Improving the Use of Immunotherapy to Treat Liver Cancer (IO-MARC)

Optimizing and Improving Immunotherapy for Hepatocellular Carcinoma: the IO-MARC Study

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.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma (HCC)
• Intervention / Treatment: Other: Blood and tissue sample

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jeroen Dekervel, MD; Phone Number: 016344225; Email: jeroen.dekervel@uzleuven.be
• Study Contact Backup: Name: Frederik Peeters, MD; Email: frederik.1.peeters@uzleuven.be

Study Locations

• Belgium
  • Antwerp, Belgium
    • Recruiting
    • UZA
    • Contact: Timon Van Damme, MD, PhD; Email: Timon.vandamme@uza.be
    • Principal Investigator: Timon Van Damme, MD, PhD
  • Hasselt, Belgium
    • Recruiting
    • Jessa Ziekenhuis
    • Contact: Elisabeth Stragier, MD; Email: Elisabeth.stragier@jessazh.be
    • Principal Investigator: Elisabeth Stragier, MD
  • Kortrijk, Belgium
    • Recruiting
    • AZ Groeninge
    • Contact: Alexander Vanden Bulcke, MD; Email: Alexander.vandenbulcke@azgroeninge.be
    • Principal Investigator: Alexander Vandenbulcke, MD
  • Roeselare, Belgium
    • Recruiting
    • AZ Delta
    • Contact: Sofie De Meulder, MD; Email: sofie.demeulder@azdelta.be
    • Principal Investigator: Sofie De Meulder, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

• General inclusion Criteria:

  1. Male or female, age > 18 years
  2. Diagnosis or suspected diagnosis of hepatocellular carcinoma based on imaging

• Specific inclusion criteria cohort 1 (retrospective/prospective data may be applicable):

  1. Pathologically confirmed HCC
  2. 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
  3. Biopsy obtained between 01/01/2018 until 01/01/2025
  4. Left-over tissue from previous diagnostic biopsies or resection specimens available
  5. Time between biopsy and initiation of systemic treatment < 1 year
  6. 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):

  1. Suspicion of hepatocellular carcinoma (imaging criteria or recurrent disease of previously treated HCC)
  2. Indication for tumor biopsy per standard of care
  3. Eligible for systemic treatment (any) after pathological confirmation of HCC
  4. 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):

  1. Suspicion of hepatocellular carcinoma (imaging criteria or recurrent disease of previously treated HCC)
  2. Indication for local treatment (resection or ablation)

  3. 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:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Cohort 1; Cohort 1 (observational): Collection of leftover archival tumour tissue of patients with advanced HCC treated with systemic therapies.; No blood collection.; Retrospective and prospective collection of data.
Other: Cohort 2; Cohort 2 (advanced HCC): Prospective collection of tumour tissue at the time of standard of care biopsy from advanced HCC patients prior to initiation of a systemic treatment (max 2 needle biopsy cylinders).; Additional collection of leftover archival tissue from previous biopsies or resection specimens is possible.; Prospective collection of blood samples at two timepoints (prior to start of systemic treatment and prior to the 2nd therapy cycle). Maximum 30ml of blood per timepoint (3x10ml EDTA tubes).; Retrospective and prospective collection of data.	Other: Blood and tissue sample; Prospective collection of additional blood and tissue samples for study-specific analyses at specific timepoints, at the same time as routine procedures.
Other: Cohort 3; Prospective collection of tumour tissue at the time of standard of care biopsy (max 2 needle biopsy cylinders) or surgical treatment (resection or ablation; 2 surgical biopsies or a piece of the resection specimen) from early HCC patients.; Additional collection of leftover archival tissue from previous biopsies or resection specimens is possible.; Prospective collection of blood samples at one timepoint (prior to resection or ablation). Maximum 30ml of blood per timepoint (3x10ml EDTA tubes).; Retrospective and prospective collection of data.	Other: Blood and tissue sample; Prospective collection of additional blood and tissue samples for study-specific analyses at specific timepoints, at the same time as routine procedures.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spatial orientation	Spatial orientation of cell types of interest in the tumour microenvironment (TME) of HCC using a variety of techniques: multiplex IHC, spatial proteomics and spatial transcriptomics. Samples from early (cohort 3) and advanced HCC (cohort 2) will be used.	Through study completion, an average of 6 months
TCR sharing	Identification of shared TCR sequences between PBMCs and tumor tissue using RNA and TCR sequencing. Exploration of the degree of TCR sharing in early and advanced HCC.	Through study completion, an average of 6 months
Antigen identification	The investigators will use tumor tissue and PBMC to construct an antigenic landscape of advanced HCC. To achieve this goal the investigators will use a unique technique called Transcriptome-Wide Screening for T cell Antigen Research (TWISTAR).	Through study completion, an average of 6 months
Biomarker validation	This study will be used to validate two candidate predictive biomarkers (CD45RA effector-memory CD8 T-cells/PDL1-expressing CXCL10+ macrophages) AND TCR sharing between tumor and blood in relation to response to immunotherapy in HCC. The investigators will compare the biomarker positive and biomarker negative groups in terms of progression-free survival and overall survival (Kaplan-Meier time-to-event) in the context of known prognostic clinical variables (multivariable cox proportional hazards model).	12 months after tissue acquisition

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Collaborators: Flemish institute of biotechnology (VIB)

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2025
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2032

Study Registration Dates

• First Submitted: February 6, 2025
• First Submitted That Met QC Criteria: May 27, 2026
• First Posted (Actual): June 3, 2026

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Biomarker; Immunotherapy; Hepatocellular carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Immunologic Techniques; Immunologic Tests; Blood Specimen Collection; Histocompatibility Testing
• Other Study ID Numbers: S69815

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No