title: Development of allogeneic NK cell adoptive transfer therapy in metastatic melanoma patients: in vitro preclinical optimization studies.
abstract: Natural killer (NK) cells have long been considered as potential agents for adoptive cell therapy for solid cancer patients. Until today most studies utilized autologous NK cells and yielded disappointing results. Here we analyze various modular strategies to employ allogeneic NK cells for adoptive cell transfer, including donor-recipient HLA-C mismatching, selective activation and induction of melanoma-recognizing lysis receptors, and co-administration of antibodies to elicit antibody-dependent cell cytotoxicity (ADCC). We show that NK cell activation and induction of the relevant lysis receptors, as well as co-administration of antibodies yield substantial anti-cancer effects, which are functionally superior to HLA-C mismatching. Combination of the various strategies yielded improved effects. In addition, we developed various clinically-compatible ex vivo expansion protocols that were optimized according to fold expansion, purity and expression of lysis receptors. The main advantages of employing allogeneic NK cells are accessibility, the ability to use a single donor for many patients, combination with various strategies associated with the mechanism of action, e.g. antibodies and specific activation, as well as donor selection according to HLA or CD16 genotypes. This study rationalizes a clinical trial that combines adoptive transfer of highly potent allogeneic NK cells and antibody therapy.
authors.affiliation: Ella Institute of Melanoma, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Besser
authors.forename: Tsipi
authors.initials: T
authors.lastname: Shoham
authors.forename: Orit
authors.initials: O
authors.lastname: Harari-Steinberg
authors.forename: Naama
authors.initials: N
authors.lastname: Zabari
authors.forename: Rona
authors.initials: R
authors.lastname: Ortenberg
authors.forename: Arkadi
authors.initials: A
authors.lastname: Yakirevitch
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Ron
authors.initials: R
authors.lastname: Loewenthal
authors.forename: Jacob
authors.initials: J
authors.lastname: Schachter
authors.forename: Gal
authors.initials: G
authors.lastname: Markel
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D060005:Genotyping Techniques; D015236:HLA-C Antigens / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D016219:Immunotherapy, Adoptive; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D009362:Neoplasm Metastasis; D054340:Receptors, KIR / Q000378:metabolism; D014019:Tissue Donors
chemical_list: D015236:HLA-C Antigens; D008024:Ligands; D054340:Receptors, KIR