title: Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma.
abstract: Immunity to self antigens on cancer is constrained by tolerance/ignorance. DNA vaccines encoding xenogeneic differentiation antigens, such as tyrosinase (TYR), mediate tumor protection and regression in implantable mouse models, and dogs with spontaneous melanoma. We conducted a trial of mouse and human TYR DNA vaccines in stage III/IV melanoma patients. Eighteen human leukocyte antigen (HLA)-A*0201(+) melanoma patients were randomized as follows: one group received three mouse TYR DNA injections followed by three human TYR DNA injections; the other group received the same vaccines in opposite sequence. The study was conducted at three dose levels: 100, 500, and 1,500 microg DNA/injection, administered intramuscularly (IM) every 3 weeks. Most toxicities were grade 1 injection site reactions. Seven patients developed CD8(+) T-cell responses, defined by a >3 SD increase in baseline reactivity to TYR peptide in tetramer or intracellular cytokine staining (ICS) assays. There was found to be no relationship between dose, assigned schedule, and T-cell response. At a median of 42 months follow-up, median survival has not been reached. Mouse and human TYR DNA vaccines were found safe and induced CD8(+) T-cell responses in 7 of 18 patients. T cells recognizing a native TYR peptide had a phenotype consistent with that of effector memory cells.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. wolchokj@mskcc.org
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.forename: Alan N
authors.initials: AN
authors.lastname: Houghton
authors.forename: Humilidad F
authors.initials: HF
authors.lastname: Gallardo
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Rasalan
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rajaram
authors.initials: R
authors.lastname: Ranganathan
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
authors.forename: Susan E
authors.initials: SE
authors.lastname: Krown
authors.forename: Philip O
authors.initials: PO
authors.lastname: Livingston
authors.forename: Melanie
authors.initials: M
authors.lastname: Heywood
authors.forename: Isabelle
authors.initials: I
authors.lastname: Riviere
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Panageas
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Terzulli
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Perales
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000906:Antibodies / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D064420:Drug-Related Side Effects and Adverse Reactions / Q000276:immunology*; D006801:Humans; D007125:Immunogenetics; D007167:Immunotherapy; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D009367:Neoplasm Staging; D010641:Phenotype; D015996:Survival Rate; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000906:Antibodies; D019444:Vaccines, DNA; D014442:Monophenol Monooxygenase