Improving the Use of Immunotherapy to Treat Liver Cancer

Overview

This project targets patients with a form of primary liver cancer, specifically "hepatocellular carcinoma". This disease often develops in the context of a chronically diseased liver, caused by viral infections, excessive alcohol consumption, or fatty liver. Primarily due to the rise of the latter risk factor, liver cancer is one of the few cancer types whose incidence continues to increase globally, year after year. As a result, liver cancer has become the third most common cause of cancer-related deaths worldwide. There exists a significant challenge in reducing the disease on all fronts: prevention, diagnosis, and treatment. This research aims to personalize the treatment of liver cancer patients, tailoring it to the individual. More specifically, this research seeks to identify patients with immunotherapy-sensitive liver cancer by biomarkers before treatment begins. Determining whether a tumor is immunotherapy-sensitive is internationally recognized as one of the most important challenges within this condition. Based on a combination of existing laboratory techniques on tumor tissue and/or blood, the investigators seek to predict the likelihood of this treatment's success before initiating it. With this knowledge, the investigators could recommend alternative treatments to patients with tumors that are unresponsive. This way, they would also avoid exposure to the side effects of an ineffective therapy.

Multicentric, low-interventional with retrospective and prospective components. No investigational medicinal product (IMP) is involved. Patient management is standard of care. Prospective tissue collection is done at the time of standard of care diagnostic biopsies or surgical procedures. Blood collection is performed at the time of routine lab evaluations. No additional study visits, venipunctures or other procedures are expected. Three hundred patients will be included in the following three cohorts: * Cohort 1 - 120 patients: archival tumor tissue of 120 patients previously treated with systemic therapies for hepatocellular carcinoma in the last 5 years will be collected. * Cohort 2 - 90 patients: prospective tumor tissue and blood samples of 90 patients with advanced HCC and candidate for systemic therapy will be collected. * Cohort 3 - 90 patients: prospective tumor tissue and blood samples of 90 patients with early HCC and candidate for local treatment will be collected. Objectives: * Aim 1: Spatial orientation of cell types of interest in the tumor microenvironment (TME) of HCC using a variety of techniques: multiplex immune histochemistry, spatial proteomics and spatial transcriptomics. Samples from early versus advanced HCC will be used. * Aim 2: Identification of shared T-cell receptor sequences between PBMCs and tumor tissue using RNA and TCR sequencing. Exploration of the degree of TCR sharing in early and advanced HCC. * Aim 3: Collecting starting material for TWISTAR, aiming to identify tumor antigens in HCC using a transcriptome-wide screen for T cell antigens. Our analysis will be powered to identify a difference in progression-free survival between the biomarker positive and negative population with a hazard ratio of 0.6 with a power of 75% and an alpha of 0.05, provided that about 30% of samples are biomarker positive. The historical samples of patients treated with a TKI will serve as a control group to detect an interaction with the biomarker and the treatment effect.