Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors.
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Oei VYS, Siernicka M, Graczyk-Jarzynka A, Hoel HJ, Yang W, Palacios D, Almåsbak H, Bajor M, Clement D, Brandt L, Önfelt B, Goodridge J, Winiarska M, Zagozdzon R, Olweus J, Kyte JA, Malmberg KJ
Cancer Immunol Res 6 (4) 467-480 [2018-04-00; online 2018-02-19]
Natural killer (NK) cells hold potential as a source of allogeneic cytotoxic effector cells for chimeric antigen receptor (CAR)-mediated therapies. Here, we explored the feasibility of transfecting CAR-encoding mRNA into primary NK cells and investigated how the intrinsic potential of discrete NK-cell subsets affects retargeting efficiency. After screening five second- and third-generation anti-CD19 CAR constructs with different signaling domains and spacer regions, a third-generation CAR with the CH2-domain removed was selected based on its expression and functional profiles. Kinetics experiments revealed that CAR expression was optimal after 3 days of IL15 stimulation prior to transfection, consistently achieving over 80% expression. CAR-engineered NK cells acquired increased degranulation toward CD19
PubMed 29459477
DOI 10.1158/2326-6066.CIR-17-0207
Crossref 10.1158/2326-6066.CIR-17-0207
pii: 2326-6066.CIR-17-0207