Causative and therapeutic viruses in hepatocellular carcinoma

The World Health Organisation (WHO) estimates that 150 and 240 million people are chronically infected with hepatitis C and B viruses (HCV/HBV) worldwide, of whom approximately 500,000 develop hepatocellular carcinoma (HCC) annually. The 5-year survival for HCC is less than 10% and up to 80% of cases are inoperable at presentation with no hope of cure. The treatment of patients with advanced HCC is frequently complicated by immunosuppression, leading to the attenuation of cancer-directed immune responses and the reactivation/exacerbation of HCV/HBV infections. In contrast, immunotherapies such as cancer selective oncolytic viruses, could theoretically suppress rather than stimulate underlying oncogenic virus infections, and improve clinical outcomes. This project investigates the potential for oncolytic viruses to be employed as dual anti-cancer and anti-viral therapies in pre-clinical models of hepatitis virus-associated HCC. The results described herein show that oncolytic virus stimulation of normal primary and malignant liver cells induces interferon secretion, leading to the inhibition of HCV. Further work using oncolytic wild-type reovirus showed that it stimulates interferon responses in primary hepatocytes, liver-resident immune cells and HCC cell lines, potently inhibiting HCV and HBV replication. Reovirus also activated liver resident natural killer cells to kill HCC, whilst infection of primary hepatocytes was non-toxic. Finally, in preclinical murine models of HCV-positive HCC, reovirus exerted a specific antiviral effect on HCV replication, detectable at very early times post-treatment, and distinct to its direct and immune-mediated tumour killing. Application of oncolytic virus therapy in an HCV/HBV positive HCC setting represents a novel, and potentially safe means of simultaneously targeting both tumours and the underlying oncogenic virus, providing a much-needed opportunity to improve clinical outcomes in HCC patients.