Using clinical characteristics of hepatocellular carcinoma (HCC) patients as predictors of their immunotherapy response

Lead Investigator: Guang Sheng Ling, University of Hong Kong
Title of Proposal Research: Using clinical characteristics of hepatocellular carcinoma (HCC) patients as predictors of their immunotherapy response
Vivli Data Request: 8853
Funding Source: Hong Kong General Research Fund: 17116622. HK’s GRF is a competitive process that supports both basic and applied research, with proposals evaluated on academic merit; contribution to academic/professional development; and potential for social, cultural or economic application
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Cancer is a growing threat to human health, especially as our lifespan increases with advances in medicine. Cancer treatment has previously evolved from surgical removal to chemotherapy, a drug treatment which kills fast-growing cells, both cancerous and non-cancerous, in the body, and the most recent advancement is the application of immunotherapy approaches. Immunotherapy drugs aims to help the immune system identify cancer cells so it can specifically attack and kill them, leaving other cells unharmed. However, the outcomes for patients with solid tumors, such as hepatocellular carcinoma (HCC), when treated with immunotherapy are still poor, where only 20% of patients will benefit from the therapy. HCC is the most common form of liver cancer and is the second leading cause of cancer-related death in Asia. It is a growing threat due to rising obesity rates, which is associated with liver dysfunction that promotes tumor development.

Chronic viral infection with hepatitis B or C virus (HBV or HCV), carcinogens (food contaminants, tobacco smoking, and environmental toxins), excessive alcohol consumption (alcoholic fatty liver disease), metabolic syndrome (diabetes and obesity), and high-calorie intake (non-alcoholic fatty liver disease) are major risk factors for HCC. Each etiology (the manner in which the disease develops) has its own pathogenesis (set of factors that cause the disease) and immune microenvironment (the cells and fluids that surround a tumor some of which may promote tumor growth and some suppress it), which may contribute to immunotherapy resistance.

Our study aims to use the patient’s clinical characteristics, such as those described above, to predict their response to immunotherapy, and therefore inform decisions related to their treatment regime. An additional factor that will be considered in our analysis is the expression of the protein programmed death-ligand 1 (PD-L1) by the patients’ cells. Current popular immunotherapy treatments target the interactions of the protein PD-L1 with its receptor programmed cell death protein 1 (PD1), expressed by CD8 T cells (the main immune cells that control and kill cancer cells). Numerous research has demonstrated that the PD1-PD-L1 interactions are a key driver of CD8 T cell dysfunction (as termed ‘exhaustion’), hence treatments that disrupt this interaction have unprecedented efficacy. Therefore, we will also consider the patients’ PD-L1 expression as an independent variable in our analysis.

Our previous work identified that the exhaustion of CD8 T cells is a key factor for immunotherapy resistance, and we provided insights into drivers of their exhaustion. Our current work on publicly available datasets (from the Cancer Genome Atlas (TCGA), International Cancer Genomics Consortium (ICGC), and Liver Cancer Institute (LCI)) suggests that HCC’s underlying etiology, the tumour’s developmental stage, and evidence of microvascular invasion (presence of tumor cells in the blood vessels) can predict CD8 T cell exhaustion, which has been shown to predict immunotherapy outcomes in other cancers. Hence, we hypothesize that these three clinical characteristics can be directly used to predict immunotherapy response among HCC patients. Our requested studies contain the clinical characteristics and immunotherapy responses required for validating this hypothesis.

Overall, our research aims to advance precision medicine through using clinical characteristics as predictors of immunotherapy response for HCC patients.

Requested Studies:

An Open-Label, Multicenter Phase Ib Study of The Safety and Efficacy of Atezolizumab (Anti-PD-L1 Antibody) Administered in Combination With Bevacizumab and/or Other Treatments in Patients With Solid Tumors
Data Contributor: Roche
Study ID: NCT02715531
Sponsor ID: GO30140

A Phase III, Open-Label, Randomized Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma
Data Contributor: Roche
Study ID: NCT03434379
Sponsor ID: YO40245