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Journal of Virology, August 2009, p. 7507-7516, Vol. 83, No. 15
0022-538X/09/$08.00+0     doi:10.1128/JVI.00495-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Coronavirus Genetically Redirected to the Epidermal Growth Factor Receptor Exhibits Effective Antitumor Activity against a Malignant Glioblastoma{triangledown}

Monique H. Verheije,1 Martine L. M. Lamfers,2 Thomas Würdinger,1,{dagger} Guy C. M. Grinwis,3 Winald R. Gerritsen,4 Victor W. van Beusechem,4 and Peter J. M. Rottier1*

Virology Division, Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, The Netherlands,1 Department of Neurosurgery, Erasmus University, Rotterdam, The Netherlands,2 Pathology Division, Department of Pathobiology, Utrecht University, Utrecht, The Netherlands,3 Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands4

Received 10 March 2009/ Accepted 6 May 2009

Coronaviruses are positive-strand RNA viruses with features attractive for oncolytic therapy. To investigate this potential, we redirected the coronavirus murine hepatitis virus (MHV), which is normally unable to infect human cells, to human tumor cells by using a soluble receptor (soR)-based expression construct fused to an epidermal growth factor (EGF) receptor targeting moiety. Addition of this adapter protein to MHV allowed infection of otherwise nonsusceptible, EGF receptor (EGFR)-expressing cell cultures. We introduced the sequence encoding the adaptor protein soR-EGF into the MHV genome to generate a self-targeted virus capable of multiround infection. The resulting recombinant MHV was viable and had indeed acquired the ability to infect all glioblastoma cell lines tested in vitro. Infection of malignant human glioblastoma U87{Delta}EGFR cells gave rise to release of progeny virus and efficient cell killing in vitro. To investigate the oncolytic capacity of the virus in vivo, we used an orthotopic U87{Delta}EGFR xenograft mouse model. Treatment of mice bearing a lethal intracranial U87{Delta}EGFR tumor by injection with MHVsoR-EGF significantly prolonged survival compared to phosphate-buffered saline-treated (P = 0.001) and control virus-treated (P = 0.004) animals, and no recurrent tumor load was observed. However, some adverse effects were seen in normal mouse brain tissues that were likely caused by the natural murine tropism of MHV. This is the first demonstration of oncolytic activity of a coronavirus in vivo. It suggests that nonhuman coronaviruses may be attractive new therapeutic agents against human tumors.

* Corresponding author. Mailing address: Virology Division, Department of Infectious Diseases and Immunology, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands. Phone: 31 30 253 2462. Fax: 31 30 253 6723. E-mail: p.rottier{at}uu.nl

{triangledown} Published ahead of print on 13 May 2009.

{dagger} Present address: Departments of Neurology and Radiology, Harvard Medical School, Boston, Massachusetts, and Neuro-oncology Research Group, Department of Neurosurgery, VU Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.

Journal of Virology, August 2009, p. 7507-7516, Vol. 83, No. 15
0022-538X/09/$08.00+0     doi:10.1128/JVI.00495-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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