*Review* **Past, Present and Future of Oncolytic Reovirus**

#### **Louise Müller** † **, Robert Berkeley** † **, Tyler Barr, Elizabeth Ilett** ‡ **and Fiona Errington-Mais \*,**‡

Leeds Institute of Medical Research (LIMR), University of Leeds, Leeds LS9 7TF, UK; lme.muller@outlook.com (L.M.); raberkeley@outlook.com (R.B.); um17tkb@leeds.ac.uk (T.B.); e.ilett@leeds.ac.uk (E.I.)


Received: 18 September 2020; Accepted: 30 October 2020; Published: 31 October 2020

**Simple Summary:** Within this review article the authors provide an unbiased review of the oncolytic virus, reovirus, clinically formulated as pelareorep. In particular, the authors summarise what is known about the molecular and cellular requirements for reovirus oncolysis and provide a comprehensive summary of reovirus-induced anti-tumour immune responses. Importantly, the review also outlines the progress made towards more efficacious combination therapies and their evaluation in clinical trials. The limitations and challenges that remain to harness the full potential of reovirus are also discussed.

**Abstract:** Oncolytic virotherapy (OVT) has received significant attention in recent years, especially since the approval of talimogene Laherparepvec (T-VEC) in 2015 by the Food and Drug administration (FDA). Mechanistic studies of oncolytic viruses (OVs) have revealed that most, if not all, OVs induce direct oncolysis and stimulate innate and adaptive anti-tumour immunity. With the advancement of tumour modelling, allowing characterisation of the effects of tumour microenvironment (TME) components and identification of the cellular mechanisms required for cell death (both direct oncolysis and anti-tumour immune responses), it is clear that a "one size fits all" approach is not applicable to all OVs, or indeed the same OV across different tumour types and disease locations. This article will provide an unbiased review of oncolytic reovirus (clinically formulated as pelareorep), including the molecular and cellular requirements for reovirus oncolysis and anti-tumour immunity, reports of pre-clinical efficacy and its overall clinical trajectory. Moreover, as it is now abundantly clear that the true potential of all OVs, including reovirus, will only be reached upon the development of synergistic combination strategies, reovirus combination therapeutics will be discussed, including the limitations and challenges that remain to harness the full potential of this promising therapeutic agent.

**Keywords:** reovirus; oncolytic virus; immunotherapy
