Abstract
Treatment of cancer with allogeneic natural killer (NK) cell therapies has seen rapid development, especially use against hematologic malignancies. Clinical trials of NK cell-based adoptive transfer to treat relapsed or refractory malignancies have used peripheral blood, umbilical cord blood and pluripotent stem cell-derived NK cells, with each approach undergoing continued clinical development. Improving the potency of these therapies relies on genetic modifications to improve tumor targeting and to enhance expansion and persistence of the NK cells. Induced pluripotent stem cell (iPSC)-derived NK cells allow for routine targeted introduction of genetic modifications and expansion of the resulting NK cells derived from a clonal starting cell population. In this review, we discuss and summarize recent important advances in the development of new iPSC-derived NK cell therapies, with a focus on improved targeting of cancer. We then discuss improvements in methods to expand iPSC-derived NK cells and how persistence of iPSC-NK cells can be enhanced. Finally, we describe how these advances may combine in future NK cell-based therapy products for the treatment of both hematologic malignancies and solid tumors.
Highlights
Over the past decade, cellular therapies have advanced from pre-clinical studies through clinical trials and to several U.S Food and Drug Administration (FDA) approved therapies
An additional manufacturing issue with autologous chimeric antigen receptor (CAR)-T cell therapies is that patients who have previously received multiple rounds Induced pluripotent stem cell (iPSC)-Derived natural killer (NK) Cell Therapies of chemotherapy may not be able to mobilize sufficient T cells for CAR-T cell production with up to 10-30% of patients that fail CART cell manufacturing [3, 5, 7]
Another approach employed by two groups used an IL-15 receptor fusion construct comprising of an IL-15 superagonist and IL-15 receptor a (IL-15SA/IL-15RA) to increase anti-tumor activity of Peripheral blood NK (PB-NK) and iPSC-NK cells, respectively, in vitro and in vivo [40, 88]
Summary
Cellular therapies have advanced from pre-clinical studies through clinical trials and to several U.S Food and Drug Administration (FDA) approved therapies Despite these successes, the FDA approved chimeric antigen receptor (CAR) T cell therapies for B-cell acute lymphoblastic leukemia (B-ALL), B-cell lymphomas and multiple myeloma are limited by their manufacturing processes and treatment-related toxicity [1]. The cost of CAR-T cell manufacturing is typically $300,000-$500,000 for each patient, even before the costs of care Due to these limitations of autologous CAR-T cells, allogenic T cell approaches and alternative cell sources for cellular therapy have been investigated. NK cells are recognized to play a key role in the anti-tumor activity of allogeneic hematopoietic cell transplantation [25] Because of these potential advantages, NK cells obtained from various sources have been tested as a specific cell population for adoptive transfer to treat cancer patients in clinical trials. The scale-up and manufacturing of NK cells starting from iPSCs can be more challenging, though has been routinely accomplished [29]
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