Natural Born Killers: NK Cells in Cancer Therapy

Abstract

Cellular therapy has emerged as an attractive option for the treatment of cancer, and adoptive transfer of chimeric antigen receptor (CAR) expressing T cells has gained FDA approval in hematologic malignancy. However, limited efficacy was observed using CAR-T therapy in solid tumors. Natural killer (NK) cells are crucial for tumor surveillance and exhibit potent killing capacity of aberrant cells in an antigen-independent manner. Adoptive transfer of unmodified allogeneic or autologous NK cells has shown limited clinical benefit due to factors including low cell number, low cytotoxicity and failure to migrate to tumor sites. To address these problems, immortalized and autologous NK cells have been genetically engineered to express high affinity receptors (CD16), CARs directed against surface proteins (PD-L1, CD19, Her2, etc.) and endogenous cytokines (IL-2 and IL-15) that are crucial for NK cell survival and cytotoxicity, with positive outcomes reported by several groups both preclinically and clinically. With a multitude of NK cell-based therapies currently in clinic trials, it is likely they will play a crucial role in next-generation cell therapy-based treatment. In this review, we will highlight the recent advances and limitations of allogeneic, autologous and genetically enhanced NK cells used in adoptive cell therapy.

Natural Killer Cells in Immunotherapy: Are We Nearly There?

“…The success achieved with the administration of genetically-modified CAR-T cells in hematological malignancies [48] has led to its adaptation to try to improve the efficacy of NK cells. It is expected that the use of genetically modified CAR-NK cells would avoid the low persistence and low efficacy of NK cells, and the failure to migrate to the tumor site [49]. Moreover, unlike CAR-T cells, CAR-NK cells would also present spontaneous cytotoxic activity, independently of target antigen [50].…”

Heterodimeric IL-15 in Cancer Immunotherapy

“…Overall, both pre-treatment with IL-15 and in vivo combination of IL-15 with CAR-T, CAR-NK and TILs provides advantages to treat cancers (for reviews, see also refs [ 130 , 131 , 132 ].…”

Heat Shock Proteins in Lymphoma Immunotherapy

“…Several investigators proposed the use of engineered NK cells as promising strategy for adoptive cell therapy in hematological malignancies (156). NK cells that are used in adoptive transfer can be allogeneic, autologous or immortalized such as NK-92 (156,157).…”

“…Several investigators proposed the use of engineered NK cells as promising strategy for adoptive cell therapy in hematological malignancies (156). NK cells that are used in adoptive transfer can be allogeneic, autologous or immortalized such as NK-92 (156,157). For research studies, NK cells can be isolated from peripheral blood or differentiated from stem cells, ex vivo expanded, activated with cytokines (IL-2, IL-15) and cocultured with g-irradiated feeder cells.…”

“…For research studies, NK cells can be isolated from peripheral blood or differentiated from stem cells, ex vivo expanded, activated with cytokines (IL-2, IL-15) and cocultured with g-irradiated feeder cells. It is important to point out that NK cells derived from peripheral blood mononuclear cells (PBMC) differ from NK cells differentiated from stem cells (156). For example, NK cells derived from cord blood showed no expression of CD57, high expression of NKG2A, lower expression of killer-immunoglobulin-like receptors (KIRs) and lower secretion of interferon-g (156,158).…”