Abstract
Systemic therapies for cancer, including pancreatic cancer, have provided only limited efficacy for patients to date. Adenovirus (Ad) has frequently been used as a backbone of oncolytic viral agents. However, unlike loco-regional therapy, systemic application of cancer gene therapy mandates different level of selectivity of gene delivery. So far, insufficient cancer selectivity at the stage of infection has greatly hampered efficacy of Ad-based therapy upon systemic administration. 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 (10^9-level) Ad-library. Mesothelin (MSLN) is highly overexpressed in pancreatic cancers. Ad with redesigned AB-loop targeted to MSLN (AdMLVTIN)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 MSLN-expression of each cell line, and the suppression of MSLN-expression with siRNA or antibody blocked the binding to MSLN-expressing cells, which indicates the vector is targeted to mesothelin. In MSLN-positive cells (Panc-1), this virus exhibited higher binding ability 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 (MSLN-positive) and MiaPaCa-2 (MSLN-negative) subcutaneous xenografts. The injection of the MSLN-retargeted oncolytic Ad showed significant antitumor effect against Panc-1 tumors, and disappearance of tumors was observed in 4 out of 8 mice. Contrarily, the same virus showed no antitumor effect in MiaPaCa-2. Viral DNA amount in the tumors correlated to the anti-tumor effect. Upon systemic administration in the nude mice with Panc-1 subcutaneous xenografts, AdML-VTIN showed significantly lower liver sequestration compared to the wild-type Ad5, and the copy number of this retargeted virus was significantly (1000-fold) higher in the tumor. These data indicates that this vector enables efficient systemic delivery and treatment of MSLN-expressing pancreatic cancer xenografts. In this study, our MSLN-targeted Ad vector exhibited selective infectivity to MSLN-positive pancreatic cancer cells in vitro and in vivo. Moreover, this virus showed dramatically augmented delivery to the tumors and significantly reduced liver sequestration upon systemic administration. This new genetically modified Ad, which is transductionally retargeted to pancreatic cancer, may embody a next generation systemic therapy for this devastating disease.
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