Anti-pd-l1 combinations for treating tumors

Abstract

The present invention relates to therapeutic combinations and methods for treating cancers using combination therapy.

We claim: 
     
         1 . A method of treating a cancer or a tumor comprising, a step of administering to a patient in need thereof, a combination comprising: 
       (i) an effective amount of a PD-L/PD-1 Axis antagonist antibody; and 
       (ii) an effective amount of a single immunotherapeutic, wherein the single immunotherapeutic is 4-amino-2-(ethoxymethyl)-a,a-di-methyl-1H-imidazo[4,5-c]quinoline-1-ethanol; 
       wherein the PD-L/PD-1 Axis antagonist antibody and the immunotherapeutic are not covalently linked to each other. 
     
     
         2 . The method of  claim 1 , wherein said PD-L/PD-1 Axis antagonist is selected from the group consisting of a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist. 
     
     
         3 . The method of  claim 2 , wherein the PD-L/PD-1 Axis antagonist is a PD-1 binding antagonist. 
     
     
         4 . The method of  claim 3 , wherein the PD-1 binding antagonist is an antibody fragment. 
     
     
         5 . The method of  claim 5 , wherein the PD-1 binding antagonist is MDX-1106, Merck 3475, CT-011, AMP-224, or AMP-514. 
     
     
         6 . The method of  claim 2 , wherein the PD-L/PD-1 Axis antagonist is a PD-L1 binding antagonist. 
     
     
         7 . The method of  claim 6 , wherein the PD-L1 binding antagonist is an antibody. 
     
     
         8 . The method of  claim 7 , wherein the PD-L1 binding antagonist is selected from the group consisting of YW243.55.S70, MPDL3280A, MDX-1105, MEDI-4736, and MSB0010718C. 
     
     
         9 . The method of  claim 2 , wherein the PD-L/PD-1 Axis antagonist is a PD-L2 binding antagonist. 
     
     
         10 . The method of  claim 9 , wherein the PD-L2 binding antagonist is an antibody. 
     
     
         11 . The method of  claim 9 , wherein the PD-L2 binding antagonist is an immunoadhesin. 
     
     
         12 . The method of  claim 1 , wherein said immunotherapeutics is a compound of any one of formula (I) to (XIXb), or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         13 . The method of  claim 1 , further comprising an effective amount of an anticancer agent. 
     
     
         14 . The method of  claim 13 , wherein said anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor, an antiandrogen agent, a GNRh modulator or mixtures thereof. 
     
     
         15 . The method of  claim 13 , wherein said anticancer agent is a chemotherapeutic agent selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, imatanib, paclitaxel, cyclophosphamide, lovastatin, minosine, gemcitabine, cytarabine, 5-fluorouracil, methotrexate, docetaxel, goserelin, vincristine, vinblastine, nocodazole, teniposide etoposide, gemcitabine, epothilone, vinorelbine, camptothecin, daunorubicin, actinomycin D, mitoxantrone, acridine, doxorubicin, epirubicin, or idarubicin. 
     
     
         16 . The method of  claim 1 , wherein said immunotherapeutic is of an amount that is capable of: 
       (1) inducing IFN-α in an enriched human blood DCs; 
       (2) inducing TNF-α in an enriched human blood DCs; 
       (3) inducing IL-12-α in an enriched human blood DCs; 
       (4) activating CD45+ immune cells in tumor microenvironment; 
       (5) activating CD4+ and CD8+ T cells in tumor microenvironment; 
       (6) activating NK cells in tumor microenvironment; 
       (7) activating plasmacytoid dendritic cells (pDC) and myeloid dendritic cells (mDc) in tumor microenvironment; 
       (8) activating macrophages and Monocytes in tumor microenvironment; and/or 
       (9) increasing migratory DCs in draining lymph nodes. 
     
     
         17 . The method of  claim 1 , wherein said cancer is selected from the group consisting of: breast cancer, colorectal cancer, diffuse large B-cell lymphoma, endometrial cancer, follicular lymphoma, gastric cancer, glioblastoma, head and neck cancer, hepatocellular cancer, lung cancer, melanoma, multiple myeloma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma. 
     
