Language
English
Publication Date
9-15-2025
Journal
Journal for ImmunoTherapy of Cancer
DOI
10.1136/jitc-2025-012841
PMID
40954078
PMCID
PMC12439146
PubMedCentral® Posted Date
9-15-2025
PubMedCentral® Full Text Version
Post-print
Abstract
First clinical trials demonstrated the safety of adoptive cell transfer with allogeneic natural killer (NK) cell products from healthy donors, making them an attractive candidate for 'off-the-shelf' chimeric antigen receptor (CAR)-immune cell therapy. However, reduced persistence and inactivation of NK cells by immunosuppressive cues likely limit the performance of CAR-redirected NK cells. Wang and colleagues demonstrate that multiplex CRISPR base editing allows optimization of the intrinsic functionality of CAR-NK cells improving their therapeutic potential. In contrast to conventional CRISPR-Cas nucleases, base editing avoided most double-stranded DNA breaks while enabling highly efficient editing at up to six sites simultaneously. The study further demonstrates the feasibility of a non-viral approach to integrate CAR transgene and multiplex base editing of several immune checkpoints in NK cells using a single electroporation. CAR-NK cells harboring up to three base edits demonstrate improved potency over unedited counterparts in vitro. Xenograft mouse models confirmed increased potency, but also indicated signs of organ toxicity - a phenomenon that will require future studies prior to clinical translation. The study demonstrates that CRISPR base editing is a powerful tool to unleash the full cytotoxic potential of NK cells, but it also warrants the question: How many internal breaks can be removed without hurting CAR-NK cell therapy's impeccable safety record?
Keywords
Killer Cells, Natural, Humans, Gene Editing, Animals, Receptors, Chimeric Antigen, Mice, Immunotherapy, Adoptive, CRISPR-Cas Systems, Natural killer - NK, Chimeric antigen receptor - CAR, Adoptive cell therapy - ACT, Immunotherapy, Immune Checkpoint Inhibitor
Published Open-Access
yes
Recommended Citation
Tobias Bexte and Dimitrios L Wagner, "Next-Generation Multiplex-Edited Car-Nk Cells: More Edits, More Power?" (2025). Faculty, Staff and Students Publications. 8694.
https://digitalcommons.library.tmc.edu/baylor_docs/8694