A cautionary note on the selectivity of oncolytic poxviruses
Received 5 October 2018
Accepted for publication 31 December 2018
Published 11 February 2019 Volume 2019:8 Pages 3—8
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Colin Mak
Peer reviewer comments 3
Editor who approved publication: Dr Faris Farassati
Bingtao Tang,1 Zong Sheng Guo,2 David L Bartlett,2 Jia Liu,3 Grant McFadden,4 Joanna L Shisler,5 Edward J Roy1
1Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA; 2Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 3Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 4Biodesign Institute, Arizona State University, Tempe, AZ, USA; 5Department of Microbiology, University of Illinois Urbana-Champaign, Urbana, IL USA
Background: Oncolytic viruses selectively infect cancer cells while avoiding infection of normal cells. Usually, selectivity is demonstrated by injecting a virus into tumor-bearing mice and observing infection and lysis of tumor cells without infection of other tissues. The general view is that this selectivity is due to tropisms of the virus. However, apparent selectivity could be due to accessibility. For example, intravenously injected virus may not gain access to cells within the central nervous system (CNS) because of the blood–brain barrier.
Purpose: We tested the CNS safety of two oncolytic poxviruses that have been demonstrated to be safe for treatment of peripheral tumors (vaccinia virus vvDD-IL15-Rα and myxoma virus vMyx-IL15Rα-tdTr).
Methods: Two poxviruses were tested for selectivity in vitro and in vivo.
Results: Both viruses infected glioma cells in vitro. In vivo, both viruses infected glioma cells and did not infect neurons when injected into a tumor or into the normal striatum. However, viral gene expression was observed in ependymal cells lining the ventricles, implying that these poxviruses were not as selective as originally predicted. For vvDD-IL15-Rα, some tumor-bearing mice died soon after virus treatment. If the same titer of vvDD-IL15-Rα was injected directly into the lateral cerebral ventricle of nontumor-bearing mice, it was uniformly fatal. Infection of ependymal cells, subventricular cells, and meninges was widespread. On the other hand, vMyx-IL15Rα-tdTr only transiently infected ependymal cells and was safe even when injected directly into the lateral cerebral ventricles. The two poxviruses also differed in their infection of dendritic cells; vvDD-IL15-Rα infected dendritic cells and lysed them but vMyx-IL15Rα-tdTr did not.
Conclusion: Vaccinia virus vvDD-IL15-Rα is very promising for treating cancer types outside of the brain. However, for cancers located within the brain, myxoma virus vMyx-IL15Rα-tdTr offers a safer alternative.
Keywords: oncolytic virus, central nervous system toxicity, glioma, safety
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