Improving the Use of Immunotherapy to Treat Liver Cancer

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.

• General inclusion Criteria:

• Male or female, age > 18 years
• Diagnosis or suspected diagnosis of hepatocellular carcinoma based on imaging
• Specific inclusion criteria cohort 1 (retrospective/prospective data may be applicable):

• Pathologically confirmed HCC
• Treated with systemic treatment [tyrosine kinase inhibitor (TKI) or immunotherapy (ICI)] in the last 7 years and follow-up data (at least one imaging on treatment) available until 01/01/2025
• Biopsy obtained between 01/01/2018 until 01/01/2025
• Left-over tissue from previous diagnostic biopsies or resection specimens available
• Time between biopsy and initiation of systemic treatment < 1 year
• Ability to sign informed consent for secondary use of archival tissue and data collection for study-specific research for patients who are alive
• Specific inclusion criteria cohort 2 (aHCC & prospective):

• Suspicion of hepatocellular carcinoma (imaging criteria or recurrent disease of previously treated HCC)
• Indication for tumor biopsy per standard of care
• Eligible for systemic treatment (any) after pathological confirmation of HCC
• Ability to sign informed consent for primary use of tissue and blood samples and data collection for study-specific research
• Specific inclusion criteria cohort 3 (eHCC & prospective):

• Suspicion of hepatocellular carcinoma (imaging criteria or recurrent disease of previously treated HCC)
• Indication for local treatment (resection or ablation)
• Ability to sign informed consent for primary use of tissue and blood samples and for data collection for study-specific research

Due to the observational nature of this study, participation in other (interventional) clinical trials is permitted, if biological materials can be collected per protocol.

• General exclusion criteria:

• Poor liver function and/or performance status which prohibits active treatment
• Pathologically proven other malignancies of the liver, including primary cholangiocarcinoma or liver metastases
• Treatment plan other than systemic treatment or local treatment (resection or ablation), such as TACE, TARE, liver transplantation