ILD-TK01: Suicide Gene Therapy for Donor Lymphocytes Infusion After Allogeneic Hematopoietic Stem Cell Transplantation

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Completed

CT.gov ID

NCT01086735

Collaborator

Paris 12 Val de Marne University (Other), Pierre and Marie Curie University (Other)

Enrollment

Location

Arm

Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main complications of allogeneic hematopoietic stem cell transplantation (HSCT) include graft-versus-host disease (GVHD) and poor immune reconstitution leading to severe infections and leukemia relapse. Mature donor T-cells present in the transplant facilitate T-cell reconstitution but also induce GVHD, which itself impairs immune reconstitution. We have developed a strategy of alloreactive T-cell depletion, using T-cells expressing the Herpes simplex thymidine kinase (TK) suicide gene combined with a ganciclovir (GCV) treatment. This system permits the selective elimination of dividing TK+ T-cells in vivo. To test this hypothesis in preclinical settings, we have previously developed several experimental models of GVHD using TK+ T-cells in mice. The demonstration that a preventive treatment with GCV administered close to the time of HSCT could control GVHD brought the proof of concept. We now propose a clinical trial to test whether donor lymphocytes infusion (DLI) using TK-transduced cells permits to induce a graft-versus-tumor (GVT) effect for treatment of relapse after HSCT, while GVHD can be controlled by GCV treatment.

Condition or Disease	Intervention/Treatment	Phase
Hematological Malignancy	Biological: donor lymphocyte infusion	Phase 1/Phase 2

Detailed Description

DLI-TK is administered either after failure of 1 or several previous standard (std-) DLI of, defined after a minimal follow-up of 2 months after the last injection. To prepare DLI-TK, donor T-cells are transduced with a retroviral vector encoding TK. Transduced cells are selected using a CliniMACS device (MYLTENYI). In case of previous std-DLI received, the DLI-TK cell dose is adjusted to be below or equal to the maximal cell dose previously received in std-DLI. No comparison is planned in the analysis.

Study Design

Study Type:

Interventional

Actual Enrollment :

11 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Suicide Gene Therapy for Donor Lymphocytes Infusion After Allogeneic Hematopoietic Stem Cell Transplantation: a Phase I/II Clinical Study

Study Start Date :

Feb 1, 2010

Actual Primary Completion Date :

Nov 1, 2012

Actual Study Completion Date :

Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: donor lymphocyte infusion Donor T-cell transduction	Biological: donor lymphocyte infusion Donor T-cell transduction

Arm

Intervention/Treatment

Experimental: donor lymphocyte infusion

Donor T-cell transduction

Biological: donor lymphocyte infusion

Donor T-cell transduction

Outcome Measures

Primary Outcome Measures

Incidence of "severe" GHVD (acute grade >II or chronic extensive) following DLI-TK and treatment with GCV [during the 12 months of follow-up]
Incidence of "severe" GHVD (acute grade >II or chronic extensive) following DLI-TK and treatment with GCV

Secondary Outcome Measures

The incidence of GVHD of any grade after DLI-TK [during the 12 months of follow-up]
The incidence of GVHD of any grade after DLI-TK
The anti-tumoral efficiency of DLI-TK to treat the relapse of the hematological malignancy [during the 12 months of follow-up]
The anti-tumoral efficiency of DLI-TK to treat the relapse of the hematological malignancy
The survival and the survival without disease after DLI-TK [during the 12 months of follow-up]
The survival and the survival without disease after DLI-TK

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Hematological malignancy.
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 without previous stdDLI.
Age > 18 years and < 70 years at the time of inclusion. For patients between 15 and 18 years of age, a case-per case inclusion will be studied.
Performance status considered on the score Eastern Cooperative Oncology Group (ECOG) <

Life expectation 1-month-old superior.
Signed written informed consent.
Negative human chorionic gonadotropin (HCG) in the 7 days preceding the inclusion for women in age of procreation.
Membership of the French national insurance.

Exclusion Criteria:

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 (alanine aminotransferase / aspartate transaminase (ALAT/ASAT) > 5 N, or bilirubin > 50 µM), or of the renal function (creatinine clearance < 30 ml / min).