Generating natural killer cells for adoptive transfer: expanding horizons

Natural killer (NK) cells are unique innate lymphoid cells that have therapeutic potential in adoptive cell transfer-based cancer immunotherapy that has been established across a range of early-phase clinical trials. NK cells for use in adoptive transfer therapies are obtained from various sources, including primary NK cells from peripheral blood or apheresis products (autologous or allogeneic) and umbilical cord blood. NK cells have also been generated from CD34+ hematopoietic progenitors, induced pluripotent stem cells, embryonic stem cells and malignant cell lines. Apheresis-derived NK cell products are often administered after brief cytokine-based ex vivo activation, ideally aiming for in vivo expansion and proliferation. NK cells from other sources or from smaller volumes of blood require a longer period of expansion prior to therapeutic use. Although ex vivo NK cell expansion introduces a concern for senescence and exhaustion, there is also an opportunity to achieve higher NK cell doses, modulate NK cell activation characteristics and apply genetic engineering approaches, ultimately generating potent effector cells from small volumes of readily available starting materials. Herein the authors review the field of clinical-grade NK cell expansion, explore the desirable features of an idealized NK cell expansion approach and focus on techniques used in recently published clinical trials.