Gene Therapy for HPV-Associated Malignancies

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DESCRIPTION (provided by applicant): In this application we propose to construct and test a novel adenovirus (Ad) vector for therapy of HPV associated cervical carcinoma that will combine a direct oncolytic effect with an induction of strong cellular immune responses against HPV-positive tumor cells. The conditionally replicating Ad vector (Ad.IR) described here will express the heat shock protein (HSP) gp96 and the HPV-16 E7 protein exclusively in tumor cells. We will employ an immunocompetent mouse model of cervical carcinoma with liver metastases derived from E7+ murine tumor cells to test the following: A. Both E7 and HSPs have an ability to increase the oncolytic activity of Ad vectors and we hypothesize that our vector will efficiently kill tumor cells as a result of tumor-specific expression of these proteins. B. Based on the immunostimulatory properties of HSPs and the potential of E7 to serve as a target for a cytotoxic T-cell (CTL) response, we hypothesize that surface expression of gp96 and overexpression of E7 will stimulate efficient anti-E7 and anti-tumor CTL responses. C. We hypothesize that the immune processing and presentation of necrotic material released from tumor cells lysed following Ad vector mediated oncolysis will augment the CTL response and that these activities will complement each other. Finally, even if the rate of tumor transduction with the viral vector is limited, an anti-tumor immune response will lead to lysis of tumor cells that were originally not transduced.