Immune Cells as a New Biomarker of Response in Patients Treated by Immunotherapy for Advanced Hepatocellular Carcinoma (IMMUNOCELL)

December 11, 2025 updated by: Assistance Publique - Hôpitaux de Paris

Assessment of Circulating Immune Cells as a Prognostic Factor in Patients With Advanced Hepatocellular Carcinoma Treated With Immunotherapy

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Treatment options for advanced HCC remain very limited. Until recently, multikinase inhibitor were the gold standard for advanced hepatocellular carcinoma but associated with poor outcome and important side effects. Recently, the positive results of the Imbrave 150 study (a randomized study comparing Atezolizumab + Bevacizumab versus Sorafenib) prompted us to redefine our management strategy for advanced hepatocellular carcinoma by proposing the combination of Atezolizumab/Bevacizumab as treatment first-line in patients with advanced hepatocellular carcinoma. However, only 1/3 of the patients will respond to the combination of treatment and identifying predictive factors of response and new immune checkpoint inhibitors in order to target more tumors appear as a major issue. In this context, recent work has underlined the importance of the activating CD226/DNAM-1 receptor as an original immunotherapeutic target in various cancers (solid and hematopoietic tumors). CD226 is a transmembrane receptor that is part of the immunoglobulin superfamily. It is expressed by most T lymphocytes (CD8+, CD4+), by Natural Killer (NK) cells, by promoting their cytotoxicity.

The investigators propose to prospectively analyze the frequency and phenotype (expression of CD226) of circulating immune cells before the initiation of treatment with Atezolizumab/Bevacizumab, 3 weeks after the first injection and its variation to determine whether this biomarker could predict the response to the treatment.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

It is now widely accepted that inflammation is an essential element in tumor development. Liver tissue is very sensitive to inflammation and harbors immune system effectors capable of preventing the onset of a chronic inflammatory response. However, in case of chronic liver diseases, chronic inflammation will favor fibrosis progression and tumor development. Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Treatment options for advanced HCC remain very limited. Until recently, multikinase inhibitor were the gold standard for advanced hepatocellular carcinoma but associated with poor outcome and important side effects. Recently, immune checkpoint inhibitors, have emerged as an innovative anti-tumor strategy to restore an anti-tumor immune response, as illustrated by recent positive results of immunotherapy in oncology with prolonged responses in some patients. The initial results of immunotherapy in advanced hepatocellular carcinoma as monotherapy have been disappointing. However, combinations of immunotherapy and anti-VEGF antibodies or between immunotherapy and tyrosine kinase inhibitors are currently being tested in order to potentiate the effect of immunotherapy and to obtain higher rates of anti-tumor response. Recently, the positive results of the Imbrave 150 study (a randomized study comparing Atezolizumab + Bevacizumab versus Sorafenib) prompted us to redefine our management strategy for advanced hepatocellular carcinoma by proposing the combination of Atezolizumab/Bevacizumab as treatment first-line in patients with advanced hepatocellular carcinoma. However, only 1/3 of the patients will respond to the combination of treatment and identifying predictive factors of response and new immune checkpoint inhibitors in order to target more tumors appear as a major issue. In this context, recent work has underlined the importance of the activating CD226/DNAM-1 receptor as an original immunotherapeutic target in various cancers (solid and hematopoietic tumors). CD226 is a transmembrane receptor that is part of the immunoglobulin superfamily. It is expressed by most T lymphocytes (CD8+, CD4+), by Natural Killer (NK) cells, by promoting their cytotoxicity. The ligands for CD226 are the molecules CD112 and CD155, which are overexpressed in many tumors and are associated with a poor prognosis for patients. Recent data show that the decrease in CD226 expression on the surface of anti-tumor-containing immune effectors may be associated with resistance to anti-PD1/PDL1 immunotherapies. To date, the involvement of CD226 and its ligands in liver tumorigenesis is completely unknown. The use of Atezolizumab/Bevacizumab in France is a unique opportunity to conduct a pilot study on clinical, biological, histological, molecular and immune prognostic and predictive factors in patients treated with the Atezolizumab/Bevacizumab combination.

