Abstract 4598: A novel systemic delivery approach for oncolytic adenovirus therapy using tumor-homing mesenchymal stem cells

Abstract Oncolytic viral (OV) therapy is a promising approach for treating metastatic cancer; however, systemic delivery remains a significant challenge due to antiviral immune responses. We previously developed a telomerase-specific OV, Telomelysin (OBP-301), which utilizes the hTERT promoter to drive the expression of E1A and E1B. OBP-301 demonstrated an abscopal effect when combined with anti-PD-1 antibodies in distant metastases in vivo murine colorectal cancer (MC38) mouse models. A p53-armed variant, OBP-702, showed potent tumor-suppressive effects in mouse models of gastroenterological cancers via intratumoral injection. However, these therapies remain limited to accessible lesions. To address these challenges, we investigated three novel approaches for systemic OV delivery. First, we encapsulated the DNA plasmids of GFP-expressing OBP-301 (OBP-401) in liposomes, which effectively reduced the production of neutralizing antibodies compared to naked OVs. Second, we explored extracellular vesicles (EVs) derived from OBP-301-infected tumors as natural carriers. These EVs demonstrated the abscopal effects to non-injected metastatic lesions in preclinical models, achieving promising therapeutic efficacy. Finally, we utilized mesenchymal stem cells (MSCs), known for their tumor-homing properties, as carriers for OBP-702. When MSCs loaded with OBP-702 (MSC-OBP-702) were intraperitoneally injected into an MC38-bearing peritoneal metastasis model, they effectively migrated to metastatic sites, significantly suppressing tumor growth and improving overall survival compared to OBP-702 alone. These findings demonstrate that MSC-OBP-702 has significant potential to overcome the challenges of systemic OV therapy through the tumor-homing capability of MSCs, providing a foundation for future clinical applications. Citation Format: Yu Mikane, Nobuhiko Kanaya, Shinji Kuroda, Hitoshi Minagi, Makoto Matsumoto, Tetsuya Katayama, Daisuke Kadowaki, Shunya Hanzawa, Masashi Hashimoto, Yoshihiko Kakiuchi, Satoru Kikuchi, Shunsuke Kagawa, Hiroshi Tazawa, Toshiyoshi Fujiwara, Yasuo Urata. A novel systemic delivery approach for oncolytic adenovirus therapy using tumor-homing mesenchymal stem cells [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 4598.