title: Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients.
abstract: OBJECTIVE
  We evaluated the feasibility, safety, and immunogenicity of mature, peptide-pulsed dendritic cell (DC) vaccines administered by different routes.
  
  
  METHODS
  We performed a randomized, phase I, dose-escalation study in 27 patients with metastatic melanoma receiving four autologous peptide-pulsed DC vaccinations. Patients were randomly assigned to an intravenous (IV), intranodal (IN), or intradermal (ID) route of administration (ROA). For each route, primary end points were dose-limiting toxicity, maximum-tolerated dose, and T-cell sensitization. Sensitization was evaluated through tetramer staining, in vitro peptide recognition assays, and delayed-type hypersensitivity (DTH) responses.
  
  
  RESULTS
  Twenty-two (81.5%) of 27 patients completed all four vaccinations. Vaccinations were well tolerated; a few patients exhibited grade 1 to 2 toxicities including rash, fever, and injection site reaction. All routes of administration induced comparable increases in tetramer-staining CD8+ T cells (five of seven IV, four of seven IN, and four of six ID patients). However, the IN route induced significantly higher rates for de novo development of CD8+ T cells that respond by cytokine secretion to peptide-pulsed targets (six [85.7%] of seven IN patients v two [33%] of six ID patients v none [0%] of six IV patients; P =.005) and de novo DTH (seven [87.5%] of eight IN patients v two [33.3%] of six ID patients v one [14.3%] of seven IV patients; P =.01) compared with other routes.
  
  
  CONCLUSIONS
  Administration of this peptide-pulsed mature DC vaccine by IN, IV, or ID routes is feasible and safe. IN administration seems to result in superior T-cell sensitization as measured by de novo target-cell recognition and DTH priming, indicating that IN may be the preferred ROA for mature DC vaccines.
authors.affiliation: Harrison Department of Surgical Research, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bedrosian
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Mick
authors.forename: Shuwen
authors.initials: S
authors.lastname: Xu
authors.forename: Harvey
authors.initials: H
authors.lastname: Nisenbaum
authors.forename: Mark
authors.initials: M
authors.lastname: Faries
authors.forename: Paul
authors.initials: P
authors.lastname: Zhang
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cohen
authors.forename: Gary
authors.initials: G
authors.lastname: Koski
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Czerniecki
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000633:toxicity; D003713:Dendritic Cells / Q000276:immunology*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed; D016219:Immunotherapy, Adoptive; D007275:Injections, Intravenous; D008198:Lymph Nodes; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017063:Outcome Assessment, Health Care; D014611:Vaccination
chemical_list: D019496:Cancer Vaccines