Loss of metabolic fitness drives tumor resistance after CAR-NK cell therapy and can be overcome by cytokine engineering
Menée à l'aide d'une xénogreffe de lymphome sur un modèle murin et d'échantillons sanguins de patients atteints d'un cancer hématologique traité par lymphocytes CAR19/IL-15 NK, cette étude identifie un mécanisme de résistance thérapeutique qui peut être partiellement levé en intégrant dans les cellules CAR19-NK un gène exprimant l'interleukine IL-15
Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells is promising, with early-phase clinical studies showing encouraging responses. However, the transcriptional signatures that control the fate of CAR-NK cells after infusion and factors that influence tumor control remain poorly understood. We performed single-cell RNA sequencing and mass cytometry to study the heterogeneity of CAR-NK cells and their in vivo evolution after adoptive transfer, from the phase of tumor control to relapse. Using a preclinical model of noncurative lymphoma and samples from a responder and a nonresponder patient treated with CAR19/IL-15 NK cells, we observed the emergence of NK cell clusters with distinct patterns of activation, function, and metabolic signature associated with different phases of in vivo evolution and tumor control. Interaction with the highly metabolically active tumor resulted in loss of metabolic fitness in NK cells that could be partly overcome by incorporation of IL-15 in the CAR construct. Loss of metabolic fitness is a mechanism of resistance after CAR-NK cell therapy that could be overcome by IL-15.
Science Advances 2023