APhase I Study of Intravenous Oncolytic Reovirus Type 3 Dearing in Patients with Advanced Cancer
Purpose:To determine the safety and feasibility of daily i.v. administration of wild-type oncolytic reovirus (type 3 Dearing) to patients with advanced cancer, assess viral excretion kinetics and antiviral immune responses, identify tumor localization and replication, and describe antitumor activity. Experimental Design: Patients received escalating doses of reovirus up to 3 10 TCID50 for 5 consecutive days every 4weeks.Viral excretionwas assessed by reverse transcription-PCRand antibody response by cytotoxicity neutralization assay. Pretreatment and post-treatment tumor biopsies were obtained to measure viral uptake and replication. Results: Thirty-three patients received 76 courses of reovirus from 1 10 for 1 day up to 3 10 TCID50 for 5 days, repeated every four weeks. Dose-limiting toxicity was not seen. Common grade1to 2 toxicities included fever, fatigue, and headache, whichwere dose and cycle independent.Viral excretion at day15 was not detected by reverse transcription-PCRat 25 cycles and only in 5 patients at 35 cycles. Neutralizing antibodies were detected in all patients and peaked at 4 weeks. Viral localization and replication in tumor biopsies were confirmed in 3 patients. Antitumor activity was seen by radiologic and tumor marker (carcinoembryonic antigen, CA19.9, and prostate-specific antigen) evaluation. Conclusions: Oncolytic reovirus can be safely and repeatedly administered by i.v. injection at doses up to 3 10 TCID50 for 5 days every 4 weeks without evidence of severe toxicities. Productive reoviral infectionof metastatic tumor deposits was confirmed. Reovirus is a safe agent that warrants further evaluation in phase II studies. There is accumulating evidence for the potential clinical utility of oncolytic viruses capable of tumor-selective replication and cytolysis. Reovirus type 3 Dearing (Reolysin; Oncolytics Biotech), a wild-type member of the Reoviridae family, is nonpathogenic in humans, and infections are usually asymptomatic or associated with only minor respiratory/enteric symptoms (1). Reovirus is ubiquitous as witnessed by the high seropositivity rate in normal adult populations (2–4). Reovirus was initially shown to be oncolytic (tumor-selective) by virtue of its ability to replicate selectively in transformed, but not normal, cells (5). NIH-3T3 cells are naturally resistant to reovirus infection but become highly permissive when transformed with the epidermal growth factor receptor gene, v-erbB, sos , or ras , which are all activators of Ras signaling (6, 7). In normal cells, reovirus infection causes phosphorylation of cellular PKR (dsRNA-activated protein kinase) and arrest of viral protein translation and replication. In contrast, in Rasactivated cells, PKR remains inactive (unphosphorylated) and is incapable of aborting viral translation, replication, and cytolysis (7, 8). Ras-activating mutations promote tumor growth, angiogenesis, and metastasis and are found in f30% of human cancers. However, two-thirds of cancers may be susceptible to reovirus therapy through Ras pathway targeting by virtue of activation or overexpression of elements upstream or downstream of Ras, such as epidermal growth factor receptor or platelet-derived growth factor receptor (9). Reovirus therapy has yielded complete tumor regressions in murine models after intratumoral and systemic delivery (8, 10, 11). Reovirus was initially evaluated in humans via the intratumoral route (12). Toxicities were mild and consisted of transient flu-like symptoms and headache. As in the murine models, tumor regressions were observed in these studies in both injected and adjacent uninjected lesions. This phase I, open-label, dose-escalation study of i.v. reovirus was conducted across two centers in the United Kingdom. The primary objective was to determine the safety and tolerability of i.v. reovirus and thereby to define the maximum tolerated dose Cancer Therapy: Clinical Authors’Affiliations: The Royal Marsden NHS FoundationTrust, London and Sutton, United Kingdom; The Institute of Cancer Research, London, United Kingdom; University of Surrey, Guildford, United Kingdom; Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota; University of Leeds, Leeds, United Kingdom; and Oncolytics Biotech, Inc., Calgary, Alberta, Canada Received 2/26/08; revised 6/3/08; accepted 6/24/08. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). K.J. Harrington andJ.S. DeBono contributed equally to this work. Requests for reprints: Kevin J. Harrington, The Institute of Cancer Research, Cancer Research UK Center for Cell and Molecular Biology, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, United Kingdom. Phone: 44207-808-2732; Fax: 44-207-808-2235; E-mail: Kevin.Harrington@icr.ac.uk. F2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-0524 www.aacrjournals.org Clin Cancer Res 2008;14(21) November1, 2008 7127 Research. on July 12, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from (MTD). Secondary objectives included analysis of viral biodistribution, antiviral immune responses, and antitumor activity.