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Virus-Associated RNA I–Deleted Adenovirus, a Potential Oncolytic Agent Targeting EBV-Associated Tumors

¹ Cancer Research UK Molecular Oncology Unit, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Queen Mary University of London; ² Division of Medicine, Hammersmith Hospital, Imperial College London; and ³ Imperial College London at St. Mary's, London, United Kingdom

Requests for reprints: Nick R. Lemoine, Cancer Research UK Molecular Oncology Unit, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London EC1 6BQ, United Kingdom. Phone: 44-20-7014-0420; E-mail: nick.lemoine{at}cancer.org.uk.

Given the growing number of tumor types recognizably associated with EBV infection, it is critically important that therapeutic strategies are developed to treat such tumors. Replication-selective oncolytic adenoviruses represent a promising new platform for anticancer therapy. Virus-associated I (VAI) RNAs of adenoviruses are required for efficient translation of viral mRNAs. When the VAI gene is deleted, adenovirus replication is impeded in most cells (including HEK 293 cells). EBV-encoded small RNA1 is uniformly expressed in most EBV-associated human tumors and can functionally substitute for the VAI RNAs of adenovirus. It enables replication to proceed through complementation of VAI-deletion mutants. We hypothesized that VAI-deleted adenovirus would selectively replicate in EBV-positive tumor cells due to the presence of EBV-encoded small RNA1 with no (or poor) replication in normal or EBV-negative tumor cells. In this report, we show that high levels of replication occurred in the VAI-deleted mutant in the EBV-positive tumor cells compared with low (or negligible) levels in EBV-negative and normal human primary cells. Correspondingly, high toxicity levels were observed in EBV-positive tumor cells but not in EBV-negative tumor or normal human primary cells. In vivo, VAI-deleted adenovirus showed superior antitumoral efficacy to wild-type adenovirus in EBV-positive tumor xenografts, with lower hepatotoxicity than wild-type adenovirus. Our data suggest that VAI-deleted adenovirus is a promising replication-selective oncolytic virus with targeting specificity for EBV-associated tumors.

Key Words: oncolytic • adenovirus • VAI RNA • EBV • experimental therapeutics

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