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FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy

Jack D. Chan, Christina M. Scheffler, Isabelle Munoz, Kevin Sek, Joel N. Lee, Yu-Kuan Huang, Kah Min Yap, Nicole Y. L. Saw, Jasmine Li, Amanda X. Y. Chen, Cheok Weng Chan, Emily B. Derrick, Kirsten L. Todd, Junming Tong, Phoebe A. Dunbar, Jiawen Li, Thang X. Hoang, Maria N. Menezes, Emma V. Petley, Joelle S. Kim, Dat Nguyen, Patrick S. K. Leung, Joan So, Christian Deguit, Joe Zhu, Imran G. House, Lev M. Kats, Andrew M. Scott, Benjamin J. Solomon, Simon J. Harrison, Jane Oliaro, Ian A. Parish, Kylie M. Quinn, Paul J. Neeson, Clare Y. Slaney, Junyun Lai (), Paul A. Beavis () and Phillip K. Darcy ()
Additional contact information
Jack D. Chan: Peter MacCallum Cancer Centre
Christina M. Scheffler: Peter MacCallum Cancer Centre
Isabelle Munoz: Peter MacCallum Cancer Centre
Kevin Sek: Peter MacCallum Cancer Centre
Joel N. Lee: Peter MacCallum Cancer Centre
Yu-Kuan Huang: Peter MacCallum Cancer Centre
Kah Min Yap: Peter MacCallum Cancer Centre
Nicole Y. L. Saw: Peter MacCallum Cancer Centre
Jasmine Li: Peter MacCallum Cancer Centre
Amanda X. Y. Chen: Peter MacCallum Cancer Centre
Cheok Weng Chan: Peter MacCallum Cancer Centre
Emily B. Derrick: Peter MacCallum Cancer Centre
Kirsten L. Todd: Peter MacCallum Cancer Centre
Junming Tong: Peter MacCallum Cancer Centre
Phoebe A. Dunbar: Peter MacCallum Cancer Centre
Jiawen Li: Peter MacCallum Cancer Centre
Thang X. Hoang: Peter MacCallum Cancer Centre
Maria N. Menezes: Peter MacCallum Cancer Centre
Emma V. Petley: Peter MacCallum Cancer Centre
Joelle S. Kim: Peter MacCallum Cancer Centre
Dat Nguyen: Peter MacCallum Cancer Centre
Patrick S. K. Leung: RMIT University
Joan So: The University of Melbourne
Christian Deguit: Peter MacCallum Cancer Centre
Joe Zhu: Peter MacCallum Cancer Centre
Imran G. House: Peter MacCallum Cancer Centre
Lev M. Kats: The University of Melbourne
Andrew M. Scott: La Trobe University
Benjamin J. Solomon: The University of Melbourne
Simon J. Harrison: The University of Melbourne
Jane Oliaro: Peter MacCallum Cancer Centre
Ian A. Parish: Peter MacCallum Cancer Centre
Kylie M. Quinn: RMIT University
Paul J. Neeson: Peter MacCallum Cancer Centre
Clare Y. Slaney: Peter MacCallum Cancer Centre
Junyun Lai: Peter MacCallum Cancer Centre
Paul A. Beavis: Peter MacCallum Cancer Centre
Phillip K. Darcy: Peter MacCallum Cancer Centre

Nature, 2024, vol. 629, issue 8010, 201-210

Abstract: Abstract Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1–4, 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 mass6–8. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07242-1

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