Allogeneic Immunotherapy of Hematological Malignancies Using Regulatory T-cell Selective Depletion

Study Overview
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Brief Summary
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Since the discovery that Treg suppress anti-tumor immune responses, inhibiting their function has become a major challenge for the development of efficient immunotherapy for cancer. In humans, we previously reported the positive results of the first clinical trial using Treg depletion for anti-tumor response amplification ( ILD-Treg-1  trial) in the field of allogeneic hematopoietic stem cell transplantation (HSCT). The present project aims at developing this anti-tumor immunotherapeutic strategy in the same setting, i.e. donor lymphocyte infusion (DLI) for relapsing hematological malignancies after HSCT, using a new selection marker: CD127. The choice of this new strategy is supported by our results of a retrospective clinical already published study and also by a pre-clinical research funded by French institutions (INCA-DGOS-INSERM). Using human cells, this last study demonstrated, in vitro and in vivo in animal murine models, that Treg depletion through CD127 positive selection is much more efficient to improve allogeneic immune responses of donor T-cells as compared to the previous strategy using the CD25 marker.

Official Title
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Allogeneic Immunotherapy of Hematological Malignancies Using Regulatory T-cell Selective Depletion

Conditions
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Hematological Malignancies, Regulatory T Cell Depletion, Relapse

Intervention / Treatment
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* Drug: T-reg depleted DLI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patient (older than 18 years old without upper limit of age) diagnosed with leukemia, myelodysplasia, myeloproliferative disorder or lymphoproliferative disorder (CLL, myeloma, lymphoma) Previous allogeneic HSCT from a matched sibling, haplo-identical or unrelated donor (any type of conditioning regimen) Haematological relapse (molecular, cytogenetic or cytological) after HSCT Patient refractory (no or partial response) to one or several previous standard unmanipulated DLI Availability of cryopreserved lymphapheresis No loss of chance by using of DLI rather than more incisive anti-tumor agents according to investigator appreciation Written informed consent before any intervention necessary for the trial Affiliation to a social security regime Negative pregnancy test for women of childbearing age participating in the study Effective contraceptive methods for men / women in line with the current CTFG recommendations version 1.1 Exclusion Criteria: Acute grade ≥ II or moderate/severe chronic GVHD at the time of inclusion Patient receiving immunosuppressive treatment for GVHD or any other reason Creatinine clearance< 50 ml/min Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) > 5.0 x upper limit of normal (ULN) Serum total bilirubin > 50µM (expect for unconjugated hyperbilirubinemia due to Gilbert's disease) Performance status ECOG>1 Severe infection according to CTCAE grading (grade>2) Pregnant or lactating women Patient under tutorship, curatorship or legal protection Ongoing participation in another interventional research protocol within the same field of immune modulation (through cell therapy or not) State medical aid

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T-reg depleted DLI<br> | Drug: T-reg depleted DLI<br>* Treg depleted Donor Lymphocytes Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cumulative incidence of GVHD in its acute grade ≥ II and/or severe chronic form (according Glucksberg-Thomas and NIH scales, respectively), and uncontrolled after a 14-day immunosuppressive course including steroids. | Composite criteria. In this evaluation, death from non-GVHD cause will be taken as a competitive event | occurring within the 2 months following d-DLI infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute and/or chronic GVHD, with corresponding grades according to NIH and Glucksberg-Thomas scales |  | at 2 and 12 month | 
| Date of putative relapse/progression for estimation of cumulative incidence (taking into account the competitive risk of death not related to relapse) |  | at 2 and 12 month | 
| Date of putative relapse/progression for estimation disease-free survival |  | at 2 and 12 month | 
| Number, causes and date of deaths |  | at 2 and 12 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLI, Regulatory T cells depletion, Hematological malignancies, Relapse