Vesicular stomatitis: An oncolytic virus that exploits tumor-specific defects in the interferon pathway

Vesicular stomatitis virus (VSV) is part of a new generation of small RNA viruses being developed as replicating cancer therapeutics. Vesicular stomatitis virus replicates in and kills a wide variety of human cancer cell lines, and is highly effective in mouse cancer models. It is exquisitely sensitive to the antiviral effects of the interferon (IFN) family of cytokines and its oncolytic activity depends on the presence of inherent defects in the IFN signaling pathway in cancer cells. Recent research has shown that IFN-inducing VSV mutants are attenuated in normal cells, but not in cancer cells. These mutants can be administered i.v. to mice at high doses, and can effect durable cures in disseminated cancer models. Other research has highlighted the potential of VSV engineered to express transgenes that could enhance the antitumor immune response, cause bystander-cell killing, or retarget VSV to receptors expressed at high levels on cancer cells. Now that several first-generation oncolytic viruses have entered into clinical trials, the lessons learned from these viruses can be applied to second-generation viruses, such as VSV, to develop more effective, safe, replicating cancer therapeutics.