Long-term outcomes of CNCT19 chimeric antigen receptor T-cell therapy in relapsed or refractory aggressive B-cell lymphoma

BACKGROUND: Most anti-CD19 chimeric antigen receptor (CAR) T-cell products have the single-chain variable fragment (scFv) derived from the FMC63 monoclonal antibody. We developed a new hybridoma clone, HI19α, which binds to distinct epitopes on CD19. CNCT19 is a second-generation CAR T-cell with a scFv derived from clone HI19α and a 4-1BB costimulatory domain. A pilot clinical trial was conducted to assess the safety and preliminary efficacy of CNCT19 cells (CNCT19s) in patients with relapsed or refractory (R/R) aggressive B-cell lymphoma. METHODS: From June 2017 to March 2019, 16 patients with R/R CD19-positive aggressive B-cell lymphoma from the Institute of Hematology and Blood Disease Hospital were enrolled. All patients received lymphodepleting chemotherapy with fludarabine (25-30 mg/m2/per day on days 4, 3, and 2) and cyclophosphamide (350 mg/m2/per day on days 4 and 2) before CNCT19s infusion. The primary objective was the safety profiles. Kaplan-Meier survival analysis was used to compare the cumulative incidence rate. RESULTS: The study cohort comprised 14 patients diagnosed with de novo diffuse large B-cell lymphoma (DLBCL), one patient with follicular lymphoma grade 3B (FL3B), and one patient with Richter's transformation. The patients had received a median of 3 (range 1-7) lines of prior therapy. Thirteen patients (81.3%) had disease resistant to the last-line therapy, and TP53 mutation and/or deletion were detected in 5 of 12 patients (41.7%). The median dose of CNCT19s infusion was 3.6 × 106 (range 1.8-6.5 × 106)/kg. Cytokine release syndrome occurred in 11 (68.8%) patients, all classified as grade 1. One patient (6.3%) experienced CAR T-cell-related encephalopathy syndrome. The overall response rate and the complete response rate were 75% (12/16) and 43.8% (7/16), respectively. After a median follow-up of 54.0 months, the estimated 5-year progression-free survival and overall survival rates were 25.0% and 37.5%, respectively. CONCLUSIONS: CNCT19s exhibited favorable safety profiles and efficacy in patients with R/R DLBCL and FL3B. Long-term follow-up confirmed the curative potential of CNCT19s in R/R aggressive B-cell lymphoma. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03029338.