title: Recombinant modified vaccinia Ankara primes functionally activated CTL specific for a melanoma tumor antigen epitope in melanoma patients with a high risk of disease recurrence.
abstract: Recombinant plasmid DNA and attenuated poxviruses are under development as cancer and infectious disease vaccines. We present the results of a phase I clinical trial of recombinant plasmid DNA and modified vaccinia Ankara (MVA), both encoding 7 melanoma tumor antigen cytotoxic T lymphocyte (CTL) epitopes. HLA-A*0201-positive patients with surgically treated melanoma received either a "prime-boost" DNA/MVA or a homologous MVA-only regimen. Ex vivo tetramer analysis, performed at multiple time points, provided detailed kinetics of vaccine-driven CTL responses specific for the high-affinity melan-A(26-35) analogue epitope. Melan-A26-35-specific CTL were generated in 2/6 patients who received DNA/MVA (detectable only after the first MVA injection) and 4/7 patients who received MVA only. Ex vivo ELISPOT analysis and in vitro proliferation assays confirmed the effector function of these CTL. Responses were seen in smallpox-vaccinated as well as vaccinia-naive patients, as defined by anti-vaccinia antibody responses demonstrated by ELISA assay. The observations that 1) CTL responses were generated to only 1 of the recombinant epitopes and 2) that the magnitude of these responses (0.029-0.19% CD8(+) T cells) was below the levels usually seen in acute viral infections suggest that to ensure high numbers of CTL specific for multiple recombinant epitopes, a deeper understanding of the interplay between CTL responses specific for the viral vector and recombinant epitopes is required.
authors.affiliation: Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, OX3 9DS, UK.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Smith
authors.forename: P Rod
authors.initials: PR
authors.lastname: Dunbar
authors.forename: Fareed
authors.initials: F
authors.lastname: Mirza
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Palmowski
authors.forename: Dawn
authors.initials: D
authors.lastname: Shepherd
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Gilbert
authors.forename: Pierre
authors.initials: P
authors.lastname: Coulie
authors.forename: Joerg
authors.initials: J
authors.lastname: Schneider
authors.forename: Eric
authors.initials: E
authors.lastname: Hoffman
authors.forename: Robert
authors.initials: R
authors.lastname: Hawkins
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D000328:Adult; D000368:Aged; D000917:Antibody Formation; D000951:Antigens, Neoplasm / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology* / Q000473:pathology; D010957:Plasmids / Q000235:genetics; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D000939:Epitopes; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic