Oncolytic Viruses for Cancer Therapy: Overcoming the Obstacles

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Abstract

Targeted therapy of cancer using oncolytic viruses has generated much interest over the past few years in the light of the limited efficacy and side effects of standard cancer therapeutics for advanced disease. In 2006, the world witnessed the first government-approved oncolytic virus for the treatment of head and neck cancer. It has been known for many years that viruses have the ability to replicate in and lyse cancer cells. Although encouraging results have been demonstrated in vitro and in animal models, most oncolytic viruses have failed to impress in the clinical setting. The explanation is multifactorial, determined by the complex interactions between the tumor and its microenvironment, the virus, and the host immune response. This review focuses on discussion of the obstacles that oncolytic virotherapy faces and recent advances made to overcome them, with particular reference to adenoviruses.

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Experimental therapy of human glioma by means of a genetically engineered virus mutant.

R Martuza, A. Malick, J M Markert … (1991)

Malignant gliomas are the most common malignant brain tumors and are almost always fatal. A thymidine kinase-negative mutant of herpes simplex virus-1 (dlsptk) that is attenuated for neurovirulence was tested as a possible treatment for gliomas. In cell culture, dlsptk killed two long-term human glioma lines and three short-term human glioma cell populations. In nude mice with implanted subcutaneous and subrenal U87 human gliomas, intraneoplastic inoculation of dlsptk caused growth inhibition. In nude mice with intracranial U87 gliomas, intraneoplastic inoculation of dlsptk prolonged survival. Genetically engineered viruses such as dlsptk merit further evaluation as novel antineoplastic agents.

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Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus.

D Stojdl, B. Lichty, S. Knowles … (2000)

Interferons are circulating factors that bind to cell surface receptors, activating a signaling cascade, ultimately leading to both an antiviral response and an induction of growth inhibitory and/or apoptotic signals in normal and tumor cells. Attempts to exploit the ability of interferons to limit the growth of tumors in patients has met with limited results because of cancer-specific mutations of gene products in the interferon pathway. Although interferon-non-responsive cancer cells may have acquired a growth/survival advantage over their normal counterparts, they may have simultaneously compromised their antiviral response. To test this, we used vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus exquisitely sensitive to treatment with interferon. VSV rapidly replicated in and selectively killed a variety of human tumor cell lines even in the presence of doses of interferon that completely protected normal human primary cell cultures. A single intratumoral injection of VSV was effective in reducing the tumor burden of nude mice bearing subcutaneous human melanoma xenografts. Our results support the use of VSV as a replication-competent oncolytic virus and demonstrate a new strategy for the treatment of interferon non-responsive tumors.

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CD46 is a cellular receptor for group B adenoviruses.

Anuj Gaggar, Dmitry Shayakhmetov, Andre Lieber (2003)

Group B adenoviruses, a subgenus of human Adenoviridae, are associated with a variety of often-fatal illnesses in immunocompromised individuals, including bone marrow transplant recipients and cancer and AIDS patients. Recently, group B adenovirus derivatives have gained interest as attractive gene therapy vectors because they can transduce target tissues, such as hematopoietic stem cells, dendritic cells and malignant tumor cells, that are refractory to infection by commonly used adenoviral vectors. Whereas many adenoviruses infect cells through the coxsackievirus and adenovirus receptor (CAR), group B adenoviruses use an alternate, as-yet-unidentified cellular attachment receptor. Using mass spectrometric analysis of proteins interacting with a group B fiber, we identified human CD46 as a cellular attachment receptor for most group B adenoviruses. We show that ectopic expression of human CD46 rendered nonhuman cells susceptible to infection with group B viruses in vitro and in vivo. In addition, both siRNA-mediated knockdown of CD46 and a soluble form of CD46 blocked infection of human cell lines and primary human cells. The discovery that group B adenoviruses use CD46, a ubiquitously expressed complement regulatory protein, as a cellular attachment receptor elucidates the diverse clinical manifestation of group B virus infections, and bears directly on the application of these vectors for gene therapy.

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Author and article information

Journal

Journal ID (nlm-ta): Viruses

Title: Viruses

Publisher: Molecular Diversity Preservation International (MDPI)

ISSN (Electronic): 1999-4915

Publication date Collection: January 2010

Publication date (Electronic): 11 January 2010

Volume: 2

Issue: 1

Pages: 78-106

Affiliations

[1 ] Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; E-Mails: h.h.wong@ 123456qmul.ac.uk (H.H.W.); director@ 123456qmcr.qmul.ac.uk (N.R.L.)

[2 ] Sino-British Research Centre for Molecular Oncology, Zhengzhou University, Zhengzhou 450052, China

Author notes

[* ]Author to whom correspondence should be addressed; E-Mail: yaohe.wang@ 123456qmul.ac.uk ; Tel.: +44-2078823596, Fax: +44-2078823884.

Article

Publisher ID: viruses-02-00078

DOI: 10.3390/v2010078

PMC ID: 2883714

PubMed ID: 20543907

SO-VID: 7cf58cf7-e5b2-4cbf-b59e-401071461acd

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This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

History

Date received : 28 October 2009

Date revision received : 2 January 2010

Date accepted : 6 January 2010

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Oncolytic Viruses for Cancer Therapy: Overcoming the Obstacles

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Most cited references 192

Experimental therapy of human glioma by means of a genetically engineered virus mutant.

Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus.

CD46 is a cellular receptor for group B adenoviruses.

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