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 or retarding an increase in localized or metastatic tumor burden using the combination of a DNA or RNA delivery system for administering an immune stimulating cytotoxic gene therapy in conjunction with one or more immune checkpoint modulating agents administered simultaneously or sequentially to an individual for the treatment of a tumour, papilloma or wart in a non-human animal or a human. 
     
     
         2 . A system as claimed in  claim 1  where said DNA delivery system being selected from a virus, a viral vector, an episomal vector, a liposome, a cationic lipid or a non-viral delivery system consisting of the DNA or RNA of interest, a moiety that recognizes and binds to a cell surface receptor or antigen, a DNA binding moiety, and a lytic moiety that enables the transport of a complex from the cell surface to the cytoplasm. 
     
     
         3 . A system as claimed in  claim 1  wherein the cytotoxic gene is contained within the said DNA or RNA and is capable of being expressed, and wherein the cytotoxic gene is adapted to code for a protein capable of enzymatically converting in vivo a prodrug that is administered to said animal or human into a toxic compound. 
     
     
         4 . A system as claimed in  claim 2 , where the viral vector is an adenoviral vector. 
     
     
         5 . The use according to  claim 2 , wherein the prodrug is ganciclovir, acyclovir, valacyclovir, valgancyclovir, famciclovir or any other available analogue. 
     
     
         6 . A system as claimed in  claim 1 , wherein the cytotoxic gene sequence is adapted to express codes for a protein selected from thymidine kinase of herpes simplex virus, a thymidine kinase of varicella zoster virus or a bacterial cytosine deaminase. 
     
     
         7 . A system as claimed in  claim 1 , wherein said one or more immune checkpoint modulating agent is selected from monoclonal antibodies with specific affinity for proteins with immune inhibitory activity such as CTLA4, PD1, PDL1, PDL2, LAG3, TIM3, B7-H3, B7-H4, CD80, CD86, BTLA, HVEM, KIR, or GAL9. 
     
     
         8 . A system as claimed in  claim 1  when adapted to treat a tumour selected from a colon, prostate, breast, lung, skin, liver, bone, pancreas, ovary, testis, bladder, kidney, brain, head or neck cancer. 
     
     
         9 . A system as claimed in  claim 1  when adapted to treat a papilloma selected from a squamous cell papilloma, a choroid plexus papilloma or a laryngeal papilloma. 
     
     
         10 . A system as claimed in  claim 1  when adapted to treat a wart selected from a genital wart, a plantar wart, an epidermodysplasia verruciformis or a malignant wart. 
     
     
         11 . The use according to  claim 1  wherein the vector carries additional exogenous genes which are interferons, colony stimulating factors, interleukins, chemokines, cytokines or costimulatory molecules. 
     
     
         12 . The use according to  claim 1  wherein the gene delivery system is administered in combination with radiotherapy or surgery in the cancer patient to further induce a systemic anti-tumour immune response.