Gene editing boosts CAR-NK efficacy against leukaemia

The researchers targeted the CD33 antigen on AML cells using chimeric antigen receptor (CAR)-modified NK cells while simultaneously disrupting the KLRC1 gene by CRISPR-Cas9-mediated knockout. This gene encodes NKG2A, an inhibitory receptor that binds to HLA-E on leukaemic cells, suppressing NK cell activity. By disrupting KLRC1, the team aimed to overcome the immune suppression in the tumour microenvironment and enhance the cytotoxic function of the CAR-NK cells.

Knockout of NKG2A resulted in significantly increased cytotoxicity in CD33-targeted CAR-NK cells, both in vitro and in vivo when tested against AML cell lines and patient-derived primary blasts. Single-cell transcriptomics and epitope analyses confirmed that the engineered cells retained their activation and maturation features, leading to improved anti-leukaemic activity. Additionally, the modified NK cells demonstrated potent killing capacity, enhanced by the elimination of inhibitory signals, which typically dampen NK cell responses.

This research - led by Tobias Bexte and Evelyn Ullrich from the Goethe University Frankfurt - was published yesterday in Nature Communications.