<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02194868</url>
  </required_header>
  <id_info>
    <org_study_id>NI 12036</org_study_id>
    <nct_id>NCT02194868</nct_id>
  </id_info>
  <brief_title>Immunoregulatory T Lymphocytes Subtypes and Haematopoietic Stem Cell Transplantation (HSCT)</brief_title>
  <acronym>REG-Allo</acronym>
  <official_title>Role and Interactions Between Immunoregulatory T Lymphocytes Subtypes After Allogeneic Haematopoietic Stem Cell Transplantation (HSCT): Identification of New Partners Implicated on the Development of GVT (Graft Versus Tumor) and Anti-infectious Responses Without GVHD (Graft Versus Host Disease)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to confirm that invariant NKT lymphocytes (iNKT) reconstitution&#xD;
      in recipient and in the graft content can predict the outcome of human allogeneic HSCT and to&#xD;
      set up an algorithm for clinical practice that would allow the prediction of acute GVHD risk&#xD;
      according to the quantity and functionality&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment&#xD;
      in most haematological malignancies. However, its anti-tumor effect (GVT) is often associated&#xD;
      with the development of a graft versus host disease (GVHD) and impaired immune&#xD;
      anti-infectious responses. The predictive and protective features of iNKT cells on the&#xD;
      development of acute GVHD (aGVHD) are not or poorly known in humans and their mechanisms of&#xD;
      action, in particular their potential interactions with the other regulatory effectors and&#xD;
      immune actors of the allogeneic response, remain to be explored.&#xD;
&#xD;
      Our project aims, first, to show that the post-transplant reconstitution and/or the content&#xD;
      of the graft in some immunoregulatory T lymphocytes can early predict the post-transplant&#xD;
      clinical outcome and, second, to explore the underlying immunological mechanisms. For that,&#xD;
      we propose to analyse, in homogeneous cohorts of allografted patients and their donors, the&#xD;
      levels of iNKT cells and other cell populations implicated in the allogeneic immune response&#xD;
      (Tregs, mucosa-associated invariant T (MAIT) cells, delta gammaT and anti-viral specific T&#xD;
      cells) and correlate the results to the post-transplant outcome (GVHD, infections, relapse,&#xD;
      survival). This study will be performed in a cohort of 80 adult allografted patients in four&#xD;
      transplant departments in Paris (hospitals of Necker, Saint Antoine, Saint Louis and La Pitié&#xD;
      Salpétrière) and in a cohort of 60 allografted paediatric patients (Robert Debré hospital in&#xD;
      Paris). Sequential blood samples of patients will be drawn to monitor the immune&#xD;
      reconstitution of the different lymphocyte populations of interest by flow cytometry and&#xD;
      perform functional studies on iNKT (ex vivo expansion capacities and cytokine production).&#xD;
      These analyses will be also performed in the corresponding donors from blood samples&#xD;
      collected before the collection process and from the grafts (obtained by the cell therapy&#xD;
      departments of Necker, La Pitié Salpétrière and Saint Louis hospitals). In addition, we plan&#xD;
      to analyse the effect of, and the mechanisms by which, human cluster of differentiation 4&#xD;
      (CD4) CD4- and CD4+ iNKT cells might control the allogeneic response in vitro, particularly&#xD;
      via their potential interactions with dendritic cells and Tregs. According to the results of&#xD;
      the mechanistic studies, we will test the effect of human subtypes of iNKT cells on the&#xD;
      GVH/GVL affects in a preclinical humanized mouse model of allogeneic HSCT.&#xD;
&#xD;
      The clinical and biological data will be anonymously entered in the electronic case report by&#xD;
      the investigators up to 3 years post transplant.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 2, 2016</start_date>
  <completion_date type="Actual">January 18, 2022</completion_date>
  <primary_completion_date type="Actual">January 18, 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Occurrence of aGVHD</measure>
    <time_frame>until 3 years post graft</time_frame>
    <description>Patients' clinical files</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>iNKT and effectors of the immune allogeneic response</measure>
    <time_frame>until 3 years post graft</time_frame>
    <description>Correlation between iNKT and regulatory effectors of the immune allogeneic response (Assessed by multiparametric flow cytometry of blood sample)</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">57</enrollment>
  <condition>Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies</condition>
  <arm_group>
    <arm_group_label>donors of hematopoietic stem</arm_group_label>
    <description>Adult and minor donors of hematopoietic stem</description>
  </arm_group>
  <arm_group>
    <arm_group_label>patients requiring allogeneic hema</arm_group_label>
    <description>Adult and minor patients (recipients) requiring allogeneic hema</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Recipients</intervention_name>
    <description>Adult recipient:&#xD;
collected 20 ml pre-transplant&#xD;
collected 30 ml for adults on day 20 post-transplant at engraftment for cell phenotype,&#xD;
collected 30 ml on days 30, 60, 90, 180, 360 days post-HSCT for cell phenotyping at all time points, functional INKT at day 60 or 90 depending on the number of cells collected and anti-viral ELISPOT studies on days 180 and 360&#xD;
Children recipients&#xD;
collected residual blood pre-transplant&#xD;
