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Cancer Immunol Res. 2018 Apr;6(4):467-480. doi: 10.1158/2326-6066.CIR-17-0207. Epub 2018 Feb 19.

Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors.

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Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Norway.
The KG Jebsen Centre for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Department of Immunology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.
Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
Science for Life Laboratory, Department of Applied Physics, KTH-Royal Institute of Technology, Solna, Sweden.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland.
Department of Oncology, Oslo University Hospital, Oslo, Norway.
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Norway.
Centre for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.


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+ targets, and maintained their intrinsic degranulation response toward CD19- K562 cells. The response of redirected NK-cell subsets against CD19+ 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+, 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. Cancer Immunol Res; 6(4); 467-80. ©2018 AACR.

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