Abstract B62: Development of infectivity-selective oncolytic adenovirus for systemic cancer therapy
Authors: Sato-Dahlman Mizuho , Yamamoto Masato 
Published: March 2020

Abstract
Adenovirus (OAd) has high potential for systemic cancer therapy. However, its efficacy upon systemic application has been quite limited to date. Unlike locoregional therapy, systemic application of cancer therapy mandates better tumor distribution and transduction. When adenoviruses are injected intravenously, most of the virus goes to the liver due to high expression of wild-type Ad receptor (coxsackie-adenovirus receptor: CAR) and capture by Kuppfer cells. The large sequestration by liver reduces tumor transduction rate and the in vivo efficacy upon systemic therapy. Therefore, the improvement of cancer-selective transduction and reduction of liver distribution would overcome the obstacles for systemic delivery and enable efficient systemic treatment of cancer with OAd. To improve the tumor transduction, we have developed a new technology and generated the large diversity Ad-fiber library in OAd format. By screening with Mesothelin (MSLN) overexpressing cell line, we obtained an infectivity-selective OAd for pancreatic cancer. MSLN-targeted OAd showed selective and powerful antitumor effect against MSLN-positive subcutaneous 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). Also, the viral copy number of MSLN-targeted OAd in the tumor was significantly higher than Ad5 WT virus. Most importantly, when antitumor effect of MSLN-targeted OAd was assessed in patient-derived xenograft (PDX) model, only the MSLN-targeted OAd showed significant antitumor effect upon intravenous administration. To further reduce liver sequestration and increase antitumor efficacy, we developed an improved vector with second modification in hexon. The MSLN-targeted OAd was additionally modified by substitution of Ad5 hexon-hypervariable region 7 (HVR7) with Ad26 hexon-HVR7. We assessed liver distribution of the double-modified vector after i.v. injection. The virus copy number after double-modified OAd was significantly lower in the liver. These data suggest that hexon modification allowed to escape from the liver. The detailed mechanism of this finding is currently being investigated and focuses on the viral uptake by hepatocytes and Kupffer cells. In summary, MSLN-targeted OAd showed remarkable antitumor effect in both systemic and local injections, and hexon modification further reduced liver sequestration. We believe that the fiber and hexon double-modified vector might be a promising vector to reduce hepatotoxicity and enhance antitumor effect for systemic treatment of pancreatic cancer.
Citation Format: Mizuho Sato-Dahlman, Masato Yamamoto. Development of infectivity-selective oncolytic adenovirus for systemic cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B62.