Clinical Trials /

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

NCT04180059

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • Hodgkin Lymphoma
  • Myelodysplastic Syndromes
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase I Study of CTL Anti-DP Infusion Post-hematopoietic Stem Cell Transplantation
  • Official 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.

Clinical Trial IDs

  • ORG STUDY ID: RC16_0157
  • NCT ID: NCT04180059

Conditions

  • Haematologic Disease

Purpose

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.

Detailed Description

      Rationale Despite graft-versus-tumor effect, relapse remains one of the main causes of
      morbidity and mortality in allo-HSCT recipients. Forty to 50% of deaths following allo-HSCT
      are due to disease relapse. In case of relapse, the prognosis is very poor and disease burden
      remains a challenge for the use of adoptive cellular therapy alone. The 3 year overall
      survival (OS) in case of post-transplant relapse is dismal. The post-transplant period is
      characterized by a prolonged phase of immunodeficiency leading to increased vulnerability to
      infections and risk of relapse. For this reason, maintenance or pre-emptive therapies for
      patients in CR (complete remission) are now considered to prevent future relapse. Following
      allo-HSCT, the recognition by donor T lymphocytes of recipient HLA antigens may result in
      different consequences. On one side, T cells may recognize antigens present on malignant
      cells and eradicate residual disease or prevent tumor relapse. On the other side, injection
      of unselected T cells may induce a graft-versus-host-disease (GVHD).

      HLA-DPB1 is one of MHC class II molecule lying centromeric to other class II loci on
      chromosome 6p21.3. Increase recombination events are found in the region between the HLA-DP
      loci and other class II loci, explaining the relative lack of linkage disequilibrium (LD)
      between HLA-DP (* HLA- DP: Human Leucocytes Antigen (DP allele))and the rest of MHC
      haplotype. For this reason, it is difficult to find a donor matched for DPB1 in addition to
      other classic HLA molecules. In sibling donors, the rate of incompatibility has been
      estimated to be as high as 10.9% and in unrelated donors a mismatch rate can be up to 89%.
      HLA-DPB1 is often not taken into consideration in donor selection. However HLA-DPB1 matching
      status has an impact on GVL 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. HLA class II molecules expression is mainly restricted to
      hematopoietic cells. Therefore, one could anticipate that a mismatched of HLA class II could
      induce a selective GVL reactivity without GVHD. However, HLA class II expression can be
      upregulated on various tissues following exposure to pro-inflammatory cytokines with a risk
      of GVHD as it is the case following some conditioning regimens or infections.

      The frequency of the different HLA-DPB1 alleles in the general population is well known:
      HLA-DPB1*04:01 is the most frequent (70.5%) HLA-DPB1*02:01 and and HLA-DPB1*03:01 represent
      32% and 20% respectively. 96% of leukemic cells could potentially be targeted with only three
      CTL clones directed against HLA-DPB1*04:01, 03:01 and 02:01.

      HLA-DP-expressing B cell and myeloid malignancies can be recognized and lysed by
      HLA-DP-specific CD4+ cells ( CD4+ : cluster of differentiation 4+). The majority of leukemic
      cells (AML, ALL, CLL) express HLA-DP. CD4+ cytotoxic T cell (CTL) clones recognizing
      specifically HLA-DPB1*04:01 can be identified and have been demonstrated to be able to kill
      HLA-DPB1*04:01 positive leukemic cells.

      In addition, it has already been shown that HLA-DP-specific CD4+ T cells can induce
      graft-versus-leukemia reactivity in the presence or absence of graft-versus-host disease. In
      this study the presence of HLA-DP-specific CD4+ T cells correlated with the clinical response
      to DLI.

      The team of the Inserm unit 1232 (H. Vié, B. Clemenceau, both co-investigators of this
      project) has developed a suicide gene-transduced CD4+ T cell clone that recognizes the
      HLA-DPB1*401, which is the most frequent HLA-DPB1 allele expressed by leukemic blasts (70%).
      This clone has been described in detailed in :"The doubling potential of T lymphocytes allows
      clinical-grade production of a bank of genetically modified monoclonal T-cell populations" by
      Vivien R et al. Cytotherapy. 2018 Mar;20(3):436-452.

      Several clinical trials have evaluated the possibility to inject, following allo-HSCT, donor
      lymphocytes transduced with a suicide gene either to treat tumor relapse or to accelerate the
      immune reconstitution. No acute infusion-related toxicity has been reported. Ganciclovir was
      used in some patients to control GVHD, leading to a rapid elimination of TK+ cells (tyrosine
      kinase +).

      The clone was obtained by performing a mixed lymphocytes culture (MLR) between two
      populations differing only by HLA-DP, and subsequently by transducing reactive T cells with
      high efficiency, and finally cloning them directly, before selecting each clone for the
      desired characteristics. Thanks to a clinical grade Herpes-simplex-virus-TK vector, the clone
      harbors a suicide gene and can be killed in presence of ganciclovir (GCV).

