Semireplication-competent vesicular stomatitis virus as a novel platform for oncolytic virotherapy
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ORIGINAL ARTICLE
Semireplication-competent vesicular stomatitis virus as a novel platform for oncolytic virotherapy Alexander Muik & Catherine Dold & Yvonne Geiß & Andreas Volk & Marina Werbizki & Ursula Dietrich & Dorothee von Laer
Received: 26 July 2011 / Revised: 3 January 2012 / Accepted: 16 January 2012 / Published online: 28 January 2012 # The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract Among oncolytic viruses, the vesicular stomatitis virus (VSV) is especially potent and a highly promising agent for the treatment of cancer. But, even though effective against multiple tumor entities in preclinical animal models, replication-competent VSV exhibits inherent neurovirulence, which has so far hindered clinical development. To overcome this limitation, replication-defective VSV vectors for cancer gene therapy have been tested and proven to be safe. However, gene delivery was inefficient and only minor antitumor efficacy was observed. Here, we present semireplicationcompetent vector systems for VSV (srVSV), composed of two trans-complementing, propagation-deficient VSV vectors. The de novo generated deletion mutants of the two VSV polymerase proteins P (phosphoprotein) and L (large catalytic subunit), VSVΔP and VSVΔL respectively, were used mutually or in combination with VSVΔG vectors. These srVSV systems copropagated in vitro and in vivo without recombinatory reversion to replication-competent virus. The srVSV systems were highly lytic for human glioblastoma cell lines, spheroids, and subcutaneous xenografts. Especially the combination of VSVΔG/VSVΔL vectors was as potent as wild-type VSV (VSV-WT) in vitro and induced long-term tumor regression in vivo without any associated adverse
Electronic supplementary material The online version of this article (doi:10.1007/s00109-012-0863-6) contains supplementary material, which is available to authorized users. A. Muik : Y. Geiß : A. Volk : M. Werbizki : U. Dietrich Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany C. Dold : D. von Laer (*) Institute for Virology, Innsbruck Medical University, Fritz-Pregl-Str. 3, A-6020 Innsbruck, Austria e-mail: [email protected]
effects. In contrast, 90% of VSV-WT-treated animals succumbed to neurological disease shortly after tumor clearance. Most importantly, even when injected into the brain, VSVΔG/ VSVΔL did not show any neurotoxicity. In conclusion, srVSV is a promising platform for virotherapeutic approaches and also for VSV-based vector vaccines, combining improved safety with an increased coding capacity for therapeutic transgenes, potentially allowing for multipronged approaches. Keywords Vesicular stomatitis virus . Oncolytic virus . Virotherapy . Malignant glioma
Introduction The use of viruses as targeted cancer therapeutics has shown significant promise in the last few years. Especially the vesicular stomatitis virus (VSV), a relatively new player in the oncolytic virotherapy field, has proven to be effective against a variety of tumor entities such as malignant
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