Manufacturing of natural killer cells for treating solid malignancies

Abstract Objectives Natural killer (NK) cells are an attractive and potent tool for cancer immunotherapy, however, ex vivo expansion of NK cells is required to achieve therapeutic cell dosages. As such, this review will discuss recent NK cell manufacturing methods applied in clinical trials for expanded NK cells for the treatment of solid tumors, as well as investigational NK cell manufacturing protocols. Given the unique challenges posed by the solid tumor microenvironment, the main objective of this review is to highlight key biological mechanisms associated with tumor homing and infiltration of NK cells and how manufacturing methods impact these functions. Key findings For efficient adoptive NK cell therapy for the treatment of solid malignancies, NK cells need to extravasate from the blood stream, migrate through the tumor extracellular matrix, lyse cancer cells, activate other immune cells, and persist in the blood stream. The NK cell manufacturing process is complex, with each parameter influencing the expansion rate, and final NK cell number, purity, phonotype, and cytotoxicity. Many investigational and clinical NK cell manufacturing protocols generate high numbers of NK cells with greater cytotoxicity than freshly isolated NK cells. The expression of factors related to homing and migration in NK cells after ex vivo expansion is largely overlooked, but the few studies which have explored this indicate manufacturing processes can affect these critical mechanisms. Conclusion The current manufacturing protocols can generate high numbers of NK cells with increased cytotoxic functions, however understanding the effect of expansion on factors related to NK cell homing and migration is also important for treating solid malignancies. Furthermore, to progress the field of expanded NK cells for the treatment of solid tumors, improving “off-the-shelf” NK cell therapies and standardizing the manufacturing protocols and release criteria should be prioritized.