Abstract 6161: Exploring BRG399, a novel microtubule-binding agent, as an inducer of immunogenic cell death in cancer therapy

Abstract Cancer therapy is transforming from traditional chemotherapeutic agents (CTAs) to innovative immunotherapies. Despite this shift, chemotherapy remains clinically stable, as CTAs are thought to convert the tumor microenvironment (TME) from immunosuppressive to immune-active by inducing immunogenic cell death (ICD) in tumor cells which leads to stimulation of immune cells. This ICD induction is thought to be crucial for enhancing the efficacy of immunotherapies. Thus, using CTAs as ICD agents—alone or in combination with immunotherapies—may offer significant anti-cancer benefits and new treatment avenues. This study investigates the potential of BRG399, a novel microtubule-binding agent, as an immunogenic cell death (ICD) inducer utilizing preclinical in vitro and in vivo models. Treatment of cancer cell lines with BRG399 showed a dose-dependent increase in surface calreticulin and secreted HSP70, measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. The enhancement of both ICD markers was comparable to that observed with established ICD agents. To explore the potential of BRG399 to exert influence on immune-regulated anti-tumor effects, in vivo studies in immune-competent syngeneic models were conducted with measurable endpoints of tumor growth inhibition and TME composition by flow cytometry and TIMS TOF spatial omics. BRG399 displayed anti-tumor activity while largely preserving tumor-associated immune cells and notably modifying the immune cell landscape within the tumor. Our findings suggest that BRG399 acts as an ICD agent, effectively modulating both tumor and immune cells within the TME and highlighting its potential for future combination therapies with immunotherapeutics. Further in vivo studies are currently being conducted to comprehensively elucidate the immune-mediated effects of BRG399 aiming to clarify its role in enhancing anti-tumor responses ultimately contributing to the development of more effective cancer therapies. Citation Format: Kaila M. Bennett, Jacob P. Matson, Sylwia Stopka, Juan J. Aristizabal-Henao, Archna Ravi, Andressa L. Mota, Dinesh Chimmanamada, Vivek K. Vishnudas, Stephane Gesta, Maria-D Nastke. Exploring BRG399, a novel microtubule-binding agent, as an inducer of immunogenic cell death in cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6161.