Carfilzomib combined with ex vivo-expanded patient autologous natural killer cells for myeloma immunotherapy

Abstract

Natural killer (NK) cell-based immunotherapy is promising, because NK cells form the first line of defense against cancer and are capable of lysing tumor cells without pre-stimulation. However, NK cells from multiple myeloma (MM) patients are always deficient in number, and the expression of certain activating receptors disables their cancer cyto-toxicity. Therefore, effective strategies to expand NK cells and increase NK cell-mediated cyto-toxicity against MM are imperative. Herein, NK cells were efficiently expanded from peripheral blood mononuclear cells (PBMCs) of newly diagnosed MM patients after co-culture with irradiated K562 cells transfected with 41BBL and membrane-bound interleukin (IL)-15 (K562-mb15-41BBL) in the presence of 200 IU/ml human IL-2. The ex vivo-expanded NK cells were demonstrated to vigorously kill both MM cells and autologous primary MM cells without significant lysis of normal patient cells. Further exploration revealed significant increase in cell surface expression of most activating receptors of NK cells and indicated that expanded NK (exp-NK) cell killing of MM cells was mediated by perforin/granzyme. NK cells are capable of lysing human leukocyte antigen (HLA) I-deficient tumor cells and carfizomib, a selective proteasome inhibitor approved for the treatment of relapsed/refractory MM patients down-regulates the expression of HLA class I, thus enhancing NK cell-mediated lysis in MM. Herein, we established for the first time that carfizomib dramatically augmented ex vivo exp-NK cell cytotoxicity against patient autologous MM cells, thus suggesting successful use of exp-NK alone or in combination with the drug in treating MM patient.