TET2 Disruption Enhances the Efficacy of CD19 CAR T-cell Therapy

Immunotherapy with autologous transfer of chimeric antigen receptor (CAR) T cells targeting CD19 have demonstrated antitumor activity in patients with chronic lymphocytic leukemia (CLL). However, insufficient CAR T-cell expansion and persistence can limit their therapeutic efficacy. To provide insight into determinants of CAR T-cell efficacy and persistence, Fraietta and colleagues evaluated the clinical response in a patient with CLL treated with CD19 CAR T-cell therapy who achieved an exceptional response. After the second adoptive transfer of autologous CD19-targeted CAR T cells, there was a delayed expansion of CAR T cells in the peripheral blood, followed by a contraction, and the patient achieved a complete response that has been sustained for more than five years. Deep sequencing of the T-cell receptor beta repertoire revealed that, at the peak of the response, 94% of the CD8⁺ CAR T cells were derived from a single clone that demonstrated massive in vivo expansion. In this clone, the lentiviral vector-mediated insertion of the CAR transgene disrupted the TET2 gene, and the patient exhibited a hypomorphic mutation in the second TET2 allele. These TET2-disrupted CAR T cells displayed a central memory phenotype at the peak of in vivo expansion and had an epigenetic profile that indicated altered T-cell differentiation. Consistent with this case report, TET2 depletion enhanced the proliferative capacity and cytokine production of CAR T cells. Taken together, these findings suggest that the antitumor response achieved in a patient with CLL was due to expansion of a single CAR T-cell clone with disruption of the TET2 locus. Further, these results suggest that TET2 modification may be beneficial to enhance the efficacy of CAR T-cell therapies in patients with cancer.

Fraietta JA, Nobles CL, Sammons MA, Lundh S, Carty SA, Reich TJ, et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 2018558:307–12.

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