Inosine induces stemness features in CAR-T cells and enhances potency

Dorota D. Klysz(Stanford University), Carley Fowler(Stanford University), Meena Malipatlolla(Stanford University), Lucille Stuani(Stanford University), Katherine A. Freitas(Stanford University), Yiyun Chen(Stanford University), Stefanie L. Meier(Gladstone Institutes), Bence Dániel(Stanford University), Katalin Sándor(Stanford University), Peng Xu(Stanford University), Jing Huang(Stanford University), Louai Labanieh(Stanford University), Vimal Keerthi(Stanford University), Amaury Leruste(Stanford University), Malek Bashti(Stanford University), Janette Mata-Alcazar(Stanford University), Nikolaos Gkitsas(Stanford University), Justin A. Guerrero(Stanford University), Chris Fisher(Stanford University), Sunny Patel(Stanford University), Kyle Asano(Stanford University), Shabnum Patel(Stanford University), Kara L. Davis(Stanford Medicine), Ansuman T. Satpathy(Parker Institute for Cancer Immunotherapy), Steven A. Feldman(Stanford University), Elena Sotillo(Stanford University), Crystal L. Mackall(Stanford Medicine)
Cancer Cell
January 25, 2024
10.1016/j.ccell.2024.01.002
Cited by 136Open Access
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Abstract

CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.

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