Abstract 61: A new serotype chimera Cancer Terminator Virus (Ad.5/3-CTV) expands the efficiency and specificity of prostate cancer gene transfer and therapy

Abstract

Abstract Conditionally replication-competent adenoviruses (CRCAs) represent potentially useful reagents for treating prostate cancer (PC). We previously constructed a unique CRCA, Cancer Terminator Virus (CTV), in which the E1A gene, necessary for adenoviral replication, is controlled by the cancer-selective Progression Elevated Gene-3 (PEG-3) promoter and which simultaneously expresses melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) from the E3 region of the adenovirus. mda-7/IL-24, a novel member of the IL-10-related cytokine gene family, displays almost ubiquitous antitumor properties in vitro and in vivo, leading to its rapid entry into the clinic, where its safety and clinical efficacy, when administered by adenovirus (Ad.mda-7; INGN 241), was observed in a phase I clinical trial in humans with advanced carcinomas and melanomas. mda-7/IL-24 preferentially induces apoptosis in cancer cells while exerting no discernible toxic effects toward normal cells and it also elicits potent “antitumor bystander activity” in distant cancer cells as a consequence of autocrine and paracrine secretion of MDA-7/IL-24. The CTV was generated on a serotype 5 background (Ad.5-CTV) with infectivity depending on Coxsackie-Adenovirus Receptors (CARs). CARs are frequently reduced in many tumor types, including PCs thereby limiting effective therapy. Using serotype chimerism, a novel CTV (Ad.5/3-CTV) was created by replacing the Ad.5 fiber knob with the Ad.3 fiber knob facilitating infection in a CAR-independent manner. We evaluated Ad.5/3-CTV in comparison with Ad.5-CTV in low CAR human PC cells, demonstrating higher efficiency in inhibiting cell viability in vitro. Moreover, Ad.5/3-CTV potently suppressed in vivo tumor growth in a nude mouse xenograft model and in a spontaneously induced PC in Hi-myc transgenic mice. Ad.5/3.CTV exerted a marked anti-tumor ‘bystander’ effect in vivo confirming therapeutic utility. In these contexts, and considering the significant responses in a Phase I clinical trial of a non-replicating Ad.5-mda-7, the use of Ad.5/3-CTV to administer therapeutic and cytotoxic mda-7/IL24 to selectively induce cytolysis and apoptosis in prostate tumor cells represents a viable treatment options. (Supported by R01 CA097318 and P01 CA104177) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 61. doi:1538-7445.AM2012-61