title: Immunologic response to xenogeneic gp100 DNA in melanoma patients: comparison of particle-mediated epidermal delivery with intramuscular injection.
abstract: OBJECTIVE
  Prior studies show that i.m. injection of xenogeneic orthologues of melanosomal antigens (tyrosinase, gp100) induces CD8(+) T-cell responses to the syngeneic protein. To further define the optimal vaccination strategy, we conducted a pilot clinical trial comparing i.m. injection with particle-mediated epidermal delivery (PMED).
  
  
  METHODS
  Human leukocyte antigen (HLA)-A*0201(+) disease-free melanoma patients were randomized to the PMED or i.m. arm, receiving eight vaccinations over 4 months. Patients received 4 microg or 2,000 microg per injection, respectively, of mouse gp100 DNA. Peripheral blood mononuclear cells were collected, cultured with gp100 peptides, and analyzed by tetramer and intracellular cytokine staining for responses to HLA-A*0201-restricted gp100 epitopes [gp100(209-217) (ITDQVPFSV) and gp100(280-288) (YLEPGPVTA)].
  
  
  RESULTS
  Twenty-seven patients with stage IIB-IV melanoma were analyzable for immune response. The only common toxicity was grade 1 injection site reaction in nine patients with no intergroup difference, and one dose-limiting toxicity of acute hypersensitivity occurred in a PMED patient with undiagnosed gold allergy. Four of 27 patients produced gp100 tetramer(+)CD8(+) T cells, all carrying the CCR7(lo)CD45RA(lo) effector-memory phenotype. Five of 27 patients generated IFN-gamma(+)CD8(+) T cells, one who was also tetramer-positive. Overall, vaccination induced a response in 30% of patients, which was not significantly associated with study arm or clinical outcome. However, the PMED group showed a trend toward increased IFN-gamma(+)CD8(+) T-cell generation (P = 0.07).
  
  
  CONCLUSIONS
  A comparable efficacy and safety profile was shown between the i.m. and PMED arms, despite a significantly decreased dose of DNA used for PMED injection.
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Ginsberg
authors.forename: Humilidad F
authors.initials: HF
authors.lastname: Gallardo
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Rasalan
authors.forename: Matthew
authors.initials: M
authors.lastname: Adamow
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Mu
authors.forename: Sapna
authors.initials: S
authors.lastname: Tandon
authors.forename: Barrett B
authors.initials: BB
authors.lastname: Bewkes
authors.forename: Ruth-Ann
authors.initials: RA
authors.lastname: Roman
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carvajal
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Panageas
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Terzulli
authors.forename: Alan N
authors.initials: AN
authors.lastname: Houghton
authors.forename: Jianda D
authors.initials: JD
authors.lastname: Yuan
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D000368:Aged; D000818:Animals; D015478:Antigens, Heterophile / Q000008:administration & dosage / Q000009:adverse effects; D019470:Biolistics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D004247:DNA / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D005260:Female; D015234:HLA-A Antigens; D015789:HLA-A2 Antigen; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D010446:Peptide Fragments; D010455:Peptides; D010865:Pilot Projects; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D058951:gp100 Melanoma Antigen
chemical_list: D015478:Antigens, Heterophile; D019496:Cancer Vaccines; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D010455:Peptides; C548642:Pmel protein, mouse; D019444:Vaccines, DNA; D058951:gp100 Melanoma Antigen; C548641:gp100(280-288) melanoma antigen peptide; D004247:DNA