Umbilical cord blood-derived CAR-NK cells: an emerging off-the-shelf platform for cancer immunotherapy.

Autologous CAR-T therapy has achieved notable success in B-cell malignancies, yet its broader application is constrained by high costs, protracted manufacturing timelines, and severe toxicities, including cytokine release syndrome (CRS) and graft-versus-host disease (GVHD). Natural killer (NK) cells offer a compelling off-the-shelf alternative, owing to their major histocompatibility complex-independent cytotoxicity and negligible GVHD risk. Among allogeneic NK sources, umbilical cord blood (UCB)-derived CAR-NK cells are distinguished by a CD56brightCD16-/dim phenotype, extended telomeres, and a transcriptional profile that facilitates >1,000-fold ex vivo expansion. These properties have supported extensive preclinical evaluation and early clinical translation. Preclinical studies have documented antitumor activity against CD19, CD123, PD-L1, ErbB3, and mesothelin, without evidence of CRS. In a landmark phase I/II trial (NCT03056339), 7 of 11 patients (64%) with relapsed or refractory CD19+ B-cell malignancies achieved complete remission, with no observed GVHD or neurotoxicity. However, relapses occurring within 2 to 3 months correlated with loss of detectable CAR-NK cells, highlighting limited in vivo persistence as a principal barrier to durable response.