Wang, Tong, Dai, Wu, and Han et al. showed that treating CD19- or CD20-CAR T cells with the methylation inhibitor decitabine (DAC) immediately following lentivirus infection boosted proliferation and memory markers, and reduced exhaustion markers. Levels and duration of tumor lysis and cytokines rose and were retained upon repeated antigen stimulation. In a murine NHL model, treated CAR T cells were cytotoxic, expanded and persisted in tumors and peripheral blood, and exhibited recall responses, as shown by their re-expansion and tumor ablation even when tumor burden was great and after tumor rechallenge, unlike untreated CAR T cells, which were no longer detected.
Contributed by Paula Hochman
ABSTRACT: Insufficient eradication capacity and dysfunction are common occurrences in T cells that characterize cancer immunotherapy failure. De novo DNA methylation promotes T cell exhaustion, whereas methylation inhibition enhances T cell rejuvenation in vivo. Decitabine, a DNA methyltransferase inhibitor approved for clinical use, may provide a means of modifying exhaustion-associated DNA methylation programmes. Herein, anti-tumour activities, cytokine production, and proliferation are enhanced in decitabine-treated chimeric antigen receptor T (dCAR T) cells both in vitro and in vivo. Additionally, dCAR T cells can eradicate bulky tumours at a low-dose and establish effective recall responses upon tumour rechallenge. Antigen-expressing tumour cells trigger higher expression levels of memory-, proliferation- and cytokine production-associated genes in dCAR T cells. Tumour-infiltrating dCAR T cells retain a relatively high expression of memory-related genes and low expression of exhaustion-related genes in vivo. In vitro administration of decitabine may represent an option for the generation of CAR T cells with improved anti-tumour properties.
Author Info: (1) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. Department of Bio-therapeutic, t
Author Info: (1) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. Department of Bio-therapeutic, the First Medical Centre, Chinese People's Liberation Army General Hospital, Beijing, China. (2) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. (3) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. (4) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. (5) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. (6) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. (7) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. (8) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. (9) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. (10) Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. (11) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. (12) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. (13) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. (14) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. (15) Department of Bio-therapeutic, the First Medical Centre, Chinese People's Liberation Army General Hospital, Beijing, China. (16) Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China. hanwdrsw69@yahoo.com. Department of Bio-therapeutic, the First Medical Centre, Chinese People's Liberation Army General Hospital, Beijing, China. hanwdrsw69@yahoo.com.
