Journal
CELL STEM CELL
Volume 28, Issue 12, Pages 2062-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2021.08.013
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Funding
- NIH [R01 CA203348, R37 AI34495, R00 HL123638, P01 CA111412, P01 CA65493, R35 CA197292]
- Fate Therapeutics
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Researchers have successfully generated a NK cell subset called iADAPT by editing induced pluripotent stem cells, which exhibited persistence in vivo and superior antitumor activity. This finding suggests that unique subsets of the immune system can be modeled through iPSC technology, providing a new approach for treating patients with advanced cancer.
Select subsets of immune effector cells have the greatest propensity to mediate antitumor responses. However, procuring these subsets is challenging, and cell-based immunotherapy is hampered by limited effector-cell persistence and lack of on-demand availability. To address these limitations, we generated a triple-gene-edited induced pluripotent stem cell (iPSC). The clonal iPSC line was engineered to express a high affinity, non-cleavable version of the Fc receptor CD16a and a membrane-bound interleukin (IL)-15/IL-15R fusion protein. The third edit was a knockout of the ecto-enzyme CD38, which hydrolyzes NAD(+). Natural killer (NK) cells derived from these uniformly engineered iPSCs, termed iADAPT, displayed metabolic features and gene expression profiles mirroring those of cytomegalovirus-induced adaptive NK cells. iADAPT NK cells persisted in vivo in the absence of exogenous cytokine and elicited superior antitumor activity. Our findings suggest that unique subsets of the immune system can be modeled through iPSC technology for effective treatment of patients with advanced cancer.
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