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.

Who is this study for? Patients HLA-DPB1*04:01 positive, with hematologic malignancies undergoing an allo-HSCT using a HLA-DPB1*04:01 negative donor
What treatments are being studied? CTL 19
Status: Recruiting
Location: See location...
Intervention Type: Combination product
Study Type: Interventional
Study Phase: Phase 1
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
Participation Requirements
Sex: All
Minimum Age: 18
Maximum Age: 75
Healthy Volunteers: f
View:

• 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)

Locations
Other Locations
France
Chu de Nantes
RECRUITING
Nantes
Contact Information
Primary
thierry GUILLAUME, MD
thierry.guillaume@chu-nantes.fr
02.40.08.48.45
Backup
Beatrice CLEMENCEAU, PhD
beatrice.clemenceau@univ-nantes.fr
02 28 08 02 30
Time Frame
Start Date: 2020-02-09
Estimated Completion Date: 2027-08
Participants
Target number of participants: 6
Treatments
Experimental: CTL 19 : T cell therapy
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)
Sponsors
Leads: Nantes University Hospital
Collaborators: Institut National de la Santé Et de la Recherche Médicale, France

This content was sourced from clinicaltrials.gov