Feasibility and Safety of a Novel CD19-Directed CAR T-Cell Therapy in Patients with R/R B-Cell Non-Hodgkin Lymphoma

Relapsed/refractory (R/R) B-cell non-Hodgkin lymphomas (NHL) present significant treatment challenges for both patients and clinicians. Despite advances in therapeutic approaches, including the approval of several chimeric antigen receptor (CAR) T-cell products in recent years, there remains a need for more effective options that improve upon existing therapies. To address this, we tested a CAR T-cell construct (UCD19) that incorporates a novel TNFRSF19 transmembrane domain alongside the FMC63 variable region and 4-1BB and CD3-zeta domains that have been used in approved CAR T-cell products manufactured in IL-7 and IL-15 in patients with R/R NHL. The primary aim of this phase 1 clinical trial was to evaluate the manufacturing feasibility and safety profile of the UCD19 product. The secondary aim was to evaluate preliminary efficacy. This trial was an open-label, single arm, single site, phase 1 study designed to assess the safety and feasibility of manufacturing and administration of UCD19 CAR T-cells. Ten patients ≥18 years with R/R B-cell NHL were infused with a fixed dose of UCD19 CAR T-cells (two dose levels) following standard lymphodepleting chemotherapy. Cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS) were observed in 30% and 10% of subjects, respectively; all were grades 1 or 2. There were no grade 3 or higher CRS/ICANS. Overall response rate was 90% across the cohort, with a CR rate of 70% at 90 days, with 60% remaining in remission at 12 months. These results demonstrate favorable safety and preliminary efficacy, supporting further investigation of the novel UCD19 CAR T-cell therapy in larger clinical trials to confirm its safety and efficacy in patients with R/R B-cell NHL. This trial was registered at www.clinicaltrials.gov as #NCT04240808.