a sub-therapeutically effective amount of one or both of the agents for the described combination therapy, T cells for adoptive cell therapy, and checkpoint inhibitor therapy (e.g., anti-PD-1 antibody and, optionally, anti-LAG3 antibody). In some embodiments, the agents are formulated for administration in separate pharmaceutical compositions. In some embodiments, any of the pharmaceutical compositions provided herein can be formulated in a dosage form suitable for each administration route.

[0280] In some embodiments, a combination therapy comprising administering a T cell therapy comprising engineered cells, such as CAR-T cell therapy, and a checkpoint inhibitor therapy is administered to a subject or patient who has cancer (e.g., NHL) or is at risk for cancer, such as a CD19-expressing cancer. In some aspects, the method treats a disease or condition, e.g., ameliorates one or more symptoms of the disease or condition, such as by reducing tumor burden in a cancer that expresses an antigen recognized by the T cell therapy, e.g., recognized by the engineered T cells.

[0281] The appropriate dosage of a PD-1 inhibitor, LAG3 inhibitor, and / or T cell therapy (e.g., CAR-expressing T cells) for disease prevention or treatment may depend on the type of disease to be treated, the specific inhibitor, cells and / or recombinant receptors expressed on the cells, the severity and course of the disease, the route of administration, whether the PD-1 and / or LAG3 inhibitor and / or T cell therapy is administered for prophylactic or therapeutic purposes, previous therapy, frequency of administration, the subject's clinical history and response to the cells, and the discretion of the treating physician. In some embodiments, the composition and cells are suitably administered to the subject once or over a series of treatments. Exemplary dosage regimens and schedules for the provided combination therapies are described.

[0282] In some embodiments, T cell therapy and checkpoint inhibitor therapy are administered as part of a further combination treatment, which can be administered simultaneously with another therapeutic intervention or sequentially, in any order. In some situations, T cell therapy, such as CAR-expressing T cells, is co-administered with another therapy close enough in time for the immunotherapy to enhance the effect of one or more additional therapeutic agents, or conversely, for the one or more additional therapeutic agents to enhance the effect of the immunotherapy. In some embodiments, the cells are administered before one or more additional therapeutic agents. In some embodiments, T cell therapy, e.g., engineered T cells, such as CAR-expressing T cells, are administered after one or more additional therapeutic agents. In some embodiments, the combination therapy method further comprises lymphodepleting therapy, such as administration of a chemotherapeutic agent. In some embodiments, the combination therapy further comprises administering another therapeutic agent, such as an anti-cancer agent, a checkpoint inhibitor, or another immunomodulatory agent. Uses include the use of the combination therapy in such methods and treatments, and the use of such compositions in the preparation of a medicament for carrying out such combination therapy methods. In some embodiments, the methods and uses thereby treat a disease or condition or disorder, such as cancer or a proliferative disease, in a subject.

[0283] In some embodiments, the cell therapy and checkpoint inhibitor therapy are administered without any other concomitant treatment. In some embodiments, the checkpoint inhibitor therapy is an anti-PD-1 antibody, and the cell therapy and checkpoint inhibitor therapy are administered without any other concomitant treatment. In some embodiments, the checkpoint inhibitor therapy is an anti-PD-1 antibody and an anti-LAG3 antibody, and the cell therapy and checkpoint inhibitor therapy are administered without any other concomitant treatment.

[0284] Before, during, or after administration of T cell therapy, such as CAR-T cell therapy, and / or checkpoint inhibitor therapy, the biological activity of the T cell therapy, e.g., the biological activity of an engineered cell population, is measured in some embodiments, e.g., by any of a number of known methods. Parameters for evaluation include the ability of the engineered cells to destroy target cells, the persistence of T cell activity, and other measures, such as those measured using any suitable method known in the art, such as the assays described further below in Section II, infra. In some embodiments, the biological activity of cells, e.g., T cells administered for T cell-based therapy, is measured by assaying cytotoxic cell killing, expression and / or secretion of one or more cytokines, proliferation or expansion, e.g., proliferation or expansion upon restimulation with an antigen. In some aspects, biological activity is measured by assessing disease burden and / or clinical outcome, such as reduction in tumor burden or burden. In some aspects, biological activity is measured by assessing the presence of neutropenia in the subject. In some embodiments, the administration of one or both agents of the combination therapy, and / or repeat administration of either of the therapies, can be determined based on the results of the assay before, during, during the course of, or after the administration of one or both agents of the combination therapy.

[0285] In some embodiments, the combined effect of checkpoint inhibitor therapy in combination with T cell therapy may be synergistic compared to treatment with checkpoint inhibitor therapy alone or cell therapy monotherapy. For example, in some embodiments, the methods, compositions, and articles of manufacture provided herein result in an increased or improved desired therapeutic effect, such as an increase or improvement in the alleviation or abrogation of one or more symptoms associated with cancer.

[0286] In some embodiments, checkpoint inhibitor therapy increases the expansion, proliferation, or cytotoxicity of engineered T cells, such as CAR T cells. In some embodiments, the increased expansion, proliferation, or cytotoxicity is observed in vivo after administration of checkpoint inhibitor therapy to a subject. In some embodiments, the increase in the number of engineered T cells, e.g., CAR-T cells, is greater than or equal to about 1.2-fold, 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, 6.0-fold, 7.0-fold, 8.0-fold, 9.0-fold, 10.0-fold, or more. In some embodiments, the increase in cytotoxicity of engineered T cells, e.g., CAR-T cells, against cancer cells is greater than or equal to about 1.2-fold, 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, 6.0-fold, 7.0-fold, 8.0-fold, 9.0-fold, 10.0-fold, or more.

[0287] In certain embodiments, the methods involve administering to a subject one or more doses of cells, including a specific number or relative number of cells or engineered cells, such as two or more subtypes in a defined ratio or composition within a composition, such as CD4 vs. CD8 T cells. In some embodiments, the engineered cells and checkpoint inhibitor therapy, or the compositions comprising the engineered cells and checkpoint inhibitor therapy, are administered in an amount effective to provide treatment for a disease or disorder. Uses include the use of T cell therapy and checkpoint inhibitor therapy, or compositions thereof, in such methods and treatments, and in the preparation of medicaments for carrying out such treatment methods. In some embodiments, the methods are carried out by administering the T cell therapy and checkpoint inhibitor therapy, or compositions comprising them, to a subject having or suspected of having a disease or condition. In some embodiments, the methods thereby treat a disease, condition, or disorder in the subject.

[0288] The general method for administering cells for adoptive cell therapy is known, and can be used in connection with the provided methods and compositions.For example, adoptive T cell therapy methods are described in, for example, Gruenberg et al., U.S. Patent Application Publication No. 2003 / 0170238; Rosenberg, U.S. Patent No. 4,690,915; Rosenberg (2011) Nat Rev Clin Oncol.8(10):577-85).For example, see Themeli et al. (2013) Nat Biotechnol.31(10):928-933; Tsukahara et al. (2013) Biochem Biophys Res Commun 438(1):84-9; Davila et al. (2013) PLoS ONE 8(4):e61338.

[0289] A. Administration of Checkpoint Inhibitor Therapy Provided herein are methods, combinations, kits, and uses of combination therapy involving the administration of checkpoint inhibitor therapy (e.g., anti-PD-1 antibody and / or anti-LAG3 antibody), which may be administered subsequent to T cell therapy, e.g., administration of CAR T cells. In some embodiments, expression of one or more checkpoint proteins, such as PD-1 and / or LAG3, may increase exhaustion of endogenous and / or administered T cells (e.g., engineered CAR T cells, e.g., CAR T cells). In some embodiments, expression of PD-1 may promote exhaustion of endogenous and / or administered CAR T cells, thereby allowing for increased survival of cancer cells. In some embodiments, LAG3 protein may promote exhaustion of endogenous and / or administered CAR T cells, thereby allowing for increased survival of cancer cells. In some embodiments, an individual may become immune to one or more checkpoint inhibitors, such as PD-1 inhibitors. In some embodiments, immunity to PD-1 blockade can be overcome by LAG3 inhibition.

[0290] In some embodiments, the checkpoint inhibitor therapy in the combination therapy is an inhibitor of PD-1 (e.g., an anti-PD-1 antibody such as nivolumab), which in some cases is involved in the exhaustion of endogenous and / or administered T cells. In some embodiments, the checkpoint inhibitor therapy in the combination therapy is an inhibitor of PD-1 (e.g., an anti-PD-1 antibody such as nivolumab) and an inhibitor of LAG3 (e.g., an anti-LAG3 antibody such as leratolimab). In some cases, expression of PD-1 and / or LAG3 is involved in the exhaustion of endogenous and / or administered T cells.

[0291] In some embodiments, checkpoint inhibitor therapy (e.g., anti-PD-1 antibody and / or anti-LAG3 antibody) reduces and / or prevents exhaustion of endogenous T cells. In some embodiments, checkpoint inhibitor therapy (e.g., anti-PD-1 antibody and / or anti-LAG3 antibody) reduces and / or prevents exhaustion of administered T cells (e.g., engineered T cells such as CAR T cells). In some cases, inhibition of LAG3 overcomes resistance to PD-1 inhibition or sensitizes a subject to PD-1 inhibition.

[0292] In some embodiments, the checkpoint inhibitor comprises an anti-PD-1 antibody (e.g., nivolumab). In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody inhibits PD-1 / PD-L1 signaling. In some embodiments, the checkpoint inhibitor comprises an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is leratolimab. In some embodiments, the anti-LAG3 antibody increases receptor occupancy of LAG3 on T cells, such as in peripheral blood and / or the tumor microenvironment. In some embodiments, the anti-LAG3 antibody reduces the amount of free, soluble LAG3, such as in peripheral blood. In some embodiments, an anti-LAG3 antibody is provided in combination with a PD-1 antibody to overcome resistance to PD-1 blockade.

[0293] In some embodiments, the PD-1 inhibitor is a compound disclosed in any of PCT Patent Application Nos. WO2006121186 and WO2015112800; U.S. Patent Application Publication Nos. 20150203579, 20180346569, and 20130017199; U.S. Patent Nos. 7,595,048, 8,008,449, 8,354,509, 8,609,089, 8,728,474, 8,735,553, 8,779,105; Anti-PD-1 antibodies, including but not limited to those described in European Patent Nos. 8900587, 8952136, 9067999, 9073994, 9683048, 9815897, and 9987500; and European Patent Nos. 1537878, 2161336, and 2170959, each of which is incorporated by reference in its entirety.

[0294] Exemplary anti-PD-1 antibodies include, but are not limited to, nivolumab, camrelizumab, cemiplimab, dostallimab, MEDI-0680, pembrolizumab, spartalizumab, SSI-361, and tislelizumab. Other exemplary anti-PD-1 antibodies include, but are not limited to, AMP224, AMP-514, JTX-4014, retifanlimab, sintilimab, and toripalimab.

[0295] In some instances, the anti-PD-1 antibody comprises a heavy chain variable (VH) region comprising CDR1, CDR2, and CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 60, 61, and 62, respectively, and a light chain variable (VL) region comprising CDR1, CDR2, and CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 63, 64, and 65, respectively. In some embodiments, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 66, and the VL region comprises the amino acid sequence set forth in SEQ ID NO: 67. In some instances, the anti-PD-1 antibody is nivolumab.

[0296] In some embodiments, the LAG3 inhibitor is an anti-LAG3 antibody, including but not limited to, those described in U.S. Patent Application Publication No. 20110150892; PCT Application Nos. WO2010019570, WO2014008218, WO2015116539, and WO2015138920; and U.S. Patent Nos. 9,505,839 and 9,908,936, each of which is incorporated by reference herein in its entirety.

[0297] Exemplary anti-LAG3 antibodies include, but are not limited to, leratolimab, favezelimab (MK-4280), and yelamilimab (LAG525). Other exemplary anti-LAG3 antibodies include, but are not limited to, REGN3767, TSR-033, Sym022, BI 754111, and FS118.

[0298] In some instances, the anti-LAG3 antibody comprises a heavy chain variable (VH) region comprising CDR1, CDR2, and CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 68, 69, and 70, respectively, and a light chain variable (VL) region comprising CDR1, CDR2, and CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 71, 72, and 73, respectively. In some embodiments, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 74, and the VL region comprises the amino acid sequence set forth in SEQ ID NO: 75. In some instances, the anti-LAG3 antibody is leratolimab.

[0299] 1. Anti-PD-1 antibody a. Compositions and Formulations In some embodiments of the combination therapy methods, combinations, kits, and uses provided herein, the combination therapy can be administered in one or more compositions, e.g., pharmaceutical compositions, containing a PD-1 inhibitor (e.g., an anti-PD-1 antibody such as nivolumab), and / or a T cell therapy, e.g., a CAR T cell therapy.

[0300] In some embodiments, compositions, e.g., pharmaceutical compositions, containing a PD-1 inhibitor, e.g., an anti-PD-1 antibody such as nivolumab, can include a carrier, such as a diluent, adjuvant, excipient, or vehicle, by which the inhibitor and / or cells are administered. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions will contain a therapeutically effective amount of a PD-1 inhibitor, e.g., an anti-PD-1 antibody, generally in purified form, together with a suitable amount of carrier to obtain the form for proper administration to a patient. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. The pharmaceutical composition may contain any one or more of diluent(s), adjuvant(s), antiadherent(s), binder(s), coating(s), filler(s), flavor(s), color(s), lubricant(s), glidant(s), preservative(s), detergent(s), adsorbent(s), emulsifier(s), pharmaceutical excipient(s), pH buffer(s), or sweetener(s), and combinations thereof. In some embodiments, the pharmaceutical composition may be in liquid, solid, lyophilized powder, gel form, and / or combinations thereof. In some aspects, the choice of carrier is determined in part by the particular inhibitor and / or method of administration.

