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 chimeric antigen receptor (CAR) T cells, 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 an OX40 costimulatory domain. Preclinical studies demonstrated potent, antigen-specific cytotoxicity in 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. Sixteen patients received infusions at a median vein-to-vein time of 7 days, at doses of 0.5 to 2 × 106 cells/kg. No severe cytokine release syndrome or neurotoxicity occurred. The overall response rate was 50%, including complete responses in 83% of patients with lymphoma. The 1-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 lymphoma. SIGNIFICANCE: This first-in-human trial demonstrates that point-of-care manufactured trispecific CD19/20/22 CAR T cells with OX40 costimulation can be rapidly produced, safely administered, and induce durable remissions in relapsed B-cell lymphoma. Findings highlight multispecific targeting to mitigate antigen escape and identify T-cell exhaustion as a key biomarker guiding future CAR T optimization. See related commentary by Merz and Luttwak, p. 652.