Genetically engineered patient T cells with chimeric T cell receptors (CAR T cells) can induce anti-tumour responses, but such responses are determined by the variable capacity of the CAR T cells to expand and persist in patients. Here the authors report on a case of a chronic lymphocytic leukaemia patient treated with CD19 CAR T cells that resulted in complete remission. Unexpectedly, CAR T cells showed expansion of a clone where insertion of the CAR transgene disrupted the endogenous TET2 gene. In addition, the remaining allele was shown to carry a hypomorphic mutation. The resulting inactivation of this methylcytosine dioxygenase induced epigenetic changes that altered T cell differentiation and function, promoting a central memory phenotype and potentiating anti-tumour effects. This finding suggests that modulating TET2 signalling could improve the efficacy of CAR T cells.
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