A cautionary note on the selectivity of oncolytic poxviruses

Abstract

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-Ralpha and myxoma virus vMyx-IL15Ralpha-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-Ralpha, some tumor-bearing mice died soon after virus treatment. If the same titer of vvDD-IL15-Ralpha 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-IL15Ralpha-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-Ralpha infected dendritic cells and lysed them but vMyx-IL15Ralpha-tdTr did not. Conclusion: Vaccinia virus vvDD-IL15-Ralpha is very promising for treating cancer types outside of the brain. However, for cancers located within the brain, myxoma virus vMyx-IL15Ralpha-tdTr offers a safer alternative.