Title: Rationally Designed Oncolytic Virus-Based Immunotherapies for Hepatocellular Carcinoma
Funder: Cancer Research UK

Abstract: The incidence and mortality from hepatocellular carcinoma (HCC) are rapidly rising in the UK. Few patients survive to 5 years due to late diagnosis, abnormal liver function and non-personalised ineffective therapies. Encouraging results are emerging using immune checkpoint modulators (ICMs), but efficacy remains low, and safety is a significant concern for patients with abnormal hepatic reserves. Rationally designed and personalised combination immunotherapies are required to improve efficacy, whilst avoiding the reversal of immune tolerance in the background liver. Our recent work shows that oncolytic viruses provide a complementary mechanism of action to ICMs. However, response is likely to depend on the underlying immunogenicity of the tumour, which is influenced by both the neoepitope load and hepatitis B/C virus (HBV/HCV) infections. We hypothesise that scheduled combinations of reovirus with rationally selected ICMs, will synergistically prime cytotoxic T-cell anti- HCC responses, without breaking tolerance in the background liver. We predict that the efficacy of reovirus-ICM therapy is dependent on the tumour neoepitope load. We anticipate that HBV/HCV-induced immunosuppression contributes to resistance to reovirus-ICM therapy, and that targeted anti-HBV/HCV therapies will sensitise malignant hepatocytes to immunotherapy. Aims • To rationally establish combinations and schedules of reovirus and ICMs for the treatment of HCC, based on safety and efficacy. • To assess the dependence of cytotoxic T-cell therapy on the HCC neoepitope load and to identify methods to increase immunogenicity in tumours with a low neoepitope load. • To assess the effects of HBV/HCV-induced immunosuppression on reovirus-ICM therapy, and whether optimal HBV/HCV inhibition improves the efficacy of immunotherapy. Methods We will utilise HCC patient-derived peripheral blood immune cells and liver resection samples to test cytotoxic T-cell function in an in vitro cytotoxic T-cell priming assay. We will correlate these functional cytotoxic T-cell immunotherapy results to the tumour neoepitope load. In vivo HCC experiments will be performed using established subcutaneous and orthotopic immunocompetent murine models. HBV/HCV effects will be investigated in the context of infectious cell line models. How the results of this research will be used These results will establish the next generation of combination immunotherapies for the treatment of HCC and enable the prediction of efficacy based on the tumour neoepitope load. Our work will strongly indicate the need for optimal anti-HBV/HCV therapies to enhance the efficacy of HCC immunotherapy and inform a future personalised oncolytic virus-ICM programme.

Lay abstract: Background The incidence and mortality from hepatocellular carcinoma (HCC) are rapidly rising in the UK. Few patients survive to 5 years due to late diagnosis, abnormal liver function and non-personalised ineffective therapies. Encouraging results are emerging using immune checkpoint modulators (ICMs), but efficacy remains low, and safety is a significant concern for patients with abnormal hepatic reserves. Rationally designed and personalised combination immunotherapies are required to improve efficacy, whilst avoiding the reversal of hepatic immune tolerance in the background liver. Our recent work shows that oncolytic viruses provide a complementary mechanism of action to ICMs. We hypothesise that scheduled combinations of reovirus with rationally selected ICMs, will synergistically prime cytotoxic T-cell anti- HCC responses. Aims • To rationally establish combinations and schedules of reovirus and ICMs for the treatment of HCC, based on safety and efficacy. • To investigate the differential response to reovirus-ICM therapy based on the underlying tumour biology. Methods We will utilise HCC patient-derived peripheral blood immune cells and liver resection samples to test cytotoxic T-cell function in an in vitro cytotoxic T-cell priming assay. In vivo HCC experiments will be performed using established subcutaneous and orthotopic immunocompetent murine models. HBV/HCV effects will be investigated in the context of infectious cell line models. How the results of this research will be used This project will establish the next generation of combination immunotherapies for the treatment of HCC and inform a future personalised oncolytic virus-ICM programme.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS