Harnessing features of adaptive NK cells to generate iPSC-derived NK cells for enhanced immunotherapy.

Autor:	Woan KV; University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA., Kim H; University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA., Bjordahl R; Fate Therapeutics, San Diego, CA 92121, USA., Davis ZB; University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA., Gaidarova S; Fate Therapeutics, San Diego, CA 92121, USA., Goulding J; Fate Therapeutics, San Diego, CA 92121, USA., Hancock B; Fate Therapeutics, San Diego, CA 92121, USA., Mahmood S; Fate Therapeutics, San Diego, CA 92121, USA., Abujarour R; Fate Therapeutics, San Diego, CA 92121, USA., Wang H; University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA., Tuininga K; University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA., Zhang B; University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA., Wu CY; University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA., Kodal B; University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA., Khaw M; University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA., Bendzick L; University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA., Rogers P; Fate Therapeutics, San Diego, CA 92121, USA., Ge MQ; Fate Therapeutics, San Diego, CA 92121, USA., Bonello G; Fate Therapeutics, San Diego, CA 92121, USA., Meza M; Fate Therapeutics, San Diego, CA 92121, USA., Felices M; University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA., Huffman J; Fate Therapeutics, San Diego, CA 92121, USA., Dailey T; Fate Therapeutics, San Diego, CA 92121, USA., Lee TT; Fate Therapeutics, San Diego, CA 92121, USA., Walcheck B; University of Minnesota, Department of Veterinary and Biomedical Sciences, St. Paul, MN 55108, USA., Malmberg KJ; KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cancer Immunotherapy, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden., Blazar BR; University of Minnesota, Department of Pediatrics, Minneapolis, MN 55455, USA., Bryceson YT; Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway; Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden., Valamehr B; Fate Therapeutics, San Diego, CA 92121, USA., Miller JS; University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA. Electronic address: mille011@umn.edu., Cichocki F; University of Minnesota, Department of Medicine, Minneapolis, MN 55455, USA. Electronic address: cich0040@umn.edu.
Jazyk:	angličtina
Zdroj:	Cell stem cell [Cell Stem Cell] 2021 Dec 02; Vol. 28 (12), pp. 2062-2075.e5. Date of Electronic Publication: 2021 Sep 14.
DOI:	10.1016/j.stem.2021.08.013
Abstrakt:	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. Competing Interests: Declaration of interests F.C. and J.S.M. are paid consultants for Fate Therapeutics, and they receive research funds from this relationship. J.S.M. serves on the Scientific Advisory Board of OnkImmune, Nektar, Magenta and is a paid consultant consult for GT BioPharma and Vycellix (all unrelated to the content of this manuscript). He receives research funds from these relationships. B.R.B is a paid consultant/advisor for Regeneron Pharmaceuticals, Incyte, Obsidian Therapeutics, Bristol-Myers Squibb, and Bluerock. He receives research support from Tmunity, Bluerock, Kadmon, and Rheos and is co-founder of Tmunity. None of these relationships conflict with the content of the published research. He also receives research support from Fate Therapeutics for research unrelated to the content of this report. R.B., S.G., S.M., R.A., P.R., M.Q.G., G.B., M.M., J.H., T.D., T.T.L., and B.V. are employees of Fate Therapeutics. Fate Therapeutics owns patents (Methods and compositions for inducing hematopoietic cell differentiation; patent: 10,626,372) covering the iPSC-derived NK cells. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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