Potential for Improving Potency and Specificity of Reovirus Oncolysis with Next-Generation Reovirus Variants

Abstract

Viruses that specifically replicate in tumor over normal cells offer promising cancer therapies. Oncolytic viruses (OV) not only kill the tumor cells directly; they also promote anti-tumor immunotherapeutic responses. Other major advantages of OVs are that they dose-escalate in tumors and can be genetically engineered to enhance potency and specificity. Unmodified wild type reovirus is a propitious OV currently in phase I–III clinical trials. This review summarizes modifications to reovirus that may improve potency and/or specificity during oncolysis. Classical genetics approaches have revealed reovirus variants with improved adaptation towards tumors or with enhanced ability to establish specific steps of virus replication and cell killing among transformed cells. The recent emergence of a reverse genetics system for reovirus has provided novel strategies to fine-tune reovirus proteins or introduce exogenous genes that could promote oncolytic activity. Over the next decade, these findings are likely to generate better-optimized second-generation reovirus vectors and improve the efficacy of oncolytic reotherapy.

Exploring Reovirus Plasticity for Improving Its Use as Oncolytic Virus

“…The recent development of a plasmid-based reverse genetics system [ 106 ] for reoviruses provided new options for reovirologists to unveil more aspects of reovirus biology as well as for improving the efficacy in oncolytic reovirus therapy. The powerful reovirus reverse genetics system has primarily been used to resolve issues where reovirus segments are involved in apoptosis, assembly or disassembly, cell tropism and pathogenesis in mice [ 59 , 107 , 108 , 109 , 110 , 111 ].…”

Multiple proteins differing between laboratory stocks of mammalian orthoreoviruses affect both virus sensitivity to interferon and induction of interferon production during infection

“…5); although this position is not in direct contact with putative catalytic sites, it is tempting to speculate that it indirectly affects either cap methylation or viral mRNA exit. As mentioned by others (Mohamed et al 2015), it will clearly be of interest to further examine the nature of the 5'-end of the viral mRNAs produced by these The involvement of the λ1 protein in the level of interferon induction came as a surprise finding in the course of this study. It remains to be determined if the protein can repress interferon signaling in T3D S , a property that is lost in T3D K , or if the T3D K protein positively contribute to the interferon induction.…”

“…It thus appears to be essential to gain a further understanding of the viral determinants that control induction of the interferon response and the sensitivity of different viral isolates to this response. This could possibly lead to better optimization of viral strains toward oncolytic activity, as many investigators believe to be possible, and as recently reviewed (Mohamed et al, 2015;Kemp et al, 2016). This is especially envisaged since the advent of plasmid-based reverse genetics to manipulate the viral genome (Lemay, 2011;van den Hengel et al, 2013;Stuart et al, 2017).…”

Novel High-throughput Approach for Purification of Infectious Virions

“…Furthermore, both reovirus and adenovirus are heavily pursued as oncolytic therapies. We and others have demonstrated that reovirus mutants exhibit differences in their oncolytic activities, and that second-generation reovirus variants may possess improved oncolytic potency17192627. We have found the Capto Core 700 slurry method to be extremely useful for purifying and comparing various natural isolates (Fig.…”