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A Phase I Study of Intravenous Oncolytic Reovirus Type 3 Dearing in Patients with Advanced Cancer

Authors' Affiliations: ¹ The Royal Marsden NHS Foundation Trust, London and Sutton, United Kingdom; ² The Institute of Cancer Research, London, United Kingdom; ³ University of Surrey, Guildford, United Kingdom; ⁴ Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota; ⁵ University of Leeds, Leeds, United Kingdom; and ⁶ Oncolytics Biotech, Inc., Calgary, Alberta, Canada

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: 44-207-808-2732; Fax: 44-207-808-2235; E-mail: Kevin.Harrington{at}icr.ac.uk.

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 x 10¹⁰ TCID₅₀ for 5 consecutive days every 4 weeks. Viral excretion was assessed by reverse transcription-PCR and 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 x 10⁸ for 1 day up to 3 x 10¹⁰ TCID₅₀ for 5 days, repeated every four weeks. Dose-limiting toxicity was not seen. Common grade 1 to 2 toxicities included fever, fatigue, and headache, which were dose and cycle independent. Viral excretion at day 15 was not detected by reverse transcription-PCR at 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 x 10¹⁰ TCID₅₀ for 5 days every 4 weeks without evidence of severe toxicities. Productive reoviral infection of metastatic tumor deposits was confirmed. Reovirus is a safe agent that warrants further evaluation in phase II studies.

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