Abstract PR001: Gene-modified iPS-derived MSC restore a ‘Hot’ immune microenvironment in high-grade serous ovarian cancer

High-grade serous ovarian carcinoma (HGSOC) is the most lethal form of epithelial ovarian cancer, responsible for the majority of disease-related deaths. Over 70% of cases are diagnosed at advanced stages, limiting curative options. Despite initial responses to surgery and platinum-based chemotherapy, over 80% of patients relapse and develop platinum resistance (PR). Existing therapies offer limited and short-lived benefit and fail to reprogram the immunosuppressive, immune-inert tumor microenvironment (TME), a major barrier to durable responses. To directly address this barrier, we developed an immunotherapeutic strategy using induced pluripotent stem cell–derived mesenchymal stem cells (iMSCs) engineered to secrete IL-7 and IL-15. iMSCs, clonally derived from iPSCs, offer superior expansion and scalable production over BM-MSCs. These iMSCs retained classical MSC morphology and proteogenomic profiles, supporting their identity and functionality. Telomere and CyTOF-based cell cycle analysis revealed high proliferative capacity. Stable transgene expression was validated using GFP-tracked clones across differentiation and expansion stages. Proprietary gene editing ensured efficient and consistent integration, providing a robust platform for cytokine delivery. IL-7/IL-15-iMSCs produced supraphysiologic cytokine levels (2,000–4,000 pg/mL), representing a nearly 20-fold increase over levels seen in historically engineered T cells. This enhanced cytokine output drove proliferation of resting and CD3/CD28-activated T cells, as confirmed via CFSE assays. CyTOF profiling revealed robust downstream STAT5 phosphorylation, pS6 activation, and BCL2 upregulation, indicative of efficient IL-7/IL-15 receptor downstream signaling. PBMCs conditioned with IL-7/IL-15-iMSCs significantly reduced the number of both platinum-sensitive (PS) and PR ovarian cancer cells. To evaluate therapeutic efficacy, we administered IL-7/IL-15-iMSCs in the ID8 murine ovarian cancer model in immunocompetent mice. Multiplex immunofluorescence demonstrated that iMSCs home to tumors, secrete cytokines locally, and promote intratumoral T cell infiltration, collectively leading to improved survival. This outcome was associated with a shift from an immune-excluded to an inflamed, immune-infiltrated TME. The ovarian TME was enriched in CD163+Arg1+PD-L1+M2-like macrophages, which exhibited a phenotypic shift toward an M1-like state, marked by Arginase-1 downregulation, in the IL-7/IL-15 treatment group. Experiments investigating activity in carboplatinum-resistant ID8 models are ongoing and will be reported. Conclusion: We demonstrate reprograming of the immunosuppressive into a “hot” ovarian TME, characterized by massive T-cell and macrophage infiltration, and restoration of T-cell functionality in HGSOC. Gene-modified iMSC-induced reprogramming of ovarian TME resulted in reduced tumor burden and improved survival in murine ovarian cancer model. Results support the potential of IL-7/IL-15 iMSCs as novel immunotherapeutic platform for overcoming immune resistance in ovarian cancer. Citation Format: Muharrem Muftuoglu, Sandeep Singh, Andrea D. Bedoy, Li Li, Dipmoy Nath, Lauren B. Ostermann, Ivo Veletic, Christopher D. Pacheco, Po Yee Mak, Edward Ayoub, Mahesh Basyal, Taeyun Kim, Sanjeev Luther, Christopher B. Rohde, Michael Andreeff. Gene-modified iPS-derived MSC restore a ‘Hot’ immune microenvironment in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr PR001.