<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/NCT04406207</url>
  </required_header>
  <id_info>
    <org_study_id>69HCL19_0851</org_study_id>
    <nct_id>NCT04406207</nct_id>
  </id_info>
  <brief_title>Endogenous Retroviruses in Acute Myeloid Leukemia</brief_title>
  <acronym>ERVAL</acronym>
  <official_title>Human Endogenous Retroviruses in Acute Myeloid Leukemia: Expression and Immune Impact</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospices Civils de Lyon</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospices Civils de Lyon</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for&#xD;
      numerous malignant hematologic diseases. Despite recent advances in the field, relapse rates&#xD;
      are still high and the first cause of death. The identification of new relevant therapeutic&#xD;
      targets is therefore urgently needed.&#xD;
&#xD;
      Human endogenous retroviruses (HERVs) are accounting for 8% of the human genome. While&#xD;
      silenced at the steady state (mainly by methylation mechanisms), HERVs reactivations have&#xD;
      been described in different conditions such as auto-immune diseases or cancer, leading to an&#xD;
      innate and adaptive immune response. Several questions are raised in the field of hematology&#xD;
      where few data are available, and the exact role of HERVs in these diseases is still to&#xD;
      define.&#xD;
&#xD;
      Our team is currently working on the role of HERVs in different types of cancer. We developed&#xD;
      a bioinformatics approach to identify overexpressed HERVs from RNAseq data. We also developed&#xD;
      in vitro assays to assess the immunogenicity of different peptides from HERVs open reading&#xD;
      frames and showed that several epitopes shared among different HERVs can induce a specific&#xD;
      CD8+ T cell response. More recently, we have analyzed 151 acute myeloid leukemia (AML) RNAseq&#xD;
      data from TCGA and identified multiple overexpressed HERVs in this disease. Immunogenicity&#xD;
      test are currently ongoing with patient's blood at diagnosis.&#xD;
&#xD;
      The main objective of this part of our project is to analyze the establishment of a&#xD;
      HERVs-specific CD8+ T cell response participating in graft-versus-leukemia effect after HSCT&#xD;
      for AML patients. Secondary objectives are to analyze relations between this response and&#xD;
      different clinical factors such as the onset of GVHD or relapse.&#xD;
&#xD;
      Peripheral blood mononuclear cells (PBMCs) from AML patients will be extracted and frozen at&#xD;
      different time point: diagnosis, complete remission (pre-HSCT) and after HSCT (M3, M6 and&#xD;
      M12). This prospective protocol is currently ongoing at the Centre Hospitalier Lyon Sud, with&#xD;
      around 30 samples already available.&#xD;
&#xD;
      After having selected relevant HERVs, specific dextramers identified by DNA barcode will be&#xD;
      synthesized. These dextramers allowing the identification of specific T cell responses&#xD;
      directed against up to 1000 epitopes, we will be able to screen specific T cells directed&#xD;
      against HERVs overexpressed in AML for most common HLA. Dextramer staining will be performed&#xD;
      on PBMCs after thawing. Positive cells will be sorted by flow cytometry and DNA will be&#xD;
      expanded by PCR before performing sequencing, allowing the identification of specific&#xD;
      sequences by its unique DNA barcode.&#xD;
&#xD;
      The analyze of HERVs-specific CD8+ T cell responses after HSCT will allow us to better define&#xD;
      HERVs role in the onset of graft-versus-leukemia effect. A specific T cell response without&#xD;
      GvHD will define the relevance of such peptides as tumor specific antigens.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    COVID-19&#xD;
  </why_stopped>
  <start_date type="Actual">June 1, 2020</start_date>
  <completion_date type="Actual">January 6, 2022</completion_date>
  <primary_completion_date type="Actual">January 6, 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>HERVs-specific CD8+ T cells responses</measure>
    <time_frame>Day 0</time_frame>
    <description>HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>HERVs-specific CD8+ T cells responses</measure>
    <time_frame>At remission &lt;- Day 0 + 1 month</time_frame>
    <description>HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>HERVs-specific CD8+ T cells responses</measure>
    <time_frame>Before transplant &lt;- Day 0 + 3 month</time_frame>
    <description>HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>HERVs-specific CD8+ T cells responses</measure>
    <time_frame>1 month</time_frame>
    <description>HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>HERVs-specific CD8+ T cells responses</measure>
    <time_frame>3 months</time_frame>
    <description>HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>HERVs-specific CD8+ T cells responses</measure>
    <time_frame>6 months</time_frame>
    <description>HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>HERVs-specific CD8+ T cells responses</measure>
    <time_frame>12 months</time_frame>
    <description>HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>HERVs-specific CD8+ T cells responses</measure>
    <time_frame>At relapse: up to 6 month after day 0</time_frame>
    <description>HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.</description>
  </primary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">0</enrollment>
  <condition>Leukemia, Myeloid</condition>
  <arm_group>
    <arm_group_label>Patients</arm_group_label>
    <description>Patients relapsing or not after hematopoietic stem cell transplantation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Demonstration of T cell responses</intervention_name>
    <description>Evaluation of HERVs-specific CD8+ T cells before and after hematopoietic stem cell transplantation. Comparison will be made in patients relapsing vs non relapsing patients.&#xD;
The measurement of these responses will be done by dextramer, allowing precise and specific measurement of the lymphocytes directed against the HERVs of interest.</description>
    <arm_group_label>Patients</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Adults &gt;= 18 years old with acute myeloid leukemia&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Acute myeloid leukemia (all subtypes)&#xD;
&#xD;
          -  Stem cell transplantation indication&#xD;
&#xD;
          -  Non opposition to the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        - Intensive care unit at diagnosis&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Vincent ALCAZER, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospices Civils de Lyon</affiliation>
  </overall_official>
  <removed_countries>
    <country>France</country>
  </removed_countries>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>May 13, 2020</study_first_submitted>
  <study_first_submitted_qc>May 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 28, 2020</study_first_posted>
  <last_update_submitted>August 18, 2022</last_update_submitted>
  <last_update_submitted_qc>August 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 22, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</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/NCT04406207
org study id: 69HCL19_0851
nct id: NCT04406207
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for
      numerous malignant hematologic diseases. Despite recent advances in the field, relapse rates
      are still high and the first cause of death. The identification of new relevant therapeutic
      targets is therefore urgently needed.

