Abstract IA02: Unlocking the Potential of Bispecific T-Cell engagers in Solid Tumors

Abstract Bispecific T-cell engagers (TCEs) represent a promising immunotherapy modality with the potential to reshape the treatment landscape for solid tumors. While early development was marked by successes in hematologic malignancies, the translation into solid tumors has highlighted key challenges and critical lessons for the field. Target selection remains paramount: inappropriate choices, as seen with EpCAM-directed approaches, underscore the importance of tumor-specific or selective expression to avoid on-target/off-tumor toxicity. Clinical advances with tarlatamab (DLL3-targeted TCE, approved for ES-SCLC in 2024) and xaluritamig (STEAP1-targeted TCE, in phase 3 for mCRPC) illustrate that careful antigen choice, combined with innovative engineering, can unlock efficacy even in difficult solid tumor settings. Affinity modulation, dual-targeting strategies, and “2+1” designs have further expanded the therapeutic index, enabling selective targeting of high-expressing tumor cells while sparing normal tissues. Clinical development strategies have also evolved. Step-up dosing and corticosteroid premedication mitigate cytokine release syndrome (CRS), enabling higher dosing and more durable responses. Timelines to clinical POC may be 1 or more years longer for TCEs compared to other modalities, highlighting the need for adaptive trial designs and early incorporation of tolerability strategies. Emerging data suggest moving rapidly into earlier disease settings, where lower tumor burden and preserved T-cell function may maximize benefit. Subcutaneous administration, with its favorable bioavailability, and reduced CRS rates, offers another path to improve patient outcomes, but its success is target dependent. Taken together, the lessons from preclinical and clinical experience emphasize three pillars for successful TCE development in solid tumors: rigorous target biology selection, creative protein engineering to widen the therapeutic index, and thoughtful clinical design to balance safety and efficacy. These principles will guide the next generation of TCEs as they expand across an increasing range of solid tumor indications. Citation Format: Jean-Charles Soria. Unlocking the Potential of Bispecific T-Cell engagers in Solid Tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr IA02.