First-in-human phase 1 study of a novel CD19-IXX chimeric antigen receptor with calibrated signaling in large B-cell lymphoma

Researchers at Memorial Sloan Kettering Cancer Center (New York, NY) developed a CD19-targeted CAR comprising a calibrated signaling module (1XX) that differs from conventional CARs and may be effective at low doses and elicit minimal toxicities. A first-in-human phase 1 trial at MSKCC included 28 patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) who underwent apheresis and received CAR T cells at four dose levels, ranging from 25 x 10⁶ to 200 x 10⁶. In the entire cohort, the objective response rate was 82% and the complete response rate was 71%. The lowest dose rate was selected for dose expansion. In patients treated a this dose rate, 88% achieved ORR and 75% CR. With a median follow-up of 24 months, the one-year event-free survival rate was 61% (95% CI 45-82). Grade ≥ 3 CRS rate was 4% and grade ≥ 3 ICANS was 7%. CAR T-cell persistence has been detected beyond 1-2 years in patients with ongoing remission. The authors conclude that 1XX CAR affords excellent efficacy at low cell doses with favorable toxicity profile among patients with R/R LBCL.