title: Two-stage phase I dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers.
abstract: OBJECTIVE
  To determine the safety and feasibility of combining intratumoral reovirus and radiotherapy in patients with advanced cancer and to assess viral biodistribution, reoviral replication in tumors, and antiviral immune responses.
  
  
  METHODS
  Patients with measurable disease amenable to palliative radiotherapy were enrolled. In the first stage, patients received radiotherapy (20 Gy in five fractions) plus two intratumoral injections of RT3D at doses between 1 x 10(8) and 1 x 10(10) TCID(50). In the second stage, the radiotherapy dose was increased (36 Gy in 12 fractions) and patients received two, four, or six doses of RT3D at 1 x 10(10) TCID(50). End points were safety, viral replication, immunogenicity, and antitumoral activity.
  
  
  RESULTS
  Twenty-three patients with various solid tumors were treated. Dose-limiting toxicity was not seen. The most common toxicities were grade 2 (or lower) pyrexia, influenza-like symptoms, vomiting, asymptomatic lymphopenia, and neutropenia. There was no exacerbation of the acute radiation reaction. Reverse transcription-PCR (RT-PCR) studies of blood, urine, stool, and sputum were negative for viral shedding. In the low-dose (20 Gy in five fractions) radiation group, two of seven evaluable patients had a partial response and five had stable disease. In the high-dose (36 Gy in 12 fractions) radiation group, five of seven evaluable patients had partial response and two stable disease.
  
  
  CONCLUSIONS
  The combination of intratumoral RT3D and radiotherapy was well tolerated. The favorable toxicity profile and lack of vector shedding means that this combination should be evaluated in newly diagnosed patients receiving radiotherapy with curative intent.
authors.affiliation: The Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom. kevin.harrington@icr.ac.uk
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
authors.forename: Eleni M
authors.initials: EM
authors.lastname: Karapanagiotou
authors.forename: Victoria
authors.initials: V
authors.lastname: Roulstone
authors.forename: Katie R
authors.initials: KR
authors.lastname: Twigger
authors.forename: Christine L
authors.initials: CL
authors.lastname: White
authors.forename: Laura
authors.initials: L
authors.lastname: Vidal
authors.forename: Debbie
authors.initials: D
authors.lastname: Beirne
authors.forename: Robin
authors.initials: R
authors.lastname: Prestwich
authors.forename: Kate
authors.initials: K
authors.lastname: Newbold
authors.forename: Merina
authors.initials: M
authors.lastname: Ahmed
authors.forename: Khin
authors.initials: K
authors.lastname: Thway
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Nutting
authors.forename: Matt
authors.initials: M
authors.lastname: Coffey
authors.forename: Dean
authors.initials: D
authors.lastname: Harris
authors.forename: Richard G
authors.initials: RG
authors.lastname: Vile
authors.forename: Hardev S
authors.initials: HS
authors.lastname: Pandha
authors.forename: Johann S
authors.initials: JS
authors.lastname: Debono
authors.forename: Alan A
authors.initials: AA
authors.lastname: Melcher
mesh_terms: D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000032:analysis; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008297:Male; D012089:Mammalian orthoreovirus 3; D008875:Middle Aged; D009369:Neoplasms / Q000532:radiotherapy / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods; D011879:Radiotherapy Dosage; D014018:Tissue Distribution; D014779:Virus Replication; D017201:Virus Shedding
chemical_list: D000914:Antibodies, Viral