title: A phase I study of immunization using particle-mediated epidermal delivery of genes for gp100 and GM-CSF into uninvolved skin of melanoma patients.
abstract: OBJECTIVE
  We examined in vivo particle-mediated epidermal delivery (PMED) of cDNAs for gp100 and granulocyte macrophage colony-stimulating factor (GM-CSF) into uninvolved skin of melanoma patients. The aims of this phase I study were to assess the safety and immunologic effects of PMED of these genes in melanoma patients.
  
  
  METHODS
  Two treatment groups of six patients each were evaluated. Group I received PMED with cDNA for gp100, and group II received PMED with cDNA for GM-CSF followed by PMED for gp100 at the same site. One vaccine site per treatment cycle was biopsied and divided for protein extraction and sectioning to assess transgene expression, gold-bead penetration, and dendritic cell infiltration. Exploratory immunologic monitoring of HLA-A2(+) patients included flow cytometric analyses of peripheral blood lymphocytes and evaluation of delayed-type hypersensitivity to gp100 peptide.
  
  
  RESULTS
  Local toxicity in both groups was mild and resolved within 2 weeks. No systemic toxicity could be attributed to the vaccines. Monitoring for autoimmunity showed no induction of pathologic autoantibodies. GM-CSF transgene expression in vaccinated skin sites was detected. GM-CSF and gp100 PMED yielded a greater infiltration of dendritic cells into vaccine sites than did gp100 PMED only. Exploratory immunologic monitoring suggested modest activation of an antimelanoma response.
  
  
  CONCLUSIONS
  PMED with cDNAs for gp100 alone or in combination with GM-CSF is well tolerated by patients with melanoma. Moreover, pathologic autoimmunity was not shown. This technique yields biologically active transgene expression in normal human skin. Although modest immune responses were observed, additional investigation is needed to determine how to best utilize PMED to induce antimelanoma immune responses.
authors.affiliation: Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Cassaday
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
authors.forename: David M
authors.initials: DM
authors.lastname: King
authors.forename: Michael D
authors.initials: MD
authors.lastname: Macklin
authors.forename: Jacek
authors.initials: J
authors.lastname: Gan
authors.forename: Tom F
authors.initials: TF
authors.lastname: Warner
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Zuleger
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Bridges
authors.forename: Heidi G
authors.initials: HG
authors.lastname: Schalch
authors.forename: Kyung Mann
authors.initials: KM
authors.lastname: Kim
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Hank
authors.forename: David M
authors.initials: DM
authors.lastname: Mahvi
authors.forename: Mark R
authors.initials: MR
authors.lastname: Albertini
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D015551:Autoimmunity; D001706:Biopsy; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000378:metabolism; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008562:Membrane Glycoproteins / Q000008:administration & dosage*; D008875:Middle Aged; D012867:Skin / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy*; D019444:Vaccines, DNA; D058951:gp100 Melanoma Antigen
chemical_list: D018076:DNA, Complementary; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; D019444:Vaccines, DNA; D058951:gp100 Melanoma Antigen; D016178:Granulocyte-Macrophage Colony-Stimulating Factor