The investigators hypothese that a decrease in CD226 expression on the surface of CD8+ T lymphocytes (CTLs) and NK cells before the initiation of treatment with Atezolizumab/Bevacizumab could be associated with decrease response to the treatment and therefore associated with poor outcome of the patient. The investigators propose to prospectively analyze the frequency and phenotype (expression of CD226) of circulating immune cells before the initiation of treatment with Atezolizumab/ Bevacizumab, 3 weeks after the first injection (day of the second infusion) and its variation to determine whether this biomarker could predict the response to the treatment. The investigators will also perform an analysis of the histological and pathology characteristics of the tumor and non-tumor liver of the same patient before the initiation of treatment with Atezolizumab/ Bevacizumab with the ultimate objective of developing a predictive prognostic score for treatment response.

Study Type

Observational

Enrollment (Actual)

4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
    • France
      • Paris, France, France, 75013
        • Service hépato-gastroentérologie, Hôpital la Pitié-Salpêtrière

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Patients with an indication for treatment with Atezolizumab / Bevacizumab for the management of an advanced disciplinary hepatocellular carcinoma in a multidisciplinary consultation meeting (RCP).

Description

Inclusion Criteria:

  • Advanced hepatocellular carcinoma with an indication of systemic therapy by Atezolizumab-Bevacizumab
  • At least one measurable untreated lesion
  • ECOS performance status of 0 or 1

Exclusion Criteria:

  • HIV/ immunosuppressive treatment
  • Active of history of autoimmune disease or immune deficiency
  • Priori history of liver transplantation or systemic porto shunt
  • Pregnant of breastfeeding women

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
patients with hepatocellular carcinoma
Patients with an indication for treatment with Atezolizumab / Bevacizumab for the management of an advanced disciplinary hepatocellular carcinoma in a multidisciplinary consultation meeting.
Other: patients with hepatocellular carcinoma
The response of the hepatocellular carcinoma to treatment will be evaluated as part of the care

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Measurement of the frequency expression of CD226 at baseline
Time Frame: at baseline
at baseline
Measurement of the frequency expression of CD226 3 weeks after the start of treatment
Time Frame: 3 weeks after the start of treatment
3 weeks after the start of treatment
Measurement of the phenotype of expression of CD226at baseline
Time Frame: at baseline
at baseline
Measurement of the phenotype of expression of CD226 3 weeks after the start of treatment
Time Frame: 3 weeks after the start of treatment
3 weeks after the start of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Frequency of expression of CD226 to predict Overall survival (OS)
Time Frame: at baseline and 3 weeks after the start of treatment
Overall survival determined according to death status or not
at baseline and 3 weeks after the start of treatment
phenotype expression of CD226 to predict Overall survival (OS)
Time Frame: at baseline and 3 weeks after the start of treatment
Overall survival determined according to death status or not
at baseline and 3 weeks after the start of treatment
Correlation between pathology features (tumoral and non-tumoral liver) and the frequency and phenotype of expression of CD226
Time Frame: At inclusion
Comparison of the immune cells (frequency and phenotype) in the blood and liver tissues (tumoral and non-tumoral liver)
At inclusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Investigators

  • Principal Investigator: Manon ALLAIRE, MD, Assistance Publique - Hôpitaux de Paris

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 8, 2023

Primary Completion (Actual)

September 22, 2025

Study Completion (Actual)

September 22, 2025

Study Registration Dates

First Submitted

July 5, 2021

First Submitted That Met QC Criteria

September 9, 2021

First Posted (Actual)

September 16, 2021

Study Record Updates

Last Update Posted (Estimated)

December 18, 2025

Last Update Submitted That Met QC Criteria

December 11, 2025

Last Verified

December 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • APHP210845

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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