Friday, 27 August 2010

Oncolytic HSV - retargeting of a wild-type virus

Despite our increasing knowledge of key pathways and systems contributing to cancer we are still struggling to bring forth novel therapeutics. One such treatment may be to use viruses to our advantage, yet using these micro-organisms is not novel idea (Kelly & Russell 2007). For decades it has been observed that cancer sufferers may go into clinical remission after contracting a viral disease. In these early days, the mechanism was unknown and the outcomes were dangerous and variable but nowadays we are in a much better position to understand and use this technology (Cattaneo et al. 2008)

Malignant gliomas, uncontrolled proliferation of the non-neuronal ‘helper’ cells which aid local homeostasis in the brain and help protect neurons, are the most common form of primary brain tumours worldwide with near universal fatality. A number of novel therapeutics are currently being developed including the use of oncolytic viral vectors which are specifically targeted to infect only those cancerous cells without harming the normal cells nearby. One strategy of targeting these viruses to particular cells is through alterations of the viral envelope glycoproteins, the proteins that are used by the virus to bind to and gain entry into certain cells via receptors on that cells surface. We no longer want the virus to infect those cells it would normally infect but to infect the ones we want it to infect and so to get around this we need to change the viral envelope glycoprotein – cell receptor interactions.

Grandi, et al. reports in Cancer Gene Therapy­ the generation of a retargeted herpes simplex virus (HSV) vector to malignant glioma cells which highly express a mutated form of epidermal growth factor receptor (EGFR) on their surface called EGFRvIII (Grandi et al. 2010). This protein, a member of the EGF-family is important in tumour cell growth and proliferation and is also found highly expressed in other cancers including breast carcinomas. The group took advantage of the previous generation of an antibody-like molecule, MR1-1 (a single-chain variable fragment, scFv) which would strongly and specifically bind to only the mutated EGFRvIII and not its wild-type cousin, EGFR. HSV infection requires the co-ordinated binding of three viral glycoproteins, gC, gB and gD to cell surface proteins in order for envelope fusion and entry to take place. At the initial step, viral gC binds to heparin sulphate, a molecule found on the surface of most cell types followed by gB and gD interactions. They removed the viruses own capacity for cell receptor binding by deletion of the part of the gC coding for binding (amino acids 33-174 corresponding to the heperain sulphate binding domain) and inserted their MR1-1 gene into the same gC gene effectively ‘retargeting’ the virus allowing it to infect only those cells expressing the cancer-related EGFRvIII.They repeatedly show the increased efficiency of infection of this virus versus wild-type HSV in human gliomas in in vitro and in vivo xenograft models.

This study further shows that specific retargeting of certain viruses is possible and can be used to increase infectivity in only certain cell types through our own design. Enhanced infectivity allows a lower concentration of virus to be administered in therapy and also increase the safety of such treatments by limiting off-target pathogenesis. Retargetting can be used in combination with other standard of care treatments as well as further viral genetic engineering in the same vector.


Cattaneo, R., Miest, T., Shashkova, E. V., & Barry, M. a. (2008). Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded. Nature reviews. Microbiology, 6(7), 529-40. doi: 10.1038/nrmicro1927.

Grandi, P., Fernandez, J., Szentirmai, O., Carter, R., Gianni, D., Breakefield, X. O., et al. (2010). Targeting HSV-1 virions for specific binding to epidermal growth factor receptor-vIII-bearing tumor cells. Cancer Gene Therapy, 17(9), 655-663. Nature Publishing Group. doi: 10.1038/cgt.2010.22.

Kelly, E., & Russell, S. J. (2007). History of Oncolytic Viruses: Genesis to Genetic Engineering. Molecular Therapy, 15(4), 651-659. doi: 10.1038/mt.sj.6300108.

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