Haploidentical NK-cell Infusion in Acute Myeloid Leukemia
Condition: Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Leukemia cells can be killed by natural killer (NK) from HLA-I mismatched donor. The proposed
      study plans to realize an adoptive anti-leukaemic immunotherapy by infusion of HLA-I
      mismatched NK cells to treat poor prognosis acute myeloid leukemia patients. NK cells will be
      selected from HLA mismatch familial donor peripheral mononuclear cells by purification
      protocol. Before NK-infusion, patients received immunosuppressive chemotherapy.
    

Detailed description: 
      NK cell-mediated cytotoxity is regulated by signals provided by surface inhibitory and
      activating receptors. Target cells will be killed in the absence of interaction between NK
      inhibitory receptors and their ligands (HLA class I molecules) on the target cells. The
      proposed phase I/II study plans to realize an adoptive anti-leukaemic immunotherapy by
      infusion of haploidentical HLA-I mismatched NK cells to treat poor prognosis AML patients.
      Familial donors of NK cells will be selected according to their HLA typing in order to choose
      a donor with NK cells expressing at least one inhibitory receptor that can not recognize any
      HLA class I molecule on recipient cells. NK cells will be selected from donor peripheral
      mononuclear cells by a two step purification protocol (CD3 negative with subsequent CD56
      positive selections). NK cells will be then activated ex vivo overnight in the presence of
      IL-2 before infusion. In vivo IL-2 injections will be performed for 14 days. Before
      NK-infusion, patients will be conditioned by a cytoreductive and immunosuppressive
      chemotherapy. An extensive biological study of NK cells will be performed in the recipient
      post-infusion, including chimerism analyses, phenotypic and functional tests in order to
      evaluate NK-cell expansion post-infusion and their capacity to mediate an antitumoral effect.
      Since donor NK cells have been selected for their potential graft versus host (GvH) and graft
      versus leukemia (GvL) reactivity, such approach might induce prolonged cytopenia due to a
      direct toxicity of NK cells against normal hematopoietic progenitors. The main goals of this
      study will be thus to evaluate (1) the hematological feasibility of allogeneic NK-cell
      infusion, (2) the expansion of the infused population, (3) an antitumoral effect mediated by
      this adoptive immunotherapy. This is an essential step before further development of such
      anti-tumoral immunotherapeutic approach, in leukemic patients but also in solid tumors that
      could be sensitive to an "NK-effect" (melanoma, kidney cancer).

      This project includes 4 clinical departments and several laboratories of cellular therapy and
      immunology that have got an expertise in the field of Acute Myeloid Leukemia (AML), cellular
      therapy and NK-cell.
    

Intervention name(s): Allogenic NK cells infusion
Intervention type(s): Drug
Intervention description(s): HLA Haploidentical selected NK cell infusion (one injection of 1x107/kg CD3-CD56+ cells) after chemotherapy associating fludarabine, cytosine arabinoside and cyclophosphamide.
Other intervention name(s): cellular therapy
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Natural killer cell; Haploidentical; Acute myeloid leukemia; Chemotherapy