Interest in adoptive cell therapy for treating cancer is exploding due to early clinical successes of autologous chimeric antigen receptor (CAR) T lymphocytes. However, limitations using T cells and autologous cell products are apparent as they 1) take weeks to generate, 2) utilize a 1:1 donor to patient model, 3) are expensive, and 4) are prone to heterogeneity and manufacturing failures. CAR T cells are also associated with significant toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and prolonged cytopenias. To overcome these issues, natural killer (NK) cells are being explored as an alternative cell source for allogeneic cell therapies. NK cells have an inherent ability to recognize cancers, mediate immune functions of killing and communication, and do not induce graft-versus-host-disease, CRS, or ICANS. NK cells can be obtained from blood, cord blood, or derived from HSPCs/iPSCs, and be expanded and cryopreserved for off-the-shelf availability. The first wave of point-of-care NK cell therapies led to the current allogeneic NK cell products being investigated in clinical trials with promising preliminary results. Basic advances in NK cells biology and cellular engineering have led to new translational strategies to block inhibition, enhance and broaden target cell recognition, optimize functional persistence, and provide stealth from patients' immunity. This review details NK cell biology, as well as NK cell product manufacturing, engineering, and combination therapies explored in the clinic leading to the next generation of potent, off-the-shelf cellular therapies for blood cancers.

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