01
TET2 guards against unchecked BATF3-induced CAR T cell expansion
Nayan Jain, et al.
Nature, 2023
This study investigates the role of the epigenetic regulator TET2 in modulating the efficacy of chimeric antigen receptor (CAR) T cell therapy. The researchers hypothesized that epigenetic programming could enhance CAR T cell performance by supporting T cell proliferation and functional persistence. They found that disrupting TET2 in human T cells before transduction with CD19 CARs enhanced tumor rejection in leukemia and prostate cancer models. However, TET2 loss also led to antigen-independent CAR T cell clonal expansions, which could result in significant systemic tissue infiltration. These expansions were dependent on bi-allelic TET2 disruption and sustained expression of the AP-1 factor BATF3, driving a MYC-dependent proliferative program. The study reveals that TET2 acts as a guardian against BATF3-induced CAR T cell proliferation and genomic instability, highlighting the potential and risks of epigenetic programming in CAR T cell therapy. The findings underscore the importance of TET2 in maintaining T cell genomic integrity and preventing uncontrolled proliferative responses, offering insights into the epigenetic control of CAR T cell fate.
DOI: 10.1038/s41586-022-05692-z
02
Shuxin Huang, et al.
Eur. J. Pharmacol, 2024
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