A new oncolytic virus platform to treat cancers with myxoma virus

Abstract

Disclosed herein, in certain embodiments, are recombinant myxoma viruses (MYXVs) and nucleic acid constructs encoding the recombinant MYXVs. In some embodiments, the MYXVs are engineered to inactivate or attenuate an activity or expression level of an M153 protein. In some embodiments, the MYXVs are engineered to express one or more transgenes such as a tumor necrosis factor (TNF), interleukin-12 (IL-12), or decorin. Also disclosed herein, in certain embodiments, are methods of using the MYXVs. Some embodiments include providing a MYXV as described herein to a subject in need thereof.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising:
 i) a myxoma virus (MYXV) having enhanced anti-cancer activity, wherein the MYXV is genetically engineered to attenuate an activity or expression level of its M153 protein; and   ii) a pharmaceutically acceptable excipient;   wherein the MYXV is effective to increase expression of at least two cytokines in a cancer cell of a subject after administration to the subject.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the activity or the expression level of the M153 protein of the MYXV is attenuated at least 80%. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein at least 80% of a nucleic acid encoding the M153 protein of the MYXV is deleted. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein at least 90% of a nucleic acid encoding the M153 protein of the MYXV is deleted. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is formulated for systemic administration. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is formulated for local administration. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is formulated for parenteral administration. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition comprises the MYXV at a dose of less than 1×10 9  focus forming units (FFU). 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition comprises the MYXV at a dose of at least 1×10 7  or at least 2×10 7  focus forming units (FFU). 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the MYXV is effective to increase expression of the at least two cytokines in the cancer cell of the subject at least about 30% compared to an untreated cancer cell. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition comprises the MYXV at a dose effective to increase expression of the at least two cytokines in the cancer cell of the subject at least about 30% compared to an untreated cancer cell. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the at least two cytokines comprise IFN-γ, IL-2, IL-6, IL-10, IL-12, or TNF-α. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the MYXV is effective to reduce viability of the cancer cell, or activate immunogenic cell death of the cancer cell. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the cancer cell comprises a solid tumor cell. 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the cancer cell comprises an osteosarcoma, triple negative breast cancer, or melanoma cell. 
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein the MYXV further comprises a nucleic acid encoding a non-viral molecule. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the non-viral molecule is tumor necrosis factor alpha (TNFα), interleukin-12 (IL-12), or decorin. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the non-viral molecule is human TNFα. 
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein the non-viral molecule is human IL-12. 
     
     
         20 . The pharmaceutical composition of  claim 17 , wherein the non-viral molecule is human decorin.