Suicide Gene Therapy for Donor Lymphocytes Infusion After Allogeneic Hematopoietic Stem Cell Transplantation

Phase 1

Completed

• Conditions: Hematological Malignancy
• Interventions: Biological: donor lymphocyte infusion

• Registration Number: NCT01086735
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

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.

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 Timeline

• Study Start: 2010-02
• Study First Submitted: 2010-03-12
• Study First Submitted QC: 2010-03-12
• Study First Posted: 2010-03-15
• Primary Completion: 2012-11
• Study Completion: 2012-11
• Status Verified: 2013-01
• Last Update Submitted: 2013-01-11
• Last Update Posted: 2013-01-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 11

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) < 2.
• 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.

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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).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
donor lymphocyte infusion	donor lymphocyte infusion	Donor T-cell transduction

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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

Trial Locations

Locations (1)

Groupe Hospitalier Albert Chenevier-Henri Mondor; 🇫🇷 Creteil, France