     
         18 . The method of  claim 1 , comprising administering to said subject a formulation comprising said immunotherapeutic in a dose of from about 0.0005 mg/kg, 0.0006 mg/kg, 0.0007 mg/kg, 0.0008 mg/kg, 0.0009 mg/kg, 0.001 mg/kg, 0.002 mg/kg, 0.003 mg/kg, 0.004 mg/kg, 0.005 mg/kg, 0.006 mg/kg, 0.007 mg/kg, 0.008 mg/kg, 0.009 mg/kg, 0.01 mg/kg, 0.02 mg/kg, 0.025 mg/kg, 0.05 mg/kg, 0.075 mg/kg, 0.1 mg/kg, 0.125 mg/kg. 0.15 mg/kg, 0.175 mg/kg, 0.2 mg/kg, 0.215 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 1.25 mg/kg, 1.5 mg/kg, 1.75 mg/kg, 2 mg/kg, 2.25 mg/kg, to about 2.5 mg/kg, all inclusive, twice daily, once daily, once every two, three, four, five or six days, or once, twice, or three times per week. 
     
     
         19 . The method of  claim 1 , comprising administering to said subject a formulation comprising said immunotherapeutic in a dose of from about 0.0005 mg/kg, to about 0.0006 mg/kg, 0.0007 mg/kg, 0.0008 mg/kg, 0.0009 mg/kg, 0.001 mg/kg, 0.002 mg/kg, 0.003 mg/kg, 0.004 mg/kg, 0.005 mg/kg, 0.006 mg/kg, 0.007 mg/kg, 0.008 mg/kg, 0.009 mg/kg, 0.01 mg/kg, 0.02 mg/kg, 0.025 mg/kg, 0.05 mg/kg, 0.075 mg/kg, 0.1 mg/kg, 0.125 mg/kg. 0.15 mg/kg, 0.175 mg/kg, 0.2 mg/kg, 0.215 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 1.25 mg/kg, 1.5 mg/kg, 1.75 mg/kg, 2 mg/kg, 2.25 mg/kg, or 2.5 mg/kg, all inclusive, twice daily, once daily, once every two, three, four, five or six days, or once, twice, or three times per week. 
     
     
         20 . The method of  claim 1 , comprising administering to said subject a formulation comprising said immunotherapeutic in a dose of less than or about 0.0005 mg/kg, 0.0006 mg/kg, 0.0007 mg/kg, 0.0008 mg/kg, 0.0009 mg/kg, 0.001 mg/kg, 0.002 mg/kg, 0.003 mg/kg, 0.004 mg/kg, 0.005 mg/kg, 0.006 mg/kg, 0.007 mg/kg, 0.008 mg/kg, 0.009 mg/kg, 0.01 mg/kg, 0.02 mg/kg, 0.025 mg/kg, 0.05 mg/kg, 0.075 mg/kg, 0.1 mg/kg, 0.125 mg/kg. 0.15 mg/kg, 0.175 mg/kg, 0.2 mg/kg, 0.215 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 1.25 mg/kg, 1.5 mg/kg, 1.75 mg/kg, 2 mg/kg, 2.25 mg/kg, or 2.5 mg/kg, twice daily, once daily, once every two, three, four, five or six days, or once, twice, or three times per week. 
     
     
         21 . The method of  claim 1 , wherein said administration is orally, sublingually, intravenously, intramuscularly, subcutaneously, or intratumorally. 
     
     
         22 . The method of  claim 1 , wherein said immunotherapeutic in said subject has a local concentration that is from about 0.005 μg/ml to about 12 μg/ml. 
     
     
         23 . The method of  claim 1 , wherein said immunotherapeutic in said subject has a local concentration that is from about 0.05 μg/ml, 0.1 μg/ml, 0.15 μg/ml, 0.2 μg/ml, 0.3 μg/ml, or 0.4 μg/ml, to about 0.5 μg/ml.