Abstract 1628: A bispecific PDL1:CD3 T-cell engager potently kills intractable primary and metastatic intracranial tumors

Abstract Introduction: Central nervous system tumors represent a huge unmet medical need. Many pediatric and adult brain cancers and cancers (e.g., lung, colon, breast) with CNS involvement remain largely intractable despite standard of care and advanced treatment strategies. We engineered a bispecific PD-L1 targeted T-cell engager (TCE) and discovered promising efficacy in a wide range of pre-clinical intracranial tumor models, including some models with intact blood brain barriers. Methods: Anti-tumor activity of a systemically administered PD-L1:CD3 TCE was interrogated in 14 intracranially implanted tumor xenografts representing poor-prognosis pediatric brain tumors, adult glioblastoma, and metastatic lung, breast, and colorectal cancers. On-target/off-cancer toxicity was evaluated in mice transgenic for human PD1/PD-L1 or CD3ε with surrogate chimeric TCEs for species appropriate binding over 2- and 4-week treatment periods with repeated dosing. Dose range finding study in non-human primates was conducted to establish the safety profile of the lead TCE. Results: Median and overall survival were significantly extended by TCE treatment in 4 of 5 models of pediatric brain tumors (2 diffuse midline glioma, 1 medulloblastoma, 2 high-grade glioma), 2 of 3 models of adult glioblastoma, and all 6 models of intracranial metastases (3 lung adenocarcinoma, 2 triple-negative breast cancer, 1 colorectal carcinoma). One of the adult GBM and the 6 metastatic models were transduced for bioluminescent monitoring of tumor burden: 53% of tumors across model types were eliminated by TCE treatment, 39% showed tumor presence without progressive growth, and 8% of tumors continued to grow with or without an initial delay. Dose range tolerability in transgenic mice showed dose dependent pharmacodynamic effects on body weight, lymphopenia, cytokine stimulation, CD3+ cell biodistribution, and tissue PD-L1 expression with no overt toxicity. A dose range finding study in non-human primates revealed the TCE was well tolerated with pharmacodynamic responses observed at 0.03 mg/kg and limited to grade 1 toxicities. At 0.3 mg/kg grade 2-4 toxicities were observed. Conclusion: Bispecific PD-L1:CD3 TCE is safe at doses that show efficacy in intracranial xenograft tumor models. This PD-L1 TCE presents a novel therapeutic strategy for patients with primary and metastatic intracranial tumors that are typically fatal. Citation Format: Emily J. Girard, Shelli M. Morris, Kristina Pilat, Alison M. Williams, Kenneth Brasel, Heather Conti, Parvathi Muthuraman, Ray Ruff, Hailey Hentschel, Steven Chen, Chunfeng Yin, Zachary Crook, Jason Price, Andrew J. Mhyre, James M. Olson, . A bispecific PDL1:CD3 T-cell engager potently kills intractable primary and metastatic intracranial tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1628.