Amplifying Graft-Versus-Tumor Effect by Donor Regulatory T-Cell Depletion Before Donor Lymphocytes Infusion

Study Overview
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Brief Summary
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The investigators have previously shown that depletion of CD4+CD25+FoxP3+ regulatory T cells (Treg) enhances the alloreactivity of T lymphocytes, as attested by an accelerated GVHD after allogeneic hematopoietic stem cell transplantation (HSCT) in mice. The investigators thus propose a clinical trial to test whether Treg-depleted donor lymphocytes infusion (dDLI) could induce an improved graft-versus-tumor (GVT) effect in patients refractory to standard DLI (stdDLI) for treatment of relapse after HSCT.

Detailed Description
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We have previously shown that depletion of CD4+CD25+FoxP3+ regulatory T cells (Treg) enhances the alloreactivity of T lymphocytes, as attested by an accelerated GVHD after allogeneic hematopoietic stem cell transplantation (HSCT) in mice. We thus propose a clinical trial to test whether Treg-depleted donor lymphocytes infusion (dDLI) could induce an improved graft-versus-tumor (GVT) effect in patients refractory to standard DLI (stdDLI) for treatment of relapse after HSCT. dDLI is administered after failure of 1 or several previous stdDLI of at least 107 CD3+ cells/kg, defined after a minimal follow-up of 2 months after the last injection. The absence of previous clinical manifestations of GVHD is required to be included. To prepare dDLI, CD25+ Treg are depleted from donor leukaphereses using anti-CD25 magnetic microbeads and a CliniMACS device (MYLTENYI). In order to evidence the potential effect of dDLI, the dDLI cell dose is adjusted to be below or equal to the maximal cell dose previously received in stdDLI. No comparison is planned in the analysis.

Official Title
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Amplifying Graft-versus-tumor Effect by Donor Regulatory T-cell Depletion Before Donor Lymphocytes Infusion: a Phase I/II Clinical Study

Conditions
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Hematologic Neoplasms, Relapse

Intervention / Treatment
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* Procedure: donor lymphocyte infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hematological malignancy except chronic myeloid leukaemia. Previous allogeneic hematopoietic stem cell transplantation. Relapse diagnosed at the molecular, cytogenetic, or cytological level. Failure of a previous stdILD or inclusion in first intention if progressive disease. Age > 18 years and < 70 years at the time of inclusion. Performance status considered on the score ECOG < 2. Life expectation 1-month-old superior. Signed written informed consent. Negative HCG in the 7 days preceding the inclusion for women in age of procreation. Membership of the French national insurance. Exclusion Criteria: Chronic myeloid leukemia Grade >II acute GVHD or chronic extensive GVHD at the time of inclusion. Patient receiving an immunosuppressive treatment for GVHD treatment at the time of inclusion. Dysfunction of liver (ALAT/ASAT > 5 N, or bilirubin > 50 µM), or of the renal function (creatinine clearance < 30 ml / min).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>1 | Procedure: donor lymphocyte infusion<br>* regulatory T cells depletion<br>* Other names: regulatory T cells depletion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of severe GHVD (grade >II) following dDLI should be inferior to 40%. |  | 4 weeks after dDLI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of GVHD of any grade after dDLI |  | during the 12 months | 
| The anti-tumoral efficiency of dDLI to treat the relapse of the hematological malignancy |  | during the 12 months | 
| The survival and the survival without disease after dDLI |  | during the 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hematological malignancy, allogeneic hematopoietic stem cell transplantation, donor lymphocyte infusion, antitumor immunotherapy, graft-versus-tumor effect, regulatory T cells, adult