Use of vdas to enhance immunomodulating therapies against tumors

Abstract

Methods for producing an anti-tumor effect in a subject suffering from a cancer or a tumor are disclosed. The methods comprise administering to the patient a Vascular Disrupting Agent (VDA) that is a combretastatin agent and one or more antibodies selected from the group consisting of: a CTLA-4 antibody, a PD-1 antibody, a PD-L1 antibody, and a PD-L2 antibody in amounts effective therefor. Examples of combretastatin include CA1P, CA4P, and their corresponding salts and prodrugs. The combination of the VDA and one or more of the antibodies produced a synergistic anti-tumor effect.

What is claimed is: 
     
         1 . A method for producing an anti-tumor effect in a subject suffering from cancer or a tumor, the method comprising administering to the patient a Vascular Disrupting Agent (VDA) that is a combretastatin agent and one or more antibodies selected from the group consisting of: a CTLA-4 antibody, a PD-1 antibody, a PD-L1 antibody, and a PD-L2 antibody in amounts effective therefor. 
     
     
         2 . The method of  claim 1 , wherein the method includes administering two or more antibodies selected from the group consisting of: a CTLA-4 antibody, a PD-1 antibody, a PD-L1 antibody, and a PD-L2 antibody. 
     
     
         3 . The method of  claim 1 , wherein the method includes administering a CTLA-4 antibody, a PD-1 antibody, a PD-L1 antibody, and a PD-L2 antibody in a therapeutically effective amount. 
     
     
         4 . The method of  claim 1 , wherein the combretastatin agent is combretastatin A1 diphosphate (CA1P) or combretastatin A4 phosphate (CA4P). 
     
     
         5 . The method of  claim 1 , wherein the CTLA-4 antibody, PD-1 antibody, PD-L1 antibody, and a PD-L2 antibody are selected from the group consisting of: Tremelimumab, Ipilumab, Nivolumab, Pembrolizumab, Pidilizumab, MEDI4736, BMS 936559, MPDL328OA, and AMP-224. 
     
     
         6 . The method of  claim 1 , wherein the compounds are simultaneously or sequentially administered. 
     
     
         7 . The method of  claim 1 , wherein the combretastatin agent is administered prior to the antibody. 
     
     
         8 . The method of  claim 7 , wherein the combretastatin agent is administered more than about 12 hours prior to the antibody. 
     
     
         9 . The method of  claim 1 , wherein said cancer is selected from the group consisting of: ovarian cancer, fallopian tube cancer, cervical cancer, breast cancer, lung cancer, melanoma, kidney, and primary cancer of the peritoneum. 
     
     
         10 . The method of  claim 9 , wherein the tumor is a solid tumor selected from the group consisting of: a melanoma, an ovarian tumor, a cervical tumor, a breast tumor, small cell lung tumor, a non-small cell lung tumor, a fallopian tube tumor, a primary tumor of the peritoneum, a glioblastoma multiforme, gliomas, astrocytomas, thyroid carcinoma, neuroendocrine tumors, soft tissue sarcomas, hepatocellular carcinoma, and gastrointestinal stromal tumors. 
     
     
         11 . The method of  claim 1 , wherein said cancer is selected from the group consisting of: hematologic malignancies, acute leukemias, chronic leukemias, lymphomas, and myelomas. 
     
     
         12 . The method of  claim 1 , wherein the combretastatin agent is a compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R a  is H, phosphate, phosphate ester, phosphonate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, phosphordiamidate, cyclic phosphorodiamidate, phosphonamidate or amino acid acyl; and 
 R b  is phosphate, phosphate ester, phosphonate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, phosphordiamidate, cyclic phosphorodiamidate, phosphonamidate or amino acid acyl. 
 
     
     
         13 . The method of  claim 1 , wherein the combretastatin agent is a compound of Formula IIb: 
       
         
           
           
               
               
           
         
       
       wherein
 R a  is H or OP(O)(OR 3 )OR 4 ; and 
 OR 1 , OR 2 , OR 3  and OR 4  are each, independently, H, —O— QH +  or —O— M + , wherein M +  is a monovalent or divalent metal cation, and Q is, independently:
 a) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + ; or 
 b) an organic amine containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation, QH + . 
 
 
     
     
         14 . The method of  claim 13 , wherein, for Formula IIb, R 3  is H or OP(O)(OR 3 )OR 4 , and R 1 , R 2 , R 3  and R 4  are each, independently, an aliphatic organic amine, alkali metals, transition metal, heteroarylene, heterocyclyl, nucleoside, nucleotide, alkaloid, amino sugar, amino nitrile, or nitrogenous antibiotic. 
     
     
         15 . The method of  claim 13 , wherein, for Formula IIb, R 1 , R 2 , R 3  and R 4  are each, independently, Na, TRIS, histidine, ethanolamine, diethanolamine, ethylenediamine, diethylamine, triethanolamine, glucamine, N-methylglucamine, ethylenediamine, 2-(4-imidazolyl)-ethylamine, choline, or hydrabamine 
     
     
         16 . The method of  claim 1 , wherein Formula II or Formula IIb is represented by a compound of Formula III: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof.