Methods for treating hematologic cancers

Abstract

The present invention relates to methods of treating hematologic cancers using a combination of inhibitors of PD-1 or PD-L1 and TIM-3, LAG-3 or CTLA4.

1 . A method of treating a subject afflicted with a hematologic cancer comprising administering to the subject a therapeutically effective amount of an inhibitor of PD-L1 or PD-1 and an inhibitor of TIM-3, LAG-3, or CTLA4. 
     
     
         2 . The method of  claim 1  wherein an inhibitor of PD-L1 is administered in combination with:
 (a) an inhibitor of TIM-3; 
 (b) an inhibitor of LAG-3; or 
 (c) an inhibitor of CTLA4. 
 
     
     
         3 . The method of  claim 1  wherein an inhibitor of PD-1 is administered in combination:
 (a) an inhibitor of TIM-3; 
 (b) an inhibitor of LAG-3; or 
 (c) an inhibitor of CTLA4. 
 
     
     
         4 .- 7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the inhibitor:
 (a) is chosen from an inhibitory nucleic acid, a soluble ligand, or an antibody or antigen-binding fragment thereof, that binds to one or more of PD-1, PD-L1, TIM-3, LAG-3, or CTLA-4;   (b) is a bispecific or multispecific antibody, or antigen binding fragment thereof, selective for PD-1 or PD-L1 and TIM-3, LAG-3, or CTLA4; or   (c) is a soluble ligand of PD-1, PD-L1, TIM-3, LAG-3, or CTLA-4.   
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein a combination of inhibitors comprising a first inhibitor that selectively inhibits or blocks PD-1 or PD-L1 and a second inhibitor that selectively inhibits or blocks TIM-3, LAG-3, or CTLA4 are administered. 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 10 , wherein the first inhibitor, second inhibitor, or both inhibitors, is an antibody or an antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1 and/or TIM-3, LAG-3, or CTLA4. 
     
     
         13 . The method of  claim 12 , wherein:
 (a) said antibody, or antigen binding fragment thereof, is murine, chimeric, humanized, composite, or human;   (b) said antibody, or antigen binding fragment thereof, is detectably labeled, comprises an effector domain, comprises an Fc domain, and/or is selected from the group consisting of Fv, Fav, F(ab′)2), Fab′, dsFv, scFv, sc(Fv)2, and diabodies fragments; or   (c) said antibody, or antigen binding fragment thereof, is conjugated to a cytotoxic agent.   
     
     
         14 .- 15 . (canceled) 
     
     
         16 . The method of  claim 13 , wherein said cytotoxic agent is selected from the group consisting of a chemotherapeutic agent, a biologic agent, a toxin, and a radioactive isotope. 
     
     
         17 . The method of  claim 8 , wherein said inhibitory nucleic acid comprises:
 (a) an RNA interfering agent which inhibits expression of PD-1, PD-L1, TIM-3, LAG-3, or CTLA-4; or   (b) an antisense oligonucleotide complementary to PD-1, PD-L1, TIM-3, LAG-3, or CTLA-4.   
     
     
         18 . The method of  claim 17 , wherein said RNA interfering agent is a small interfering RNA (siRNA), small hairpin RNA (shRNA), or a microRNA (miRNA). 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein said inhibitor comprises:
 (a) a peptide or peptidomimetic that inhibits or blocks PD-1, PD-L1, TIM-3, LAG-3, or CTLA-4;   (b) a small molecule that inhibits or blocks PD-1, PD-L1, TIM-3, LAG-3, or CTLA-4; or   (c) an aptamer that inhibits or blocks PD-1, PD-L1, TIM-3, LAG-3, or CTLA-4.   
     
     
         21 .- 22 . (canceled) 
     
     
         23 . The method of  claim 1 , wherein said inhibitor is administered in a pharmaceutically acceptable formulation. 
     
     
         24 . The method of  claim 1 , further comprising administering to the subject a therapeutic agent for treating the hematologic cancer. 
     
     
         25 . The method of  claim 1 , further comprising a step of transient or complete lymphodepletion, wherein:
 (a) sublethal whole body irradiation is used for transient lymphodepletion; or   (b) the step of lymphodepletion occurs before, concurrently with, or after the step of agent administration.   
     
