Bispecific antibodies serve as a safe and effective bridging therapy prior to CD19 CAR T-cell therapy/combinational therapy of CD19 CAR-T cell and HDT/ASCT in patients with R/R DLBCL

Abstract

Abstract Background: Bispecific antibodies (BsAbs) and chimeric antigen receptor T-cell (CAR-T) therapy are highly regarded immunotherapeutic approaches, serving as critical treatments for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Both modalities eradicate tumor cells by leveraging sophisticated immune mechanisms. Although typically administered sequentially in clinical practice, emerging in vitro and in vivo evidence suggests potential synergy between them. This retrospective study investigated the efficacy and safety of BsAbs-containing bridging therapy administered prior to CD19-specific CAR-T therapy alone or in combination with high-dose therapy and autologous stem cell transplantation (HDT/ASCT). Methods: We assessed patient demographics, clinical characteristics, and prior lines of treatment. Responses were evaluated using PET-CT. Key endpoints included complete response rate (CRR), objective response rate (ORR) before and after cellular therapy, progression-free survival (PFS), and overall survival (OS). Safety profiles of BsAbs and CAR-T therapy were also evaluated. Results: Eleven patients (median age 54 years, range 37-65; male/female ratio 5:6) were enrolled. Most patients (81.8%, 9/11) had advanced-stage disease (Ann Arbor stage III-IV); 36.4% (4/11) presented with B symptoms. Pathologically, 72.7% (8/11) were DLBCL NOS, while the remainder were DLBCL transformed from indolent B-cell lymphoma (follicular lymphoma or marginal zone lymphoma). TP53 abnormalities (deletion or mutation) were detected in 55.6% (5/9) of tested patients. Molecular subtypes were distributed as follows: MCD (22.2%, 2/9), BN2 (22.2%, 2/9), EZB (22.2%, 2/9), A53 (11.1%, 1/9), and other (33.3%, 3/9). The median number of prior treatment lines before bridging therapy was 2 (range 1-4). Bridging therapy consisted of glofitamab monotherapy (3 patients) or glofitamab combined with chemotherapy (GVM [gemcitabine, vinorelbine, mitoxantrone hydrochloride liposome] in 4 patients; GemOx [gemcitabine, oxaliplatin] in 4 patients). All patients were planned for combination CD19 CAR-T therapy with HDT/ASCT. However, 3 patients received CD19 CAR-T therapy alone due to autologous hematopoietic stem cell mobilization failure. Response to BsAbs-containing bridging therapy before cellular therapy was: complete remission (CR) in 27.3% (3/11), partial remission (PR) in 54.5% (6/11), stable disease (SD) in 9.1% (1/11), and progressive disease (PD) in 9.1% (1/11). The best response after CAR-T therapy by PET-CT was CR in 81.8% (9/11) and PR in 18.2% (2/11), yielding an ORR of 100%. With a median follow-up of 12 months (range 4-16 months), no patient experienced disease progression or death. Adverse events included cytokine release syndrome (CRS): 63.6% (7/11) after BsAbs (all grade 1, predominantly after the first two doses) and 90.9% (10/11) after CD19 CAR-T therapy (with or without HDT/ASCT; all grade 1). No immune effector cell-associated neurotoxicity syndrome (ICANS) occurred during treatment. Conclusions: These preliminary data suggest that BsAbs-containing bridging therapy prior to CD19-specific CAR-T therapy, either alone or combined with HDT/ASCT, is effective and safe in DLBCL. More detailed data will be presented at the conference.