[0301] Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citric acid, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; serum albumin; The PD-1 inhibitor may include, but is not limited to, proteins such as albumin, gelatin, or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants, stabilizers, and / or preservatives such as polyethylene glycol (PEG). Compositions containing PD-1 inhibitors, e.g., anti-PD-1 antibodies such as nivolumab, can also be lyophilized.

[0302] In some embodiments, the pharmaceutical composition can be formulated for administration by any route known to those skilled in the art, including intramuscular, intravenous, intradermal, intralesional, intraperitoneal injection, subcutaneous, intratumoral, epidural, nasal, oral, vaginal, rectal, topical, local, otic, inhalation, buccal (e.g., sublingual), and transdermal administration, or any route. In some embodiments, other administration mechanisms are also contemplated. In some embodiments, administration is by bolus injection, injection, for example, intravenous or subcutaneous injection, intraocular injection, periocular injection, subretinal injection, intravitreal injection, transseptal injection, subscleral injection, intrachoroidal injection, intracameral injection, subconjectival injection, subconjunctival injection, sub-Tenon injection, retrobulbar injection, peribulbar injection, or posterior juxtascleral delivery. In some embodiments, administration is parenteral, intrapulmonary, and intranasal, and, if desired for localized treatment, by intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0303] In some embodiments, the compositions can also be administered with other bioactive agents, either sequentially, intermittently, or in the same composition. In some embodiments, administration can also include controlled release systems, including controlled release formulations and device-controlled release, such as with pumps. In some embodiments, administration is oral.

[0304] In some embodiments, PD-1 inhibitors, e.g., anti-PD-1 antibodies such as nivolumab, are typically formulated and administered in unit dosage forms or multiple dosage forms. Each unit dosage contains a predetermined amount of a therapeutically active PD-1 inhibitor, e.g., nivolumab, sufficient to produce the desired therapeutic effect, along with any necessary pharmaceutical carriers, vehicles, or diluents. In some embodiments, unit dosage forms include, but are not limited to, tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, and oil-water emulsions, each containing an appropriate amount of a PD-1 inhibitor, e.g., nivolumab. Unit dosage forms may be contained in ampoules and syringes or individually packaged tablets or capsules. Unit dosage forms may be administered in fractions or multiples thereof. In some embodiments, multiple dosage forms are multiple identical unit dosage forms packaged in a single container to be administered in segregated unit dosage forms. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.

[0305] b. Medication In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a PD-1 inhibitor, and optionally a LAG3 inhibitor) and T cell therapy (e.g., CAR T cells) to a subject. In some embodiments, provided methods of combination therapy involve initiating administration of checkpoint inhibitor therapy (e.g., a PD-1 inhibitor, and optionally a LAG3 inhibitor) subsequent to initiation of T cell therapy (e.g., CAR T cells). In some embodiments, provided methods of combination therapy involve initiating administration of checkpoint inhibitor therapy (e.g., a PD-1 inhibitor, and optionally a LAG3 inhibitor) between about 1 day and about 3 weeks after initiation of administration of T cell therapy (e.g., CAR T cells). In some embodiments, initiation of administration of checkpoint inhibitor therapy (e.g., a PD-1 inhibitor, and optionally a LAG3 inhibitor) is between about 1 week and about 2 weeks after initiation of administration of T cell therapy (e.g., CAR T cells).

[0306] In some embodiments, provided methods of combination therapy involve administering T cell therapy (e.g., CAR T cells) starting on day 1. In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a PD-1 inhibitor and, optionally, a LAG3 inhibitor) starting between about days 2 and 20. In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a PD-1 inhibitor and, optionally, a LAG3 inhibitor) starting on about day 8 or day 15. In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a PD-1 inhibitor and, optionally, a LAG3 inhibitor) starting on about day 8. In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a PD-1 inhibitor and, optionally, a LAG3 inhibitor) starting on about day 15.

[0307] In some embodiments, the methods involve initiating administration of checkpoint inhibitor therapy (e.g., a PD-1 inhibitor, and optionally a LAG3 inhibitor) after activation-induced cell death (AICD) of the T cell therapy cells (e.g., CAR T cells) has peaked.

[0308] In some embodiments, the combination therapy provided includes: (1) administering to a subject with a CD19-expressing cancer a cell therapy on day 1, the cell therapy including a dose of engineered cells including T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) administering to the subject a PD-1 inhibitor in a dosing regimen including administration of at least two doses, wherein (i) administration of the first dose is between day 2 and day 20, inclusive; and (ii) the doses are administered about every two weeks (Q2W) or about every four weeks (Q4W) in an amount of at or about 140 mg to 580 mg or about 580 mg, inclusive.

[0309] In some embodiments, a combination therapy is provided comprising: (1) administering to a subject with a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); and (2) administering to the subject a dosing regimen comprising administering at least two doses of a PD-1 inhibitor, wherein (i) administration of a first dose of the PD-1 inhibitor occurs between days 2 and 20, inclusive; and (ii) each dose of the PD-1 inhibitor is between 140 mg or about 140 mg and 580 mg or about 580 mg, inclusive. In some embodiments, each subsequent dose of the PD-1 inhibitor is administered about 2 weeks, about 3 weeks, or about 4 weeks after the previous dose of the PD-1 inhibitor.

[0310] In some embodiments, a combination therapy is provided comprising: (1) administering to a subject with a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administering at least two doses, wherein (i) administration of a first dose of the PD-1 inhibitor occurs between days 2 and 20, inclusive, and (ii) each subsequent dose of the PD-1 inhibitor is administered about 2 weeks, about 3 weeks, or about 4 weeks after the previous dose of the PD-1 inhibitor. In some embodiments, each dose of the PD-1 inhibitor is between or about 140 mg and 580 mg, inclusive.

[0311] In some embodiments, the first dose of the PD-1 inhibitor is administered between day 8 and day 15, inclusive. In some embodiments, the first dose of the PD-1 inhibitor is administered on day 8. In some embodiments, the first dose is administered on day 15. In some embodiments, the PD-1 inhibitor is administered for a period not exceeding about 3 months. In some embodiments, the final dose of the PD-1 inhibitor is administered between about day 80 and about day 90. In some embodiments, the final dose of the PD-1 inhibitor is administered on about day 85.

[0312] In some embodiments, each dose of the PD-1 inhibitor is at or between about 160 mg and 560 mg. In some embodiments, each dose of the PD-1 inhibitor is at or between about 240 mg and 480 mg or about 480 mg. In some embodiments, each dose of the PD-1 inhibitor is 240 mg. In some embodiments, each dose of the PD-1 inhibitor is 480 mg.

[0313] In some embodiments, at least one dose of the PD-1 inhibitor is 240 mg and at least one dose of the PD-1 inhibitor is 480 mg. In some embodiments, at least four doses of the PD-1 inhibitor are administered. In some embodiments, four doses, five doses, or six doses of the PD-1 inhibitor are administered.

[0314] In some embodiments, the first three doses of the PD-1 inhibitor are administered every two weeks (Q2W). In some embodiments, each dose of the PD-1 inhibitor is administered every two weeks (Q2W).

[0315] In some embodiments, the fourth dose of the PD-1 inhibitor is administered about 3 weeks or about 4 weeks after the previous dose of the PD-1 inhibitor. In some embodiments, the fourth dose of the PD-1 inhibitor is administered about 3 weeks after the previous dose of the PD-1 inhibitor. In some embodiments, the fourth dose of the PD-1 inhibitor is administered about 4 weeks after the previous dose of the PD-1 inhibitor.

[0316] In some embodiments, five doses of the PD-1 inhibitor are administered. In some embodiments, the first three doses of the PD-1 inhibitor are about 240 mg, and the fourth and fifth doses of the inhibitor are about 480 mg. In some cases, five doses of the PD-1 inhibitor are administered on days 8, 22, 36, 57, and 85. In some cases, five doses of the PD-1 inhibitor are administered on days 15, 29, 43, 57, and 85.

[0317] In some embodiments, five doses of the PD-1 inhibitor are administered, hi some embodiments, the fifth dose of the PD-1 inhibitor is administered about four weeks after the fourth dose of the PD-1 inhibitor.

[0318] In some embodiments, about 240 mg of the PD-1 inhibitor is administered on each of days 8, 22, and 36. In some embodiments, about 240 mg of the PD-1 inhibitor is administered on each of days 15, 29, and 43. In some embodiments, about 480 mg of the PD-1 inhibitor is administered on each of days 8, 36, 64, and 85. In some embodiments, about 480 mg of the PD-1 inhibitor is administered on each of days 15, 43, 64, and 85.

[0319] In some embodiments, 240 mg of the PD-1 inhibitor is administered on each of days 8, 22, 36, 57, 71, and 85. In some embodiments, 240 mg of the PD-1 inhibitor is administered on each of days 15, 29, 43, 57, 71, and 85.

[0320] In some embodiments, 240 mg of the PD-1 inhibitor is administered on each of days 8, 22, and 36, and 480 mg of the PD-1 inhibitor is administered on days 57 and 85. In some embodiments, 240 mg of the PD-1 inhibitor is administered on each of days 15, 29, and 43, and 480 mg of the PD-1 inhibitor is administered on days 57 and 85.

[0321] In some embodiments, 480 mg of the PD-1 inhibitor is administered on each of days 8, 36, 64, and 85. In some embodiments, 480 mg of the PD-1 inhibitor is administered on each of days 15, 43, 64, and 85.

[0322] In some embodiments, the amount of PD-1 inhibitor is at or between about 160 mg and 560 mg. In some embodiments, the amount of PD-1 inhibitor is at or between about 240 mg and 480 mg. In some embodiments, the amount of PD-1 inhibitor is 240 mg. In some embodiments, the amount of PD-1 inhibitor is 480 mg. In some embodiments, the dose is administered about every two weeks (Q2W). In some embodiments, the dose is administered about every four weeks (Q4W).

[0323] In some embodiments, the PD-1 inhibitor in an amount of about 240 mg is administered Q2W, hi some embodiments, the PD-1 inhibitor in an amount of about 480 mg is administered Q4W.

[0324] In some embodiments, the PD-1 inhibitor is administered in the first cycle and the second cycle, as further described below.

[0325] 1) First Cycle In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a PD-1 inhibitor, and optionally a LAG3 inhibitor) and T cell therapy (e.g., CAR T cells) to a subject, wherein the checkpoint inhibitor therapy is administered in a first cycle and a second cycle.

[0326] In some embodiments, at least one dose of the PD-1 inhibitor is administered in the first cycle. In some embodiments, at least two doses of the PD-1 inhibitor are administered in the first cycle. In some embodiments, at least three doses of the PD-1 inhibitor are administered in the first cycle. In some embodiments, two doses of the PD-1 inhibitor are administered in the first cycle. In some embodiments, three doses of the PD-1 inhibitor are administered in the first cycle.

[0327] In some embodiments, the first dose of the PD-1 inhibitor in the first cycle is administered following administration of T cell therapy. In some embodiments, the first dose of the PD-1 inhibitor in the first cycle is administered between about 1 day and 3 weeks after initiation of administration of T cell therapy. In some embodiments, the first dose of the PD-1 inhibitor in the first cycle is administered about 1 week after initiation of administration of T cell therapy. In some embodiments, the first dose of the PD-1 inhibitor in the first cycle is administered about 2 weeks after initiation of administration of T cell therapy.

[0328] In some embodiments, the T cell therapy is administered on day 1. In some embodiments, the first dose of the PD-1 inhibitor of the first cycle is administered between about day 2 and about day 20. In some embodiments, the first dose of the PD-1 inhibitor of the first cycle is administered between about day 8 and about day 15. In some embodiments, the first dose of the PD-1 inhibitor of the first cycle is administered on about day 8. In some embodiments, the first dose of the PD-1 inhibitor of the first cycle is administered on about day 15.

[0329] In some embodiments, a dose of the PD-1 inhibitor is administered on days 8, 15, 22, 29, 36, and / or 43. In some embodiments, a dose of the PD-1 inhibitor is administered on day 15. In some embodiments, a dose of the PD-1 inhibitor is administered on day 22. In some embodiments, a dose of the PD-1 inhibitor is administered on day 29. In some embodiments, a dose of the PD-1 inhibitor is administered on day 36. In some embodiments, a dose of the PD-1 inhibitor is administered on day 43. In some embodiments, a dose of the PD-1 inhibitor is administered on days 8 and 36. In some embodiments, a dose of the PD-1 inhibitor is administered on days 8, 22, and 36. In some embodiments, a dose of PD-1 is administered on days 15, 29, and 43.

