Cancer-specific viral delivery platforms based on modified VSV-GIN 2190

Abstract Description Oncolytic viruses (OVs) have proven to be a powerful tool in cancer immunotherapy, but clinically approved agents all require local injection. The lack of tumor-specific targeting machinery, non-specific biodistribution of OVs, and consequent exclusion of potent immune-activating payloads in these viral agents to avoid systemic toxicity represent major hurdles for the development of safe and effective OVs for cancers that are not surgically reachable. To overcome these hurdles, we have developed a cancer-specific OV by modifying the Indiana serotype of the vesicular stomatitis virus (VSV) glycoprotein (G protein, VSV-GIN). We employed a “cap-linker” strategy to modify VSV-GIN (“Pro-VSV-GIN”) to inhibit its ability to bind its cognate receptor until present in the tumor microenvironment. The cap serves as an inhibitory domain to VSV-GIN and is released upon proteolytic cleavage of the linker which connects the inhibitory domain to VSV-GIN at its N’-terminus. Upon linker cleavage, and consequent release of the cap, the binding activity of VSV-GIN is restored, allowing for the rescue of the ability of the virus to infect the cancer cell. Pro-VSV-GIN pseudotyped VSV results in better guided tumor-specific viral infection following systemic administration, and greater accumulation in the site of the tumor. Additionally, when armed with a single-chain IL-12 (Pro-VSVIN-IL-12) payload and systemically injected into MC38 tumor-bearing mice, Pro-VSVIN-IL-12 eradicates tumors. Funding Sources This work was supported by: UConn/NIDCR training grant T90-DE021989; 1R01CA262430 NIH/NCI (PI-Wang) Topic Categories Translational and Interventional Immunology (TI)