Preliminary safety and efficacy of anti-CD19/CD20 bispecific CAR-T cell therapy (JWCAR201) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: Results from an ongoing phase I study

Abstract Background Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) represents a significant therapeutic challenge, with historical overall response rates of 26-35% to salvage regimens and median overall survival of 6-10 months. While CD19-directed CAR-T therapies have demonstrated efficacy in R/R DLBCL, treatment resistance remains a critical limitation, often attributed to antigen escape mechanisms. JWCAR201 is a novel bispecific CAR-T cell product simultaneously targeting CD19 and CD20 antigens, designed to potentially overcome single-antigen escape and enhance anti-lymphoma activity. We report preliminary safety and efficacy data from an ongoing investigator-initiated phase I study. Methods This open-label, single-arm, dose-escalation study enrolled patients with histologically confirmed CD19⁺ and/or CD20⁺ B-cell NHL who experienced relapse or progression after ≥2 prior therapies, including an anthracycline-containing regimen and anti-CD20 monoclonal antibody, or following autologous stem cell transplantation. Following lymphodepleting chemotherapy (fludarabine 25 mg/m²/day × 3 days, cyclophosphamide 250 mg/m²/day × 3 days), patients received a single intravenous infusion of JWCAR201 across three dose levels using a modified continual reassessment method: DL1 (25×10⁶ CAR⁺ T cells), DL2 (50×10⁶ CAR⁺ T cells), and DL3 (100×10⁶ CAR⁺ T cells). Bridging therapy was permitted. Primary endpoints included safety, tolerability, dose-limiting toxicities (DLTs), and recommended phase 2 dose determination. Secondary endpoints encompassed overall response rate (ORR), complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and pharmacokinetic/pharmacodynamic profiles. Response assessment utilized PET-CT imaging according to Lugano 2014 criteria at months 1, 3, 6, 9, and 12. Results As of July 28, 2025, seven patients with DLBCL were enrolled and received JWCAR201 infusion (median age 55 years, range 43-68; 42.9% male). The cohort exhibited high-risk features: 57.1% had non-germinal center B-cell-like DLBCL, 57.1% had International Prognostic Index ≥3, 71.4% had double-expressor lymphoma (MYC⁺/BCL2⁺), 28.6% had bulky disease (≥7 cm), and 42.9% harbored TP53 aberrations. Regarding treatment history, 42.9% had received ≥3 prior lines, 71.4% had primary refractory disease, and 85.7% were refractory to their most recent therapy. Bridging therapy was administered to 85.7% of patients. At 3-month assessment, all seven patients were evaluable for efficacy. The best ORR was 100% (7/7), with a CRR of 71.4% (5/7) and partial response rate of 28.6% (2/7). All responses were achieved by month 1 and maintained through month 3. Median DOR, PFS, and OS have not been reached with a median follow-up of 3.2 months (range 1.1-5.8). JWCAR201 demonstrated a manageable safety profile with no DLTs, treatment-related deaths, or study discontinuations due to adverse events. All patients (100%) experienced treatment-related adverse events, predominantly expected hematologic toxicities: Grade ≥3 neutropenia (100%), thrombocytopenia (85.7%), and anemia (71.4%). Cytokine release syndrome occurred in 42.9% of patients (all Grade 1; median onset day 3, median duration 2 days). Immune effector cell-associated neurotoxicity syndrome was observed in one patient (14.3%, Grade 1). Prolonged cytopenia (>28 days) occurred in 28.6% of patients (all Grade 1-2). One patient (14.3%) developed Grade 2 infection successfully managed with antimicrobials. Conclusions In this preliminary analysis of heavily pretreated R/R DLBCL patients with adverse prognostic factors, JWCAR201 demonstrated exceptional early efficacy with 100% ORR and 71.4% CRR, accompanied by a manageable safety profile characterized by mild CRS and minimal neurotoxicity. The dual CD19/CD20 targeting strategy appears promising for overcoming resistance mechanisms observed with single-antigen CAR-T therapies. Dose escalation continues with longer follow-up to establish durability of responses, optimal dosing, and confirm the therapeutic potential of bispecific CAR-T cell therapy in R/R B-NHL. Clinical Trial Registration: NCT06517004