[0330] In some embodiments, a first amount of the PD-1 inhibitor is administered for each dose of the first cycle. In some embodiments, the first amount of the PD-1 inhibitor is between about 100 mg and about 600 mg, between about 100 mg and about 550 mg, between about 100 mg and about 500 mg, between about 100 mg and about 450 mg, between about 100 mg and about 400 mg, between about 100 mg and about 350 mg, between about 100 mg and about 300 mg, between about 100 mg and about 250 mg, between about 100 mg and about 200 mg, between about 100 mg and about 150 mg, between about 150 mg and about 600 mg, between about 150 mg and about 550 mg, or between about 150 mg and about 500 mg. mg, between about 150mg and about 450mg, between about 150mg and about 400mg, between about 150mg and about 350mg, between about 150mg and about 300mg, between about 150mg and about 250mg, between about 150mg and about 200mg, between about 200mg and about 600mg, between about 200mg and about 550mg, between about 200mg and about 500mg, between about 200mg and about 450mg, between about 200mg and about 400mg, between about 200mg and about 350mg, between about 200mg and about 300mg, between about 200mg and about 250mg Between about 250mg and 600mg, Between about 250mg and about 550mg, Between about 250mg and about 500mg, Between about 250mg and about 450mg, Between about 250mg and about 400mg, Between about 250mg and about 350mg, Between about 250mg and about 300mg, Between about 300mg and about 600mg, Between about 300mg and about 550mg, Between about 300mg and about 500mg, Between about 300mg and about 450mg, Between about 300mg and about 400mg, Between about 300mg and about 350mg, Between about 350mg and about 600mg, Between 350mg and about 550mg, between about 350mg and about 500mg, between about 350mg and about 450mg, between about 350mg and about 400mg, between about 400mg and about 600mg, between about 400mg and about 550mg, between about 400mg and about 500mg, between about 400mg and about 450mg, between about 450mg and about 550mg, between about 450mg and about 500mg, between about 500mg and about 600mg, between about 500mg and about 550mg, or between about 550mg and about 600mg.

[0331] In some embodiments, the first amount of the PD-1 inhibitor is between about 140 mg and about 580 mg. In some embodiments, the first amount of the PD-1 inhibitor is between about 180 mg and about 540 mg. In some embodiments, the first amount of the PD-1 inhibitor is about 240 mg or about 480 mg. In some embodiments, the first amount of the PD-1 inhibitor is about 240 mg. In some embodiments, the first amount of the PD-1 inhibitor is about 480 mg.

[0332] In some embodiments, provided methods of combination therapy include: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds Cluster of Differentiation 19 (CD19); and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of a first amount of 140, or about 140-340 mg, or about 340 mg, inclusive, of the PD-1 inhibitor once every two weeks (Q2W) or once every four weeks (Q4W) for a first cycle, wherein at least two doses of the first amount of the PD-1 inhibitor are administered in the first cycle, and the first dose of the first cycle is administered between days 2 and 20, inclusive.

[0333] In some embodiments, provided methods of combination therapy include: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds Cluster of Differentiation 19 (CD19); and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of a first amount of 380 mg, or about 380 mg to 580 mg, or about 580 mg, inclusive, of the PD-1 inhibitor for a first cycle, wherein at least one dose of the first amount of the PD-1 inhibitor is administered in the first cycle, and the first dose of the first cycle is administered between days 2 and 20.

[0334] In some embodiments, 240 mg, or about 240 mg, of the PD-1 inhibitor is administered on days 8, 22, and 36. In some embodiments, 480 mg, or about 480 mg, of the PD-1 inhibitor is administered on days 8 and 36. In some embodiments, 240 mg, or about 240 mg, of the PD-1 inhibitor is administered on days 15, 29, and 43. In some embodiments, 480 mg, or about 480 mg, of the PD-1 inhibitor is administered on day 15.

[0335] In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab, camrelizumab, cemiplimab, dostarlimab, MEDI-0680, pembrolizumab, spartalizumab, SSI-361, tislelizumab, or a combination thereof. In some embodiments, the anti-PD-1 antibody is nivolumab.

[0336] 2) Second Cycle In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a PD-1 inhibitor, and optionally a LAG3 inhibitor) and T cell therapy (e.g., CAR T cells) to a subject, wherein the checkpoint inhibitor therapy is administered in a first cycle and a second cycle.

[0337] In some embodiments, at least one dose of the PD-1 inhibitor is administered in the second cycle. In some embodiments, at least two doses of the PD-1 inhibitor are administered in the second cycle. In some embodiments, two doses of the PD-1 inhibitor are administered in the second cycle.

[0338] In some embodiments, the first dose of the PD-1 inhibitor in the second cycle is administered between about 6 and 10 weeks after initiation of administration of T cell therapy. In some embodiments, the first dose of the PD-1 inhibitor in the second cycle is administered about 8 weeks after initiation of administration of T cell therapy. In some embodiments, the first dose of the PD-1 inhibitor in the second cycle is administered about 9 weeks after initiation of administration of T cell therapy.

[0339] In some embodiments, the T cell therapy is administered on day 1. In some embodiments, the first dose of the PD-1 inhibitor of the second cycle is administered between about day 50 and about day 65. In some embodiments, the first dose of the PD-1 inhibitor of the second cycle is administered on about day 50. In some embodiments, the second dose of the PD-1 inhibitor of the second cycle is administered between about day 78 and about day 92. In some embodiments, the second dose of the PD-1 inhibitor of the second cycle is administered on about day 85.

[0340] In some embodiments, a dose of the PD-1 inhibitor is administered on day 57. In some embodiments, a dose of the PD-1 inhibitor is administered on day 85. In some embodiments, the PD-1 inhibitor is administered on days 57 and 85.

[0341] In some embodiments, a second amount of the PD-1 inhibitor is administered for each dose of the second cycle. In some embodiments, the second amount of the PD-1 inhibitor is between about 100 mg and about 600 mg, between about 100 mg and about 550 mg, between about 100 mg and about 500 mg, between about 100 mg and about 450 mg, between about 100 mg and about 400 mg, between about 100 mg and about 350 mg, between about 100 mg and about 300 mg, between about 100 mg and about 250 mg, between about 100 mg and about 200 mg, between about 100 mg and about 150 mg, between about 150 mg and about 600 mg, between about 150 mg and about 550 mg, or between about 150 mg and about 500 mg. mg, between about 150mg and about 450mg, between about 150mg and about 400mg, between about 150mg and about 350mg, between about 150mg and about 300mg, between about 150mg and about 250mg, between about 150mg and about 200mg, between about 200mg and about 600mg, between about 200mg and about 550mg, between about 200mg and about 500mg, between about 200mg and about 450mg, between about 200mg and about 400mg, between about 200mg and about 350mg, between about 200mg and about 300mg, between about 200mg and about 250mg Between about 250mg and 600mg, Between about 250mg and about 550mg, Between about 250mg and about 500mg, Between about 250mg and about 450mg, Between about 250mg and about 400mg, Between about 250mg and about 350mg, Between about 250mg and about 300mg, Between about 300mg and about 600mg, Between about 300mg and about 550mg, Between about 300mg and about 500mg, Between about 300mg and about 450mg, Between about 300mg and about 400mg, Between about 300mg and about 350mg, Between about 350mg and about 600mg, Between 350mg and about 550mg, between about 350mg and about 500mg, between about 350mg and about 450mg, between about 350mg and about 400mg, between about 400mg and about 600mg, between about 400mg and about 550mg, between about 400mg and about 500mg, between about 400mg and about 450mg, between about 450mg and about 550mg, between about 450mg and about 500mg, between about 500mg and about 600mg, between about 500mg and about 550mg, or between about 550mg and about 600mg.

[0342] In some embodiments, the second amount of the PD-1 inhibitor is between about 140 mg and about 580 mg. In some embodiments, the second amount of the PD-1 inhibitor is between about 180 mg and about 540 mg. In some embodiments, the second amount of the PD-1 inhibitor is about 240 mg or about 480 mg. In some embodiments, the second amount of the PD-1 inhibitor is about 240 mg. In some embodiments, the second amount of the PD-1 inhibitor is about 480 mg.

[0343] In some embodiments, provided methods of combination therapy include: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds Cluster of Differentiation 19 (CD19); and (2) (i) administering a first amount of a PD-1 inhibitor of at least two doses of 140 mg to about 140 mg, inclusive, once every two weeks (Q2W) or once every four weeks (Q4W) for a first cycle, wherein the first amount of the PD-1 inhibitor is administered in at least two doses in the first cycle. wherein the first dose of the first cycle is administered between days 2 and 20, inclusive; and (ii) administration of a second amount of the PD-1 inhibitor of 140 mg or about 140 mg to 580 mg or about 580 mg, inclusive, about once every four weeks (Q4W) for a second cycle, wherein at least two doses of the second amount are administered in the second cycle, and the first dose of the second cycle is administered between days 50 and 65.

[0344] In some embodiments, provided methods of combination therapy include: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) (i) administering a first amount of a PD-1 inhibitor of at or about 380 mg to 580 mg or about 580 mg, inclusive, for a first cycle, wherein at least one dose of the first amount of the PD-1 inhibitor is administered in the first cycle. and (ii) administering a second amount of the PD-1 inhibitor of 380 mg, or about 380 mg to 580 mg, or about 580 mg, inclusive, about once every four weeks (Q4W) for a second cycle, wherein at least two doses of the second amount are administered in the second cycle, and the first dose of the second cycle is administered between days 50 and 65.

[0345] In some embodiments, 480 mg, or about 480 mg, of the PD-1 inhibitor is administered on day 57. In some embodiments, 480 mg, or about 480 mg, of the PD-1 inhibitor is administered on day 85. In some embodiments, 480 mg, or about 480 mg, of the PD-1 inhibitor is administered on days 57 and 85.

[0346] In some embodiments, 240 mg, or about 240 mg, of the PD-1 inhibitor is administered on days 8, 22, and 36, and 480 mg, or about 480 mg, of the PD-1 inhibitor is administered on days 57 and 85. In some embodiments, 480 mg, or about 480 mg, of the PD-1 inhibitor is administered on days 8 and 36, and 480 mg, or about 480 mg, of the PD-1 inhibitor is administered on days 57 and 85. In some embodiments, 240 mg, or about 240 mg, of the PD-1 inhibitor is administered on days 15, 29, and 43, and 480 mg, or about 480 mg, of the PD-1 inhibitor is administered on days 57 and 85. In some embodiments, 480 mg, or about 480 mg, of the PD-1 inhibitor is administered on day 15, and 480 mg, or about 480 mg, of the PD-1 inhibitor is administered on days 57 and 85.

[0347] In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab, camrelizumab, cemiplimab, dostarlimab, MEDI-0680, pembrolizumab, spartalizumab, SSI-361, tislelizumab, or a combination thereof. In some embodiments, the anti-PD-1 antibody is nivolumab.

[0348] 2. Anti-LAG3 antibody a. Compositions and Formulations In some embodiments of the combination therapy methods, combinations, kits and uses provided herein, the combination therapy can be administered in one or more compositions, e.g., pharmaceutical compositions, containing a LAG3 inhibitor (e.g., an anti-LAG3 antibody such as leratolimab), and / or a T cell therapy, e.g., a CAR T cell therapy.

[0349] In some embodiments, compositions, e.g., pharmaceutical compositions, containing a LAG3 inhibitor, e.g., an anti-LAG3 antibody such as leratolimab, can include a carrier, such as a diluent, adjuvant, excipient, or vehicle, by which the inhibitor and / or cells are administered. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions will contain a therapeutically effective amount of a LAG3 inhibitor, e.g., an anti-LAG3 antibody, generally in purified form, together with a suitable amount of carrier to obtain the form for proper administration to a patient. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. The pharmaceutical composition may contain any one or more of diluent(s), adjuvant(s), antiadherent(s), binder(s), coating(s), filler(s), flavor(s), color(s), lubricant(s), glidant(s), preservative(s), detergent(s), adsorbent(s), emulsifier(s), pharmaceutical excipient(s), pH buffer(s), or sweetener(s), and combinations thereof. In some embodiments, the pharmaceutical composition may be a liquid, solid, lyophilized powder, gel form, and / or combinations thereof. In some aspects, the choice of carrier is determined, in part, by the particular inhibitor and / or by the method of administration.

[0350] Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol); low molecular weight (less than about 10 residues) polypeptides; serum albumin; The composition may include, but is not limited to, proteins such as albumin, gelatin, or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants, stabilizers, and / or preservatives, such as polyethylene glycol (PEG). The composition containing a LAG3 inhibitor, for example, an anti-LAG3 antibody such as leratolimab, can also be lyophilized.

[0351] In some embodiments, the pharmaceutical compositions can be formulated for administration by any route known to those skilled in the art, including intramuscular, intravenous, intradermal, intralesional, intraperitoneal injection, subcutaneous, intratumoral, epidural, nasal, oral, vaginal, rectal, topical, local, otic, inhalation, buccal (e.g., sublingual), and transdermal administration, or any route. In some embodiments, other administration mechanisms are also contemplated. In some embodiments, administration is by bolus injection, injection, e.g., intravenous or subcutaneous injection, intraocular injection, periocular injection, subretinal injection, intravitreal injection, transseptal injection, subscleral injection, intrachoroidal injection, intracameral injection, subconjunctival injection, subconjunctival injection, sub-Tenon injection, retrobulbar injection, peribulbar injection, or juxtascleral posterior delivery. In some embodiments, administration is parenteral, intrapulmonary, intranasal, and, if desired for localized treatment, by intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0352] In some embodiments, the compositions can also be administered with other bioactive agents, either sequentially, intermittently, or in the same composition. In some embodiments, administration can also include controlled release systems, including controlled release formulations and devices where release is controlled by pumps, etc. In some embodiments, administration is oral.

