Chan, Scheffler, and Munoz et al. analyzed the epigenome and transcriptome of CAR T cells cultured in the presence of IL-15, and identified the enrichment of a Foxo1 gene signature. Overexpression of a constitutively active variant of FOXO1 (FOXO1-ADA) in HER2-specific murine CAR T cells improved metabolic fitness and persistence compared to TCF7, and significantly enhanced CAR T cell therapeutic activity in multiple syngeneic models. FOXO1 (wild-type) overexpression in human CAR T cells induced an epigenetic and transcriptional landscape that promoted stemness and led to enhanced tumor regression in mice.
Contributed by Shishir Pant
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 myeloma(1-4), but the efficacy of CAR T cell therapy in solid tumours has been limited(5). 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 mass(6-8). 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.
Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Vi
Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (2) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (3) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (4) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (5) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (8) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (9) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (10) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (12) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (13) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (14) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (15) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (16) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (17) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (18) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (19) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (20) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (21) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (22) School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia. (23) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (24) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (25) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (26) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (27) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (28) Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia. Faculty of Medicine, The University of Melbourne, Parkville, Victoria, Australia. (29) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (30) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Clinical Haematology and Centre of Excellence for Cellular Immunotherapies, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia. (31) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (32) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (33) School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. (34) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (35) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (36) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. junyun.lai@unimelb.edu.au. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. junyun.lai@unimelb.edu.au. (37) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. paul.beavis@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. paul.beavis@petermac.org. (38) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. phil.darcy@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. phil.darcy@petermac.org. Clinical Haematology and Centre of Excellence for Cellular Immunotherapies, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia. phil.darcy@petermac.org. Department of Immunology, Monash University, Clayton, Victoria, Australia. phil.darcy@petermac.org.
