article · Nature Communications
Natural killer cells engineered with chimeric antigen receptors possess antileukaemic activity against acute myeloid leukaemia in vivo. However, their tumour-killing efficacy is frequently hindered when human leukocyte antigen E interacts with an inhibitory receptor termed NKG2A. To overcome this immune checkpoint inhibition, primary natural killer cells were engineered to target CD33 on acute myeloid leukaemia cells alongside CRISPR/Cas9 gene disruption of KLRC1, the gene encoding NKG2A. Single-cell multi-omics analyses revealed that these modified cells maintain transcriptional profiles linked to activation and maturation, even following contact with leukaemia cells. Furthermore, the NKG2A-deficient CAR natural killer cells demonstrated potent antileukaemic killing when tested against acute myeloid leukaemia cell lines and primary blasts both in vitro and in vivo. These findings indicate that removing NKG2A enables CAR-NK cells to overcome tumour-mediated immune suppression.
Acute myeloid leukaemia frequently evades immune responses by activating inhibitory checkpoints that limit the killing power of cellular therapies. Demonstrating that gene editing can remove the NKG2A checkpoint while equipping natural killer cells with leukaemia-targeting receptors offers a clearer route to preventing tumour escape. This helps advance cell-based immunotherapies designed to treat resistant blood cancers without being silenced by protective immune evasion mechanisms.
This technology could enable developers of cancer immunotherapies and cellular therapy biotechs to design more potent natural killer cell treatments for acute myeloid leukaemia. Because the approach has been evaluated in cell cultures and animal models, it remains at the early-stage research phase. Substantial preclinical validation, manufacturing scale-up, and human clinical trials will be necessary before any clinical application or commercial adoption.
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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-KLRC1<sup>ko</sup>-NK cells, which are preserved following exposure to AML cells. Moreover, CAR33-KLRC1<sup>ko</sup>-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.
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DOI: 10.1038/s41467-024-52388-1
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