Cancer immunotherapy based on genetically redirecting T-cells has been used successfully to treat B-cell malignancies [1][2][3] . In this strategy, the T-cell genome is modified by integration of viral vectors or transposons encoding chimeric antigen receptors (CARs) that direct tumor cell killing. However, this approach is often limited by the extent of expansion and persistence of CAR Tcells 4,5 . Here we report mechanistic insights from studies of a chronic lymphocytic leukemia (CLL) patient treated with CAR T-cells targeting the CD19 protein. Following CAR T-cell infusion, anti-tumor activity was evident in the peripheral blood, lymph nodes and bone marrow, and was accompanied by complete remission. Unexpectedly, at the peak of the response, 94% of CAR T-cells originated from a single clone in which lentiviral vector-mediated insertion of the CAR transgene disrupted the methylcytosine dioxygenase TET2 gene. Further analysis revealed a hypomorphic mutation in this patient's second TET2 allele. TET2-disrupted CAR T-cells exhibited an epigenetic profile consistent with altered T-cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knock-down of TET2 recapitulated the potency-enhancing effect of TET2 dysfunction in this patient's CAR T-cells.These findings suggest that the progeny of a single CAR T-cell induced leukemia remission and that TET2 modification may be useful for improving immunotherapies.

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