CRISPR/Cas9 editing of NKG2A improves the efficacy of primary CD33-directed chimeric antigen receptor natural killer cells

Tobias Bexte, Nawid Albinger, Ahmad Al Ajami, Philipp Wendel, Leon Buchinger, Alec Gessner, Jamal Alzubi, Vinzenz Särchen, Meike Vogler, Hadeer Mohamed Rasheed, Beate Anahita Jung, Sebastian Wolf, Raj Bhayadia, Thomas Oellerich, Jan-Henning Klusmann, Olaf Penack, Nina Möker, Toni Cathomen, Michael A. Rieger, Katharina Imkeller and Evelyn Ullrich ()
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Tobias Bexte: Experimental Immunology and Cell Therapy
Nawid Albinger: Experimental Immunology and Cell Therapy
Ahmad Al Ajami: Frankfurt Cancer Institute
Philipp Wendel: Experimental Immunology and Cell Therapy
Leon Buchinger: Experimental Immunology and Cell Therapy
Alec Gessner: Frankfurt Cancer Institute
Jamal Alzubi: Medical Center – University of Freiburg
Vinzenz Särchen: Institute for Experimental Pediatric Hematology and Oncology
Meike Vogler: Institute for Experimental Pediatric Hematology and Oncology
Hadeer Mohamed Rasheed: Oncology and Tumor Immunology
Beate Anahita Jung: Oncology and Tumor Immunology
Sebastian Wolf: Frankfurt Cancer Institute
Raj Bhayadia: Department of Pediatrics
Thomas Oellerich: Frankfurt Cancer Institute
Jan-Henning Klusmann: Department of Pediatrics
Olaf Penack: Oncology and Tumor Immunology
Nina Möker: Miltenyi Biotec B.V. & Co. KG
Toni Cathomen: Medical Center – University of Freiburg
Michael A. Rieger: Frankfurt Cancer Institute
Katharina Imkeller: Frankfurt Cancer Institute
Evelyn Ullrich: Experimental Immunology and Cell Therapy

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Chimeric antigen receptor (CAR)-modified natural killer (NK) cells show antileukemic activity against acute myeloid leukemia (AML) in vivo. However, NK cell-mediated tumor killing is often impaired by the interaction between human leukocyte antigen (HLA)-E and the inhibitory receptor, NKG2A. Here, we describe a strategy that overcomes CAR-NK cell inhibition mediated by the HLA-E-NKG2A immune checkpoint. We generate CD33-specific, AML-targeted CAR-NK cells (CAR33) combined with CRISPR/Cas9-based gene disruption of the NKG2A-encoding KLRC1 gene. Using single-cell multi-omics analyses, we identified transcriptional features of activation and maturation in CAR33-KLRC1ko-NK cells, which are preserved following exposure to AML cells. Moreover, CAR33-KLRC1ko-NK cells demonstrate potent antileukemic killing activity against AML cell lines and primary blasts in vitro and in vivo. We thus conclude that NKG2A-deficient CAR-NK cells have the potential to bypass immune suppression in AML.

Date: 2024
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DOI: 10.1038/s41467-024-52388-1

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