      Human endogenous retroviruses (HERVs) are accounting for 8% of the human genome. While
      silenced at the steady state (mainly by methylation mechanisms), HERVs reactivations have
      been described in different conditions such as auto-immune diseases or cancer, leading to an
      innate and adaptive immune response. Several questions are raised in the field of hematology
      where few data are available, and the exact role of HERVs in these diseases is still to
      define.

      Our team is currently working on the role of HERVs in different types of cancer. We developed
      a bioinformatics approach to identify overexpressed HERVs from RNAseq data. We also developed
      in vitro assays to assess the immunogenicity of different peptides from HERVs open reading
      frames and showed that several epitopes shared among different HERVs can induce a specific
      CD8+ T cell response. More recently, we have analyzed 151 acute myeloid leukemia (AML) RNAseq
      data from TCGA and identified multiple overexpressed HERVs in this disease. Immunogenicity
      test are currently ongoing with patient's blood at diagnosis.

      The main objective of this part of our project is to analyze the establishment of a
      HERVs-specific CD8+ T cell response participating in graft-versus-leukemia effect after HSCT
      for AML patients. Secondary objectives are to analyze relations between this response and
      different clinical factors such as the onset of GVHD or relapse.

      Peripheral blood mononuclear cells (PBMCs) from AML patients will be extracted and frozen at
      different time point: diagnosis, complete remission (pre-HSCT) and after HSCT (M3, M6 and
      M12). This prospective protocol is currently ongoing at the Centre Hospitalier Lyon Sud, with
      around 30 samples already available.

      After having selected relevant HERVs, specific dextramers identified by DNA barcode will be
      synthesized. These dextramers allowing the identification of specific T cell responses
      directed against up to 1000 epitopes, we will be able to screen specific T cells directed
      against HERVs overexpressed in AML for most common HLA. Dextramer staining will be performed
      on PBMCs after thawing. Positive cells will be sorted by flow cytometry and DNA will be
      expanded by PCR before performing sequencing, allowing the identification of specific
      sequences by its unique DNA barcode.

      The analyze of HERVs-specific CD8+ T cell responses after HSCT will allow us to better define
      HERVs role in the onset of graft-versus-leukemia effect. A specific T cell response without
      GvHD will define the relevance of such peptides as tumor specific antigens.
observational model: Cohort
time perspective: Prospective
measure: HERVs-specific CD8+ T cells responses
time frame: Day 0
description: HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.
measure: HERVs-specific CD8+ T cells responses
time frame: At remission <- Day 0 + 1 month
description: HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.
measure: HERVs-specific CD8+ T cells responses
time frame: Before transplant <- Day 0 + 3 month
description: HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.
measure: HERVs-specific CD8+ T cells responses
time frame: 1 month
description: HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.
measure: HERVs-specific CD8+ T cells responses
time frame: 3 months
description: HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.
measure: HERVs-specific CD8+ T cells responses
time frame: 6 months
description: HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.
measure: HERVs-specific CD8+ T cells responses
time frame: 12 months
description: HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.
measure: HERVs-specific CD8+ T cells responses
time frame: At relapse: up to 6 month after day 0
description: HERVs-specific CD8+ T cells responses will be monitored using DNA-barcode dextramers.
arm group label: Patients
description: Patients relapsing or not after hematopoietic stem cell transplantation.
intervention type: Other
intervention name: Demonstration of T cell responses
description: Evaluation of HERVs-specific CD8+ T cells before and after hematopoietic stem cell transplantation. Comparison will be made in patients relapsing vs non relapsing patients.
The measurement of these responses will be done by dextramer, allowing precise and specific measurement of the lymphocytes directed against the HERVs of interest.
arm group label: Patients
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Vincent ALCAZER, MD
role: Principal Investigator
affiliation: Hospices Civils de Lyon
country: France
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute