Abstract 2156: Combination therapy of platinum chemotherapy and HIF1α/c-MET peptide vaccine suppresses tumor growth and intraperitoneal metastasis by modulating tumor microenvironment in high grade serous ovarian carcinoma

Abstract Ovarian cancer is the most lethal form of gynecological cancer. Approximately 75% of patients are diagnosed at stage 3 or 4, where the cancer has a high metastasis and mortality rate. Platinum chemotherapy is the standard first line treatment for ovarian cancer. However, 60% of patients with advanced stage disease experience drug resistance and side effects, with recurrence occurring within a few years. Resultantly, the five year survival rate for patients with advanced stage ovarian cancer is only 20-30%. Among the mechanisms proposed to explain platinum resistance, tumor hypoxia is known to contribute to the acquisition of several aggressive tumor characteristics, including increased cellular proliferation, inhibition of apoptosis, enhanced invasion and metastasis, chemoresistance, and immune evasion. Thus, immune checkpoint inhibitors are not the current central treatment in ovarian cancer. In this study, we aimed to investigate the role of tumor hypoxia in the development of platinum resistance and to explore the effect of a strong Type I immunity in overcoming platinum resistance in ovarian cancer. In ovarian cancer cell line, we evaluated the effect of tumor hypoxia on resistance to carboplatin and related proteins. We observed in hypoxia, the expression of relevant proteins was increased compared to normoxia, and the IC50 of carboplatin was also elevated in ovarian cancer cell line. On the contrary, treatment with IFN-γ in vitro induced a reduction in the expression of these proteins in hypoxia, and showed a synergy with carboplatin in cell death. Based on these findings, we identified HIF-1α and c-MET as potential therapeutic targets and developed a HIF1α/MET derived peptide vaccine to enhance local IFN-γ production via helper T-cell immunity. We evaluated the efficacy of a HIF1α/MET peptide vaccine in a high grade serous ovarian carcinoma mouse model (C57BL/6 mice). The mice were divided into four groups: control, carboplatin, vaccine, and combination of carboplatin and vaccine. After three vaccinations, tumor cells were injected, followed by carboplatin treatment, and the tumor suppression effect was evaluated. Tumor growth was significantly suppressed in both monotherapy compared to the control, with the combination demonstrating the most pronounced tumor inhibition. Immunohistochemical analysis revealed reduced expression of HIF-1α & c-MET and an increased infiltration of CD8+ T cells in both monotherapy, with the combination showing the greatest effect. In conclusion, immunotherapy using a HIF-1α/c-MET-derived peptide vaccine, a key player of tumor hypoxia, synergy with carboplatin by modulating the tumor microenvironment and enhancing antitumor immunity. This approach represents a promising strategy for overcoming hypoxia driven resistance in ovarian cancer. Citation Format: Soon Young Lim, Jinhwa Hong, DongGeRaMi Moon, Hye Yeon Roh, Ju Won Kim, Jiwon Lee, Kyong Hwa Park. Combination therapy of platinum chemotherapy and HIF1α/c-MET peptide vaccine suppresses tumor growth and intraperitoneal metastasis by modulating tumor microenvironment in high grade serous ovarian carcinoma [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 2156.