title: A vaccinia virus armed with interleukin-10 is a promising therapeutic agent for treatment of murine pancreatic cancer.
abstract: OBJECTIVE
  Vaccinia virus has strong potential as a novel therapeutic agent for treatment of pancreatic cancer. We investigated whether arming vaccinia virus with interleukin-10 (IL10) could enhance the antitumor efficacy with the view that IL10 might dampen the host immunity to the virus, increasing viral persistence, thus maximizing the oncolytic effect and antitumor immunity associated with vaccinia virus.
  
  
  METHODS
  The antitumor efficacy of IL10-armed vaccinia virus (VVLΔTK-IL10) and control VVΔTK was assessed in pancreatic cancer cell lines, mice bearing subcutaneous pancreatic cancer tumors and a pancreatic cancer transgenic mouse model. Viral persistence within the tumors was examined and immune depletion experiments as well as immunophenotyping of splenocytes were carried out to dissect the functional mechanisms associated with the viral efficacy.
  
  
  RESULTS
  Compared with unarmed VVLΔTK, VVLΔTK-IL10 had a similar level of cytotoxicity and replication in vitro in murine pancreatic cancer cell lines, but rendered a superior antitumor efficacy in the subcutaneous pancreatic cancer model and a K-ras-p53 mutant-transgenic pancreatic cancer model after systemic delivery, with induction of long-term antitumor immunity. The antitumor efficacy of VVLΔTK-IL10 was dependent on CD4(+) and CD8(+), but not NK cells. Clearance of VVLΔTK-IL10 was reduced at early time points compared with the control virus. Treatment with VVLΔTK-IL10 resulted in a reduction in virus-specific, but not tumor-specific CD8(+) cells compared with VVLΔTK.
  
  
  CONCLUSIONS
  These results suggest that VVLΔTK-IL10 has strong potential as an antitumor therapeutic for pancreatic cancer.
authors.affiliation: Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Louisa S
authors.initials: LS
authors.lastname: Chard
authors.affiliation: Center for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Eleni
authors.initials: E
authors.lastname: Maniati
authors.affiliation: Sino-British Research Centre for Molecular Oncology, Zhengzhou University, Zhengzhou, China.
authors.forename: Pengju
authors.initials: P
authors.lastname: Wang
authors.affiliation: Sino-British Research Centre for Molecular Oncology, Zhengzhou University, Zhengzhou, China.
authors.forename: Zhongxian
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Sino-British Research Centre for Molecular Oncology, Zhengzhou University, Zhengzhou, China.
authors.forename: Dongling
authors.initials: D
authors.lastname: Gao
authors.affiliation: Sino-British Research Centre for Molecular Oncology, Zhengzhou University, Zhengzhou, China.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Sino-British Research Centre for Molecular Oncology, Zhengzhou University, Zhengzhou, China.
authors.forename: Fengyu
authors.initials: F
authors.lastname: Cao
authors.affiliation: Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Jahangir
authors.initials: J
authors.lastname: Ahmed
authors.affiliation: Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Margueritte
authors.initials: M
authors.lastname: El Khouri
authors.affiliation: Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hughes
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Shengdian
authors.initials: S
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Li
authors.affiliation: Center for Health Disparities and Molecular Medicine, Loma Linda University, Loma Linda, California.
authors.forename: Bela
authors.initials: B
authors.lastname: Denes
authors.affiliation: Center for Health Disparities and Molecular Medicine, Loma Linda University, Loma Linda, California.
authors.forename: Istvan
authors.initials: I
authors.lastname: Fodor
authors.affiliation: Center for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hagemann
authors.affiliation: Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Sino-British Research Centre for Molecular Oncology, Zhengzhou University, Zhengzhou, China. Yaohe.wang@qmul.ac.uk bci-director@qmul.ac.uk.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Lemoine
authors.affiliation: Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Sino-British Research Centre for Molecular Oncology, Zhengzhou University, Zhengzhou, China. Yaohe.wang@qmul.ac.uk bci-director@qmul.ac.uk.
authors.forename: Yaohe
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016753:Interleukin-10 / Q000235:genetics*; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy*; D014616:Vaccinia virus / Q000235:genetics*; D014779:Virus Replication
chemical_list: D016753:Interleukin-10