Piv5 as an oncolytic agent

Abstract

The present invention includes the Paramyxovirus Parainfluenza Virus 5 (PIV5) as an oncolytic agent for treating various cancers, including, but not limited to breast cancer, lung cancer and melanoma. PIV5 oncolytic agents include both wild type PIV5 and various recombinant PIV5 constructs. Recombinant PIV5 constructs may include PIV5 lacking the conserved C-terminus of the V protein (PIV5VΔC), PIV5 with mutations in the N-terminus of the V/P protein (PIV5CPI−), and PIV5 expressing MDA-7/IL-24 (rPIV5-MDA7), rPIV5-V/P-CPI−, rPIV5-CPI+, rPIV5-Rev, rPIV5-RL, rPIV5-P-S157A, rPIV5-P-S308A, rPIV5-L-A1981D, rPIV5-F-S443P, rPIV5-MDA7, rPIV5ΔSH-CPI−, or rPIV5ΔSH-Rev. Also included are methods of making and using such oncolytic agents and compositions including such oncolytic agents.

What is claimed is: 
     
         1 . A method of treating a subject with a cancer, the method comprising administering to the subject an effective amount of a composition comprising an isolated recombinant parainfluenza virus 5 (PIV5), wherein the PIV5 comprises one or more mutations. 
     
     
         2 . The method of  claim 1 , wherein the subject is a companion animal. 
     
     
         3 . The method of  claim 2 , wherein the companion animal is a dog. 
     
     
         4 . A method of imaging a tumor in a subject, the method comprising administering to the subject a recombinant parainfluenza virus 5 (PIV5) expressing a fluorescent polypeptide or detectable agent. 
     
     
         5 . The method of  claim 1  wherein the tumor is a primary tumor and/or a metastatic tumor. 
     
     
         6 . The method of  claim 1 , wherein the tumor is selected from the group consisting of melanoma, basal cell carcinoma, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer (including small-cell lung carcinoma and non-small-cell lung carcinoma, leukemia, lymphoma, sarcoma, ovarian cancer, Kaposi's sarcoma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, head and neck cancers, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, kidney cancer, endometrial cancer, glioblastoma, and adrenal cortical cancer. 
     
     
         7 . The method of  claim 1 , wherein administration of PIV5 is intratumoral, subcutaneous, intravenous, intranasal, intraperitoneal, intracranial, oral, or in situ. 
     
     
         8 . The method of  claim 1  further comprising administration of an additional therapeutic agent. 
     
     
         9 . The method of  claim 1 , wherein a mutation comprises a mutation of the V/P gene, a mutation of the shared N-terminus of the V and P proteins, a mutation of residues 26, 32, 33, 50, 102, and/or 157 of the shared N-terminus of the V and P proteins, a mutation lacking the C-terminus of the V protein, a mutation lacking the small hydrophobic (SH) protein, a mutation of the fusion (F) protein, a mutation of the phosphoprotein (P), a mutation of the large RNA polymerase (L) protein, a mutation incorporating residues from canine parainfluenza virus, and/or a mutation that enhances synctial formation. 
     
     
         10 . The method of  claim 1 , wherein a mutation is selected from the group consisting of rPIV5-V/P-CPI−, rPIV5-CPI−, rPIV5-CPI+, rPIV5VΔC, rPIV-Rev, rPIV5-RL, rPIV5-P-S157A, rPIV5-P-S308A, rPIV5-L-A1981D and rPIV5-F-S443P, rPIV5-MDA7, rPIV5ΔSH-CPI−, or rPIV5ΔSH-Rev, and combinations thereof. 
     
     
         11 . The method of  claim 1 , wherein the PIV5 further comprises nucleotide sequences encoding a tumor killing heterologous polypeptide and/or heterologous RNA. 
     
     
         12 . The method of  claim 11 , wherein the heterologous polypeptide comprises MDA7. 
     
     
         13 . An oncolytic agent comprising a mutant parainfluenza virus 5 (PIV5) comprising one or more the mutations selected from the group consisting of a mutation of the V/P gene, a mutation of the shared N-terminus of the V and P proteins, a mutation of residues 26, 32, 33, 50, 102, and/or 157 of the shared N-terminus of the V and P proteins, a mutation lacking the C-terminus of the V protein, a mutation lacking the small hydrophobic (SH) protein, a mutation of the fusion (F) protein, a mutation of the phosphoprotein (P), a mutation of the large RNA polymerase (L) protein, a mutation incorporating residues from canine parainfluenza virus, and/or a mutation that enhances synctial formation. 
     
     
         14 . The oncolytic agent of  claim 13 , wherein a mutation is selected from the group consisting of rPIV5-V/P-CPI−, rPIV5-CPI−, rPIV5-CPI+, rPIV5VΔC, rPIV-Rev, rPIV5-RL, rPIV5-P-S157A, rPIV5-P-S308A, rPIV5-L-A1981D and rPIV5-F-S443P, rPIV5-MDA7, rPIV5ΔSH-CPI, rPIV5ΔSH-Rev, and combinations thereof. 
     
     
         15 . The oncolytic agent of  claim 13 , wherein the mutant PIV5 further comprises nucleotide sequences encoding a tumor killing polypeptide or RNA. 
     
     
         16 . The oncolytic agent of  claim 15 , wherein the heterologous polypeptide comprises MDA7. 
     
     
         17 . A composition comprising an oncolytic agent of  claim 13  and a pharmaceutically acceptable carrier.