Enhancement of vesiculovirus oncolysis by expression of exotic envelope proteins

Abstract

Viral treatment of cancer has been described since the beginning of the twentieth century. With the increasing need for effective targeted cancer therapies, the oncolytic virus platform has been revisited. Clinical trials have demonstrated that oncolytic viruses are well tolerated, but their ability to eliminate tumor burden or effectuate cures is poor. This thesis attempts to address enhancing the oncolytic virus efficacy. The strategy is to modulate characteristics of the rhabdovirus by adding or swapping envelope genes of interest in order to enhance oncolytic activity, specifically by addressing tumor spread, immune evasion and safety. The fusogenic protein from reovirus is used to generate a recombinant VSV to enhance viral spread within the tumor. Similarly, recombinant VSVs are generated with envelope proteins either from other vesiculovirus members or from a beta-retrovirus, and used to demonstrate tumor infectivity in the presence of neutralizing antibodies. The recombinant VSV expressing the beta-retrovirus envelope protein demonstrates altered viral tropism, and like the replication incompetent VSV/FAST recombinant is not neurotoxic in animal models.