Production of cytotoxic, KIR-negative NK cells from CD34+ cord blood cells with the use of Notch signaling.

The use of natural killer (NK) cells as cell therapy against acute leukemia is an active area of investigation. The optimal source of cytotoxic NK cells for therapeutic use is presently unknown. With funds from the National Blood Foundation, the author's lab has developed in vitro culture systems that use the Notch receptor ligand Delta4 for the differentiation and expansion of functional NK cells from CD34+ cord blood hematopoietic progenitor cells. These Notch-induced NK (N-NK) cells display a predominantly immature, CD56(bright) surface phenotype, with expression of activating receptors important for leukemia cell recognition and killing, but with an absence of inhibitory receptors that bind major histocompatibility complex (MHC) class I, making them free of restriction by self-MHC. They are capable of directly killing hematopoietic tumor cell lines and primary leukemia cells in vitro. Thus, cytotoxic, HLA-independent N-NK cells may represent a novel cell therapy for hematopoietic malignancy.