304. Therapeutic Efficacy of a Mesothelin Promoter-Based Conditionally Replicative Adenovirus Monitored by In Vivo Imaging of an Ovarian Cancer Model

Although a number of advances in ovarian cancer treatment have occurred in the last decade, most patients will experience a recurrence after standard surgical and chemotherapeutic approaches. Therefore, new therapeutic approaches are necessary for ovarian cancer. Recently, virotherapy has been proposed as a therapeutic approach for many kinds of malignancies, including ovarian cancer. Conditionally replicative adenovirus (CRAd) contains tumor- specific promoters that restrict virus replication to cancer cells and has shown particular promise as oncolytic viral agents. However, the lack of a tumor-volume monitoring system hinders the evaluation of CRAd impact on cancer treatment. Therefore, methods for analyzing CRAd efficacy and tumor response are required. Mesothelin, a cell surface glycoprotein, is overexpressed in ovarian cancer but not in normal ovarian tissues. The purpose of this study was to explore the therapeutic utility of a mesothelin promoter- based CRAd in a murine model of ovarian cancer, using a non- invasive biological imaging system. We constructed a mesothelin promoter based CRAd which also contains a modified fiber (Ad5/3 fiber) previously shown to improve infectivity of many ovarian cancer cells (Ad5/3MSLN). Viral replication and oncolysis were assessed in OV-3, SK-OV-3, OV-4, and Hey ovarian cancer cell lines. Ad5/3MSLN achieved a 10- to 10000-fold higher cell killing effect and 60- to 120-fold higher levels of viral replication in all ovarian cancer cell lines tested, compared to wild type Ad5. To test the oncolytic efficacy of Ad5/3MSLN in murine model, firefly luciferase-expressing SK-OV-3-luc cells were injected intraperitoneally (i.p.), followed by an i.p. injection of Ad5/3MSLN, or control viruses. Bioluminescence imaging of tumor luciferase activity was carried out following i.p. injection of D-luciferin. In vivo tumor imaging confirmed that Ad5/3MSLN significantly inhibited tumor growth, while the untreated mice had rapid tumor growth (p