title: A recombinant modified vaccinia ankara vaccine encoding Epstein-Barr Virus (EBV) target antigens: a phase I trial in UK patients with EBV-positive cancer.
abstract: OBJECTIVE
  Epstein-Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses.
  
  
  METHODS
  Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 10(7) and 5 × 10(8) plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations.
  
  
  RESULTS
  Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively.
  
  
  CONCLUSIONS
  MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 10(8) pfu) is recommended for investigation in current phase IB and II trials.
authors.affiliation: Cancer Research UK Centre, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Graham S
authors.initials: GS
authors.lastname: Taylor
authors.affiliation: Cancer Research UK Centre, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Hui
authors.initials: H
authors.lastname: Jia
authors.affiliation: Division of Cancer Biology, The Institute of Cancer Research/The Royal Marsden Hospital, London, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Harrington
authors.affiliation: Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Lip Wai
authors.initials: LW
authors.lastname: Lee
authors.affiliation: Cancer Research UK Centre, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Turner
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Cancer Research UK Centre, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Manjit
authors.initials: M
authors.lastname: Tanday
authors.affiliation: Division of Cancer Biology, The Institute of Cancer Research/The Royal Marsden Hospital, London, United Kingdom.
authors.forename: Jen
authors.initials: J
authors.lastname: Matthews
authors.affiliation: Cancer Research UK Centre, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Roberts
authors.affiliation: Cancer Research UK Drug Development Office, London, United Kingdom.
authors.forename: Ceri
authors.initials: C
authors.lastname: Edwards
authors.affiliation: Cancer Research UK Drug Development Office, London, United Kingdom.
authors.forename: Lesley
authors.initials: L
authors.lastname: McGuigan
authors.affiliation: Cancer Research UK Centre, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hartley
authors.affiliation: Health Protection Agency, West Midlands Public Health Laboratory, Heart of England Foundation Trust, Bordesley Green East, Birmingham, United Kingdom.
authors.forename: Steve
authors.initials: S
authors.lastname: Wilson
authors.affiliation: Partner State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Hong Kong Cancer Institute and Li Ka Shing Institute for Health Sciences, Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Hui
authors.affiliation: Partner State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Hong Kong Cancer Institute and Li Ka Shing Institute for Health Sciences, Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Cancer Research UK Centre, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Rickinson
authors.affiliation: Cancer Research UK Centre, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom. n.m.steven@bham.ac.uk.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Steven
mesh_terms: D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D003131:Combined Modality Therapy; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000821:virology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000276:immunology*; D005260:Female; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000209:etiology* / Q000517:prevention & control / Q000628:therapy*; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D014611:Vaccination; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*; D019562:Viral Load
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D019309:Epstein-Barr Virus Nuclear Antigens