This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, W. Q. Articles by Forsyth, P. A. Search for Related Content PubMed PubMed Citation Articles by Yang, W. Q. Articles by Forsyth, P. A.

Efficacy and Safety Evaluation of Human Reovirus Type 3 in Immunocompetent Animals

Racine and Nonhuman Primates

¹ Departments of Oncology and Clinical Neurosciences, University of Calgary, and Tom Baker Cancer Centre, Calgary, Alberta, Canada; ² Faculty of Medicine, University of Toronto, Toronto, Canada; ³ Department of Epidemiology, Prevention and Screening, Tom Baker Cancer Centre, Calgary, Alberta, Canada; ⁴ Pathology Department and ⁵ Department of Neurosurgery, Foothills Hospital, University of Calgary, Calgary, Alberta, Canada; ⁶ Departments of Microbiology and Immunology, Dalhousie University, Halifax, Canada; Departments of ⁷ Biochemistry and Molecular Biology and ⁸ Psychology, University of Calgary, Canada; ⁹ Department of Virology, Provincial Laboratory of Alberta, Calgary, Canada; ¹⁰ Department of Pathology, Division of Neuropathology, University of Alabama at Birmingham, Birmingham, Alabama; and ¹¹ Oncolytics Biotechnology Incorporated, Calgary, Canada

Purpose: Human reovirus type 3 has been proposed to kill cancer cells with an activated Ras signaling pathway. The purpose of this study was to investigate the efficacy of reovirus in immunocompetent glioma animal models and safety/toxicity in immunocompetent animals, including nonhuman primates.

Experimental Design: Racine glioma cells 9L and RG2 were implanted s.c. or intracranially in Fisher 344 rats with or without reovirus antibodies, followed by treatment of reovirus. To study whether reovirus kills contralateral tumors in the brain and to determine viral distribution, we established an in situ dual tumor model followed by reovirus intratumoral inoculation only into the ipsilateral tumor. To evaluate neurotoxicity/safety of reovirus, Cynomolgus monkeys and immunocompetent rats were given intracranially with reovirus, and pathological examination and/or behavioral studies were done. Viral shedding and clinical biochemistry were systematically studied in monkeys.

Results: Intratumorally given reovirus significantly suppressed the growth of both s.c. and intracranially tumors and significantly prolonged survival. The presence of reovirus-neutralizing antibodies did not abort the reovirus’ antitumor effect. Reovirus inhibited glioma growth intracranially in the ipsilateral but not the contralateral tumors; viral load in ipsilateral tumors was 15 to 330-fold higher than the contralateral tumors. No encephalitis or behavioral abnormalities were found in monkeys and rats given reovirus intracranially. No treatment-related clinical biochemistry changes or diffuse histopathological abnormality were found in monkeys inoculated intracranially with Good Manufacturing Practice prepared reovirus. Microscopic changes were confined to the region of viral inoculation and were dose related, suggesting reovirus intracranially was well tolerated in nonhuman primates.

Conclusions: These data show the efficacy and safety of reovirus when it is used in the treatment of gliomas in immunocompetent hosts. Inoculation of reovirus into the brain of nonhuman primates did not produce significant toxicities.

This article has been cited by other articles:

				X. Q. Lun, H. Zhou, T. Alain, B. Sun, L. Wang, J. W. Barrett, M. M. Stanford, G. McFadden, J. Bell, D. L. Senger, et al. Targeting Human Medulloblastoma: Oncolytic Virotherapy with Myxoma Virus Is Enhanced by Rapamycin Cancer Res., September 15, 2007; 67(18): 8818 - 8827. [Abstract] [Full Text] [PDF]

				X. Lun, D. L. Senger, T. Alain, A. Oprea, K. Parato, D. Stojdl, B. Lichty, A. Power, R. N. Johnston, M. Hamilton, et al. Effects of Intravenously Administered Recombinant Vesicular Stomatitis Virus (VSV{Delta}M51) on Multifocal and Invasive Gliomas. J Natl Cancer Inst, November 1, 2006; 98(21): 1546 - 1557. [Abstract] [Full Text] [PDF]

				K. Shinozaki, O. Ebert, A. Suriawinata, S. N. Thung, and S. L. C. Woo Prophylactic Alpha Interferon Treatment Increases the Therapeutic Index of Oncolytic Vesicular Stomatitis Virus Virotherapy for Advanced Hepatocellular Carcinoma in Immune-Competent Rats J. Virol., November 1, 2005; 79(21): 13705 - 13713. [Abstract] [Full Text] [PDF]

				X. Lun, W. Yang, T. Alain, Z.-Q. Shi, H. Muzik, J. W. Barrett, G. McFadden, J. Bell, M. G. Hamilton, D. L. Senger, et al. Myxoma Virus Is a Novel Oncolytic Virus with Significant Antitumor Activity against Experimental Human Gliomas Cancer Res., November 1, 2005; 65(21): 9982 - 9990. [Abstract] [Full Text] [PDF]