Abstract 5916: Engineering an oncolytic adenovirus targeted to the CXCR4 chemokine receptor for breast cancer therapy

Abstract

Abstract Breast cancer is the most commonly diagnosed cancer in women under 60. Localized breast cancer is easily treated, resulting in high survival rates. However, treatments for advanced disease are inadequate, resulting in poor five-year survival rates at less 24%. Thus, there is a great need for new therapies capable of increasing treatment efficacy. Oncolytic virotherapy using the human adenovirus is a novel therapeutic approach designed to specifically target cancer cells while sparing normal tissues. As a well-characterized vector, adenovirus is easily manipulated and results in high gene transfer efficiency. Combined with systemic stability, low pathogenicity and the ability to infect a broad range of dividing and non-dividing cells, this vector is uniquely suited for oncolytic virotherapy. Used as an oncolytic therapy, replication of the vector within cancer cells causes the lysis of the cells and subsequent spread of progeny virions within the surrounding tumor stroma. One challenge to targeting cancer cells with adenovirus has been the low expression of the endogenous adenovirus receptor, the Coxsackie and adenovirus receptor (CAR), prompting the search for new targets. This study engineered an adenovirus vector to target CXCR4, a seven-membrane spanning G-protein-coupled receptor, whose role is implicated in a wide variety of tumors, including breast cancer. Altered expression of CXCR4 drives cancer cell migration and invasion, which has been associated with metastasis. Previously, we developed a bispecific adaptor molecule targeting CXCR4 to retarget a replication-deficient adenovirus to breast cancer cells overexpressing CXCR4. In the current study, we have engineered a replication-competent oncolytic adenovirus targeting CXCR4, by replacing the adenovirus fiber gene with a modified fiber containing the SDF-1 ligand of CXCR4. The modified fiber was constructed using the T4 fibritin protein fused to the tail of the adenovirus fiber and attached to the CXCL12 ligand via a spacer protein. Also, the red fluorescent protein (RFP) sequence was fused to the capsid protein IX (pIX) gene for visual tracking. The virus was then rescued and amplified in HEK-293 cells for characterization and downstream applications. We confirmed the presence of a modified fiber and the specificity of CXCR4 binding. Subsequently, the vector was tested in a panel of breast cancer cells for infection and cell killing efficiency. Together these studies addressed the hypothesis that constructing a retargeted oncolytic adenovirus using the CXCL12 ligand provide selective infection and killing of breast cancer cells overexpressing CXCR4. These results provide a strong rationale for further developing the retargeted vector for oncolytic virotherapy in patients. Citation Format: Samia M. O'Bryan, J. Michael Mathis. Engineering an oncolytic adenovirus targeted to the CXCR4 chemokine receptor for breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5916.