Use of pentoxifylline with immune checkpoint-blockade therapies for the treatment of melanoma

Abstract

Methods of treating a PD-1-resistant cancer are provided and comprise administering to a subject in need thereof a therapeutically effective amount of a c-Rel inhibitor and a therapeutically effective amount of a PD-1 inhibitor. A pharmaceutical combination comprising a therapeutically effective amount of a c-Rel inhibitor, and a therapeutically effective amount of a PD-1 inhibitor is also provided. Finally, methods of treating a cancer such as a CTLA-4-resistant cancer, a CD137-resistant cancer, and an OX-4-resistant cancer are provided and comprise administering to a subject in need thereof a therapeutically effective amount of a c-Rel inhibitor and a therapeutically effective amount of a CLTA-4, CD137 or OX-4 inhibitor, respectively.

What is claimed is: 
     
         1 . A method of treating a PD-1-resistant cancer comprising administering to a subject in need thereof a therapeutically effective amount of a c-Rel inhibitor and a therapeutically effective amount of a PD-1 inhibitor. 
     
     
         2 . The method of  claim 1 , wherein the c-Rel inhibitor is a herein-described active agent. 
     
     
         3 . The method of  claim 1 , wherein the c-Rel inhibitor is a member selected from the group consisting of pentoxifylline, a pentoxifylline analog, dehydroxymethylepoxyquinomicin (DHMEQ), pyrimidinetrione and its derivatives including IT-603, and any combination thereof. 
     
     
         4 . The method of  claim 3 , wherein the pentoxifylline analog is selected from the group consisting of lisofylline, torbafylline, propentafylline, A81-138, IT-603, dyfylline, doxofylline, theophylline, isobutyl methylxanthine (IBMX), caffeine, and any combination thereof. 
     
     
         5 . The method of  claim 4 , wherein the pentoxifylline analog is selected from the group consisting of torbafylline, propentafylline, A81-138, and any combination thereof. 
     
     
         6 . The method of  claim 1 , wherein the PD-1 inhibitor is an anti-PD-1 antibody or an anti-PDL-1 antibody or a biologically active fragment or variant thereof. 
     
     
         7 . The method of  claim 6 , wherein the anti-PD-1 antibody or the anti-PDL-1 antibody is a humanized monoclonal antibody. 
     
     
         8 . The method of  claim 1 , wherein the effective amount of the c-Rel inhibitor is about 0.1 mg/day to about 5 g/day and the amount of the PD-1 inhibitor is about 0.1 mg/day to about 5 g/day. 
     
     
         9 . The method of  claim 8 , wherein the effective amount of the c-Rel inhibitor is about 400 mg/day to about 1800 mg/day and the amount of the PD-1 inhibitor is about 1 mg/kg/2 weeks to about 10 mg/kg/week. 
     
     
         10 . The method of  claim 1 , wherein the effective amount of the c-Rel inhibitor is about 0.5 mg/day to about 2500 mg/day, about 1 mg/day to about 750 mg/day, about 5 mg to about 500 mg/day or about 10 mg/day to about 100 mg/day. 
     
     
         11 . The method of  claim 1 , wherein the effective amount of the c-Rel inhibitor is about 2500 mg/day, about 2400 mg/day, about 2000 mg/day, about 1800 mg/day, about 1600 mg/day, about 1200 mg/day, about 1000 mg/day, about 800 mg/day, about 600 mg/day, about 500 mg/day, about 400 mg/day, about 200 mg/day, about 100 mg/day, about 50 mg/day, about 25 mg/day, about 10 mg/day, about 5 mg/day, or between about 1 mg/day and 200 mg/day. 
     
     
         12 . The method of  claim 1 , wherein the effective amount of the PD-1 inhibitor is about 1 mg/kg, about 2 mg/kg, about 5 mg/kg, about 7.5 mg/kg, or about 10 mg/kg, administered every week or every two weeks. 
     
     
         13 . The method of  claim 1 , wherein the effective amount of the PD-1 inhibitor is about 200 micrograms, given every 2-3 days by injection. 
     
     
         14 . The method of  claim 1 , wherein the PD-1-resistant cancer is a melanoma. 
     
     
         15 . The method of  claim 14 , wherein the melanoma is a B16F1 melanoma or a B16F10 metastatic melanoma. 
     
     
         16 . The method of  claim 1 , wherein the PD-1-resistant cancer is selected from the group consisting of melanoma, metastatic melanoma, ovarian cancer, fibrosarcoma, breast cancer, lung cancer, non-small cell carcinoma, and colon cancer. 
     
     
         17 . The method of  claim 1 , wherein the PD-1-resistant cancer is selected from the group consisting of B16F1 (melanoma), B16F10 (metastatic melanoma), Id8 (ovarian cancer), Sa1N (fibrosarcoma), TUBO (mammary carcinoma), TC-1 (lung sarcoma), BRaf CA , Pten loxP , Tyr::CreER T2  (melanoma), MC38 (colon carcinoma), and CT-26 (colon carcinoma). 
     
     
         18 . A pharmaceutical combination comprising
 a) a therapeutically effective amount of a c-Rel inhibitor, and   b) a therapeutically effective amount of a PD-1 inhibitor.   
     
     
         19 . The pharmaceutical combination of  claim 18 , wherein the c-Rel inhibitor is a herein described active agent. 
     
     
         20 . The pharmaceutical combination of  claim 19 , wherein the active agent is a member selected from the group consisting of pentoxifylline, a pentoxifylline analog, IT-603, and any combination thereof. 
     
     
         21 . The pharmaceutical combination of  claim 20 , wherein the pentoxifylline analog is selected from the group consisting of lisofylline, torbafylline, propentafylline, A81-138, IT-603, dyfylline, doxofylline, theophylline, isobutyl methylxanthine (IBMX), caffeine, and any combination thereof. 
     
     
         22 . The pharmaceutical combination of  claim 21 , wherein the pentoxifylline analog is selected from the group consisting of torbafylline, propentafylline, A81-138, and any combination thereof. 
     
     
         23 . The pharmaceutical combination of  claim 18 , wherein the therapeutically effective amount of the c-Rel inhibitor and the therapeutically effective amount PD-1 inhibitor each are about 0.1 mg to about 5 g. 
     
     
         24 . The pharmaceutical combination of  claim 23 , wherein the therapeutically effective amount of the c-Rel inhibitor and the therapeutically effective amount PD-1 inhibitor each are about 400 mg to about 1800 mg. 
     
     
         25 . The pharmaceutical combination of  claim 18 , wherein the PD-1 inhibitor is an anti-PD-1 antibody, an anti-PDL-1 antibody or a biologically active fragment or variant thereof. 
     
     
         26 . The pharmaceutical combination of  claim 18 , wherein the anti-PD-1 antibody or anti-PDL-1 antibody is a monoclonal antibody. 
     
     
         27 . The pharmaceutical combination of  claim 26 , wherein the anti-PD-1 monoclonal antibody is humanized. 
     
     
         28 . A method of treating a cancer selected from the group consisting of a CTLA-4-resistant cancer, a CD137-resistant cancer, and an OX-4-resistant cancer comprising administering to a subject in need thereof a therapeutically effective amount of a c-Rel inhibitor and a therapeutically effective amount of a CLTA-4, CD137 or OX-4 inhibitor, respectively. 
     
     
         29 . The method of  claim 28 , wherein the CLTA-4 inhibitor is anti-CTLA-4 mAb, the CD137 inhibitor is anti-CD137 mAb and the OX-4 inhibitor is anti-OX-40 mAb.