Abstract 5914: The porcine model for onocolytic adenovirus-based therapy

Abstract

Abstract Oncolytic adenoviruses (Ad) are promising tools in the development of cancer therapeutics. A majority of Ad-based therapies utilize serotypes of species C, with Adenovirus type 5 (Ad5) being the most commonly employed. Previously, clinical trials have demonstrated the low efficiency of Ad5 vectors, mainly due to absence of the Ad5 primary receptor (Coxsackie Adenovirus Receptor, CAR) in cancer cells. Engineering Ad vectors utilizing the species B (Ad3, Ad35, Ad11) receptors have greatly improved the oncolytic potential of Ad-based therapies. However, the lack of a viable animal model has impeded clinical translation of these tropism-modified vectors. Mouse models are insufficient because Ad does not replicate in murine tissue. Non-human apes are not feasible due to availability and cost. Cotton rats and Syrian hamsters, although permissive of Ad5 replication, are not suitable for Ad3-, Ad35-, and Ad11-retargeted vectors due to the lack of species B primary receptors (CD46 and desmoglein 2) in rodent systems. In this study, we explored pigs as a model to study performance of the group B oncolytic adenoviruses by employing the fiber-modified Ad5/Ad3 chimeric vector. As a control, the Ad5 fiber-unmodified virus was used. First, we demonstrated the ability of swine cell lines to support replication of both Ad5 and Ad5/Ad3. Second, we analyzed binding, gene transfer, cytolytic, and replication ability of Ad5 and Ad5/Ad3 in various non-human cell lines (swine, hamster, murine, rat, bovine, canine). Our data confirmed that while hamster cell lines (HP1 and HapT1) were able to support binding and replication of Ad5-based vectors, they failed to support that with the Ad3-retargeted vectors. Additionally, we showed that among all tested cell lines, only porcine cells (PK15 and PTK75) were supportive of both binding and replication of the Ad3-retargeted virus. Of note, Ad5/Ad3 outperformed Ad5 in its cytolytic effect in porcine cell lines. These in vitro results prompted evaluation of the vectors in vivo. Immunocompetent Yorkshire pigs were systemically injected with a single dose of Ad5- and Ad5/3- expressing luciferase (Luc) from the Ad E3 region. Quantitative PCR analyses of the primary organs collected 7 days post-infection revealed Ad5 and Ad5/3 viral DNA in the lungs and spleen. Replication-dependent Luc expression was also observed in these tissue samples suggesting active viral replication. The quantity of viral DNA in other tissue such as the kidneys, liver, and pancreas was negligible. The results of these in vitro and in vivo studies indicate that pigs are a promising model to assess unmodified and tropism-modified adenoviral vectors. Citation Format: Malavika Chandrashekar, Lisa Koodie, Michele Dunning, George Ruth, Richard Bianco, Masato Yamamoto, Julia Davydova. The porcine model for onocolytic adenovirus-based 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 5914.