Safety and clinical outcomes of a first-in-human trial of point-of-care manufactured trispecific CAR T cells targeting CD19, CD20, and CD22

Disease recurrence is the main cause of treatment failure after CD19-directed CAR T cells and is often due to CD19 antigen loss, stability and/or coverage. To overcome single-antigen escape, we evaluated a trispecific CAR targeting CD19, CD20, and CD22 with OX40 co-stimulatory domain. Preclinical studies demonstrated potent, antigen-specific cytotoxicity in both in vitro and in vivo lymphoma models. We then conducted a first-in-human phase I trial in patients with relapsed/refractory B-cell malignancies. Fifteen patients received fresh infusions at a median vein to vein time of 7 days, at doses of 0.5-2×10⁶ cells/kg. No severe cytokine release syndrome nor immune effector cell-associated neurotoxicity syndrome occurred. Overall response rate was 50%, including complete responses in 83% of lymphoma patients. One-year overall survival rate was 61%, with durable remissions observed in lymphoma. CAR T expansion did not correlate with dose or response. T-cell exhaustion in apheresis cells correlated with progressive disease. Trispecific CAR T cells are safe and potentially active in non-Hodgkin lymphoma.