Pancreatic cancer is an aggressive malignant disease. Despite extensive efforts, systemic therapies have provided only limited efficacy for patients with this disease. Oncolytic Adenovirus (OAd) is a promising therapeutics, and it is also known for its efficient in vivo gene delivery. However, when adenovirus vectors are injected intravenously into mice, most of the virus goes to the liver and can lead to liver toxicity at high dosage. One of the reason for liver tropism is that hepatocytes express high levels of the primary adenovirus receptor, and non-parenchymal liver cells, such as Kupffer cell and epithelial cell, also capture the viral particle. As a consequence of large sequestration of adenovirus by liver, the tumor transduction rate is low and the in vivo efficacy is limited. Therefore, the improvement of cancer selective transduction and vector distribution to avoid liver sequestration would overcome the obstacles for systemic delivery required for efficient systemic treatment of spread and/or metastatic lesions of pancreatic cancer with OAd.
To improve the tumor transduction, we have generated the pancreatic cancer-targeted OAd by high-throughput screening of Ad-fiber library in mesothelin (MSLN) expressing cells. The pancreatic cancer-targeted OAd binds to MSLN protein, which is overexpressed on the surface of pancreatic cancer. MSLN-targeted OAd showed selective and powerful anti-tumor effect against Panc-1 xenograft tumor model in both intratumoral (i.t.) and intravenous (i.v.) injection. Importantly, when we assessed viral distribution after i.v. injection, the liver sequestration of MSLN-targeted OAd was lower than untargeted OAd (Ad5 WT virus) at 48 hrs after injection. By day 7, the viral copy number of MSLN-targeted OAd in the tumor was significantly higher than Ad5 WT virus. These results suggest that systemic injection of the tumor targeted-OAd showed significantly lower liver sequestration and better tumor accumulation. Additionally, we performed multiple time point injection of MSLN-targeted OAd against regrown tumors. Four out of six tumors were controlled with repeated injection. Next, antitumor effect of MSLN-targeted OAd was assessed in patient-derived xenograft (PDX) model. After intravenous administration, only the MSLN-targeted OAd showed significant antitumor effect compared to the untreated group (p<0.05), while the growth of Ad5 WT virus injected group was same as untreated group.
In this study, systemic injection of MSLN-targeted OAd showed remarkable anti-tumor effect in both systemic and intratumoral injections at low dose. Our results indicated that tumor targeted-OAd can embody efficient systemic treatment for pancreatic cancer which are mostly found with spread or metastatic lesions.
Citation Format: Mizuho Sato-Dahlman, Yoshiaki Miura, Praveensingh Hajeri, Hideki Yoshida, Kari Jacobsen, Chikako Yanagiba, Masato Yamamoto. Systemic treatment with mesothelin-targeted oncolytic adenovirus shows efficacy patient-derived xenograft of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5921.