Haploidentical NK-cell Infusion in Bad Prognosis AML Patients: Evaluation of Feasibility and Antitumoral Effect

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.