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

NCT04180059 | Recruiting Phase 1 DMC

• 1 other identifier: RC16_0157
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Haematologic Disease

Keywords

hematopoietic stem cell transplantation; lymphocyte infusion; cytotoxic T lymphocyte; HLA-DP; T cell therapy

Outcome Measures

Primary Outcomes (1)

• 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 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)

  4 weeks after CTL injection

Secondary Outcomes (8)

• survival and persistence of the clone injected

  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

• immune reconstitution

  day of clone injection, 30 days after clone injection, 60 days after clone injection, 9 months after clone injection, 12 months after clone injection

• incidence of relapse

  12 months post allograft

• survival

  12 months post allograft

• GVHD incidence

  12 months post allograft

Study Arms (1)

CTL 19 : T cell therapy

EXPERIMENTAL

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)

Combination Product: CTL 19

Interventions

CTL 19 COMBINATION_PRODUCT

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.

Also known as: T cell therapy

CTL 19 : T cell therapy

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• Nantes University Hospital: lead
• Institut National de la Santé Et de la Recherche Médicale, France: collaborator

Study Sites (1)

Chu de Nantes

Nantes, France

RECRUITING

MeSH Terms

Conditions

Hematologic Diseases

Interventions

Immunotherapy, Adoptive

Condition Hierarchy (Ancestors)

Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Adoptive Transfer; Immunization, Passive; Immunization; Immunotherapy; Immunomodulation; Biological Therapy; Therapeutics; Immunologic Techniques; Investigative Techniques

Central Study Contacts

thierry GUILLAUME, MD

CONTACT

02.40.08.48.45; thierry.guillaume@chu-nantes.fr

Beatrice CLEMENCEAU, PhD

CONTACT

02 28 08 02 30; beatrice.clemenceau@univ-nantes.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Biological, T cell clone A standard phase 1 dose-escalation study will be used: Level 1: 1 x 10\^4 cells/kg of recipient, Level 2: 5 x 10\^4 cells/kg, Level 3: 25 x 10\^4 cells/kg, Level 4: 50 x 10\^4 cells/kg, Level 5: 100 x 10\^4 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)

Study Record Dates

• First Submitted: November 25, 2019
• First Posted: November 27, 2019
• Study Start: February 9, 2020
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): August 1, 2027
• Last Updated: January 26, 2026

Record last verified: 2026-01

Locations

FR (1)