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

Assistance Publique - Hôpitaux de Paris

Status and phase

Completed

Phase 2

Phase 1

Conditions

Hematological Malignancy

Treatments

Biological: donor lymphocyte infusion

Study type

Interventional

Funder types

Other

Identifiers

NCT01086735

P010506

Details and patient eligibility

About

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.

Full 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.

Enrollment

11 patients

Sex

All

Ages

18 to 70 years old

Volunteers

No 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) < 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).