Hepatocellular Carcinoma (HCC)
Conditions
Keywords
Biomarker, Hepatocellular carcinoma, Immunotherapy
Brief summary
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.
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.
Interventions
OTHERBlood 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.
Sponsors
Universitaire Ziekenhuizen KU Leuven
Flemish institute of biotechnology (VIB)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Three patient cohorts are defined, depending on the therapeutic scenario patients undertake. Patient management is standard of care. No investigational medicinal product (IMP) is involved. Trial is considered low interventional due to addition of extra blood and tissue samples, otherwise would be observational.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Spatial orientation | Through study completion, an average of 6 months | 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. |
| TCR sharing | Through study completion, an average of 6 months | 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. |
| Antigen identification | Through study completion, an average of 6 months | 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). |
| Biomarker validation | 12 months after tissue acquisition | 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). |
Countries
Belgium
Contacts
CONTACTJeroen Dekervel, MD
CONTACTFrederik Peeters, MD
Outcome results
None listed