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- W4362561093 abstract "<div>Abstract<p>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<sup>+</sup> targets, and maintained their intrinsic degranulation response toward CD19<sup>−</sup> K562 cells. The response of redirected NK-cell subsets against CD19<sup>+</sup> targets was dependent on their intrinsic thresholds for activation determined through both differentiation and education by killer cell immunoglobulin-like receptors (KIR) and/or CD94/NKG2A binding to self HLA class I and HLA-E, respectively. Redirected primary NK cells were insensitive to inhibition through NKG2A/HLA-E interactions but remained sensitive to inhibition through KIR depending on the amount of HLA class I expressed on target cells. Adaptive NK cells, expressing NKG2C, CD57, and self-HLA–specific KIR(s), displayed superior ability to kill CD19<sup>+</sup>, HLA low, or mismatched tumor cells. These findings support the feasibility of primary allogeneic NK cells for CAR engineering and highlight a need to consider NK-cell diversity when optimizing efficacy of cancer immunotherapies based on CAR-expressing NK cells. <i>Cancer Immunol Res; 6(4); 467–80. ©2018 AACR</i>.</p></div>" @default.
- W4362561093 created "2023-04-06" @default.
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- W4362561093 date "2023-04-03" @default.
- W4362561093 modified "2023-09-24" @default.
- W4362561093 title "Data from Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors" @default.
- W4362561093 doi "https://doi.org/10.1158/2326-6066.c.6549229" @default.
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