Exponential Enhancement of Oncolytic VSV Potency by Vector-Mediated Suppression of Inflammatory Responses In Vivo

Oncolytic virotherapy is a promising strategy for treatment of malignancy, although its effectiveness is hampered by host anti-viral inflammatory responses. Indeed the treatment efficacy of oncolytic Vesicular Stomatitis Virus (VSV) in rats bearing multi-focal Hepatocellular Carcinoma (HCC) can be substantially elevated by antibody-mediated depletion of NK cells. To test the hypothesis that the oncolytic potency of VSV could be exponentially elevated by evading inflammatory responses in vivo, we constructed a recombinant VSV vector expressing equine herpesvirus-1 glycoprotein G, which is a broad-spectrum viral chemokine binding protein (rVSV-gG). Hepatic artery infusion of rVSV-gG in immune-competent rats bearing syngeneic and multi-focal HCC in the livers resulted in a reduction of NK and NKT cells in the tumors and a one-log enhancement of intratumoral virus titer over a reference rVSV vector. The treatment led to elevated tumor necrosis and substantially prolonged animal survival without toxicities. These results indicate that rVSV-gG could be developed as an effective and safe oncolytic agent to treat advanced HCC patients in the future. Furthermore, the novel concept that oncolytic potency can be substantially enhanced by vector-mediated suppression of host anti-viral inflammatory responses might have general applicability in the field of oncolytic virotherapy for cancer.