Amplifying Graft-Versus-Tumor Effect by Donor Regulatory T-Cell Depletion Before Donor Lymphocytes Infusion (ILD-Treg)

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

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.

Study Overview

• Status: Completed
• Conditions: Hematologic Neoplasms; Relapse
• Intervention / Treatment: Procedure: donor lymphocyte infusion

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Créteil, France, 94000
    • Hôpital Henri Mondor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1	Procedure: donor lymphocyte infusion; regulatory T cells depletion; Other Names: regulatory T cells depletion

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Pierre and Marie Curie University; Université Paris XII
• Investigators: Principal Investigator: Sébastien Maury, MD Ph, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Maury S, Lemoine FM, Hicheri Y, Rosenzwajg M, Badoual C, Cherai M, Beaumont JL, Azar N, Dhedin N, Sirvent A, Buzyn A, Rubio MT, Vigouroux S, Montagne O, Bories D, Roudot-Thoraval F, Vernant JP, Cordonnier C, Klatzmann D, Cohen JL. CD4+CD25+ regulatory T cell depletion improves the graft-versus-tumor effect of donor lymphocytes after allogeneic hematopoietic stem cell transplantation. Sci Transl Med. 2010 Jul 21;2(41):41ra52. doi: 10.1126/scitranslmed.3001302.

Study record dates

Study Major Dates

• Study Start: December 1, 2005
• Primary Completion (ACTUAL): December 1, 2009
• Study Completion (ACTUAL): December 1, 2009

Study Registration Dates

• First Submitted: September 30, 2009
• First Submitted That Met QC Criteria: September 30, 2009
• First Posted (ESTIMATE): October 1, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): January 24, 2011
• Last Update Submitted That Met QC Criteria: January 21, 2011
• Last Verified: September 1, 2009

More Information

Terms related to this study

• Keywords: adult; allogeneic hematopoietic stem cell transplantation; regulatory T cells; hematological malignancy; donor lymphocyte infusion; antitumor immunotherapy; graft-versus-tumor effect
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Hematologic Diseases; Hematologic Neoplasms
• Other Study ID Numbers: P040441