Biology of NK Cells and NK Cells in Clinic

Natural killer (NK) cells are innate lymphoid cells with the capacity to detect and destroy malignant cells without requiring prior sensitization. As a result of their innate ability to target malignant cells, these cells are an attractive candidate for immune therapies for cancer. Initial studies following hematopoietic cell transplants for cancer therapy illuminated a potential role for NK cells in exerting a graft versus leukemia effect without initiating graft versus host disease (GVHD). The use of NK cells in non-transplant settings showed that infusion of NK cells from HLA-haploidentical donors in combination with IL-2 after lymphodepletion lead to remission in a number of patients with poor prognosis AML. Since then, various methods of activating and expanding NK cells for use in the clinical setting have been investigated. Preliminary studies show promise for the use of NK cells in a vast range of solid and liquid tumor settings including glioblastoma, colorectal cancer and ovarian cancer. Activation of peripheral blood derived NK cells with cytokines has been shown to induce a memory-like phenotype which results in expansion and persistence in vivo pre-clinical models as well as augmented response against tumor targets in vitro. These memory-like NK cells are currently being investigated in clinical trials for a range of cancer types and offer great promise for the future. Utilization of cord blood derived NK cells as well as iPSC-differentiated NK cells and immortalized NK cell lines are also being investigated with the hope to offer off-the shelf immunotherapies for malignant diseases. This chapter will discuss the biology of NK cells, their development from progenitor cells in the bone marrow and the balance of inhibitory and activating receptors that govern their interactions with both healthy and malignant cells. Methods for culture and expansion of NK cells both from peripheral blood cord blood and iPSC-differentiated NK cells will also be discussed as well as potential future directions for the use of CAR-NK cells.