Collateral Lethal Effects of Complementary Oncolytic Viruses

Abstract

Virus-infected cells release type 1 interferons, which induce an antiviral state in neighboring cells. Naturally occurring viruses are therefore equipped with stealth replication strategies to limit virus sensing and/or with combat strategies to prevent or reverse the antiviral state. Here we show that oncolytic viruses with simple RNA genomes whose spread was suppressed in tumor cells pretreated with interferon were able to replicate efficiently when the cells were coinfected with a poxvirus known to encode a diversity of innate immune combat proteins. In vivo the poxvirus was shown to reverse the intratumoral antiviral state, rescuing RNA virus replication in an otherwise restrictive syngeneic mouse tumor model leading to antitumor efficacy. Pairing of complementary oncolytic viruses is a promising strategy to enhance the antitumor activity of this novel class of anticancer drugs.

Polycytidine tract deletion from microRNA-detargeted oncolytic Mengovirus optimizes the therapeutic index in a murine multiple myeloma model

“… 6 MC 24 -NC was previously reported to be a safe and relatively potent oncolytic virus, with varying efficacy depending on the tumor model. 6 , 7 , 8 For the purpose of the current study we generated two additional vectors carrying either a full deletion of the polyC tract (MC 0 -NC) or a long polyC tract (MC 37 -NC) with the sequence C 26 UC 10 ( Figure 2 A). The use of Mengovirus with a wild-type polyC length (C 44 UC 10 ) raises several safety concerns because of its zoonotic potential.…”

“… 3 , 4 , 5 Mengovirus MC 24 -NC, an attenuated and microRNA (miRNA)-detargeted picornavirus, was previously shown to be a safe and efficacious OV in a murine multiple myeloma model. 6 However, a consistently curative therapy with complete and durable response across multiple tumor models was not achieved, 7 , 8 which suggested that the virus may have been over-attenuated and that the therapeutic outcome might be improved if certain attenuating mutations were reversed.…”

The long-lasting enigma of polycytidine (polyC) tract

“…miRNA-targeting elements recognized by miRNA overexpressed in the brain and cardiac muscular tissues inserted in MC 24 NCRs (MC 24 -NC) significantly reduced replication in the target tissues even at extremely high titers and increased the safety profile of MC 24 . Oncolytic therapy with MC 24 -NC was able to delay tumor growth and even completely clear tumors in multiple myeloma models, but its efficacy is not consistent across the board [ 51 , 120 ]. Through the use of miRNA-targeting platform, it is now possible to reintroduce the full-length polyC tract in Mengovirus and investigate the oncolytic potential of long-tract Mengovirus while preserving safety.…”