     
         26 .- 28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein the hematologic cancer is selected from the group consisting of:
 (a) multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, Waldenstrom's macroglobulinemia, B-cell lymphoma and diffuse large B-cell lymphoma, precursor B-lymphoblastic leukemia/lymphoma, B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone B-cell lymphoma (with or without villous lymphocytes), hairy cell leukemia, plasma cell myeloma/plasmacytoma, extranodal marginal zone B-cell lymphoma of the MALT type, nodal marginal zone B-cell lymphoma (with or without monocytoid B cells), Burkitt's lymphoma; precursor T-lymphoblastic lymphoma/leukemia, T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK cell leukemia, adult T-cell lymphoma/leukemia (HTLV 1-positive), nasal-type extranodal NK/T-cell lymphoma, enteropathy-type T-cell lymphoma, hepatosplenic γ-δ T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides/Sézary syndrome, anaplastic large cell lymphoma (T/null cell, primary cutaneous type), anaplastic large cell lymphoma (T-/null-cell, primary systemic type), peripheral T-cell lymphoma not otherwise characterized, angioimmunoblastic T-cell lymphoma, polycythemia vera (PV), myelodysplastic syndrome (MDS), indolent Non-Hodgkin's Lymphoma (iNHL), and aggressive Non-Hodgkin's Lymphoma (aNHL); or   (b) B-cell lymphoma, myeloid leukemia, and multiple myeloma.   
     
     
         30 .- 31 . (canceled) 
     
     
         32 . The method of  claim 1 , wherein the subject is a human. 
     
     
         33 . A kit for treating a subject afflicted with a hematologic cancer comprising one or more agents, wherein at least one agent selectively inhibits or blocks PD-1 or PD-L1 and TIM-3, LAG-3, or CTLA4. 
     
     
         34 . The kit of  claim 33 , wherein the agent is a bispecific or multispecific antibody, or antigen binding fragment thereof, selective for PD-1 or PD-L1 and TIM-3, LAG-3, or CTLA4. 
     
     
         35 . A kit for treating a subject afflicted with a hematologic cancer comprising a first agent that selectively inhibits or blocks PD-1 or PD-L1 and a second agent that selectively inhibits or blocks TIM-3, LAG-3, or CTLA4. 
     
     
         36 . The kit of  claim 35 , wherein:
 (a) said first agent and/or second agent is an antibody, or an antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1 protein and/or TIM-3, LAG-3, or CTLA4 protein; or   (b) said agent is selected from the group consisting of a) an RNA interfering agent which inhibits expression of PD-L1 or PD-1 and TIM-3, LAG-3, or CTLA4, optionally wherein said RNA interfering agent is an small interfering RNA (siRNA), small hairpin RNA (shRNA), or a microRNA (miRNA); b) an antisense oligonucleotide complementary to PD-1 or PD-L1 and/or TIM-3, LAG-3, or CTLA4; c) a peptide or peptidomimetics that inhibits or blocks PD-1 or PD-L1 and/or TIM-3, LAG-3, or CTLA4; d) a small molecule that inhibits or blocks PD-1 or PD-L1 and/or TIM-3, LAG-3, or CTLA4, optionally wherein said small molecule inhibits a protein-protein interaction between PD-1 or PD-L1 and/or TIM-3, LAG-3 or CTLA4 and a receptor; and e) an aptamer that inhibits or blocks PD-1 or PD-L1 and/or TIM-3, LAG-3, or CTLA4.   
     
     
         37 . The kit of  claim 35 , wherein said antibody, or antigen binding fragment thereof:
 (a) is murine, chimeric, humanized, composite, or human;   (b) is detectably labeled, comprises an effector domain, comprises an Fe domain, and/or is selected from the group consisting of Fv, Fav, F(ab′)2), Fab′, dsFv, scFv, sc(Fv)2, and diabodies fragments; or   (c) is conjugated to a cytotoxic agent, wherein said cytotoxic agent is selected from the group consisting of a chemotherapeutic agent, a biologic agent, a toxin, and a radioactive isotope.   
     
     
         38 .- 41 . (canceled)