Decitabine-Primed CAR T-Cell Therapy for Relapsed/Refractory Non-Hodgkin's Lymphoma: A Phase 1/2 Clinical Study Demonstrating Enhanced Efficacy and Prolonged Survival

Relapsed/refractory Non-Hodgkin's lymphoma (R/R NHL) remains a therapeutic challenge despite advances in immune checkpoint inhibitors (ICIs). While chimeric antigen receptor (CAR) T-cell therapy has shown promise in hematologic malignancies, its efficacy in NHL is limited by T-cell exhaustion and tumor microenvironment (TME) immunosuppression. Preclinical studies suggest that low-dose decitabine, a DNA hypomethylating agent, can epigenetically reprogram T cells to enhance cytotoxicity and persistence. This open-label phase 1/2 trial (NCT04697940) enrolled 33 R/R NHL patients (aged 16–73 years) to evaluate the safety and efficacy of decitabine-primed CAR T cells targeting CD19/CD20 (CART19/20). Patients received lymphodepletion followed by escalating doses (0.5–5×10^6 cells/kg) of decitabine-activated CAR T cells. Primary endpoints included dose-limiting toxicities (DLTs) and objective response rate (ORR); secondary endpoints encompassed progression-free survival (PFS) and mechanistic analyses of T-cell dynamics.In the phase 1 cohort (n=18), no severe cytokine release syndrome (CRS) or neurotoxicity was observed, establishing 5×10^6 cells/kg as the recommended phase 2 dose (RP2D). Among 15 evaluable patients in phase 2, the ORR reached 86.7% (13/15), with a complete remission (CR) rate of 60% (9/15). Median PFS was 22.1 months, significantly surpassing historical controls of PD-1 monotherapy (median PFS: 12–15 months). Mechanistic studies revealed that decitabine pretreatment upregulated AP-1 transcription factor JunD in CAR T cells, promoting clonal expansion of progenitor-exhausted CD8+ T cells and enhancing tumor infiltration.