Abstract T-cell–engaging bispecific antibodies have emerged as a highly active therapeutic class in B-cell lymphomas, demonstrating robust and durable responses across relapsed/refractory settings. CD20×CD3 bispecifics such as mosunetuzumab, glofitamab, epcoritamab, and odronextamab provide effective, off-the-shelf alternatives to cellular therapies, with manageable safety profiles and, in some cases, fixed-duration treatment. While bispecifics have shown remarkable activity as monotherapy, some patients remain refractory or relapse, shifting focus toward determinants of response, resistance, and rational combinations to maximize treatment outcomes. While acute CRS was an early safety concern, subcutaneous formulation and step-up dosing have reduced CRS risk and improved safety and shifted attention to long-term tolerability. T-cell bispecifics directly engage T cells, offering a mechanism distinct from cytotoxic and cellular therapies. Both innate and acquired resistance mechanisms are emerging. Tumor-intrinsic innate resistance may be driven by high proliferative capacity and MYC-driven biology, which are associated with inferior outcomes and may limit the effectiveness of T cell redirection. In contrast, acquired resistance due to CD20 loss, likely reflects selective pressure from effective target engagement. The tumor microenvironment (TME) also plays a critical role in modulating activity. Multimodal biomarker analyses highlight the importance of TME context with immune-poor or “cold” microenvironments, such as those described in certain germinal center B-cell–like lymphomas, and distinct TME architectural subtypes (e. g. LymphoMAP), limiting effective T-cell activation. While no single biomarker currently defines response, emerging data support an integrated model in which clinical, tumor-intrinsic, and tumor-microenvironment features influence benefit from bispecific antibodies. These insights provide a rationale for combination strategies to overcome resistance. Cytotoxic or debulking approaches, including chemotherapy or antibody–drug conjugates such as polatuzumab vedotin, may reduce tumor burden and improve immune engagement, while immunomodulatory agents such as lenalidomide may enhance T-cell function. Recent clinical studies demonstrate complementary activity, although optimal sequencing and personalized patient treatment remain to be defined. In parallel, biomarkers such as circulating tumor DNA, deeper TME profiling, and T-cell exhaustion in blood are being explored to guide treatment duration and sequencing. As the field evolves, the role of bispecific antibodies will depend on integration into rational treatment paradigms, including optimized combinations, anticipation of resistance, and strategic sequencing relative to antibody-drug conjugates, CAR T-cell therapy, and other immune-based approaches. Undoubtedly, correlative data from these studies will inform therapeutic vulnerabilities to further drive cures in B-cell lymphoma. Citation Format: Elicia Penuel. Bispecific antibodies in B-cell lymphomas: Redefining immune engagement in the therapeutic landscape abstract. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7 (3Suppl): Abstract nr IA009.
Elicia Penuel (Wed,) studied this question.