Abstract / Summary
Abstract The efficacy of immunotherapy depends on the composition of immune cells, including cytotoxic T cells (CTLs), etc., in the tumor microenvironment (TME). However, a significant proportion of patients with pre-existing immunity fail to respond to current immunotherapy, indicating the search of drugs/combinations with therapeutic potential for unmet medical needs for patients with CTL-low immune phenotypes is an urgent task, and the exploring of strategies by combining different agents like vascular endothelial growth factor receptor (VEGFR) inhibitors with additional immunomodulatory agents is still under extensive studies. Here, by using murine colon carcinoma (CT26) allograft and xenograft models, we examined the efficacy of a novel epigenetic immunomodulator (GNTbm-38) combined with regorafenib. TME reprogramming was assessed using flow cytometry and RNA sequencing to elucidate the novel mechanisms and their correlation with therapeutic effects in mice with significant treatment responses. Notably, CT26-bearing mice treated with GNTbm-38 plus regorafenib showed significant objective response rates (ORRs) and overall survival (OS). After treatment, analyses of immunohistochemistry (IHC) and flow cytometry revealed increased infiltration of activated CD8+ T cells in the TME, triggering a reprogramming mechanism by attenuating immunosuppressive cells and restoring T-cell activation to enhance ORR and OS. This result suggests that GNTbm-38-mediated TME reprogramming, combined with regorafenib, produces a synergistic effect, making it advantageous for achieving high ORR and maintaining long-lasting anti-tumor activity.