Review
Oncolytic viruses in radiation oncology

https://doi.org/10.1016/j.radonc.2011.05.078Get rights and content

Abstract

Oncolytic viruses are investigational cancer treatments. They are currently being assessed as single agents or in combination with standard therapies such as external beam radiotherapy – a DNA damaging agent that is a standard of care for many tumour types. Preclinical data indicate that combinations of oncolytic viruses and radiation therapy are promising, showing additional or synergistic antitumour effects in in vitro and in vivo studies. This interaction has the potential to be multifaceted: viruses may act as radiosensitizing agents, but radiation may also enhance viral oncolysis by increasing viral uptake, replication, gene expression and cell death (apoptosis, autophagy or necrosis) in irradiated cells. Phase I and II clinical trials investigating combinations of viruses and radiation therapy have been completed, paving the way for ongoing phase III studies. The aim of this review is to focus on the therapeutic potential of these combinations and to highlight their mechanistic bases, with particular emphasis on the role of the DNA damage response.

Section snippets

Principles of viral therapies in oncology

Viruses have been widely studied as vectors for therapeutic genes. Gene therapy consists of the introduction of genetic material into cells for a therapeutic purpose. Recombinant viruses have been shown to be an efficient means of achieving gene transfer both in vitro and in vivo. Many viruses, such as adenovirus, adeno-associated virus (AAV), retrovirus, lentivirus, herpes simplex virus (HSV), poxvirus, measles virus, simian virus 40 recombinant (SV40r) and vesicular stomatitis virus have been

Antitumour activity

Antitumour activities in vitro and in vivo of various viral agents in combination with EBRT have been investigated in a variety of tumour models. The combination of viruses and EBRT has shown additive or synergistic therapeutic effects in vitro and in subcutaneous prostate, head and neck, lung, colon, thyroid and cholangiocarcinomas, as well as melanoma and malignant glioma [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25].

In

DNA damage signalling

Ionizing radiation produces a wide variety of lesions in DNA, including base damage, single- and double-strand breaks (DSB) and DNA–DNA or DNA–protein crosslinks [54]. These lesions can be topographically grouped and clustered within the same region of DNA to comprise so-called “complex damage” [55]. DSBs breaks play an important role in cell death induced by radiation. Two major mechanisms of repair of DSBs have been described: the non-homologous end-joining (NHEJ) mechanisms and homologous

Conclusion

Viral therapies are unlikely to be used widely in the clinic as single agents. However, it is increasingly recognized that combining viral therapies with EBRT represents a promising approach. Preclinical studies support this strategy showing that combination regimens yield increased antitumour effects as compared with single treatment modalities. A number of potential mechanisms of interaction between viruses and radiation have been described. Radiation can increase viral uptake, gene

Authors’ declaration of personal interests

K.J. Harrington has received unrestricted educational grants in support of laboratory and clinical research from Oncolytics Biotech Inc. and Genelux GmbH.

Acknowledgements

Y. Touchefeu has received a doctoral research grant from the Institut National du Cancer and a research grant from the Société Nationale Française de Gastro-Entérologie (Robert Tournut grant). Part of this work was undertaken in The Royal Marsden NHS Foundation Trust who received a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS Executive. This work was supported by The Institute of Cancer

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