Hematological Malignancy
Conditions
Keywords
hematological malignancy, allogeneic hematopoietic stem cell transplantation, donor lymphocyte infusion, antitumor immunotherapy, graft-versus-tumor effect, gene therapy, relapse, adult
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.
Interventions
BIOLOGICALdonor lymphocyte infusion
Donor T-cell transduction
Sponsors
Paris 12 Val de Marne University
Pierre and Marie Curie University
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of severe GHVD (acute grade >II or chronic extensive) following DLI-TK and treatment with GCV | during the 12 months of follow-up | Incidence of severe GHVD (acute grade \>II or chronic extensive) following DLI-TK and treatment with GCV |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The incidence of GVHD of any grade after DLI-TK | during the 12 months of follow-up | The incidence of GVHD of any grade after DLI-TK |
| The anti-tumoral efficiency of DLI-TK to treat the relapse of the hematological malignancy | during the 12 months of follow-up | The anti-tumoral efficiency of DLI-TK to treat the relapse of the hematological malignancy |
| The survival and the survival without disease after DLI-TK | during the 12 months of follow-up | The survival and the survival without disease after DLI-TK |
Countries
France
Outcome results
None listed