Methods of cytotoxic gene therapy to treat tumors

Abstract

A method is disclosed for decreasing or retarding an increase in the size of a localized or metastatic tumor by using a combination of an immune stimulating cytotoxic gene therapy and immune-checkpoint modulating agent, in conjunction with other therapies, including radiation therapy, chemotherapy, surgery, and immunotherapies.

1 . A method of decreasing tumor burden or micrometastasis in a mammal, comprising:
 i.) administering a replication-incompetent adenoviral vector encoding thymidine kinase or cytosine deaminase to the mammal with a tumor intratumorally or to a tumor resection site in the mammal;   ii.) administering a prodrug to the mammal orally or intravenously, the prodrug being activated by thymidine kinase or cytosine deaminase, the prodrug being ganciclovir, acyclovir, valacyclovir, valgancyclovir, famiciclovir, or an active analog thereof such that the prodrug is activated by the thymidine kinase; and   iii.) administering a monoclonal antibody that recognizes a checkpoint protein which is PDL1, PDL2, CTLA4, TIM3, LAG3, B7-H4, CD80, CD86, BTLA, HVEM, KIR, or GALS to the mammal intravenously such that the antibody reduces the immune repressive response caused by the checkpoint protein, thereby allowing T cell activation,   wherein the activated prodrug and enhanced T cell activation decrease tumor burden or decrease micrometastasis.   
     
     
         2 - 12 . (canceled) 
     
     
         13 . The method of  claim 1 , further comprising administering radiotherapy and/or chemotherapy to, and/or performing surgery on, the mammal before, during or following administrating the vector, prodrug, and monoclonal antibody. 
     
     
         14 . The method of  claim 1 , wherein the replication-incompetent adenoviral vector encodes thymidine kinase. 
     
     
         15 . The method of  claim 1 , wherein the replication-incompetent adenoviral vector encodes cytosine deaminase. 
     
     
         16 . The method of  claim 1 , wherein the monoclonal antibody recognizes PDL1, CTLA4, or TIM3. 
     
     
         17 . The method of  claim 14 , wherein the monoclonal antibody recognizes PDL1, CTLA4, or TIM3. 
     
     
         18 . The method of  claim 15 , wherein the monoclonal antibody recognizes PDL1, CTLA4, or TIM3. 
     
     
         19 . The method of  claim 1 , wherein the monoclonal antibody recognizes PDL1. 
     
     
         20 . A method of reducing micrometastasis in a mammal with tumor resection, comprising:
 i.) administering a replication-incompetent adenoviral vector encoding thymidine kinase or cytosine deaminase to a tumor resection site in the mammal;   ii.) administering a prodrug to the mammal orally or intravenously, the prodrug being activated by thymidine kinase or cytosine deaminase, the prodrug being ganciclovir, acyclovir, valacyclovir, valgancyclovir, famiciclovir, or an active analog thereof, such that the prodrug is activated by the thymidine kinase; and   iii.) administering a monoclonal antibody that recognizes a checkpoint protein which is PDL1, PDL2, CTLA4, TIM3, LAG3, B7-H4, CD80, CD86, BTLA, HVEM, KIR, or GALS to the mammal intravenously such that the antibody reduces the immune repressive response caused by the checkpoint protein, thereby allowing enhanced T cell activation,   wherein the activated prodrug and enhanced T cell activation reduce micrometastasis in the mammal.   
     
     
         21 . The method of  claim 20 , further comprising administering radiotherapy and/or chemotherapy to, and/or performing surgery on, the mammal before, during or following administrating the vector, prodrug, and monoclonal antibody. 
     
     
         22 . The method of  claim 20 , wherein the prodrug is activated by thymidine kinase. 
     
     
         23 . The method of  claim 20 , wherein the prodrug is activated by cytosine deaminase. 
     
     
         24 . The method of  claim 22 , wherein the monoclonal antibody recognizes PDL1, CTLA4, or TIM3. 
     
     
         25 . The method of  claim 23 , wherein the monoclonal antibody recognizes PDL1, CTLA4, or TIM3. 
     
     
         26 . The method of  claim 20 , wherein the monoclonal antibody recognizes PDL1.