collected residual blood on day 20 post-transplant at engraftment for cell phenotype,&#xD;
collected residual blood on days 20, 30, 90, 180 and 360 post-HSCT</description>
    <arm_group_label>patients requiring allogeneic hema</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Donors</intervention_name>
    <description>Adult donors :&#xD;
collected 20 ml of blood, (if possible before granulocyte colony-stimulating factor (GCSF) administration)&#xD;
collected 1 ml of the stem cell graft for adult recipient or 2 ml of bone marrow for children recipients These samples will be collected at the same time of those needed for transplant.&#xD;
Children donors samples&#xD;
collected residual blood&#xD;
2ml of bone marrow (bottom of tube)</description>
    <arm_group_label>donors of hematopoietic stem</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Whole blood, hematopoietic stem cell of bone marrow&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        The eligible patients will be select by the responsible physicians from clinical teams&#xD;
        involved in this study at their BMT staff. These physicians will propose the study to&#xD;
        selected patients and provide the informed consent.&#xD;
&#xD;
        Grafts and blood from donors of patients involved in this study will be provided by the&#xD;
        different cell therapy departments related to the clinical groups.&#xD;
&#xD;
        Peripheral blood from healthy donors will be obtained from volunteer donations to the&#xD;
        &quot;Etablissement Français du Sang&quot; (EFS).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Criteria for adults:&#xD;
&#xD;
               -  Allogeneic HSCT with peripheral blood stem cell (PBSC) graft&#xD;
&#xD;
               -  Patients transplanted in cytologic Complete Remission (CR)&#xD;
&#xD;
               -  HLA 10/10 on HLA A, B, Cw, DRB1 and DQ molecules, from an intrafamilial or an&#xD;
                  unrelated donor&#xD;
&#xD;
               -  - Fludarabine-ivBusulfan-ATG based reduced intensity/toxicity conditioning. Iv&#xD;
                  Busulfan doses between 6.4 mg/kg to 9.6 mg/kg or Fludarabine - TBI ≤ 8 Gy are&#xD;
                  accepted. ATG should be thymoglobuline at 5 mg/kg&#xD;
&#xD;
               -  Consent form signed by the patient&#xD;
&#xD;
               -  Consent form signed by the donor&#xD;
&#xD;
               -  Affiliated or beneficiary of a health insurance regimen&#xD;
&#xD;
          2. Criteria for pediatric patients:&#xD;
&#xD;
               -  Allogeneic HSCT with bone marrow grafts&#xD;
&#xD;
               -  Myeloablative conditioning (either TBI 12 Gy with Cyclophosphamide or iv Busulfan&#xD;
                  (12.8 mg/kg) and cyclophosphamide or Fludarabine - TBI &gt; 8 Gy)- HLA 10/10 on HLA&#xD;
                  A, B, Cw, DRB1 and DQ molecules, from an intrafamilial or an unrelated donor&#xD;
&#xD;
               -  Consent form signed by the parents&#xD;
&#xD;
               -  Consent form signed by the donor or his legal representative if it is minor&#xD;
&#xD;
               -  Beneficiary of a health insurance regimen&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of previous autologous or allogeneic haematopoietic stem cell transplantation&#xD;
&#xD;
          -  Disease non in cytologic CR at transplant&#xD;
&#xD;
          -  Other type of conditioning than Fludarabine-ivBusulfan-ATG based reduced&#xD;
             intensity/toxicity.&#xD;
&#xD;
          -  Donor graft with any HLA mismatch including haploidentical and cord blood grafts&#xD;
&#xD;
          -  Graft having one or more mismatch with the recipient HLA&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Marie-Thérèse Rubio, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>CHU Nancy</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Olivier Hermine, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hopital Necker</name>
      <address>
        <city>Paris</city>
        <zip>75015</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>July 17, 2014</study_first_submitted>
  <study_first_submitted_qc>July 17, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 18, 2014</study_first_posted>
  <last_update_submitted>September 26, 2022</last_update_submitted>
  <last_update_submitted_qc>September 26, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 27, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Allogeneic hematopoietic stem cell transplantation,</keyword>
  <keyword>Immunoregulatory T lymphocytes,</keyword>
  <keyword>acute graft versus host disease</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hematologic Neoplasms</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02194868
org study id: NI 12036
nct id: NCT02194868
lead sponsor: 
has dmc: No
The purpose of this study is to confirm that invariant NKT lymphocytes (iNKT) reconstitution
      in recipient and in the graft content can predict the outcome of human allogeneic HSCT and to
      set up an algorithm for clinical practice that would allow the prediction of acute GVHD risk
      according to the quantity and functionality
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment
      in most haematological malignancies. However, its anti-tumor effect (GVT) is often associated
      with the development of a graft versus host disease (GVHD) and impaired immune
      anti-infectious responses. The predictive and protective features of iNKT cells on the
      development of acute GVHD (aGVHD) are not or poorly known in humans and their mechanisms of
      action, in particular their potential interactions with the other regulatory effectors and
      immune actors of the allogeneic response, remain to be explored.

