Acute Myeloid Leukemia Clinical Trial
Official title:
Haploidentical NK-cell Infusion in Bad Prognosis AML Patients: Evaluation of Feasibility and Antitumoral Effect
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.
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.
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