Loss of metabolic fitness drives tumor resistance after CAR-NK cell therapy and can be overcome by cytokine engineering

• DOI: 10.1126/sciadv.add6997
• Publication Date: 2023-07-26T18:00:10Z
• Authors: Li Li; Vakul Mohanty; Jinzhuang Dou; Yuefan Huang; Pinaki P. Banerjee; Qi Miao; Jens G. Lohr; Tushara Vijaykumar; Julia Frede; Birgit Knoechel; Luis Muniz-Feliciano; Tamara J. Laskowski; Shaoheng Liang; Judy S. Moyes; Vandana Nandivada; Rafet Basar; Mecit Kaplan; May Daher; Enli Liu; Ye Li; Sunil Acharya; Paul Lin; Mayra Shanley; Hind Rafei; David Marin; Stephan Mielke; Richard E. Champlin; Elizabeth J. Shpall; Ken Chen; Katayoun Rezvani
• Keywords: Adoptive Cell Transfer; Mass cytometry

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 fate CAR-NK after infusion and factors influence tumor remain poorly understood. We performed single-cell RNA sequencing mass cytometry to study heterogeneity their in vivo evolution adoptive transfer, from phase relapse. Using a preclinical model noncurative lymphoma samples responder nonresponder patient treated CAR19/IL-15 NK cells, we observed emergence cell clusters distinct patterns activation, function, metabolic signature associated different phases control. Interaction highly metabolically active resulted loss fitness could be partly overcome by incorporation IL-15 CAR construct.