      Our project aims, first, to show that the post-transplant reconstitution and/or the content
      of the graft in some immunoregulatory T lymphocytes can early predict the post-transplant
      clinical outcome and, second, to explore the underlying immunological mechanisms. For that,
      we propose to analyse, in homogeneous cohorts of allografted patients and their donors, the
      levels of iNKT cells and other cell populations implicated in the allogeneic immune response
      (Tregs, mucosa-associated invariant T (MAIT) cells, delta gammaT and anti-viral specific T
      cells) and correlate the results to the post-transplant outcome (GVHD, infections, relapse,
      survival). This study will be performed in a cohort of 80 adult allografted patients in four
      transplant departments in Paris (hospitals of Necker, Saint Antoine, Saint Louis and La Pitié
      Salpétrière) and in a cohort of 60 allografted paediatric patients (Robert Debré hospital in
      Paris). Sequential blood samples of patients will be drawn to monitor the immune
      reconstitution of the different lymphocyte populations of interest by flow cytometry and
      perform functional studies on iNKT (ex vivo expansion capacities and cytokine production).
      These analyses will be also performed in the corresponding donors from blood samples
      collected before the collection process and from the grafts (obtained by the cell therapy
      departments of Necker, La Pitié Salpétrière and Saint Louis hospitals). In addition, we plan
      to analyse the effect of, and the mechanisms by which, human cluster of differentiation 4
      (CD4) CD4- and CD4+ iNKT cells might control the allogeneic response in vitro, particularly
      via their potential interactions with dendritic cells and Tregs. According to the results of
      the mechanistic studies, we will test the effect of human subtypes of iNKT cells on the
      GVH/GVL affects in a preclinical humanized mouse model of allogeneic HSCT.

      The clinical and biological data will be anonymously entered in the electronic case report by
      the investigators up to 3 years post transplant.
observational model: Cohort
time perspective: Prospective
measure: Occurrence of aGVHD
time frame: until 3 years post graft
description: Patients' clinical files
measure: iNKT and effectors of the immune allogeneic response
time frame: until 3 years post graft
description: Correlation between iNKT and regulatory effectors of the immune allogeneic response (Assessed by multiparametric flow cytometry of blood sample)
arm group label: donors of hematopoietic stem
description: Adult and minor donors of hematopoietic stem
arm group label: patients requiring allogeneic hema
description: Adult and minor patients (recipients) requiring allogeneic hema
intervention type: Biological
intervention name: Recipients
description: Adult recipient:
collected 20 ml pre-transplant
collected 30 ml for adults on day 20 post-transplant at engraftment for cell phenotype,
collected 30 ml on days 30, 60, 90, 180, 360 days post-HSCT for cell phenotyping at all time points, functional INKT at day 60 or 90 depending on the number of cells collected and anti-viral ELISPOT studies on days 180 and 360
Children recipients
collected residual blood pre-transplant
collected residual blood on day 20 post-transplant at engraftment for cell phenotype,
collected residual blood on days 20, 30, 90, 180 and 360 post-HSCT
arm group label: patients requiring allogeneic hema
intervention type: Biological
intervention name: Donors
description: Adult donors :
collected 20 ml of blood, (if possible before granulocyte colony-stimulating factor (GCSF) administration)
collected 1 ml of the stem cell graft for adult recipient or 2 ml of bone marrow for children recipients These samples will be collected at the same time of those needed for transplant.
Children donors samples
collected residual blood
2ml of bone marrow (bottom of tube)
arm group label: donors of hematopoietic stem
Whole blood, hematopoietic stem cell of bone marrow
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Marie-Thérèse Rubio, MD, PhD
role: Principal Investigator
affiliation: CHU Nancy
last name: Olivier Hermine, MD, PhD
role: Study Director
affiliation: Assistance Publique - Hôpitaux de Paris
facility: 
country: France
responsible party type: Sponsor
mesh term: Hematologic Neoplasms