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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Hematological Malignancy

Intervention / Treatment
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* Biological: donor lymphocyte infusion


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: donor lymphocyte infusion<br>Donor T-cell transduction | Biological: donor lymphocyte infusion<br>* Donor T-cell transduction<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hematological malignancy, allogeneic hematopoietic stem cell transplantation, donor lymphocyte infusion, antitumor immunotherapy, graft-versus-tumor effect, gene therapy, relapse, adult