title: A phase I study of intravenous oncolytic reovirus type 3 Dearing in patients with advanced cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Patients received escalating doses of reovirus up to 3 x 10(10) TCID(50) 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 10(8) for 1 day up to 3 x 10(10) TCID(50) 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 10(10) TCID(50) 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.
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Sutton, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Vidal
authors.forename: Hardev S
authors.initials: HS
authors.lastname: Pandha
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
authors.forename: Christine L
authors.initials: CL
authors.lastname: White
authors.forename: Katie
authors.initials: K
authors.lastname: Twigger
authors.forename: Richard G
authors.initials: RG
authors.lastname: Vile
authors.forename: Alan
authors.initials: A
authors.lastname: Melcher
authors.forename: Matt
authors.initials: M
authors.lastname: Coffey
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
authors.forename: Johann S
authors.initials: JS
authors.lastname: DeBono
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000914:Antibodies, Viral / Q000032:analysis; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D012089:Mammalian orthoreovirus 3 / Q000276:immunology; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*
chemical_list: D000914:Antibodies, Viral