Introduction

Hepatocellular carcinoma (HCC) is responsible for more than 500,000 yearly deaths worldwide. The lack of effective therapies for this disease necessitates novel therapeutic approaches. Oncolytic viral vectors, such as vesicular stomatitis virus (VSV), are a promising new anticancer platform for HCC. In addition to direct cytopathology, VSV infection of cancer cells elicits specific and nonspecific immune responses, thus overcoming immunological tolerance to the tumor. The type III IFN family of cytokines (IFN-λ1, 2, and 3) have antiviral and immunomodulatory properties, and inhibit tumor progression in several different cancer models. We hypothesize that IFN-λ expression from VSV will improve oncolytic activity by both immunostimulatory effects and through increased selectivity of the virus for tumor cells.

Methods

We generated recombinant VSV vectors expressing mouse IFN-l2 either from the fifth position or the more highly expressing first position of the viral genome, and measured virus replication in cell culture and mice. Using a mouse model of HCC, we are examining the hypothesis that IFN-l expression from VSV will augment its antitumor activity.

Results

We found that IFN-l is expressed, secreted, and active when produced by VSV-infected cells. In cell culture, IFN-l expression from VSV attenuated virus replication in type III IFN-responsive cells, but not in type III IFN-nonresponsive cells, and after intranasal delivery to mice in vivo (Guayasamin et al., J. Virol., 2014). In vitro virus infection and spread assays demonstrate that VSV vectors expressing IFN-l are selectively cytopathic for type III IFN-nonresponsive liver cancer cells but not normal hepatocytes. Mouse models of HCC are being used to determine the antitumor potency of the VSV vectors and are ongoing.

Conclusion

These studies demonstrate the ability of the type III interferon cytokine family to enhance VSV oncolytic activity by increasing selectivity of the virus for type III IFN-resistant tumor cells.