Clinical trial NCT01086735: Suicide Gene Therapy for Donor Lymphocytes Infusion After Allogeneic Hematopoietic Stem Cell Transplantation
Official title: Suicide Gene Therapy for Donor Lymphocytes Infusion After Allogeneic Hematopoietic Stem Cell Transplantation: a Phase I/II Clinical Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hematological Malignancy
Keywords: hematological malignancy
allogeneic hematopoietic stem cell transplantation
donor lymphocyte infusion
antitumor immunotherapy
graft-versus-tumor effect
gene therapy
relapse
adult
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Paris 12 Val de Marne University
name: Pierre and Marie Curie University
First posted: 2010-03-15
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Incidence of "severe" GHVD (acute grade >II or chronic extensive) following DLI-TK and treatment with GCV
timeFrame: during the 12 months of follow-up
Secondary outcomes:
measure: The incidence of GVHD of any grade after DLI-TK
timeFrame: during the 12 months of follow-up
measure: The anti-tumoral efficiency of DLI-TK to treat the relapse of the hematological malignancy
timeFrame: during the 12 months of follow-up
measure: The survival and the survival without disease after DLI-TK
timeFrame: during the 12 months of follow-up
Other outcomes:
Locations:
city: Creteil
country: France
facility: Groupe Hospitalier Albert Chenevier-Henri Mondor
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Sébastien Maury, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: