Discoveries in the prediction, prevention and treatment of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) occurs almost exclusively in patients with chronic liver diseases (CLD). The burden of HCC can be reduced with accurate risk prediction to target surveillance, risk reduction from disease-modifying therapies for CLD and the discovery of novel treatments. In order to make meaningful inroads into HCC outcomes, knowledge gaps in each of these areas need to be addressed. This thesis aims to achieve this through clinical and laboratory studies.

There are three clinical chapters investigating HCC risk prediction and reduction in patients with CLD, primarily chronic hepatitis B (CHB). It was discovered that the neither the presence nor severity of hepatic steatosis measured by transient elastography (TE) predicted for HCC development. Instead, the degree of liver fibrosis (also measured using TE) was an independent predictor. However, a substantial number of patients undergoing TE have uninterpretable fibrosis readings in the grey zone. The HCC risk of these patients was shown to be intermediate and could further be clarified with either liver biopsy and/or repeat TE. HCC risk in CHB patients can be modified with antiviral therapy. In this thesis, tenofovir disoproxil fumarate, was found to be associated with a 53% reduction in HCC risk in CHB patients with cirrhosis compared to no treatment.

Two further laboratory chapters investigate a novel approach to treat HCC combining vascular normalisation and immune checkpoint inhibition on three established mouse liver tumour models. It was shown that CD5-2 can normalise liver tumour vasculature and had anti-tumour effects either used alone or with anti-PD1 antibody at different timepoints during hepatocarcinogenesis. The combination of CD5-2 and anti-PD1 was able to enhance the tumour immune infiltrate into an immunosupportive one.

This thesis provides novel information on the prediction, prevention and treatment of HCC which has clinical applicability to help reduce the future burden of HCC.