Abstract 2164: BAL0891 as a dual kinase inhibitor inducing anti-tumor immunity: A promising partner for immune checkpoint inhibitors

Abstract BAL0891 is a first-in-class dual inhibitor targeting threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1). These kinases collaborate to activate the mitotic spindle assembly checkpoint (SAC) at the kinetochore, ensuring proper chromosome alignment and segregation prior to mitotic exit. Dual inhibition of TTK and PLK1 by BAL0891 rapidly disrupts the SAC, leaving tumor cells insufficient time for proper chromosome segregation, thereby exerting potent anti-cancer effects. Recent studies have underscored the potential of cell cycle inhibitors, including TTK and PLK1 inhibitors, as therapeutic partners for immune checkpoint inhibitors in various cancers. Given these findings, we investigated whether BAL0891 induces anti-cancer immune responses and evaluated its potential for combination therapy with immune checkpoint inhibitors.Our results demonstrate that BAL0891 induces aberrant cell cycle progression in cancer cells, leading to elevated levels of cytosolic DNA, a well-known activator of the cGAS/STING signaling pathway. Activation of this pathway by BAL0891 promotes cellular senescence and enhances anti-tumor immunity through the secretion of pro-inflammatory cytokines and chemokines. Notably, BAL0891 treatment increases pro-inflammatory factors such as IFNβ1, CXCL10, and CXCL11. Among these, IFNβ1 plays a pivotal role in upregulating PD-L1 expression on cancer cells, potentially enhancing the efficacy of immune checkpoint inhibitors like anti-PD-1/PD-L1 agents. Furthermore, CXCL10 and CXCL11 contribute to recruiting immune cells to the tumor microenvironment, further amplifying immune responses. In an in vivo syngeneic mouse model, BAL0891 treatment increased the presence of CD4+ T cells, CD11c+ dendritic cells (DCs), and NK1.1+ NK/NKT cells, while reducing immunosuppressive populations such as regulatory T cells (CD25+ FoxP3+ CD4+) and myeloid-derived suppressor cells (Gr-1+ CD11b+) in tumors and tumor-draining lymph nodes. These results demonstrate BAL0891’s potential to reshape the tumor microenvironment in favor of anti-tumor immunity.This study highlights the potential of BAL0891 as a combination partner for immune checkpoint inhibitors in cancer therapy. By dual inhibition of TTK and PLK1, BAL0891 not only exerts potent anti-cancer activity but also enhances anti-tumor immunity through activation of the cGAS/STING pathway and modulation of the tumor microenvironment. These results support further investigation of BAL0891 in preclinical and clinical studies, particularly in combination immunotherapy strategies. Citation Format: MinKyung Kang, Sanghee Yoo, Seunghyun Ma. BAL0891 as a dual kinase inhibitor inducing anti-tumor immunity: A promising partner for immune checkpoint inhibitors [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 2164.