title: Rapid induction of specific cytotoxic T lymphocytes against melanoma-associated antigens by a recombinant vaccinia virus vector expressing multiple immunodominant epitopes and costimulatory molecules in vivo.
abstract: A specific cellular immune response directed against a panel of three defined tumor-associated antigen (TAA) epitopes was induced in metastatic melanoma patients by a prime-boost strategy taking advantage of an innovative recombinant vaccinia virus as evaluated by quantitative assessment of cytotoxic T lymphocytes (CTLs) with corresponding specificity. The immunization protocol consisted of the administration of psoralen-UV-treated and replication-incompetent recombinant vaccinia virus encoding the three immunodominant HLA-A*0201-restricted epitopes Melan-A(27-35), gp100(280-288), and tyrosinase(1-9) together with two costimulatory molecules, B7.1 and B7.2, in the context of systemic granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment. Boosts were subsequently applied with corresponding synthetic nonapeptides and GM-CSF. Specific CTL induction was assessed by tetramer staining and CTL precursor (CTLp) frequency evaluation. Within 12 days of injection of the recombinant vector, cytotoxic T cell responses specific for engineered epitopes were detectable in three of three patients. During the vaccination treatment, antigen-specific CTLp frequencies exceeding 1:10,000 peripheral CD8(+) T cells could be observed. Tetramer staining also revealed significant increases in specific CD8(+) T cell numbers. We conclude that active specific antitumor vaccination can raise a concurrent and specific cellular immune response against a panel of molecularly defined antigens, thereby increasing the chance of an immune hit against neoplastic cells with heterogeneous antigen expression. Data from this study emphasize the potency of a recombinant vaccinia virus vector encoding multiple minigenes and costimulatory molecules in the context of exogenously administered GM-CSF. Clinical effectiveness of this immunologically active protocol should therefore be explored in appropriately selected groups of patients.
authors.affiliation: Division of General Surgery, Department of Surgery, University Hospital Basel, CH-4031 Basel, Switzerland. doertli@uhbs.ch
authors.forename: Daniel
authors.initials: D
authors.lastname: Oertli
authors.forename: Walter R
authors.initials: WR
authors.lastname: Marti
authors.forename: Paul
authors.initials: P
authors.lastname: Zajac
authors.forename: Christoph
authors.initials: C
authors.lastname: Noppen
authors.forename: Thomas
authors.initials: T
authors.lastname: Kocher
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Padovan
authors.forename: Michel
authors.initials: M
authors.lastname: Adamina
authors.forename: Reto
authors.initials: R
authors.lastname: Schumacher
authors.forename: Felix
authors.initials: F
authors.lastname: Harder
authors.forename: Michael
authors.initials: M
authors.lastname: Heberer
authors.forename: Giulio C
authors.initials: GC
authors.lastname: Spagnoli
mesh_terms: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D007167:Immunotherapy; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014616:Vaccinia virus / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D016056:Immunodominant Epitopes; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins