title: Prolonged survival of dendritic cell-vaccinated melanoma patients correlates with tumor-specific delayed type IV hypersensitivity response and reduction of tumor growth factor beta-expressing T cells.
abstract: OBJECTIVE
  The aim of this work was to assess immunologic response, disease progression, and post-treatment survival of melanoma patients vaccinated with autologous dendritic cells (DCs) pulsed with a novel allogeneic cell lysate (TRIMEL) derived from three melanoma cell lines.
  
  
  METHODS
  Forty-three stage IV and seven stage III patients were vaccinated four times with TRIMEL/DC vaccine. Specific delayed type IV hypersensitivity (DTH) reaction, ex vivo cytokine production, and regulatory T-cell populations were determined. Overall survival and disease progression rates were analyzed using Kaplan-Meier curves and compared with historical records.
  
  
  RESULTS
  The overall survival for stage IV patients was 15 months. More than 60% of patients showed DTH-positive reaction against the TRIMEL. Stage IV/DTH-positive patients displayed a median survival of 33 months compared with 11 months observed for DTH-negative patients (P = .0014). All stage III treated patients were DTH positive and remained alive and tumor free for a median follow-up period of 48 months (range, 33 to 64 months). DTH-positive patients showed a marked reduction in the proportion of CD4+ transforming growth factor (TGF) beta+ regulatory T cells compared to DTH-negative patients (1.54% v 5.78%; P < .0001).
  
  
  CONCLUSIONS
  Our findings strongly suggest that TRIMEL-pulsed DCs provide a standardized and widely applicable source of melanoma antigens, very effective in evoking antimelanoma immune response. To our knowledge, this is the first report describing a correlation between vaccine-induced reduction of CD4+TGFbeta+ regulatory T cells and in vivo antimelanoma immune response associated to improved patient survival and disease stability.
authors.affiliation: Millennium Nucleus on Immunology and Immunotherapy, Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Mercedes N
authors.initials: MN
authors.lastname: López
authors.forename: Cristian
authors.initials: C
authors.lastname: Pereda
authors.forename: Gabriela
authors.initials: G
authors.lastname: Segal
authors.forename: Leonel
authors.initials: L
authors.lastname: Muñoz
authors.forename: Raquel
authors.initials: R
authors.lastname: Aguilera
authors.forename: Fermín E
authors.initials: FE
authors.lastname: González
authors.forename: Alejandro
authors.initials: A
authors.lastname: Escobar
authors.forename: Alexandra
authors.initials: A
authors.lastname: Ginesta
authors.forename: Diego
authors.initials: D
authors.lastname: Reyes
authors.forename: Rodrigo
authors.initials: R
authors.lastname: González
authors.forename: Ariadna
authors.initials: A
authors.lastname: Mendoza-Naranjo
authors.forename: Milton
authors.initials: M
authors.lastname: Larrondo
authors.forename: Alvaro
authors.initials: A
authors.lastname: Compán
authors.forename: Carlos
authors.initials: C
authors.lastname: Ferrada
authors.forename: Flavio
authors.initials: F
authors.lastname: Salazar-Onfray
mesh_terms: D000328:Adult; D019496:Cancer Vaccines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D008875:Middle Aged; D012878:Skin Neoplasms / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D019496:Cancer Vaccines; D016212:Transforming Growth Factor beta