Abstract 3308: Systemic administration of fiber redesigned infectivity-selective oncolytic adenovirus for pancreatic cancer.

Adenovirus (Ad) has frequently been used as a backbone of oncolytic viral agents, while lack of selectivity to cancer cells at the stage of infection has greatly hampered in vivo efficacy. Unlike loco-regional therapy, systemic application of cancer gene therapy mandates different level of selectivity of gene delivery. The controlled distribution and selective transduction of the vector would overcome the obstacles for systemic delivery and enable efficient systemic treatment of cancer. We have recently developed transductionally-targeted Ads by high-throughput screening of high-diversity (10ˆ9-level) Ad-library. Mesothelin (MSLN) is highly over-expressed in pancreatic cancers. Ad with redesigned AB-loop targeting MSLN, AdML-VTIN, was successfully isolated from the high throughput screening of Ad library by infectivity for MSLN-expressing 293 cells (293-MSLN). The in vitro binding of AdML-VTIN corresponded to the level of MSLN-expression and the suppression of MSLN with siRNA or antibody significantly reduced the binding to MSLN-expressing cells, which indicates that mesothelin is a receptor moiety for the isolated targeting ligand. The binding ability of this virus in Panc-1 (MSLN-positive) was higher than that of Ad with 5/3 modified fiber which is known to exhibit highest infectivity in pancreatic cancer cells. The in vivo antitumor effect was compared in Panc-1 and MiaPaCa-2 (MSLN-negative) subcutaneous xenografts. The injection of the MSLN-retargeted oncolytic Ad showed significant antitumor effect against Panc-1 tumors, and about half of the tumor disappeared. Contrarily, the same virus showed no antitumor effect in MiaPaCa-2. Viral DNA quantitation also supported the selective viral replication in Panc-1. Upon systemic administration in the nude mice with Panc-1 subcutaneous xenografts, the sequestration of AdML-VTIN to the liver was significantly lower than that of wild-type Ad5, and the copy number of this retargeted virus was significantly (1000 fold) higher in the tumor. These data indicates the systemic delivery of this vector is efficient for MSLN-expression pancreatic cancer xenografts. In this study, our MSLN-targeted Ad vector exhibited significant infectivity to MSLN-positive pancreatic cancer cells in vitro and in vivo. Moreover, this virus showed significantly reduced liver sequestration as well as dramatically augmented delivery to the tumors upon systemic administration. This new genetically modified Ad transductionally retargeted to pancreatic cancer may embody a next generation targeting for this devastating disease in clinical settings. Citation Format: Yoshiaki Miura, Joohee Han, Julia Davydova, Masato Yamamoto. Systemic administration of fiber redesigned infectivity-selective oncolytic adenovirus for pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3308. doi:10.1158/1538-7445.AM2013-3308 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.