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Published on: May 6, 2015
Rodents Versus Pig Model for Assessing the Performance of Serotype Chimeric Ad5/3 Oncolytic Adenoviruses
Lisa Koodie1, Matthew G Robertson2, Malavika Chandrashekar3
1Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, 55455 MN, USA. kood0006@umn.edu.
Abstract:
Oncolytic adenoviruses (Ad) are promising tools for cancer therapeutics. Most Ad-based therapies utilize species C serotypes, with Adenovirus type 5 (Ad5) most commonly employed. Prior clinical trials demonstrated low efficiency of oncolytic Ad5 vectors, mainly due to the absence of Ad5 primary receptor (Coxsackie and Adenovirus Receptor, CAR) on cancer cells. Engineering serotype chimeric vectors (Ad5/3) to utilize Adenovirus type 3 (Ad3) receptors has greatly improved their oncolytic potential. Clinical translation of these infectivity-enhanced vectors has been challenging due to a lack of replication permissive animal models. In this study, we explored pigs as a model to study the performance of fiber-modified Ad5/3 chimeric vectors. As a control, the Ad5 fiber-unmodified virus was used. We analyzed binding, gene transfer, replication, and cytolytic ability of Ad5 and Ad5/3 in various non-human cell lines (murine, hamster, canine, porcine). Among all tested cell lines only porcine cells supported active binding and replication of Ad5/3. Syrian hamster cells supported Ad5 replication but showed no evidence of productive viral replication after infection with Ad5/3 vectors. Transduction and replication ability of Ad5/3 in porcine cells outperformed Ad5, a phenomenon often observed in human cancer cell lines. Replication of Ad5 and Ad5/3 was subsequently evaluated in vivo in immunocompetent pigs. Quantitative PCR analyses 7 days post infection revealed Ad5 and Ad5/3 DNA and replication-dependent luciferase activity in the swine lungs and spleen indicating active replication in these tissues. These studies demonstrated the flaws in using Syrian hamsters for testing serotype chimeric Ad5/3 vectors. This is the first report to validate the pig as a valuable model for preclinical testing of oncolytic adenoviruses utilizing Adenovirus type 3 receptors. We hope that these data will help to foster the clinical translation of oncolytic adenoviruses including those with Ad3 retargeted tropism.
Insights
Pigs effectively model oncolytic adenoviruses (Ad) with Adenovirus type 3 (Ad3) receptors, unlike hamsters. This validates pigs for preclinical testing of Ad5/3 vectors, advancing cancer therapy development.
Area of Science:
- Virology
- Oncology
- Gene Therapy
Background:
- Oncolytic adenoviruses (Ad) show therapeutic promise but Ad5 vectors face efficiency issues due to CAR receptor absence on cancer cells.
- Engineering Ad5/3 chimeric vectors to use Ad3 receptors enhances oncolytic potential but lacks suitable animal models for testing.
- Clinical translation is hindered by the absence of replication-permissive animal models for infectivity-enhanced Ad vectors.
Purpose of the Study:
- To evaluate pigs as a preclinical model for oncolytic adenovirus (Ad) vector performance, specifically fiber-modified Ad5/3 chimeric vectors.
- To compare the binding, gene transfer, replication, and cytolytic capabilities of Ad5 and Ad5/3 vectors in various non-human cell lines and in vivo.
- To assess the suitability of Syrian hamsters versus pigs for testing Ad5/3 vectors.
Main Methods:
- In vitro analysis of Ad5 and Ad5/3 vector binding, gene transfer, and replication in murine, hamster, canine, and porcine cell lines.
- In vivo evaluation of Ad5 and Ad5/3 replication in immunocompetent pigs via quantitative PCR and luciferase activity.
- Comparative analysis of Ad5 and Ad5/3 vector performance in Syrian hamster and porcine models.
Main Results:
- Porcine cells supported active binding and replication of Ad5/3 vectors, outperforming Ad5, mirroring human cancer cell line behavior.
- Syrian hamster cells supported Ad5 replication but not productive Ad5/3 replication.
- In vivo studies in pigs demonstrated active replication of both Ad5 and Ad5/3 vectors in the lungs and spleen.
Conclusions:
- Pigs serve as a valuable and validated preclinical model for oncolytic adenoviruses utilizing Adenovirus type 3 receptors.
- Syrian hamsters are unsuitable for testing serotype chimeric Ad5/3 vectors due to lack of permissiveness.
- This study facilitates the clinical translation of oncolytic adenoviruses, particularly those with Ad3 retargeted tropism.
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