Project BioGvHD (Toward immune Biomarkers for Tolerance and GvHD in Humans) | ANR - Agence Nationale de la Recherche ANR funded project | ANR - Agence Nationale de la Recherche

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ANR funded project

Programme de Recherche Translationnelle en Santé (PRTS)
Edition 2013


BioGvHD


Toward immune Biomarkers for Tolerance and GvHD in Humans

Toward immune Biomarkers for Tolerance and GvHD in Humans
Graft-versus-Host Disease (GVHD), is the most frequent and severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). Much of our knowledge on the pathophysiology of GVHD has been gained from experimental models but far less from the study of the disease in humans.

Development of biomarker could predict GVHD severity
Recent developments in basic biology open new avenues to the development of biomarker sets that could predict GVHD severity and prognosis that could be tested and validated through well-designed multicenter clinical trials.
The main goal of this project is to further our understanding of the pathogenic mechanisms of human GVHD on one hand, and of functional immune tolerance on the other. Furthermore, this study aims at setting up a clinically relevant biomarker set in human GVHD and immune tolerance in a discovery cohort,

The objectives of this project are:
1. To define phenotypic, functional and molecular correlates of acute GVHD early after HSCT/at its onset
2. To study thymic reconstitution and the T-cell repertoire after HSCT during period 2
3. To identify functional and molecular correlates of immune tolerance in long-term survivors of HSCT
4. Preparing for biomarker validation into a clinical trial.

Materials and methods
We propose a prospective analysis of patients transplanted from an HLA-identical sibling . Analyses will be performed during 3 critical, clinically relevant, periods.
1. Period 1: Analysis at the onset of GVHD, and 90 days after HSCT.
2. Period 2: Thymic function analysis using measurements of T-cell receptor excision circles (TREC) will be performed at 6 and 12 months post-transplant for all patients. T-cell receptor analysis on sorted T-cell populations will be performed by NGS.
3. Period 3: In “tolerant” patients (patients more than 2 years after HSCT not requiring immunosuppressive treatment), or in patients still requiring immunosuppressive therapy after 2 years. We will also analyze the corresponding immune parameters for each donor.
The longitudinal design of this study will allow us to provide an integrated view of GVHD pathophysiology and mechanisms of immune tolerance in human.

Results

The main points addressed will include:
1. Mortality associated to transplantation (is estimated at 20% at 2 years)
2. The fact that such mortality associated with transplantation is first related to GvHD
3. The incidence of GvHD (acute and chronic) is on the order of 40%
4. The patients will be examined prospectively
5. The highlight of the project to a biological prospective cohort funded by an «investissment d'avenir« : Cryostem.

Outlook

Prospectively identified phenotypic, molecular or functional biomarkers will then be tested, in a subsequent study, from biological materials prospectively collected within the French wide CryoStem cohort. Thus, as the final task of this project, we will perform statistical analyses taking into account confounding clinical variables influencing the outcome (i.e. GVHD-related death or tolerance). Preparing for a clinical trial will need moving from classical Bioinformatics analyses into clinically relevant statistical analyses that include sequential biological measurement in the discovery set cohort.

Scientific outputs and patents

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Partners

AP-HP Assistance Publique Hôpitaux de Paris :Hôpital Saint-Louis - Département de Biostatistique et Informatique Médicale

AP-HP Assistance Publique Hôpitaux de Paris Hôpital Saint-Louis - Service immunologie et histocomptabilité

AP-HP Equipe « Génome et Cancer »- Hôpital Saint-Louis

IP Institut Pasteur-Unité immunorégulation

ANR grant: 142 433 euros
Beginning and duration: mars 2014 - 48 mois

Submission abstract

Graft-versus-Host Disease (GVHD), is the most frequent and severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). Much of our knowledge on the pathophysiology of GVHD has been gained from experimental models but far less from the study of the disease in humans. Recent developments in basic biology open new avenues to the development of biomarker sets that could predict GVHD severity and prognosis that could be tested and validated through well designed multicenter clinical trials.
The main goal of this project is to further our understanding of the pathogenic mechanisms of human GVHD on one hand, and of functional immune tolerance on the other. Furthermore, this study aims at setting up a clinically relevant biomarker set in human GVHD and immune tolerance in a discovery cohort.
The objectives of this project are:
1. To define phenotypic, functional and molecular correlates of acute GVHD early after HSCT/at its onset
2. To study thymic reconstitution and the T-cell repertoire after HSCT during period 2
3. To identify functional and molecular correlates of immune tolerance in long-term survivors of HSCT
4. Preparing for biomarker validation into a clinical trial
We propose a prospective analysis of a cohort of 80 patients transplanted from an HLA-identical sibling donor at Saint Louis hospital. Analyses will be performed during 3 critical, clinically relevant, periods.
1. Period 1: Analysis at the onset of GVHD, or at the time of engraftment 30 days after HSCT in patients not developing GVHD. An additional blood sample will also be analyzed 90 days after HSCT.
2. Period 2: Thymic function analysis using measurements of T-cell receptor excision circles (TREC) will be performed at 6 and 12 months post-transplant for all patients. T-cell receptor analysis on sorted T-cell populations will be performed by NGS.
3. Period 3: In “tolerant” patients (patients more than 2 years after HSCT not requiring immunosuppressive treatment), or in patients still requiring immunosuppressive therapy after 2 years. We will also analyze the corresponding immune parameters for each donor.
The longitudinal design of this study will allow us to provide an integrated view of GVHD pathophysiology and mechanisms of immune tolerance in human.

Prospectively identified phenotypic, molecular or functional biomarkers will then be tested, in a subsequent study, from biological materials prospectively collected within the French wide CryoStem cohort. Thus, as the final task of this project, we will perform statistical analyses taking into account confounding clinical variables influencing the outcome (i.e. GVHD-related death or tolerance). Preparing for a clinical trial will need moving from classical Bioinformatics analyses into clinically relevant statistical analyses that include sequential biological measurement in the discovery set cohort. Main points that will be taken into accounts for this task are the followings;
1. Transplant-related mortality (TRM) can be estimated in the range of 20%; 2year post-allogeneic HSCT
2. TRM is mostly (even if totally) due to GVHD and its associated immune deficiency
3. GVHD cumulative incidence can be estimated in the range of 40%
4. 80 patients will be prospectively studied and 30 patients will be analyzed (cross sectional study) for part 3 only.
5. Since GVHD-related mortality and tolerance are mutually exclusive situation the optimal calculation for the validation cohort can be expected
6. This later calculation will be the basis for the proposal of an interventional clinical trial.

 

ANR Programme: Programme de Recherche Translationnelle en Santé (PRTS) 2013

Project ID: ANR-13-PRTS-0002

Project coordinator:
Monsieur Gérard SOCIE (Equipe « Génome et Cancer »- Hôpital Saint-Louis)

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.