Phase I Study of CTL Anti-DP Infusion Post-hematopoietic Stem Cell Transplantation

Condition(s) studied

Investigational drug(s) / intervention(s)

CTL 19: Patients candidate for allogeneic transplantation who are both HLA-DPB1\*04:01 and with a HLA-DPB1\*04:01-expressing hematological malignancy (almost 100% of cases) with a donor HLA-DPB1\*04:01 negative, will be proposed to receive one single infusion of the T cell clone at 4-5 months post-transplantation, once the immunosuppression by cyclosporine and/or mycophenolate mofetil has been discontinued.

Study summary

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.

Eligibility

Primary outcome measure(s)

• 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. — 4 weeks after CTL injection
  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 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 After study of toxicity of the 4 injected patients, choice has been made to stop the CRM method to choose the dose and to test only 2 doses for each last patients : 100 x 10\^4 cells/kg (actual level 5) and 500 x 10\^4 cells/kg (choice based on compassionnal injections data at the level 5)

Trial sites (1)

More Nantes University Hospital trials in France