Treatment of multi-focal colorectal carcinoma metastatic to the liver of immune-competent and syngeneic rats by hepatic artery infusion of oncolytic vesicular stomatitis virus

Abstract

Viruses that replicate selectively in cancer cells hold considerable promise as novel therapeutic agents for the treatment of malignancy. We report an orthotopic model of multi-focal colorectal cancer (CRC) metastases in the livers of syngeneic and immune-competent rats, which permitted rigorous testing of oncolytic virus vectors as novel therapeutic agents through hepatic arterial infusion for efficacy and safety. Vesicular stomatitis virus (VSV) is a negative-strand RNA virus with intrinsic oncolytic specificity due to attenuated anti-viral responses in many tumors. After administration at the maximum tolerated dose, the recombinant VSV vector gained access to multi-focal hepatic CRC lesions that led to tumor-selective viral replication and oncolysis. No relevant vector-associated toxicities were noted and in particular, no damage to the hepatic parenchyma was seen. Moreover, the survival rate of vector-treated rats was significantly improved over that of animals in the control treatment group (p = 0.015). Our results demonstrate that hepatic arterial administration of oncolytic VSV is both effective and safe in an immune-competent and syngeneic rat model of multi-focal CRC liver metastasis, suggesting that it can be developed into an effective therapeutic modality in patients in the future.