[0353] In some embodiments, LAG3 inhibitors, such as anti-LAG3 antibodies such as leratolimab, are typically formulated and administered in unit dosage forms or multiple dosage forms. Each unit dosage contains a predetermined amount of a therapeutically active LAG3 inhibitor, such as leratolimab, sufficient to produce the desired therapeutic effect, along with the necessary pharmaceutical carrier, vehicle, or diluent. In some embodiments, unit dosage forms include, but are not limited to, tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, and oil-water emulsions containing an appropriate amount of a LAG3 inhibitor, such as leratolimab. Unit dosage forms may be contained in ampoules and syringes, or in individually packaged tablets or capsules. Fractions or multiples of a unit dosage form may be administered. In some embodiments, multiple dosage forms are multiple identical unit dosage forms packaged in a single container that can be administered in separate unit dosage forms. Examples of multiple dose forms include vials; bottles of tablets or capsules; or bottles of pints or gallons.

[0354] In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are formulated as a single composition. In some embodiments, co-administration of the PD-1 inhibitor and the LAG3 inhibitor to a subject comprises administration of a single composition comprising the PD-1 inhibitor and the LAG3 inhibitor. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered together in a single composition over at or about 15 minutes, at or about 30 minutes, at or about 45 minutes, at or about 60 minutes, at or about 75 minutes, or at or about 90 minutes. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered together in a single composition over at or about 15 minutes. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered together in a single composition over at or about 30 minutes. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered together in a single composition over at or about 45 minutes. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered together as a single composition over at or about 60 minutes. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered together as a single composition over at or about 75 minutes. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered together as a single composition over at or about 90 minutes.

[0355] In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are administered sequentially as separate compositions. In some embodiments, a first composition comprising one of the PD-1 inhibitor and the LAG3 inhibitor is formulated for administration, and a second composition comprising the other of the PD-1 inhibitor and the LAG3 inhibitor is formulated for administration. Thus, in some embodiments, administering the PD-1 inhibitor and the LAG3 comprises administering multiple separate compositions. In some embodiments, the first composition comprises the PD-1 inhibitor.

[0356] In some embodiments, the composition comprising the PD-1 inhibitor is administered over at or about 15 minutes, at or about 30 minutes, at or about 45 minutes, or at or about 60 minutes. In some embodiments, the composition comprising the PD-1 inhibitor is administered over at or about 15 minutes. In some embodiments, the composition comprising the PD-1 inhibitor is administered over at or about 30 minutes. In some embodiments, the composition comprising the PD-1 inhibitor is administered over at or about 45 minutes.

[0357] In some embodiments, administration of the second composition is initiated 5 or about 5 minutes, 10 or about 10 minutes, 15 or about 15 minutes, 20 or about 20 minutes, 25 or about 25 minutes, 30 or about 30 minutes, 35 or about 35 minutes, 40 or about 40 minutes, or 45 or about 45 minutes after administration of the first composition is complete. In some embodiments, administration of the second composition is initiated 15 or about 15 minutes after administration of the first composition is complete. In some embodiments, administration of the second composition is initiated 30 or about 30 minutes after administration of the first composition is complete. In some embodiments, the first composition comprises a PD-1 inhibitor. In some embodiments, the second composition comprises 960 mg or about 960 mg of a LAG3 inhibitor and is administered 30 or about 30 minutes after administration of the first composition comprising a PD-1 inhibitor.

[0358] In some embodiments, a composition comprising a LAG3 inhibitor is administered over at or about 30 minutes, at or about 45 minutes, at or about 60 minutes, or at or about 75 minutes. In some embodiments, a composition comprising a LAG3 inhibitor is administered over at or about 45 minutes, at or about 60 minutes, or at or about 75 minutes. In some embodiments, a composition comprising a LAG3 inhibitor is administered over at or about 30 minutes. In some embodiments, a composition comprising a LAG3 inhibitor is administered over at or about 45 minutes. In some embodiments, a composition comprising a LAG3 inhibitor is administered over at or about 60 minutes. In some embodiments, a composition comprising a LAG3 inhibitor is administered over at or about 75 minutes.

[0359] In some embodiments, the composition comprising the PD-1 inhibitor is administered first. In some embodiments, the composition comprising the PD-1 inhibitor is administered over 30 minutes or about 30 minutes. In some embodiments, administration of the composition comprising the LAG3 inhibitor begins about 15 minutes to about 30 minutes after administration of the PD-1 inhibitor has ended. In some embodiments, the composition comprising the LAG3 inhibitor is administered over 30 minutes or about 30 minutes. Thus, in some embodiments, the composition comprising the PD-1 inhibitor is administered over about 30 minutes, and then the composition comprising the LAG3 inhibitor is administered over the subsequent 30 minutes about 15 to 30 minutes after administration of the PD-1 inhibitor has ended.

[0360] b. Medication In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a PD-1 inhibitor and a LAG3 inhibitor) and T cell therapy (e.g., CAR T cells) to a subject. In some embodiments, provided methods of combination therapy involve initiating administration of checkpoint inhibitor therapy (e.g., a PD-1 inhibitor and a LAG3 inhibitor) subsequent to initiation of T cell therapy (e.g., CAR T cells). In some embodiments, provided methods of combination therapy involve initiating administration of checkpoint inhibitor therapy (e.g., a PD-1 inhibitor and a LAG3 inhibitor) between about 1 day and about 3 weeks after initiation of administration of T cell therapy (CAR T cells). In some embodiments, initiation of administration of checkpoint inhibitor therapy (e.g., a PD-1 inhibitor and a LAG3 inhibitor) is between about 1 week and about 2 weeks after initiation of administration of T cell therapy (e.g., CAR T cells).

[0361] In some embodiments, provided methods of combination therapy involve administering T cell therapy (e.g., CAR T cells) starting on day 1. In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., PD-1 inhibitor and LAG3 inhibitor) starting between about day 2 and about day 20. In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., PD-1 inhibitor and LAG3 inhibitor) starting on about day 8 or day 15. In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., PD-1 inhibitor and LAG3 inhibitor) starting on about day 8. In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., PD-1 inhibitor and LAG3 inhibitor) starting on about day 15.

[0362] In some embodiments, the methods involve initiating administration of checkpoint inhibitor therapy (e.g., a PD-1 inhibitor and a LAG3 inhibitor) after activation-induced cell death (AICD) of the T cell therapy cells (e.g., CAR T cells) has peaked.

[0363] In some embodiments, provided combination therapies include: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy including a dose of engineered cells including T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) administering to the subject a PD-1 inhibitor and a LAG3 inhibitor in a dosing regimen including administration of at least two doses of a PD-1 inhibitor and at least two doses of a LAG3 inhibitor, wherein (i) administration of the first dose is between day 2 and day 20, inclusive; and (ii) the dose of the PD-1 inhibitor and the dose of the LAG3 inhibitor are administered in an amount of at or about 140 mg to 580 mg or about 580 mg, inclusive, about every two weeks (Q2W) or about every four weeks (Q4W).

[0364] In some embodiments, the first dose of the LAG3 inhibitor is administered between days 8 and 15, inclusive. In some embodiments, the first dose of the LAG3 inhibitor is administered on day 8. In some embodiments, the first dose of the LAG3 inhibitor is administered on day 15. In some embodiments, the amount of the PD-1 inhibitor is at or between about 160 mg and 560 mg.

[0365] In some embodiments, the method comprises administering a dose of the LAG3 inhibitor about every two weeks (Q2W) or about every four weeks (Q4W). In some embodiments, the method comprises administering a dose of the LAG3 inhibitor about every two weeks (Q2W). In some embodiments, the method comprises administering a dose of the LAG3 inhibitor about every four weeks (Q4W). In some embodiments, the method comprises administering a LAG3 inhibitor to the subject in a dosing regimen comprising administering a dose of the LAG3 inhibitor on each of the same days that a dose of the PD-1 inhibitor is administered.

[0366] In some embodiments, the combination therapy provided includes: (1) administering to a subject having a CD19-expressing cancer on day 1 a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor; and (3) administering to the subject a LAG3 inhibitor.

[0367] In some embodiments, the first dose of the LAG3 inhibitor is administered between days 2 and 20, inclusive. In some embodiments, the first dose of the LAG3 inhibitor is administered between days 8 and 15, inclusive. In some embodiments, the first dose of the LAG3 inhibitor is administered on day 8. In some embodiments, the first dose of the LAG3 inhibitor is administered on day 15. In some embodiments, the first dose of the PD-1 inhibitor and the first dose of the LAG3 inhibitor are each independently administered between days 2 and 20, inclusive. In some embodiments, the first dose of the PD-1 inhibitor and the first dose of the LAG3 inhibitor are administered on the same day. In some embodiments, each subsequent dose of the PD-1 inhibitor is administered about 2 weeks, about 3 weeks, or about 4 weeks after the previous dose of the PD-1 inhibitor.

[0368] In some embodiments, each dose of the LAG3 inhibitor is between about 60 mg and about 540 mg, inclusive. In some embodiments, each dose of the LAG3 inhibitor is between about 120 mg and about 480 mg. In some embodiments, each dose of the LAG3 inhibitor is about 120 mg. In some embodiments, each dose of the LAG3 inhibitor is about 240 mg. In some embodiments, each dose of the LAG3 inhibitor is about 480 mg.

[0369] In some embodiments, at least three doses of the LAG3 inhibitor are administered. In some embodiments, three doses, four doses, or six doses of the LAG3 inhibitor are administered.

[0370] In some embodiments, three doses of the LAG3 inhibitor are administered. In some embodiments, the second dose of the LAG3 inhibitor is administered about four weeks after the first dose of the LAG3 inhibitor. In some embodiments, each dose of the LAG3 inhibitor is about 240 mg. In some embodiments, the third dose of the LAG3 inhibitor is administered about five weeks after the second dose of the LAG3 inhibitor. In some embodiments, about 240 mg of the LAG3 inhibitor is administered on each of days 8, 36, and 71. In some embodiments, the third dose of the LAG3 inhibitor is administered about four weeks after the second dose of the LAG3 inhibitor. In some embodiments, about 240 mg of the LAG3 inhibitor is administered on each of days 15, 43, and 71.

[0371] In some embodiments, four doses of the LAG3 inhibitor are administered. In some embodiments, each dose of the LAG3 inhibitor is about 240 mg. In some embodiments, about 240 mg of the LAG3 inhibitor is administered on each of days 8, 36, 64, and 85. In some embodiments, about 240 mg of the LAG3 inhibitor is administered on each of days 15, 43, 64, and 85. In some embodiments, each dose of the LAG3 inhibitor is about 480 mg. In some embodiments, about 480 mg of the LAG3 inhibitor is administered on each of days 8, 36, 64, and 85. In some embodiments, about 480 mg of the LAG3 inhibitor is administered on each of days 15, 43, 64, and 85.

[0372] In some embodiments, six doses of the LAG3 inhibitor are administered. In some embodiments, the second and third doses of the LAG3 inhibitor are each administered about two weeks after the previous dose of the LAG3 inhibitor. In some embodiments, the second, third, fifth, and sixth doses of the LAG3 inhibitor are each administered about two weeks after the previous dose of the LAG3 inhibitor. In some embodiments, the fourth dose of the LAG3 inhibitor is administered about three weeks after the previous dose of the LAG3 inhibitor. In some embodiments, each dose of the LAG3 inhibitor is about 120 mg. In some embodiments, about 120 mg of the LAG3 inhibitor is administered on each of days 8, 22, 36, 57, 71, and 85. In some embodiments, each dose of the LAG3 inhibitor is about 240 mg. In some embodiments, about 240 mg of the LAG3 inhibitor is administered on each of days 8, 22, 36, 57, 71, and 85. In some embodiments, each dose of the LAG3 inhibitor is administered every two weeks (Q2W). In some embodiments, each dose of the LAG3 inhibitor is about 120 mg. In some embodiments, about 120 mg of the LAG3 inhibitor is administered on each of days 15, 29, 43, 57, 71, and 85. In some embodiments, each dose of the LAG3 inhibitor is about 240 mg. In some embodiments, about 240 mg of the LAG3 inhibitor is administered on each of days 15, 29, 43, 57, 71, and 85.

[0373] In some embodiments, the dose of the PD-1 inhibitor and the dose of the LAG3 inhibitor are administered at the same frequency. In some embodiments, each dose of the PD-1 inhibitor is administered on the same day as the dose of the LAG3 inhibitor, or each dose of the LAG3 inhibitor is administered on the same day as the dose of the PD-1 inhibitor. In some embodiments, each dose of the PD-1 inhibitor is administered on the same day as the dose of the LAG3 inhibitor. In some embodiments, each dose of the LAG3 inhibitor is administered on the same day as the dose of the PD-1 inhibitor. In some embodiments, each dose of the PD-1 inhibitor is administered on the same day as the dose of the LAG3 inhibitor, or each dose of the LAG3 inhibitor is administered on the same day as the dose of the PD-1 inhibitor.

[0374] In some embodiments, the dose of the LAG3 inhibitor is administered half as frequently as the dose of the PD-1 inhibitor. In some embodiments, each dose of the PD-1 inhibitor is twice the dose of the LAG3 inhibitor. In some embodiments, each dose of the PD-1 inhibitor is the same as the dose of the LAG3 inhibitor. In some embodiments, the PD-1 inhibitor and the LAG3 inhibitor are formulated in a single composition, such as those described in Section IA4.

