Updated clinical outcomes of a Phase I/II trial of bispecific CD19/CD20-targeted CAR-T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma

Abstract Background: Non-Hodgkin lymphoma (NHL) is a common hematologic malignancy, and treatment options remain limited for patients with relapsed or refractory (R/R) disease, particularly those with diffuse large B-cell lymphoma (DLBCL). Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising immunotherapeutic approach for R/R hematologic malignancies. However, relapse following CAR-T therapy can occur, often due to the loss of CAR-T cell persistence or antigen escape. One strategy to mitigate antigen loss is to simultaneously target multiple antigens. Tandem CAR-T cells targeting CD19 and CD22 have demonstrated promising efficacy in R/R B-acute lymphoblastic leukemia (B-ALL). We previously reported encouraging results from a Phase I/II trial (n=11) of bispecific CD19/20 CAR-T cells in patients with R/R B-cell malignancies. Methods: We conducted an updated analysis of an open-label, single-arm Phase I/II clinical trial evaluating bispecific CD19/20 CAR-T cell therapy in patients with R/R NHL treated at our center between May 2021 and November 2024. The primary endpoint was safety. Secondary endpoints included overall response rate (ORR), duration of response, progression-free survival (PFS), and overall survival. Results: In this updated analysis, 32 patients with R/R NHL—including 27 with DLBCL—received CD19/20 CAR-T cell infusions at doses ranging from 0.3 × 10⁶ to 2.7 × 10⁶ cells/kg following lymphodepleting chemotherapy. The best overall response rate was 77%, with a complete response (CR) rate of 60%. At a median follow-up of 12.6 months, the median PFS was 6.8 months (95% CI, 3.9 to not reached). Cytokine release syndrome (CRS) occurred in 17 patients (53%), with 41% experiencing grade 1–2 CRS and 12% experiencing grade ≥3. Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 3 patients (9%). Conclusions: These findings support the potential of bispecific CD19/20 CAR-T cell therapy to achieve durable remissions in patients with R/R NHL, with a manageable safety profile characterized by a moderate incidence of CRS and low rates of neurotoxicity.