      This clone presents several important characteristics in terms of efficiency and safety. The
      clone is stable following thawing. It can be grown and amplified in vitro following thawing
      (at least more than one million times), while maintaining its cytotoxic capacity. It produces
      TH1-type cytokines in large amounts.

      Regarding the safety of the CTL antiDP under study, we emphasized on two major points:
      Specificity and sensitivity to ganciclovir:

      Specificity. The clone is specific for HLA-DPB1*04:01. The clone was selected against a donor
      homozygous for HLA-DPB1*04:01 (and identical for HLA-A, B, C, DQ, DR). Specificity testing
      confirmed the recognition of HLA-DPB1*:04:01. Yet, HLA-DPB1 alleles described are numerous
      (447 proteins to date IMGT (ImMunoGeneTics database)/HLA release,
      www.ebi.ac.uk/ipd/index.html), and it is just impossible to anticipate the cross reactions
      exhaustively (beyond some against HLA-DPB1*04:02 and HLA-DPB1*05:01 that have been observed
      against particular cell lines). The risk, since we are in a context of allo-HSCT, would be
      the recognition of donor cells and thus a possibility of graft rejection. For this reason, we
      will perform a pre-inclusion testing where donor cells will be used as targets for the clone.

      Sensitivity to ganciclovir (GCV) : The proliferation tests in the presence of GCV confirms
      the efficacy of GCV with sufficient margin according to GCV blood levels reached during a
      conventional treatment.

      Data from our colleagues show a low number of T cells detectable during the first months
      post-transplant, with a relative increased of Treg cells meaning that the clone may not be
      eliminated rapidly by donor T-cells.

      The reasons to administer a suicide gene-transduced CD4+ T cell clone recognizing
      HLA-DPB1*04:01 following allogeneic transplantation can be summarized in the following points
      :

      1. Relapse of the hematological malignancy remains a serious concern in these types of
      transplantation.

      3. The immune reconstitution is very delayed allowing for injection of a third party T cell
      clone.

      4. In case of GVHD following the CTL infusion, the CTL clone can be rapidly eliminated using
      ganciclovir.

      Hypothesis We hypothesize that the infusion of a third party suicide gene-transduced T cell
      clone directed against HLA-DPB1*04:01 following allogeneic transplantation can be safe and
      might protect against possible relapse of hematological malignancies

      Detailed description of the methodology (number of necessary subjects) Patients candidate for
      allogeneic transplantation who are both HLA-DPB1*04:01 and with aHLA-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. The expression of HLA-DPB1* by tumor cells will be checked by
      cytometry or immunohistochemistry. Any possible cross-reactivity of the clone against donor
      cells will also be excluded

      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.

      Conditioning regimens : no restriction

      The use of DLI in case of mixed chimerism or relapse is permitted after the clone infusion if
      necessary. In case of acute GVHD post CTL clone infusion, ganciclovir will be administered
      (at the dose of 5 mg/kg twice daily) for 14 days.
    

Trial Arms

NameTypeDescriptionInterventions
CTL 19 : T cell therapyExperimentalLevel 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.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Patients HLA-DPB1*04:01 positive, with confirmed diagnosis of hematologic malignancies
                 (AML, Myelodysplasic 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.
          
    Maximum Eligible Age:75 Years
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:determine maximal tolerated dose f 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.
    Time Frame:4 weeks after CTL injection
    Safety Issue:
    Description: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.

    Secondary Outcome Measures

    Measure:survival and persistence of the clone injected
    Time Frame:60 first days post injection, 6 months post injection, 12 months post injection
    Safety Issue:
    Description: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
    Measure:immune reconstitution
    Time Frame:day of clone injection, 30 days after clone injection, 60 days after clone injection, 9 months after clone injection, 12 months after clone injection
    Safety Issue:
    Description:T cell reconstitution will be evaluated by measuring the levels of CD4+, CD8+, Natural Killer cells
    Measure:incidence of relapse
    Time Frame:12 months post allograft
    Safety Issue:
    Description:Cumulative incidence of relapse
    Measure:survival
    Time Frame:12 months post allograft
    Safety Issue:
    Description:event free survival, overall survival
    Measure:GVHD incidence
    Time Frame:12 months post allograft
    Safety Issue:
    Description:cumulative incidence of acute and chronic GVHD
    Measure:mortality
    Time Frame:12 months post allograft
    Safety Issue:
    Description:death not related to relapse
    Measure:complete remission
    Time Frame:12 months post allograft
    Safety Issue:
    Description:for lymphoma patients in partial response before allograft
    Measure:side effects of Clone
    Time Frame:12 months post allograft
    Safety Issue:
    Description:events related to clone (except GVHD)

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Nantes University Hospital

    Trial Keywords

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

    Last Updated

    November 28, 2019