Development of delivery, targeting, and imaging strategies to improve oncolytic vesicular stomatitis virus therapy for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a disease with rising incidence, limited treatment options and poor prognosis, representing a major worldwide health concern. Due to the vast deficit of viable treatment options, oncolytic viruses have emerged as promising alternative therapies to specifically target and lyse tumor cells. We have previously demonstrated the safety and efficacy of oncolytic vesicular stomatitis virus (VSV) applied via hepatic arterial infusion to treat orthotopic HCC in immune-competent rats, and based on encouraging data such as these, a recombinant VSV vector has recently entered the clinic in phase I trials for HCC in patients. Although systemic administration of oncolytic viral therapies is ideal for targeting metastatic disease, the efficacy of such an approach is extremely compromised due to rapid clearance from circulation as a result of neutralizing blood components and non-specific uptake by liver and spleen. Furthermore, the complex microenvironment in the liver poses a unique set of challenges to the fate of oncolytic viral therapies directed at hepatic tumors. Although attempts to shield viruses from adverse interactions have led to increased circulation times in vivo, they are also associated with decreased infectivity of the target cells. We have therefore developed several strategies, including novel cell carrier and synthetic shielding approaches, to simultaneously protect VSV from nonspecific interactions and deliver it specifically to the tumor target, where it can exert its oncolytic effect. Because a variety of immune cells possess the inherent ability to take up oncolytic virus and subsequently home to tumor beds, they offer the unique dual benefit of delivering viruses in stealth, while contributing to antitumor immune responses. Alternatively, synthetic polymers can provide highly effective shielding through surface modification of oncolytic viruses and have the advantage of being adaptable to optimize the shielding effect. Through the incorporation of targeting ligands or selectively cleavable linkers, the ability of the virus to infect is then rescued locally and specifically at the tumor site. Furthermore, advancement of imaging technologies allows us the possibility to monitor the biodistribution of these shielded viruses to observe the circulation time and replication kinetics noninvasively and in real-time, which will further facilitate the clinical translation of oncolytic virus therapies. A summary of these novel approaches to enhance oncolytic VSV accumulation within orthotopic HCC tumors and improve the therapy outcome, as well as virus imaging strategies, will be presented.