FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy

• DOI: 10.1038/s41586-024-07242-1
• Publication Date: 2024-04-10T16:01:48Z
• Authors: Jack D. Chan; Christina M. Sche...; 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. de 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; Phillip K. Darcy
• Keywords: Cell therapy

Abstract Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B lymphoma and multiple myeloma 1–4 , but efficacy CAR in solid tumours been limited 5 . This is owing to a number factors, including immunosuppressive tumour microenvironment that gives rise poorly persisting metabolically dysfunctional cells. Analysis anti-CD19 cells used clinically shown positive outcomes are associated with more ‘stem-like’ phenotype increased mitochondrial mass 6–8 We therefore sought identify transcription factors could enhance fitness against tumours. Here we show overexpression FOXO1 promotes stem-like derived from either healthy human donors or patients, which correlates improved fitness, persistence therapeutic vivo. work thus reveals an engineering approach genetically enforce favourable metabolic high translational potential improve