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

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

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.

Study Overview

• Status: Completed
• Conditions: Hematological Malignancy
• Intervention / Treatment: Biological: donor lymphocyte infusion

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 Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Creteil, France, 94
    • Groupe Hospitalier Albert Chenevier-Henri Mondor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Pierre and Marie Curie University; Paris 12 Val de Marne University
• Investigators: Principal Investigator: Sébastien Maury, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: March 12, 2010
• First Submitted That Met QC Criteria: March 12, 2010
• First Posted (Estimate): March 15, 2010

Study Record Updates

• Last Update Posted (Estimate): January 14, 2013
• Last Update Submitted That Met QC Criteria: January 11, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: adult; relapse; gene therapy; allogeneic hematopoietic stem cell transplantation; hematological malignancy; donor lymphocyte infusion; antitumor immunotherapy; graft-versus-tumor effect
• Additional Relevant MeSH Terms: Behavioral Symptoms; Neoplasms by Site; Hematologic Diseases; Self-Injurious Behavior; Neoplasms; Hematologic Neoplasms; Suicide
• Other Study ID Numbers: P010506