[0375] In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 160 mg or about 160 mg to 1040 mg or about 1040 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 160 mg or about 160 mg to 320 mg or about 320 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 240 mg or about 240 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 400 mg or about 400 mg to 560 mg or about 560 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 480 mg or about 480 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 880 mg or about 880 mg to 1040 mg or about 1040 mg. In some embodiments, each dose of the LAG3 inhibitor is administered in an amount of 960 mg or about 960 mg.

[0376] In some embodiments, the LAG3 inhibitor is administered in an amount of about 240 mg or about 480 mg Q2W. In some embodiments, the LAG3 inhibitor is administered in an amount of about 240 mg Q2W. In some embodiments, the LAG3 inhibitor is administered in an amount of about 480 mg Q2W. In some embodiments, the LAG3 inhibitor is administered in an amount of about 960 mg Q4W.

[0377] In some embodiments, a LAG3 inhibitor is administered in the first cycle and the second cycle, as further described below.

[0378] 1) First Cycle In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a PD-1 inhibitor and a LAG3 inhibitor) and T cell therapy (e.g., CAR T cells) to a subject, wherein the checkpoint inhibitor therapy is administered in a first cycle and a second cycle.

[0379] In some embodiments, at least one dose of the LAG3 inhibitor is administered in the first cycle. In some embodiments, at least two doses of the LAG3 inhibitor are administered in the first cycle. In some embodiments, at least three doses of the LAG3 inhibitor are administered in the first cycle. In some embodiments, two doses of the LAG3 inhibitor are administered in the first cycle. In some embodiments, three doses of the LAG3 inhibitor are administered in the first cycle.

[0380] In some embodiments, the first dose of the LAG3 inhibitor in the first cycle is administered following administration of T cell therapy. In some embodiments, the first dose of the LAG3 inhibitor in the first cycle is administered between about 1 day and about 3 weeks after initiation of administration of T cell therapy. In some embodiments, the first dose of the LAG3 inhibitor in the first cycle is administered about 1 week after initiation of administration of T cell therapy. In some embodiments, the first dose of the LAG3 inhibitor in the first cycle is administered about 2 weeks after initiation of administration of T cell therapy.

[0381] In some embodiments, the T cell therapy is administered on day 1. In some embodiments, the first dose of the LAG3 inhibitor of the first cycle is administered between about day 2 and about day 20. In some embodiments, the first dose of the LAG3 inhibitor of the first cycle is administered between about day 8 and about day 15. In some embodiments, the first dose of the LAG3 inhibitor of the first cycle is administered on about day 8. In some embodiments, the first dose of the LAG3 inhibitor of the first cycle is administered on about day 15.

[0382] In some embodiments, a dose of the LAG3 inhibitor is administered on days 8, 15, 22, 29, 36, and / or 43. In some embodiments, a dose of the LAG3 inhibitor is administered on day 15. In some embodiments, a dose of the LAG3 inhibitor is administered on day 22. In some embodiments, a dose of the LAG3 inhibitor is administered on day 29. In some embodiments, a dose of the LAG3 inhibitor is administered on day 36. In some embodiments, a dose of the LAG3 inhibitor is administered on day 43. In some embodiments, a dose of the LAG3 inhibitor is administered on days 8 and 36. In some embodiments, a dose of the LAG3 inhibitor is administered on days 8, 22, and 36. In some embodiments, a dose of the LAG3 inhibitor is administered on days 15, 29, and 43.

[0383] In some embodiments, a first amount of the LAG3 inhibitor is administered for each dose of the first cycle. In some embodiments, the first amount of the LAG3 inhibitor is between about 100 mg and about 1050 mg, between about 100 mg and about 1000 mg, between about 100 mg and about 900 mg, between about 100 mg and about 850 mg, between about 100 mg and about 800 mg, between about 100 mg and about 750 mg, between about 100 mg and about 700 mg, between about 100 mg and about 650 mg, between about 100 mg and about 600 mg, between about 100 mg and about 550 mg, between about 100 mg and about 500 mg, between about 100 mg and about 450 mg, between about 100 mg and about 400 mg, or between about 100 mg and about 550 mg. Between about 100mg and about 350mg, between about 100mg and about 300mg, between about 100mg and about 250mg, between about 100mg and about 200mg, between about 100mg and about 150mg, between about 150mg and about 1050mg, between about 150mg and about 1000mg, between about 150mg and about 900mg, between about 150mg and about 850mg, between about 150mg and about 800mg, between about 150mg and about 750mg, between about 150mg and about 700mg, between about 150mg and about 650mg, between about 150mg and about 600mg, between about 150mg and about 550mg g, between about 150mg and about 500mg, between about 150mg and about 450mg, between about 150mg and about 400mg, between about 150mg and about 350mg, between about 150mg and about 300mg, between about 150mg and about 250mg, between about 150mg and about 200mg, between about 200mg and about 1050mg, between about 200mg and about 1000mg, between about 200mg and about 900mg, between about 200mg and about 850mg, between about 200mg and about 800mg, between about 200mg and about 750mg, between about 200mg and about 700mg, between about 200mg between about 200mg and about 650mg, between about 200mg and 600mg, between about 200mg and about 550mg, between about 200mg and about 500mg, between about 200mg and about 450mg, between about 200mg and about 400mg, between about 200mg and about 350mg, between about 200mg and about 300mg, between about 200mg and about 250mg, between about 250mg and about 1050mg, between about 250mg and about 1000mg, between about 250mg and about 900mg, between about 250mg and about 850mg, between about 250mg and about 800mg, between about 250mg and about 750mgBetween about 250mg and about 700mg, between about 250mg and about 650mg, between about 250mg and about 600mg, between about 250mg and about 550mg, between about 250mg and about 500mg, between about 250mg and about 450mg, between about 250mg and about 400mg, between about 250mg and about 350mg, between about 250mg and about 300mg, between about 300mg and about 1050mg, between about 300mg and about 1000mg, between about 300mg and about 900mg, between about 300mg and about 850mg, between about 300mg and about 800mg, between about 300mg and about 750mg, between about 300mg and about Between about 300mg and about 650mg, between about 300mg and about 600mg, between about 300mg and about 550mg, between about 300mg and about 500mg, between about 300mg and about 450mg, between about 300mg and about 400mg, between about 300mg and about 350mg, between about 350mg and about 1050mg, between about 350mg and about 1000mg, between about 350mg and about 900mg, between about 350mg and about 850mg, between about 350mg and about 800mg, between about 350mg and about 750mg, between about 350mg and about 700mg, between about 350mg and about 650mg, Between 350mg and 600mg, between about 350mg and about 550mg, between about 350mg and about 500mg, between about 350mg and about 450mg, between about 350mg and about 400mg, between about 400mg and about 1050mg, between about 400mg and about 1000mg, between about 400mg and about 900mg, between about 400mg and about 850mg, between about 400mg and about 800mg, between about 400mg and about 750mg, between about 400mg and about 700mg, between about 400mg and about 650mg, between about 400mg and about 600mg, between about 400mg and about 550mg, between about 400mg and about 500mg mg, between about 400 mg and about 450 mg, between about 450 mg and about 1050 mg, between about 450 mg and about 1000 mg, between about 450 mg and about 900 mg, between about 450 mg and about 850 mg, between about 450 mg and about 800 mg, between about 450 mg and about 750 mg, between about 450 mg and about 700 mg, between about 450 mg and about 650 mg, between about 450 mg and about 600 mg, between about 450 mg and about 550 mg, between about 450 mg and about 500 mg, between about 500 mg and about 600 mg, between about 500 mg and about 550 mg, or between about 550 mg and about 600 mg.

[0384] In some embodiments, the first amount of the LAG3 inhibitor is between about 140 mg and about 1040 mg. In some embodiments, the first amount of the LAG3 inhibitor is between about 180 mg and about 1000 mg. In some embodiments, the first amount of the LAG3 inhibitor is between about 180 mg and about 300 mg. In some embodiments, the first amount of the LAG3 inhibitor is about 240 mg. In some embodiments, the first amount of the LAG3 inhibitor is between about 380 mg and 560 mg. In some embodiments, the first amount of the LAG3 inhibitor is about 480 mg. In some embodiments, the first amount of the LAG3 inhibitor is between about 840 mg and 1060 mg. In some embodiments, the first amount of the LAG3 inhibitor is about 960 mg.

[0385] In some embodiments, provided combination therapies include: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds Cluster of Differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administering a first amount of 140, or about 140-340 mg, or about 340 mg, inclusive, of the PD-1 inhibitor once every two weeks (Q2W) or once every four weeks (Q4W) for a first cycle, wherein at least two doses of the first amount of the PD-1 inhibitor are administered in the first cycle, the first dose of the first cycle being administered between days 2 and 20, inclusive; and (3) administering to the subject a dose of a LAG3 inhibitor about every two weeks (Q2W) or about every four weeks (Q4W).

[0386] In some embodiments, provided methods of combination therapy include: (1) administering to a subject having a CD19-expressing cancer a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds Cluster of Differentiation 19 (CD19) on day 1; (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of a first amount of 140 or between about 140 and 340 mg or about 340 mg, inclusive, of the PD-1 inhibitor once every two weeks (Q2W) or once every four weeks (Q4W) for a first cycle, wherein at least two doses of the first amount of the PD-1 inhibitor are administered in the first cycle, the first dose of the first cycle being administered between days 2 and 20, inclusive; and (3) administering to the subject a dose of a LAG3 inhibitor in a dosing regimen comprising administration of a dose of the LAG3 inhibitor on each of the same days that a dose of the PD-1 inhibitor is administered.

[0387] In some embodiments, provided methods of combination therapy include: (1) administering to a subject having a CD19-expressing cancer a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds Cluster of Differentiation 19 (CD19) on day 1; (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of a first amount of 380 mg or between about 380 mg and 580 mg or about 580 mg, inclusive, of the PD-1 inhibitor for a first cycle, wherein at least one dose of the first amount of the PD-1 inhibitor is administered in the first cycle, and the first dose of the first cycle is administered between days 2 and 20; and (3) administering to the subject a dose of a LAG3 inhibitor about every two weeks (Q2W) or about every four weeks (Q4W).

[0388] In some embodiments, provided methods of combination therapy include: (1) administering to a subject having a CD19-expressing cancer a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds Cluster of Differentiation 19 (CD19) on day 1; (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of a first amount of 380 mg, or about 380 mg to 580 mg, or about 580 mg, inclusive, of the PD-1 inhibitor for a first cycle, wherein at least one dose of the first amount of the PD-1 inhibitor is administered in the first cycle, and the first dose of the first cycle is administered between days 2 and 20; and (3) administering to the subject a dose of a LAG3 inhibitor in a dosing regimen comprising administration of a dose of the LAG3 inhibitor on each of the same days that a dose of the PD-1 inhibitor is administered.

[0389] In some embodiments, each dose of the LAG3 inhibitor is administered in a first amount during a first cycle and in a second amount during a second cycle.

[0390] In some embodiments, the first amount of the LAG3 inhibitor is between at or about 160 mg and at or about 320 mg. In some embodiments, the first amount of the LAG3 inhibitor is between at or about 200 mg and at or about 280 mg. In some embodiments, the first amount of the LAG3 inhibitor is between at or about 240 mg and at or about 240 mg. In some embodiments, the first amount of the LAG3 inhibitor is between at or about 400 mg and at or about 560 mg. In some embodiments, the first amount of the LAG3 inhibitor is between at or about 440 mg and at or about 520 mg. In some embodiments, the first amount of the LAG3 inhibitor is 480 mg or about 480 mg. In some embodiments, the first amount of the LAG3 inhibitor is between at or about 880 mg and at or about 1040 mg. In some embodiments, the first amount of the LAG3 inhibitor is between at or about 920 mg and at or about 1000 mg, hi some embodiments, the first amount of the LAG3 inhibitor is at or about 960 mg.

[0391] In some embodiments, 240 mg, or about 240 mg, of the LAG3 inhibitor is administered on days 8, 22, and 36. In some embodiments, 480 mg, or about 480 mg, of the LAG3 inhibitor is administered on days 8, 22, and 36. In some embodiments, 480 mg, or about 480 mg, of the LAG3 inhibitor is administered on days 8 and 36. In some embodiments, 960 mg, or about 960 mg, of the LAG3 inhibitor is administered on days 8 and 36. In some embodiments, 240 mg, or about 240 mg, of the LAG3 inhibitor is administered on days 15, 29, and 43. In some embodiments, 480 mg, or about 480 mg, of the LAG3 inhibitor is administered on days 15, 29, and 43. In some embodiments, 480 mg, or about 480 mg, of the LAG3 inhibitor is administered on day 15. In some embodiments, 960 mg or about 960 mg of the LAG3 inhibitor is administered on the 15th day.

[0392] In some embodiments, the LAG3 inhibitor is an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is selected from the group consisting of leratolimab, MK-4280, and yeramilimab, or a combination thereof. In some embodiments, the anti-LAG3 antibody is leratolimab.

[0393] 2) Second Cycle In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a PD-1 inhibitor and a LAG3 inhibitor) and T cell therapy (e.g., CAR T cells) to a subject, wherein the checkpoint inhibitor therapy is administered in a first cycle and a second cycle.

