FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy

Chan, Jack D. and Scheffler, Christina M. and Munoz, Isabelle and Sek, Kevin and Lee, Joel N. and Huang, Yu-Kuan and Yap, Kah Min and Saw, Nicole Y. L. and Li, Jasmine and Chen, Amanda X. Y. and Chan, Cheok Weng and Derrick, Emily B. and Todd, Kirsten L. and Tong, Junming and Dunbar, Phoebe A. and Li, Jiawen and Hoang, Thang X. and de Menezes, Maria N. and Petley, Emma V. and Kim, Joelle S. and Nguyen, Dat and Leung, Patrick S. K. and So, Joan and Deguit, Christian and Zhu, Joe and House, Imran G. and Kats, Lev M. and Scott, Andrew M. and Solomon, Benjamin J. and Harrison, Simon J. and Oliaro, Jane and Parish, Ian A. and Quinn, Kylie M. and Neeson, Paul J. and Slaney, Clare Y. and Lai, Junyun and Beavis, Paul A. and Darcy, Phillip K. (2024) FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy. Nature. ISSN 0028-0836

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Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1,2,3,4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more ‘stem-like’ phenotype and increased mitochondrial mass6,7,8. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.

Item Type: Article
Subjects: Eurolib Press > Multidisciplinary
Depositing User: Managing Editor
Date Deposited: 11 Apr 2024 09:18
Last Modified: 11 Apr 2024 09:18

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