Clinical trial NCT00987987: Amplifying Graft-Versus-Tumor Effect by Donor Regulatory T-Cell Depletion Before Donor Lymphocytes Infusion
Official title: Amplifying Graft-versus-tumor Effect by Donor Regulatory T-cell Depletion Before Donor Lymphocytes Infusion: a Phase I/II Clinical Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hematologic Neoplasms
Relapse
Keywords: hematological malignancy
allogeneic hematopoietic stem cell transplantation
donor lymphocyte infusion
antitumor immunotherapy
graft-versus-tumor effect
regulatory T cells
adult
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Université Paris XII
name: Pierre and Marie Curie University
First posted: 2009-10-01
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Incidence of "severe" GHVD (grade >II) following dDLI should be inferior to 40%.
timeFrame: 4 weeks after dDLI
Secondary outcomes:
measure: The incidence of GVHD of any grade after dDLI
timeFrame: during the 12 months
measure: The anti-tumoral efficiency of dDLI to treat the relapse of the hematological malignancy
timeFrame: during the 12 months
measure: The survival and the survival without disease after dDLI
timeFrame: during the 12 months
Other outcomes:
Locations:
city: Créteil
country: France
facility: Hopital Henri Mondor
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Sébastien Maury, MD Ph
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.