Reovirus: A Targeted Therapeutic—Progress And Potential

Abstract

Medical therapy of patients with malignancy requires a paradigm shift through development of new drugs with a good safety record and novel mechanisms of activity. While there is no dearth of such molecules, one particular agent, “reovirus” is promising by its ability to target cancer cells with aberrant signaling pathways. This double stranded RNA virus has been therapeutically formulated and has rapidly progressed from pre-clinical validation of anti cancer activity to a phase III registration study in platinum refractory metastatic squamous cell carcinoma of the head and neck. During this process, reovirus has demonstrated safety both as a single agent when administered intratumorally and intravenously, as well as in combination therapy, with multiple chemotherapeutics such as gemcitabine, carboplatin/paclitaxel, and docetaxel; and similarly with radiation. The scientific rationale for its development as an anticancer agent stems from the fact that it preferentially replicates in and induces lyses of cells with an activated Kras pathway. As documented in many previous studies, the initial observation of greater tropism in Kras compromised situation might certainly not be the sole and possibly not even the predominant reason for enhanced virulence. All the same, scientists have emphasized on Kras optimistically due to its high prevalence in various types of cancers. Incidence of Kras mutation has been found to be highest in pancreatic cancer (85–90%) followed by colorectal (35–45%) and lung (25–30%). Reovirus, in fact has the potential not only as a therapy but also as a tool to unravel the aberrant cellular pathway leading to carcinogenicity.

Amino acids substitutions in σ1 and μ1 outer capsid proteins of a Vero cell-adapted mammalian orthoreovirus are required for optimal virus binding and disassembly

“…This has led to numerous clinical studies as reviewed by others (Black and Morris, 2012;Clements et al, 2014;Harrington et al, 2010;Kelly et al, 2009;Maitra et al, 2012). Despite the fact that reoviruses are naturally oncolytic without prior genetic modifications, there is still a significant research effort ongoing to obtain novel virus variants better adapted to infect, replicate in, and kill cancer cells while sparing non-transformed cells (van den Hengel et al, 2013;Kim et al, 2011;Rudd and Lemay, 2005;Shmulevitz et al, 2012;van den Wollenberg et al, 2009van den Wollenberg et al, , 2012.…”

Oncolytic viruses: From bench to bedside with a focus on safety

“…As excellently summarized by Harrington et al and Maitra et al, 137,143 these trials have shown safety with regards to toxicity of mORV-T3D administration to patients with various solid tumors without dose limiting toxicities, while having some appreciable anti-tumor effects in phase II/III trials.…”

“…mORV-T3D was isolated from the intestinal tract of a child with diarrhea, and is used most in (pre)clinical oncolytic virus research. 137 mORV-T3D replicates in cells with dysfunctional cell signaling cascades, most importantly (but not exclusively) KRAS-overexpression and subsequent PKR inhibition, making it an inherent oncolytic virus, meaning that it is tumor-specific contributing to safety. 138,139 A multitude of cancer types have been shown to respond to mORV-T3D treatment in (animal) models.…”

“…Cellular immunity has been found to be important for increasing antitumor efficacy. 137 The absence or inaccessibility of the JAM-A/1 receptor is perceived as a possible limitation for mORV-T3D infection of tumor cells. 140 As such, bio-selection through passaging has been attempted to retarget mORV-T3D to other receptors, although this strategy is probably limited by the quasispecies presence in mORV-T3D isolates.…”

“…137,143 Limited mORV shedding has been observed in clinical trials in patient samples of urine, saliva and feces, mostly with high intravenous administrations. 137 As an RNA virus with a viral RNA polymerase, mORV genome replication is prone to errors which can lead to mutations in offspring. Furthermore, since wild-type isolates are in use, these probably represent several quasispecies.…”