Haematologic Disease Clinical Trial
— CTL-DP 01Official title:
A Phase 1 Dose-escalation Study Testing the Feasibility and the Tolerance of Infusion of a Specific Third Party Suicide Gene-transduced Anti-HLA-DPB1*0401 CD4+ T Cell Clone in HLA-DPB1*04:01 Positive Tumor Recipients Receiving an Allotransplant From a HLA-DPB1*04:01 Negative Donor.
For several decades, allogeneic hematopoietic stem cell trans-plantation (allo-HSCT) has remained an important strategy in the management of patients with high-risk hematological malignancies. The acceptance of umbilical cord blood (UCBT) and haploidentical grafts (Haplo) as viable alternative donors for allo-HSCT has increased the options for patients with no matched donors and now ensures that a donor can be identified for virtually all patients. Relapsed disease is a principal threat to these patients and affects 30-50% of them. The therapeutic options for these relapsing patients are diverse but remain largely ineffective in altering their long-term outcomes. Therefore, pre-emptive treatment post allo-HSCT is considered. MHC (major histocompatibility complex) class II molecules are a family of molecules normally found only on hematopoietic cells. cell-surface proteins are responsible for the regulation of the immune system in humans and are important in disease defense. They are the major cause of organ transplant rejections. Different HLA-DPB1 alleles exist in the general population. HLA-DPB1*04:01 is the most frequent (70.5%) while HLA-DPB1*02:01 represents 32% and HLA-DPB1*03:01 20%. In allo-HSCT, the donor and the recipient may express different HLA-DPB1 molecules. HLA-DPB1 matching status has an impact on GVL (graft versus leukemia) and GVHD. In recipients of HSCT, a match for DPB1 is associated with a significantly increased risk of disease relapse, irrespective of the matching status of other HLA molecules.. Therefore, one could anticipate that a mismatched of HLA class II could induce a selective GVL reactivity without GVHD. HLA-DP-expressing B cell and myeloid malignancies can be recognized and lysed by HLA-DP-specific T cells. The majority of leukemic cells (Acute Myeloid Leukemia, Acute Lymphoid Leukemia, Chronic Lymphoid Leukemia) express HLA-DP. A T cell clone recognizing specifically HLA-DPB1*0401 has been developed as a permanent cell line This clone has been demonstrated to be able to kill HLA-DPB1*0401 positive leukemic cells. In addition, this clone harbors a special suicide gene allowing the destruction of the clone in presence of a specific anti-viral drug named ganciclovir. We hypothesize that infusion of a third party suicide gene-transduced T cell clone directed against HLA-DPB1*401 might protect against possible relapse of hematological malignancies. We propose to inject iv escalating dose of a third party clone recognizing HLA-DPB1*04:01, 4 to 5 months following transplantation (when immunosuppressive drugs have been discontinued) in patients HLA-DPB1*04:01 positive with a donor HLA-DPB1*04:01 negative to evaluate the feasibility, toxicity, benefits of this immune intervention.
Status | Recruiting |
Enrollment | 20 |
Est. completion date | September 2025 |
Est. primary completion date | February 2025 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 75 Years |
Eligibility | Inclusion Criteria: - Patients HLA-DPB1*04:01 positive, with confirmed diagnosis of hematologic malignancies (AML, Myelodysplasic and myeloproliferative syndrome, ALL, non-Hodgkin's lymphoma, Hodgkin's disease, CLL), undergoing an allo-HSCT using a HLA-DPB1*04:01 negative donor. - The graft can be PBSC (peripheric blood stem cells) or bone marrow. - Patients aged between 18-75 years. - Patients in complete remission or >50% of response (for lymphoma) at time of transplant. - have a donor with no contra-indications for mobilization of peripheral blood stem cells using G-CSF (colony-stimulating factors) - Affiliation number to the National Health Care System - Lack of reactivity of the clone against the donor's cells (PHA-blasts prepared for from PBMCs). - For cord blood transplants: cord blood must be HLA-DPB1*04:01 negative and the HLA compatibility (A, B, DR) between the cord blood and the recipient must be 4/6, 5/6 or 6/6. - ECOG <=2 or Karnofsky >60% - neutrophils = 1 000 cells /µl and/or platelets = 50 000 cells/µl (growth factor allowed) Exclusion Criteria: - pregnant or breastfeeding woman - patient refusing contraception measure - minor - Adult patients under guardianship, curatorship or justice protection - Patients with post-transplant relapse within the clone injection time (before D100) - Karnofsky performance score below 60%or ECOG >2 - Acute and chronic heart failure (NYHA Class III or IV) or symptomatic ischemic heart disease. - Severe liver failure (bilirubin >30 µmoles/L, SGPT (Serum Glutamo-Oxalacetic Transaminase)> 4 X upper limit of normal). - Impaired renal function (creatinine clearance < 30 ml/min) - Acute GVHD > grade 1 - Active uncontrolled infection. - Denied to provide informed consent - Severe neurological or psychiatric disorders as determined by the study physician. - Treatment with other investigational drugs following allogeneic transplantation. |
Country | Name | City | State |
---|---|---|---|
France | Chu de Nantes | Nantes |
Lead Sponsor | Collaborator |
---|---|
Nantes University Hospital | INSERM U01232 CRCINA |
France,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | determine maximal tolerated dose of infusion of a third party suicide gene-transduced anti-HLA-DPB1*04:01 CD4+ T cell clone in HLA-DPB1*04:01 tumor positive recipients receiving an allo-HSCT from a HLA-DPB1*04:01 negative alternative donor. | the most likely side effects of the injection of the clone is the induction of an acute GVHD (severity measured by organ staging and overall clinical grading).
acute GVHD will be evaluated for each patient. Maximal tolerated dose is defined as : none acute GVHD for 3 patients on 3 or for at least 5 patients on 6. A standard 3 + 3 phase 1 dose-escalation study will be used: Level 1: 1 x 104 cells/kg of recipient, Level 2: 5 x 104 cells/kg, Level 3: 25 x 104 cells/kg, Level 4: 50 x 104 cells/kg, Level 5: 100 x 104 cells/kg. |
4 weeks after CTL injection | |
Secondary | survival and persistence of the clone injected | The survival of the clone will be tracked by PCR (polymerase chain reaction) during the 60 first days post injection as well as 6 and 12 months post injection in the blood and in the marrow | 6 hours after clone injection, 8 days post-injection, 15 days post-injection, 30 days post-injection, 60 days post-injection, 6 months post injection, 12 months post injection | |
Secondary | immune reconstitution | T cell reconstitution will be evaluated by measuring the levels of CD4+, CD8+, Natural Killer cells | day of clone injection, 30 days after clone injection, 60 days after clone injection, 9 months after clone injection, 12 months after clone injection | |
Secondary | incidence of relapse | Cumulative incidence of relapse | 12 months post allograft | |
Secondary | survival | event free survival, overall survival | 12 months post allograft | |
Secondary | GVHD incidence | cumulative incidence of acute and chronic GVHD | 12 months post allograft | |
Secondary | mortality | death not related to relapse | 12 months post allograft | |
Secondary | complete remission | for lymphoma patients in partial response before allograft | 12 months post allograft | |
Secondary | side effects of Clone | events related to clone (except GVHD) | 12 months post allograft |
Status | Clinical Trial | Phase | |
---|---|---|---|
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