Demethylation-primed tandem CD19/CD20 CAR T cells in relapsed/refractory B-cell lymphoma: a phase I/II trial.

Despite the success of CAR T therapy in non-Hodgkin lymphoma (NHL), recurrence remains challenging. Previously, we showed that ex vivo priming with decitabine (DAC) enhances CAR T persistence and efficacy. Here, we report on an open-label non-randomised phase I/II trial (NCT04697940) evaluating DAC-primed CD19/CD20 dual-targeted CAR T cells (dCAR T) in 23 patients with relapsed or refractory NHL. Primary endpoints are safety and dose-toxicity for phase I, and overall response rate and complete response rate (CRR) for phase II. Secondary endpoints include progression-free survival (PFS), overall survival, and duration of response. This trial has met pre-specified endpoints. Treatment is well tolerated and achieves durable responses, with an 87% CRR and a 2-year PFS of 77% (median follow-up, 24.3 months). Compared with historically unmodified CAR T cohorts, dCAR T cells exhibited robust in vivo expansion and sustained persistence. Single-cell sequencing indicates that DAC priming enriches for memory-like progenitors, which maintain cytotoxic and memory signatures, and upregulates genes associated with T cell fitness and engagement of endogenous immunity. These data establish DAC-priming as a clinically feasible epigenetic reprogramming strategy enhanceing CAR T durability and efficacy, offering a generalizable paradigm for engineered cell therapies in malignant tumors.