[0394] In some embodiments, at least one dose of the LAG3 inhibitor is administered in the second cycle. In some embodiments, at least two doses of the LAG3 inhibitor are administered in the second cycle. In some embodiments, two doses of the LAG3 inhibitor are administered in the second cycle.

[0395] In some embodiments, the first dose of the LAG3 inhibitor in the second cycle is administered between about 6 and 10 weeks after initiation of administration of T cell therapy. In some embodiments, the first dose of the LAG3 inhibitor in the second cycle is administered about 8 weeks after initiation of administration of T cell therapy. In some embodiments, the first dose of the LAG3 inhibitor in the second cycle is administered about 9 weeks after initiation of administration of T cell therapy.

[0396] In some embodiments, the T cell therapy is administered on day 1. In some embodiments, the first dose of the LAG3 inhibitor of the second cycle is administered between about day 50 and about day 65. In some embodiments, the first dose of the LAG3 inhibitor of the second cycle is administered on about day 50. In some embodiments, the second dose of the LAG3 inhibitor of the second cycle is administered between about day 78 and about day 92. In some embodiments, the second dose of the LAG3 inhibitor of the second cycle is administered on about day 85.

[0397] In some embodiments, a dose of the LAG3 inhibitor is administered on day 57. In some embodiments, a dose of the LAG3 inhibitor is administered on day 85. In some embodiments, the LAG3 inhibitor is administered on days 57 and 85.

[0398] In some embodiments, a second amount of the LAG3 inhibitor is administered for each dose of the second cycle. In some embodiments, the second amount of the LAG3 inhibitor is between about 300 mg and 1100 mg, between about 300 mg and 1000 mg, between about 300 mg and 900 mg, between about 300 mg and 800 mg, between about 300 mg and 700 mg, between about 300 mg and 600 mg, between about 300 mg and about 550 mg, between about 300 mg and about 500 mg, or between about 300 mg and about 450 mg. , between about 400mg and 1100mg, between about 400mg and 1000mg, between about 400mg and 900mg, between about 400mg and 800mg, between about 400mg and 700mg, between about 400mg and 600mg, between about 400mg and about 550mg, between about 400mg and about 500mg, between about 400mg and about 450mg, between about 500mg and 1100mg, about 500mg Between about 500mg and 900mg, Between about 500mg and 800mg, Between about 500mg and 700mg, Between about 500mg and about 600mg, Between about 500mg and about 550mg, Between about 600mg and 1100mg, Between about 600mg and 1000mg, Between about 600mg and 900mg, Between about 600mg and 800mg, Between about 600mg and 700mg , between about 700 mg and 1100 mg, between about 700 mg and 1000 mg, between about 700 mg and 900 mg, between about 700 mg and 800 mg, between about 800 mg and 1100 mg, between about 800 mg and 1000 mg, between about 800 mg and 900 mg, between about 900 mg and 1100 mg, between about 1000 mg and 1000 mg, or between about 1000 mg and 1100 mg.

[0399] In some embodiments, the second amount of the LAG3 inhibitor is between about 360 mg and about 1080 mg. In some embodiments, the second amount of the LAG3 inhibitor is between about 880 mg and about 1040 mg. In some embodiments, the second amount of the LAG3 inhibitor is about 960 mg. In some embodiments, the second amount of the LAG3 inhibitor is between about 360 mg and about 540 mg. In some embodiments, the second amount of the LAG3 inhibitor is about 480 mg.

[0400] In some embodiments, provided methods of combination therapy include: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds Cluster of Differentiation 19 (CD19); and (2) (i) administering a first amount of a PD-1 inhibitor of 140, or about 140-340 mg, or about 340 mg, inclusive, once every two weeks (Q2W) or once every four weeks (Q4W) for a first cycle, wherein at least two doses of the first amount of the PD-1 inhibitor are administered in the first cycle, and the first dose of the first cycle is and (ii) administering a second amount of the PD-1 inhibitor of 140 mg or about 140 mg to 580 mg or about 580 mg, inclusive, about once every four weeks (Q4W) for a second cycle, wherein at least two doses of the second amount are administered in the second cycle, and the first dose of the second cycle is administered between days 50 and 65; and (3) administering a dose of the LAG3 inhibitor to the subject about every two weeks (Q2W) or about every four weeks (Q4W).

[0401] In some embodiments, provided methods of combination therapy include: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds Cluster of Differentiation 19 (CD19); and (2) (i) administering a first amount of a PD-1 inhibitor of 140, or about 140-340 mg, or about 340 mg, inclusive, once every two weeks (Q2W) or once every four weeks (Q4W) for a first cycle, wherein at least two doses of the first amount of the PD-1 inhibitor are administered in the first cycle, and the first dose of the first cycle is administered between days 2 and 20 (both Q2W and Q4W). and (ii) administering a second amount of the PD-1 inhibitor of 140 mg or about 140 mg to 580 mg or about 580 mg, inclusive, about once every four weeks (Q4W) for a second cycle, wherein at least two doses of the second amount are administered in the second cycle and the first dose of the second cycle is administered between days 50 and 65; (3) administering a dose of the LAG3 inhibitor to the subject in a dosing regimen comprising administration of a dose of the LAG3 inhibitor on each of the same days that a dose of the PD-1 inhibitor is administered.

[0402] In some embodiments, provided methods of combination therapy include: (1) administering to a subject having a CD19-expressing cancer a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds Cluster of Differentiation 19 (CD19) on day 1; and (2) (i) administering a first amount of a PD-1 inhibitor of at or about 380 mg to 580 mg or about 580 mg, inclusive, for a first cycle, wherein at least one dose of the first amount of the PD-1 inhibitor is administered in the first cycle, and the first dose of the first cycle is administered on days 2 to 20. and (ii) administering a second amount of the PD-1 inhibitor of 380 mg, or about 380 mg to 580 mg, or about 580 mg, inclusive, about once every four weeks (Q4W) for a second cycle, wherein at least two doses of the second amount are administered in the second cycle, and the first dose of the second cycle is administered between days 50 and 65; and (3) administering a dose of the LAG3 inhibitor to the subject about every two weeks (Q2W) or about every four weeks (Q4W).

[0403] In some embodiments, provided are methods of combination therapy comprising: (1) administering to a subject having a CD19-expressing cancer on day 1 a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds Cluster of Differentiation 19 (CD19); and (2) (i) administering a first amount of a PD-1 inhibitor of at or about 380 mg to 580 mg or about 580 mg, inclusive, for a first cycle, wherein at least one dose of the first amount of the PD-1 inhibitor is administered in the first cycle, and the first dose of the first cycle is administered between days 2 and 20. and (ii) administering to the subject a second amount of the PD-1 inhibitor of 380 mg, or about 380 mg to 580 mg, or about 580 mg, inclusive, about once every four weeks (Q4W) for a second cycle, wherein at least two doses of the second amount are administered in the second cycle, and the first dose of the second cycle is administered between days 50 and 65; (3) administering to the subject a dose of a LAG3 inhibitor in a dosing regimen that includes administration of a dose of the LAG3 inhibitor on each of the same days that a dose of the PD-1 inhibitor is administered.

[0404] In some embodiments, 480 mg, or about 480 mg, of the LAG3 inhibitor is administered on day 57. In some embodiments, 960 mg, or about 960 mg, of the LAG3 inhibitor is administered on day 57. In some embodiments, 480 mg, or about 480 mg, of the LAG3 inhibitor is administered on day 85. In some embodiments, 960 mg, or about 960 mg, of the LAG3 inhibitor is administered on day 85. In some embodiments, 480 mg, or about 480 mg, of the LAG3 inhibitor is administered on days 57 and 85. In some embodiments, 960 mg, or about 960 mg, of the LAG3 inhibitor is administered on days 57 and 85.

[0405] In some embodiments, 240 mg or about 240 mg of the LAG3 inhibitor is administered on days 8, 22, and 36, and 480 mg or about 480 mg of the LAG3 inhibitor is administered on days 57 and 85. In some embodiments, 480 mg or about 480 mg of the LAG3 inhibitor is administered on days 8, 22, and 36, and 960 mg or about 960 mg of the LAG3 inhibitor is administered on days 57 and 85. In some embodiments, 480 mg or about 480 mg of the LAG3 inhibitor is administered on days 8 and 36, and 480 mg or about 480 mg of the LAG3 inhibitor is administered on days 57 and 85. In some embodiments, 960 mg or about 960 mg of the LAG3 inhibitor is administered on days 8 and 36, and 960 mg or about 960 mg of the LAG3 inhibitor is administered on days 57 and 85. In some embodiments, 240 mg or about 240 mg of the LAG3 inhibitor is administered on days 15, 29, and 43, and 480 mg or about 480 mg of the LAG3 inhibitor is administered on days 57 and 85. In some embodiments, 480 mg or about 480 mg of the LAG3 inhibitor is administered on days 15, 29, and 43, and 960 mg or about 960 mg of the LAG3 inhibitor is administered on days 57 and 85. In some embodiments, 480 mg or about 480 mg of the LAG3 inhibitor is administered on day 15, and 480 mg or about 480 mg of the LAG3 inhibitor is administered on days 57 and 85. In some embodiments, 960 mg or about 960 mg of the LAG3 inhibitor is administered on day 15, and 960 mg or about 960 mg of the LAG3 inhibitor is administered on days 57 and 85.

[0406] In some embodiments, the LAG3 inhibitor is an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is selected from the group consisting of leratolimab, MK-4280, and yeramilimab, or a combination thereof. In some embodiments, the anti-LAG3 antibody is leratolimab.

[0407] 3. Medication In some embodiments, a subject is administered a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds a CD19 inhibitor, and a checkpoint inhibitor therapy in a dosing regimen that includes: (i) administration of the dose of engineered cells on day 1; and (ii) administration of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) in first and second cycles, wherein the first dose of the first cycle is administered between about day 2 and about day 20, and the first dose of the second cycle is administered between about day 50 and about day 65.

[0408] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a PD-1 inhibitor that is 240 mg administered on days 8, 22, and 36, and (ii) administration of a second amount of a PD-1 inhibitor that is 480 mg administered on days 57 and 85.

[0409] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19) on day 1; and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor on days 8, 36, 57, and 85.

[0410] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a PD-1 inhibitor that is 240 mg administered on days 15, 29, and 43, and (ii) administration of a second amount of a PD-1 inhibitor that is 480 mg administered on days 57 and 85.

[0411] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19) on day 1; and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor on days 15, 57, and 85.

[0412] In some embodiments, the subject is administered a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to a CD19 inhibitor, and a checkpoint inhibitor therapy in a dosing regimen that includes: (i) administration of the dose of engineered cells on day 1; and (ii) administration of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) and a LAG3 inhibitor (e.g., an anti-LAG3 antibody) in first and second cycles, wherein the first dose of the first cycle is administered between about days 2 and 20, and the first dose of the second cycle is administered between about days 50 and 65.

[0413] In some embodiments, a method of treating a subject includes: (1) administering to a subject with a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of the PD-1 inhibitor, the first amount being 240 mg, administered on days 8, 22, and 36, and (ii) administration of a second amount of the PD-1 inhibitor, the second amount being 480 mg, administered on days 57 and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising: (i) administration of a first amount of the LAG3 inhibitor, the first amount being 240 mg, administered on days 8, 22, and 36, and (ii) administration of a second amount of the LAG3 inhibitor, the second amount being 480 mg, administered on days 57 and 85.

[0414] In some embodiments, a method of treating a subject includes: (1) administering to a subject with a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of the PD-1 inhibitor, the first amount being 240 mg, administered on days 8, 22, and 36, and (ii) administration of a second amount of the PD-1 inhibitor, the second amount being 480 mg, administered on days 57 and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising: (i) administration of a first amount of the LAG3 inhibitor, the first amount being 480 mg, administered on days 8, 22, and 36, and (ii) administration of a second amount of the LAG3 inhibitor, the second amount being 960 mg, administered on days 57 and 85.

[0415] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor on days 8, 36, 57, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 480 mg of the LAG3 inhibitor on days 8, 36, 57, and 85.

[0416] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administering 480 mg of the PD-1 inhibitor on days 8, 36, 57, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administering 960 mg of the LAG3 inhibitor on days 8, 36, 57, and 85.

[0417] In some embodiments, a method of treating a subject includes: (1) administering to a subject with a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of the PD-1 inhibitor, the first amount being 240 mg, administered on days 15, 29, and 43, and (ii) administration of a second amount of the PD-1 inhibitor, the second amount being 480 mg, administered on days 57 and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising: (i) administration of a first amount of the LAG3 inhibitor, the first amount being 240 mg, administered on days 15, 29, and 43, and (ii) administration of a second amount of the LAG3 inhibitor, the second amount being 480 mg, administered on days 57 and 85.

[0418] In some embodiments, a method of treating a subject includes: (1) administering to a subject with a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of the PD-1 inhibitor, the first amount being 240 mg, administered on days 15, 29, and 43, and (ii) administration of a second amount of the PD-1 inhibitor, the second amount being 480 mg, administered on days 57 and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising: (i) administration of a first amount of the LAG3 inhibitor, the first amount being 480 mg, administered on days 15, 29, and 43, and (ii) administration of a second amount of the LAG3 inhibitor, the second amount being 960 mg, administered on days 57 and 85.

