**8. Reovirus Clinical Trials**

Reovirus T3D is the subject of one of the largest clinical trial programmes in oncolytic virotherapy (OVT). The clinical grade formulation of reovirus is now marketed as pelareorep (formerly Reolysin®) by Oncolytics Biotech Inc. (Calgary, AB, Canada). The virus is listed in 26 trials identified on www.clinicaltrials.gov. As of 2018, reovirus holds orphan drug status from the FDA for glioma, ovarian, pancreatic, peritoneal and gastric cancers, and from the European Medicines Agency (EMA, Amsterdam, The Netherlands) for ovarian and pancreatic cancer.

The first-in-man phase I study of reovirus, REO-001, enrolled 19 patients with accessible, advanced malignancies, who were treated intra-tumourally with ascending doses of the virus. No dose-limiting toxicities were observed, all being grade two or below, with nausea, headache or vomiting being the most common [168]. Tumour responses were apparent in 37% of patients. Based on this and its promising safety profile in animal models, reovirus progressed quickly into trials of systemic treatment. Intravenous delivery was first tested in REO-004. Eighteen patients with advanced solid tumours received virus doses of up to 3 <sup>×</sup> <sup>10</sup><sup>10</sup> TCID<sup>50</sup> without identifying dose-limiting toxicity. In fact, only two patients experienced grade two events, even when multiple doses were given on successive days [169]. When corroborated by other phase I trials [112,170], these results demonstrated that when delivered by infusion as a very large, non-physiological bolus, reovirus is remarkably

well tolerated. Interestingly, i.v. administration of reovirus in a phase I trial of heavily pre-treated patients with advanced cancers increased the number of CD4+ve T cells, CD8+ve T cells and NK cells, as well as cytokine levels, in the blood, suggesting the onset of an immune response. Significantly, i.v. administration of reovirus in brain tumours also led to a local IFN response with recruitment of CTLs [109].

Reovirus has now undergone further evaluation in phase I and II clinical trials across a range of indications; summarised in Table 1. Historically, the tumours most heavily targeted within the reovirus programme have been melanoma, myeloma and glioma [142,171,172], although trials have also included pancreatic, lung, breast, colorectal, prostate, and head and neck cancers [108,109,173–176]. Initial trials deployed reovirus as a monotherapy, the majority utilising i.v. administration; safety was established in the almost total absence of serious adverse events [177], with equivocal outcomes reported in phase II trials [142,178]. The mixed outcomes of patient response in clinical trials have made the therapeutic potential of reovirus a topic of debate. It is accurate to state that i.v. reovirus has often shown very modest activity, particularly as a monotherapy [142]. However, it reliably gains access to tumour lesions when administered systemically [109,133]. Currently, the virus is no longer under active investigation as a monotherapy and Oncolytics Biotech Inc. is instead developing combination programmes (www.oncolyticsbiotech.com).



**Table 1.** Summary of Reovirus Clinical Trials.




MTD: maximum tolerated dose, PD-L1: anti-programmed death-ligand 1, BM: bone marrow, OS: overall survival.
