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

Hematological Malignancy Clinical Trial

— ILD-TK01  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01086735
• Other study ID #: P010506
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: March 12, 2010
• Last updated: January 11, 2013
• Start date: February 2010
• Est. completion date: November 2012

Study information

• Verified date: January 2013
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 11
• Est. completion date: November 2012
• Est. primary completion date: November 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hematological Malignancy

Intervention

Biological:
• donor lymphocyte infusion
Donor T-cell transduction

Locations

Country	Name	City	State
France	Groupe Hospitalier Albert Chenevier-Henri Mondor	Creteil

Sponsors (3)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Paris 12 Val de Marne University, Pierre and Marie Curie University

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	Yes