[0419] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 480 mg of the PD-1 inhibitor on days 15, 57, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 480 mg of the LAG3 inhibitor on days 15, 57, and 85.

[0420] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administering 480 mg of the PD-1 inhibitor on days 15, 57, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administering 960 mg of the LAG3 inhibitor on days 15, 57, and 85.

[0421] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19) on day 1; (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 240 mg of the PD-1 inhibitor on days 8, 22, 36, 57, 71, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 240 mg of the LAG3 inhibitor on days 8, 36, and 71.

[0422] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 240 mg of the PD-1 inhibitor on days 15, 29, 43, 57, 71, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 240 mg on days 15, 43, and 71.

[0423] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 240 mg of the PD-1 inhibitor on days 8, 22, 36, 57, 71, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 240 mg of the LAG3 inhibitor on days 8, 22, 36, 57, 71, and 85.

[0424] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19) on day 1; (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administration of 240 mg of the PD-1 inhibitor on days 15, 29, 43, 57, 71, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administration of 240 mg of the LAG3 inhibitor on days 8, 15, 29, 43, 57, 71, and 85.

[0425] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a PD-1 inhibitor that is 240 mg administered on days 8, 22, and 36, and (ii) administration of a second amount of a PD-1 inhibitor that is 480 mg administered on days 57 and 85.

[0426] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to Cluster of Differentiation 19 (CD19); and (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising: (i) administration of a first amount of a PD-1 inhibitor that is 240 mg administered on days 15, 29, and 43, and (ii) administration of a second amount of a PD-1 inhibitor that is 480 mg administered on days 57 and 85.

[0427] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administering 240 mg of the PD-1 inhibitor on days 8, 22, 36, 57, 71, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administering 120 mg of the LAG3 inhibitor on days 8, 22, 36, 57, 71, and 85.

[0428] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administering 240 mg of the PD-1 inhibitor on days 15, 29, 43, 57, 71, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administering 120 mg of the LAG3 inhibitor on days 15, 29, 43, 57, 71, and 85.

[0429] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administering 480 mg of the PD-1 inhibitor on days 8, 36, 64, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administering 240 mg of the LAG3 inhibitor on days 8, 36, 64, and 85.

[0430] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administering 480 mg of the PD-1 inhibitor on days 15, 43, 64, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administering 240 mg of the LAG3 inhibitor on days 15, 43, 64, and 85.

[0431] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administering 480 mg of the PD-1 inhibitor on days 8, 36, 64, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administering 480 mg of the LAG3 inhibitor on days 8, 36, 64, and 85.

[0432] In some embodiments, a method of treating a subject includes: (1) administering to a subject having a CD19-expressing cancer a cell therapy on day 1 comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19); (2) administering to the subject a PD-1 inhibitor in a dosing regimen comprising administering 480 mg of the PD-1 inhibitor on days 15, 43, 64, and 85; and (3) administering to the subject a LAG3 inhibitor in a dosing regimen comprising administering 480 mg of the LAG3 inhibitor on days 15, 43, 64, and 85.

[0433] 4. Co-formulation of anti-PD-1 and anti-LAG3 antibodies a. Compositions and Formulations In some embodiments of the combination therapy methods, combinations, kits, and uses provided herein, the combination therapy can be administered in a single composition, e.g., a pharmaceutical composition, containing a PD-1 inhibitor (e.g., an anti-PD-1 antibody such as nivolumab) and a LAG3 inhibitor (e.g., an anti-LAG3 antibody such as leratolimab). In some embodiments, the pharmaceutical composition contains nivolumab and leratolimab.

[0434] In some embodiments, compositions, e.g., pharmaceutical compositions, containing a PD-1 inhibitor and a LAG3 inhibitor, e.g., an anti-PD-1 antibody such as nivolumab and an anti-LAG3 antibody such as leratolimab, can include a carrier, such as a diluent, adjuvant, excipient, or vehicle, by which the inhibitors are administered. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions will contain a therapeutically effective amount of a PD-1 inhibitor and a LAG3 inhibitor, e.g., an anti-PD-1 antibody and an anti-LAG3 antibody, generally in purified form, together with a suitable amount of carrier to obtain the form for proper administration to a patient. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. The pharmaceutical composition may contain any one or more of diluent(s), adjuvant(s), antiadherent(s), binder(s), coating(s), filler(s), flavor(s), color(s), lubricant(s), glidant(s), preservative(s), detergent(s), adsorbent(s), emulsifier(s), pharmaceutical excipient(s), pH buffer(s), or sweetener(s), and combinations thereof. In some embodiments, the pharmaceutical composition may be a liquid, solid, lyophilized powder, gel form, and / or combinations thereof. In some aspects, the choice of carrier is determined, in part, by the particular inhibitor and / or by the method of administration.

[0435] Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed and include, but are not limited to, buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; serum albumin; The composition may include, but is not limited to, proteins such as amine, gelatin, or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants, stabilizers, and / or preservatives, such as polyethylene glycol (PEG). Compositions containing PD-1 inhibitors and LAG3 inhibitors, e.g., anti-PD-1 antibodies such as nivolumab and anti-LAG3 antibodies such as leratolimab, can also be lyophilized.

[0436] In some embodiments, the pharmaceutical composition can be formulated for administration by any route known to those skilled in the art, including intramuscular, intravenous, intradermal, intralesional, intraperitoneal injection, subcutaneous, intratumoral, epidural, nasal, oral, vaginal, rectal, topical, local, otic, inhalation, buccal (e.g., sublingual), and transdermal administration, or any route. In some embodiments, other modes of administration are also contemplated. In some embodiments, administration is by bolus injection, by injection, for example, intravenous or subcutaneous injection, intraocular injection, periocular injection, subretinal injection, intravitreal injection, transseptal injection, subscleral injection, intrachoroidal injection, intracameral injection, subconjectval injection, subconjunctival injection, sub-Tenon injection, retrobulbar injection, peribulbar injection, or posterior juxtascleral delivery. In some embodiments, administration is parenteral, intrapulmonary, and intranasal, and if desired for local treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition can be formulated for intravenous (IV) administration. In some embodiments, the pharmaceutical composition contains nivolumab and leratolimab and is formulated for IV administration.

[0437] In some embodiments, the compositions can also be administered with other bioactive agents, either sequentially, intermittently, or in the same composition. In some embodiments, administration can also include controlled release systems, including controlled release formulations and devices where release is controlled by pumps, etc. In some embodiments, administration is oral.

[0438] In some embodiments, PD-1 inhibitors and LAG3 inhibitors, e.g., anti-PD-1 antibodies such as nivolumab and relatolimab, are typically formulated and administered in unit dosage forms or multiple dosage forms. Each unit dosage contains a predetermined amount of a therapeutically active PD-1 and LAG3 inhibitor, e.g., nivolumab and relatolimab, sufficient to produce the desired therapeutic effect, along with the necessary pharmaceutical carrier, vehicle, or diluent. In some embodiments, unit dosage forms include, but are not limited to, tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, and oil-water emulsions containing an appropriate amount of PD-1 and LAG3 inhibitors, e.g., nivolumab and relatolimab. Unit dosage forms may be contained in ampoules and syringes or individually packaged tablets or capsules. Unit dosage forms may be administered in fractions or multiples thereof. In some embodiments, the multiple dose form is a plurality of identical unit dosage forms packaged in a single container that can be administered in separate unit dose forms. Examples of multiple dose forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.

[0439] b. Medication In some embodiments, provided methods of combination therapy involve administering to a subject: (1) checkpoint inhibitor therapy (e.g., a single composition comprising a PD-1 inhibitor and a LAG3 inhibitor); and (2) T cell therapy (e.g., CAR T cells). In some embodiments, provided methods of combination therapy involve initiating administration of checkpoint inhibitor therapy (e.g., a composition comprising a PD-1 inhibitor and a LAG3 inhibitor) subsequent to initiation of T cell therapy (e.g., CAR T cells). In some embodiments, provided methods of combination therapy involve initiating administration of checkpoint inhibitor therapy (e.g., a composition comprising a PD-1 inhibitor and a LAG3 inhibitor) between about 1 day and about 3 weeks after initiation of administration of T cell therapy (e.g., CAR T cells). In some embodiments, initiation of administration of checkpoint inhibitor therapy (e.g., a composition comprising a PD-1 inhibitor and a LAG3 inhibitor) is between about 1 week and about 2 weeks after initiation of administration of T cell therapy (e.g., CAR T cells).

[0440] In some embodiments, provided methods of combination therapy involve administering T cell therapy (e.g., CAR T cells) starting on day 1. In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a composition comprising a PD-1 inhibitor and a LAG3 inhibitor) starting between about days 2 and 20. In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a composition comprising a PD-1 inhibitor and a LAG3 inhibitor) starting on about day 8 or day 15. In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a composition comprising a PD-1 inhibitor and a LAG3 inhibitor) starting on about day 8. In some embodiments, provided methods of combination therapy involve administering checkpoint inhibitor therapy (e.g., a composition comprising a PD-1 inhibitor and a LAG3 inhibitor) starting on about day 15.

[0441] In some embodiments, the methods involve initiating administration of checkpoint inhibitor therapy (e.g., a composition comprising a PD-1 inhibitor and a LAG3 ...

Claims

1. 1. A cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against a CD19-expressing cancer, an anti-PD-1 antibody, and an anti-LAG3 antibody for use in a method of treating cancer, said method comprising: (1) administering the cell therapy to a subject having a CD19-expressing cancer; (2) administering to the subject the anti-PD-1 antibody in an amount between 140 mg and 580 mg; (3) administering the anti-LAG3 antibody to the subject in an amount between 60 mg and 1040 mg. Cellular therapy, including:

2. A cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against a CD19-expressing cancer for use in a method of treating cancer, the method comprising: (1) administering the cell therapy to a subject having a CD19-expressing cancer; (2) administering to the subject an anti-PD-1 antibody in an amount of between 140 mg and 580 mg; (3) administering to the subject an anti-LAG3 antibody in an amount of between 60 mg and 1040 mg; Cellular therapy, including:

3. An anti-PD-1 antibody for use in a method for treating a CD19-expressing cancer, the method comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against said cancer; (2) administering to the subject the anti-PD-1 antibody in an amount between 140 mg and 580 mg; (3) administering to the subject an anti-LAG3 antibody in an amount of between 60 mg and 1040 mg; An anti-PD-1 antibody comprising:

4. An anti-LAG3 antibody for use in a method of treating a CD19-expressing cancer, the method comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against said cancer; (2) administering to the subject an anti-PD-1 antibody in an amount of between 140 mg and 580 mg; (3) administering the anti-LAG3 antibody to the subject in an amount between 60 mg and 1040 mg. An anti-LAG3 antibody comprising:

5. An anti-PD-1 antibody and an anti-LAG3 antibody for use in a method of treating a CD19-expressing cancer, the method comprising: (1) administering to a subject having a CD19-expressing cancer a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) against said cancer; (2) administering to the subject the anti-PD-1 antibody in an amount between 140 mg and 580 mg; (3) administering the anti-LAG3 antibody to the subject in an amount between 60 mg and 1040 mg. An anti-PD-1 antibody and an anti-LAG3 antibody.

6. A cell therapy, an anti-PD-1 antibody, and an anti-LAG3 antibody for use as described in claim 1, wherein the CAR binds to cluster of differentiation 19 (CD19); a cell therapy for use as described in claim 2; an anti-PD-1 antibody for use as described in claim 3; an anti-LAG3 antibody for use as described in claim 4; or an anti-PD-1 antibody and an anti-LAG3 antibody for use as described in claim 5.

7. A cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use as described in claim 1 or claim 6, wherein the first dose of anti-PD-1 antibody and the first dose of anti-LAG3 antibody, respectively, are administered between 1 and 19 days after administration of the cell therapy; a cell therapy for use as described in claim 2 or claim 6; an anti-PD-1 antibody for use as described in claim 3 or claim 6; an anti-LAG3 antibody for use as described in claim 4 or claim 6; or an anti-PD-1 antibody and anti-LAG3 antibody for use as described in claim 5 or claim 6.

8. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to claim 7, wherein the first dose of the anti-PD-1 antibody and the first dose of the anti-LAG3 antibody are administered on the same day; the cell therapy for use; the anti-PD-1 antibody for use; the anti-LAG3 antibody for use; or the anti-PD-1 antibody and anti-LAG3 antibody for use.

9. 1. A cell therapy comprising a dose of engineered T cells expressing a chimeric antigen receptor (CAR) against a CD19-expressing cancer for use in a method of treating cancer, the method comprising: (1) administering a cell therapy to a subject having a CD19-expressing cancer; (2) administering to a subject an anti-PD-1 antibody in a dosing regimen comprising administration of at least two doses, (i) the administration of the first dose of the anti-PD-1 antibody is between 1 and 19 days, inclusive, after administration of the cell therapy; (ii) administering each dose of the anti-PD-1 antibody at or about 140 mg to at or about 580 mg, inclusive. Cellular therapy, including:

10. A cell therapy, an anti-PD-1 antibody, and an anti-LAG3 antibody for use as described in any of claims 1 and 6-8, wherein each dose of the anti-PD-1 antibody is from or about 140 mg to or about 580 mg, inclusive; a cell therapy for use as described in any of claims 2 and 6-9; an anti-PD-1 antibody for use as described in any of claims 3 and 6-8; an anti-LAG3 antibody for use as described in any of claims 4 and 6-8; or an anti-PD-1 antibody and an anti-LAG3 antibody for use as described in any of claims 5-8.

11. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, and 10, wherein each dose of the anti-PD-1 antibody is at or about 160 mg to at or about 560 mg; the cell therapy for use according to any of claims 2 and 6-10; the anti-PD-1 antibody for use according to any of claims 3, 6-8, and 10; the anti-LAG3 antibody for use according to any of claims 4, 6-8, and 10; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, and 10.

12. The cell therapy, anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10 and 11, wherein each dose of the anti-PD-1 antibody is at or about 240 mg or at or about 480 mg; the cell therapy for use according to any of claims 2 and 6-11; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10 and 11; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10 and 11; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10 and 11.

13. A cell therapy, an anti-PD-1 antibody, and an anti-LAG3 antibody for use as described in any of claims 1, 6-8, and 10-12, wherein at least four doses of the anti-PD-1 antibody are administered; a cell therapy for use as described in any of claims 2, and 6-12; an anti-PD-1 antibody for use as described in any of claims 3, 6-8, and 10-12; an anti-LAG3 antibody for use as described in any of claims 4, 6-8, and 10-12; or an anti-PD-1 antibody and an anti-LAG3 antibody for use as described in any of claims 5-8, and 10-12.

14. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody of claim 13, wherein the first three doses of the anti-PD-1 antibody are administered every two weeks (Q2W); or the anti-PD-1 antibody; or the cell therapy; or the anti-PD-1 antibody and anti-LAG3 antibody for use; or the anti-LAG3 antibody for use.

15. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, and 10-14, comprising administering to a subject a dosing regimen comprising administration of at least two doses of the anti-PD-1 antibody, with each dose of the anti-PD-1 antibody being administered every two weeks (Q2W); the cell therapy for use according to any of claims 2, and 6-14; the anti-PD-1 antibody for use according to any of claims 3, 6-8, and 10-14; the anti-LAG3 antibody for use according to any of claims 4, 6-8, and 10-14; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, and 10-14.

16. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, and 10-14, wherein each dose of the anti-PD-1 antibody is administered every four weeks (Q4W); the cell therapy for use according to any of claims 2, and 6-14; the anti-PD-1 antibody for use according to any of claims 3, 6-8, and 10-14; the anti-LAG3 antibody for use according to any of claims 4, 6-8, and 10-14; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, and 10-14.

17. The cell therapy of claim 9, further comprising administering an anti-LAG3 antibody to a subject.

18. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, and 10-16, comprising administering to a subject a dosing regimen comprising administration of at least two doses of an anti-LAG3 antibody, where a first dose of the anti-LAG3 antibody is administered 1 to 19 days, inclusive, after administration of the cell therapy; the cell therapy for use according to any of claims 2, 6-8, 10-14, and 17; the anti-PD-1 antibody for use according to any of claims 3, 6-8, and 10-16; the anti-LAG3 antibody for use according to any of claims 4, 6-8, and 10-16; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, and 10-16.

19. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18, comprising administering to a subject in a dosing regimen comprising administration of at least two doses of anti-LAG3 antibody, each dose of anti-LAG3 antibody being from about 60 mg to about 540 mg, inclusive; the cell therapy for use according to any of claims 2, 6-8, 10-14, 17, and 18; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18.

20. The cell therapy, anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, 18 and 19, comprising administering to a subject in a dosing regimen comprising administration of at least two doses of anti-LAG3 antibody, each dose of the anti-LAG3 antibody being from about 120 mg to about 480 mg or 160 mg or from about 160 mg to 320 mg or about 320 mg; the cell therapy, for use according to any of claims 2, 6-8, 10-14 and 17-19; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, 18 and 19; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, 18 and 19; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, 18 and 19.

21. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-20, wherein at least three doses of the anti-LAG3 antibody are administered; the cell therapy, for use according to any of claims 2, 6-8, 10-14, and 17-20; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-20; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-20; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-20.

22. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-21, wherein at least three doses of the anti-LAG antibody are administered, and the first three doses of the anti-LAG3 antibody are administered every two weeks (Q2W); the cell therapy for use according to any of claims 2, 6-8, 10-14, and 17-21; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-20; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-21; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-21.

23. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-22, wherein each dose of the anti-LAG3 antibody is administered every two weeks (Q2W); the cell therapy for use according to any of claims 2, 6-8, 10-14, and 17-22; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-22; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-22; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-22.

24. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-21, wherein each dose of the anti-LAG3 antibody is administered about every four weeks (Q4W); the cell therapy for use according to any of claims 2, 6-8, 10-14, and 17-21; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-21; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-21; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-21.

25. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-24, wherein the dose of anti-PD-1 antibody and the dose of anti-LAG3 antibody are administered at the same frequency; the cell therapy for use according to any of claims 2, 6-8, 10-14, and 17-24; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-24; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-24; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-24.

26. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-25, wherein each dose of the anti-LAG3 antibody is administered on the same day as a dose of the anti-PD-1 antibody; the cell therapy for use according to any of claims 2, 6-8, 10-14, and 17-25; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-25; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-25; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-25.

27. A cell therapy, an anti-PD-1 antibody, and an anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-24, wherein the dose of the anti-LAG3 antibody is administered at half the frequency of the dose of the anti-PD-1 antibody; a cell therapy for use according to any of claims 2, 6-8, 10-14, and 17-24; an anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-24; an anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-24; or an anti-PD-1 antibody and an anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-24.

28. The cell therapy for use according to any of claims 1, 6-8, 10-16, 18-21, 25 and 26, wherein each dose of the anti-PD-1 antibody is at or about 480 mg and is administered every four weeks (Q4W), and each dose of the anti-LAG3 antibody is at or about 160 mg and is administered every four weeks (Q4W); any of claims 2, 6-8, 10-14, 17-21, 25 and 26 an anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, 18-21, 25 and 26; an anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, 18-21, 25 and 26; or an anti-PD-1 antibody and an anti-LAG3 antibody for use according to any of claims 5-8, 10-16, 18-21, 25 and 26.

29. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use as recited in any of claims 1, 6-8, 10-16, 18-26, and 28, wherein the anti-PD-1 antibody and the anti-LAG3 antibody are formulated in a single composition; the cell therapy, for use as recited in any of claims 2, 6-8, 10-14, 17-26, and 28; the anti-PD-1 antibody for use as recited in any of claims 3, 6-8, 10-16, 18-26, and 28; the anti-LAG3 antibody for use as recited in any of claims 4, 6-8, 10-16, 18-26, and 28; or the anti-PD-1 antibody and anti-LAG3 antibody for use as recited in any of claims 5-8, 10-16, 18-26, and 28.

30. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to claim 29, wherein the anti-PD-1 antibody and anti-LAG3 antibody are formulated in a single composition for intravenous administration; or the anti-LAG3 antibody for use; the cell therapy, or the anti-PD-1 antibody for use; or the anti-LAG3 antibody for use; or the anti-PD-1 antibody and anti-LAG3 antibody for use.

31. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-30, wherein the anti-PD-1 antibody comprises a heavy chain variable (VH) region comprising CDR1, CDR2, and CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 60, 61, and 62, respectively, and a light chain variable (VL) region comprising CDR1, CDR2, and CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 63, 64, and 65, respectively; the cell therapy for use according to any of claims 2, 6-14, and 17-30; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-30; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-30; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-30.

32. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-31, wherein the anti-PD-1 antibody is nivolumab; the cell therapy, anti-PD-1 antibody for use according to any of claims 2, 6-14, and 17-31, and the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-31; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-31; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-31.

33. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-32, wherein the anti-PD-1 antibody and the anti-LAG3 antibody are administered in a fixed-dose combination; the cell therapy, for use according to any of claims 2, 6-8, 10-14, and 17-32; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-32; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-32; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-32.

34. The cell therapy, anti-PD-1 antibody, and the anti-LAG3 antibody for use according to any one of claims 1, 6-8, 10-16, and 18-33, wherein the anti-LAG3 antibody comprises a heavy chain variable (VH) region comprising CDR1, CDR2, and CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 68, 69, and 70, respectively, and a light chain variable (VL) region comprising CDR1, CDR2, and CDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 71, 72, and 73, respectively. An anti-LAG3 antibody; a cell therapy for use according to any of claims 2, 6-8, 10-14, and 17-33; an anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-33; an anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-33; or an anti-PD-1 antibody and an anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-33.

35. 35. The cell therapy for use, anti-PD-1 antibody, and anti-LAG3 antibody of claim 34, wherein the VH region comprises the amino acid sequence set forth in SEQ ID NO:74 and the VL region comprises the amino acid sequence set forth in SEQ ID NO:75; or the anti-LAG3 antibody for use; the cell therapy for use; or the anti-PD-1 antibody for use; or the anti-LAG3 antibody for use; or the anti-PD-1 antibody and anti-LAG3 antibody for use.

36. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-35, wherein the anti-LAG3 antibody is leratolimab; the cell therapy for use according to any of claims 2, 6-8, 10-14, and 17-35; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-35; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-35; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-35.

37. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use of any of claims 1, 6-8, 10-16, and 18-35, further comprising administering to the subject a lymphodepletion therapy prior to administration of the dose of engineered T cells; the cell therapy for use of any of claims 2, 6-14, and 17-36; the anti-PD-1 antibody for use of any of claims 3, 6-8, 10-16, and 18-36; the anti-LAG3 antibody for use of any of claims 4, 6-8, 10-16, and 18-36; or the anti-PD-1 antibody and anti-LAG3 antibody for use of any of claims 5-8, 10-16, and 18-36.

38. 38. The cell therapy for use according to claim 37, an anti-PD-1 antibody, and an anti-LAG3 antibody; or an anti-LAG3 antibody for use; a cell therapy for use; an anti-PD-1 antibody for use; an anti-LAG3 antibody for use; or an anti-PD-1 antibody and an anti-LAG3 antibody for use, wherein the lymphodepleting therapy comprises administration of fludarabine and / or cyclophosphamide.

39. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-38, wherein CD19 is human CD19; the cell therapy, anti-PD-1 antibody for use according to any of claims 2, 6-14, and 17-38; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-38; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-38; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-38.

40. The chimeric antigen receptor (CAR) of any one of claims 1, 6-8, 10-16, and 18-39, comprising an scFv comprising the variable heavy and variable light regions of the antibody FMC63, a spacer of 15 amino acids or less containing an immunoglobulin hinge region or a modified version thereof, a transmembrane domain, and an intracellular signaling domain comprising a costimulatory signaling region that is the signaling domain of the CD3-zeta (CD3ζ) chain and the signaling domain of 4-1BB. A cell therapy, an anti-PD-1 antibody, and an anti-LAG3 antibody for use; a cell therapy for use according to any of claims 2, 6-14, and 17-39; an anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-39; an anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-39; or an anti-PD-1 antibody and an anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-39.

41. 41. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to claim 40, wherein the immunoglobulin hinge region or modified version thereof is an IgG1 hinge, an IgG4 hinge, or a modified version thereof; or an anti-LAG3 antibody for use; a cell therapy, or an anti-PD-1 antibody for use; or an anti-LAG3 antibody for use; or an anti-PD-1 antibody and an anti-LAG3 antibody for use.

42. 42. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to claim 40 or claim 41, wherein the spacer comprises a sequence set forth in SEQ ID NO:1, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34, or a variant of any of the foregoing having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the sequence set forth in SEQ ID NO:1, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:

34.

43. 43. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 40 to 42, wherein the transmembrane domain is the transmembrane domain of CD28; or the anti-LAG3 antibody for use; the cell therapy, or the anti-PD-1 antibody for use; or the anti-LAG3 antibody for use; or the anti-PD-1 antibody and anti-LAG3 antibody for use.

44. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-43, wherein the dose of engineered T cells comprises CD4+ T CAR-expressing cells and CD8+ CAR-expressing T cells; the cell therapy, anti-PD-1 antibody for use according to any of claims 2, 6-14, and 17-43; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-43; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-43; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-43.

45. The dose of engineered T cells was approximately 5×10 ７ CAR-expressing T cells to about 1.1 x 10 ８ The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any one of claims 1, 6-8, 10-16, and 18-44, comprising 1 CAR-expressing T cells (inclusive); the cell therapy, anti-PD-1 antibody for use according to any one of claims 2, 6-14, and 17-44; the anti-PD-1 antibody for use according to any one of claims 3, 6-8, 10-16, and 18-44; the anti-LAG3 antibody for use according to any one of claims 4, 6-8, 10-16, and 18-44; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any one of claims 5-8, 10-16, and 18-44.

46. The cell therapy, anti-PD-1 antibody, and anti-LAG3 antibody for use according to any of claims 1, 6-8, 10-16, and 18-45, wherein the CD19 expressing cancer is a B-cell malignancy; the cell therapy for use according to any of claims 2, 6-14, and 17-45; the anti-PD-1 antibody for use according to any of claims 3, 6-8, 10-16, and 18-45; the anti-LAG3 antibody for use according to any of claims 4, 6-8, 10-16, and 18-45; or the anti-PD-1 antibody and anti-LAG3 antibody for use according to any of claims 5-8, 10-16, and 18-45, wherein the CD19 expressing cancer is a B-cell malignancy.

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