Attenuated Semliki Forest virus for cancer treatment in dogs: safety assessment in two laboratory Beagles

Abstract

BackgroundDogs suffer from spontaneous tumors which may be amenable to therapies developed for human cancer patients, and dogs may serve as large-animal cancer models. A non-pathogenic Semliki Forest virus vector VA7-EGFP previously showed promise in targeting human tumor xenografts in mice, but the oncolytic capacity of the virus in canine cancer cells and the safety of the virus in higher mammals such as dogs, are not known. We therefore assessed the oncolytic potency of VA7-EGFP against canine cancer cells by infectivity and viability assays in two dog solid tumor cell lines. Furthermore we performed a 3-week safety study in two adult Beagles which received a single intravenous injection of ~2 × 105 plaque forming units of parental A7(74) strain.ResultsVA7-EGFP was able to replicate in and kill both canine cancer cell lines tested. No adverse events were observed in either of the two virus-injected adult Beagles and no infective virus could be recovered from any of the biological samples collected over the course of the study. Neutralizing antibodies to Semliki Forest virus became detectable in the dogs at 5 days post infection and remained elevated until study termination.ConclusionsBased on these results, testing of the oncolytic potential of attenuated Semliki Forest virus in canine cancer patients appears feasible.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-015-0498-2) contains supplementary material, which is available to authorized users.

Safe and Effective Treatment of Experimental Neuroblastoma and Glioblastoma Using Systemically Delivered Triple MicroRNA-Detargeted Oncolytic Semliki Forest Virus

“…The SFV A7/74 strain has been successfully tested safe for use as an oncolytic agent in several preclinical models for glioblastoma multiforme and other cancer types (8,31,32). However, type-I IFN responsive gliomas are resistant to A7/74 virotherapy in murine models (14).…”

New frontiers in oncolytic viruses: optimizing and selecting for virus strains with improved efficacy

“… 95 Furthermore, SFV-VA7-EGFP particles demonstrated efficient replication and killing of two canine-tumor cell lines, and no adverse events occurred in beagle dogs after intravenous administration of 2×10 5 particles. 96 …”

On the potential of oncolytic virotherapy for the treatment of canine cancers

“…More importantly for oncolytic virus research, studies have been published that report the safety profiles of replicating MYXV, modified adenovirus, and attenuated vesicular stomatitis and Semliki Forest viruses in healthy dogs ( Table 4 ). 35 , 51 – 57 Table 4 also summarizes the current studies using replicating oncolytic viruses in canine cancer patients. 39 Clinical trials using oncolytic virotherapy in dogs are the next step toward advancing treatment options for dogs with cancer.…”

“…Very recently, an attenuated Semliki Forest virus (VA7-EGFP) was shown to induce cell death in two canine osteocarcoma cell lines. 57 Semliki Forest virus is a positive single stranded RNA virus classified in the Alphavirus genus of the Togavirus family. Although a virulent Semliki Forest virus strain caused neurologic disease in young dogs when administered by intra-peritoneal or intrecerebral injection, the attenuated form used in this study was safe in Beagles when given intravenously at 2 × 10 5 pfu.…”

“…Although a virulent Semliki Forest virus strain caused neurologic disease in young dogs when administered by intra-peritoneal or intrecerebral injection, the attenuated form used in this study was safe in Beagles when given intravenously at 2 × 10 5 pfu. 57 , 90 …”