Oncolytic virotherapy for hepatocellular carcinoma

Abstract

Oncolytic vesicular stomatitis virus (VSV) is a promising novel therapeutic agent for the treatment of hepatocellular carcinoma (HCC). We report that VSV, after a single hepatic arterial infusion at the maximal tolerable dose (MTD), was capable of accessing multifocal lesions of HCC in the livers of rats, which resulted in tumor-selective viral replication, oncolysis, and prolonged survival of the treated animals. We constructed a novel recombinant VSV vector capable of inducing syncytia formation between tumor cells through membrane fusion at neutral pH, which led to enhanced viral transmission and oncolysis of HCC in the livers of rats. To improve treatment outcome we show that repeated administrations of the syncytia-inducing VSV, through a permanent cannula surgically implanted into the hepatic artery, led to sustained tumor-selective virus replication and substantially enhanced its oncolytic potential in the treatment of advanced multi-focal HCC in the liver of rats. We also demonstrate that VSV, when administered at doses above the MTD, can cause neurotoxicity as manifested by limb paralysis and/or acute lethal hepatotoxicity in immune-competent rats. Exogenous administration of IFN-alpha at a clinically relevant dose allows VSV treatment at doses above the MTD but is still highly oncolytic in multi-focal HCC-bearing rats, thereby improving its therapeutic index. This treatment regimen should be considered in the future development of VSV-mediated virotherapy as a novel therapeutic modality for patients with advanced HCC.