title: Limited induction of tumor cross-reactive T cells without a measurable clinical benefit in early melanoma patients vaccinated with human leukocyte antigen class I-modified peptides.
abstract: OBJECTIVE
  The progressive immune dysfunctions that occur in patients with advanced melanoma make them unlikely to efficiently respond to cancer vaccines. A multicenter randomized phase II trial was conducted to test whether immunization with modified HLA class I tumor peptides in the context of adjuvant therapy results in better immunologic responses and improved clinical outcomes in patients with early melanoma (stages IIB/C-III).
  
  
  METHODS
  Forty-three patients were enrolled to undergo vaccination (n = 22) or observation (n = 21). The vaccine included four HLA-A*0201-restricted modified peptides (Melan-A/MART-1([27L]), gp100([210M]), NY-ESO-1([165V]), and Survivin([97M])) emulsified in Montanide ISA51 and injected subcutaneously in combination with cyclophosphamide (300 mg/m(2)) and low-dose IL-2 (3 × 10(6) IU). The immune responses were monitored using ex vivo IFN-γ-ELISpot, HLA/multimer staining, and in vitro short-term peptide sensitization assays.
  
  
  RESULTS
  Vaccination induced a rapid and persistent increase in specific effector memory CD8(+) T cells in 75% of the patients. However, this immunization was not associated with any significant increase in disease-free or overall survival as compared with the observation group. An extensive immunologic analysis revealed a significantly reduced cross-recognition of the corresponding native peptides and, most importantly, a limited ability to react to melanoma cells.
  
  
  CONCLUSIONS
  Adjuvant setting is an appealing approach for testing cancer vaccines because specific CD8(+) T cells can be efficiently induced in most vaccinated patients. However, the marginal antitumor activity of the T cells induced by modified peptides in this study largely accounts for the observed lack of benefit of vaccination. These findings suggest reconsidering this immunization strategy, particularly in early disease.
authors.affiliation: Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Filipazzi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pilla
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.forename: Roberto
authors.initials: R
authors.lastname: Patuzzo
authors.forename: Chiara
authors.initials: C
authors.lastname: Castelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Camisaschi
authors.forename: Andrea
authors.initials: A
authors.lastname: Maurichi
authors.forename: Agata
authors.initials: A
authors.lastname: Cova
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Rigamonti
authors.forename: Felicetta
authors.initials: F
authors.lastname: Giardino
authors.forename: Annabella
authors.initials: A
authors.lastname: Di Florio
authors.forename: Marco
authors.initials: M
authors.lastname: Asioli
authors.forename: Paola
authors.initials: P
authors.lastname: Frati
authors.forename: Gloria
authors.initials: G
authors.lastname: Sovena
authors.forename: Paola
authors.initials: P
authors.lastname: Squarcina
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
authors.forename: Riccardo
authors.initials: R
authors.lastname: Danielli
authors.forename: Vanna
authors.initials: V
authors.lastname: Chiarion-Sileni
authors.forename: Antonello
authors.initials: A
authors.lastname: Villa
authors.forename: Claudia
authors.initials: C
authors.lastname: Lombardo
authors.forename: Gabrina
authors.initials: G
authors.lastname: Tragni
authors.forename: Mario
authors.initials: M
authors.lastname: Santinami
authors.forename: Giorgio
authors.initials: G
authors.lastname: Parmiani
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
mesh_terms: D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016022:Case-Control Studies; D003429:Cross Reactions / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D058965:MART-1 Antigen / Q000737:chemistry / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D009367:Neoplasm Staging; D010455:Peptides / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D058965:MART-1 Antigen; D010455:Peptides; D022223:Vaccines, Subunit