A phase I study of immunization using particle-mediated epidermal delivery of genes for gp100 and GM-CSF into uninvolved skin of melanoma patients.
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.
Cassaday
Ryan D
RD
Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792, USA.
Sondel
Paul M
PM
King
David M
DM
Macklin
Michael D
MD
Gan
Jacek
J
Warner
Tom F
TF
Zuleger
Cindy L
CL
Bridges
Alan J
AJ
Schalch
Heidi G
HG
Kim
Kyung Mann
KM
Hank
Jacquelyn A
JA
Mahvi
David M
DM
Albertini
Mark R
MR
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
D018076:DNA, Complementary; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; D019444:Vaccines, DNA; D058951:gp100 Melanoma Antigen; D016178:Granulocyte-Macrophage Colony-Stimulating Factor