This study examined how an immature CD16-CD161- double-negative (DN) NK cell subset in cord blood-derived CAR NK cell products contributes to treatment failure, and whether pre-manufacturing depletion of this subset can restore antitumor potency across hematologic and solid tumor models.
DN-derived CAR NK cells accumulated cognate antigen via exaggerated trogocytosis, forming an intra-product 'trogocytic-antigen sink' (TAS) that diverted CAR engagement away from tumors, drove CD16+CD161+ effector exhaustion, fratricide, and reduced persistence. Pre-manufacturing DN depletion eliminated the TAS and restored antitumor activity.
Findings are primarily preclinical (in vitro and tumor models); clinical validation of the DN-depletion manufacturing strategy in prospective trials is not yet reported. Donor heterogeneity effects are described but the breadth of cord blood donors tested is not specified in the abstract.
Screening cord blood donors for the DN (CD16-CD161-) NK subset and depleting it before CAR engineering may be a practical manufacturing step to improve CAR NK cell potency and consistency. Clinicians using off-the-shelf CAR NK therapies should be aware that donor subset composition—not just CAR design—can drive product dysfunction.
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