Phase I/II study of GM-CSF DNA as an adjuvant for a multipeptide cancer vaccine in patients with advanced melanoma.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances immune responses by inducing proliferation, maturation, and migration of dendritic cells (DCs) as well as expansion and differentiation of B and T lymphocytes. The potency of DNA vaccines can be enhanced by the addition of DNA encoding cytokines, acting as molecular adjuvants. We conducted a phase I/II trial of human GM-CSF DNA in conjunction with a multipeptide vaccine (gp100 and tyrosinase) in stage III/IV melanoma patients. Nineteen human leukocyte antigen (HLA)-A*0201+ patients were treated. Three dose levels were studied: 100, 400, and 800 microg DNA/injection, administered subcutaneously every month with 500 microg of each peptide. In the dose-ranging study, three patients were treated at each dose level. The remaining patients were then treated at the highest dose. Most toxicities were grade 1 injection-site reactions. Eight patients (42%) developed CD8+ T-cell responses, defined by a > or =3 SD increase in baseline reactivity to tyrosinase or gp100 peptide in tetramer or intracellular cytokine staining (ICS) assays. There was no relationship between dose and T-cell response. Responding T cells had an effector memory cell phenotype. Polyfunctional T cells were also demonstrated. At a median of 31 months follow-up, median survival has not been reached. Human GM-CSF DNA was found to be a safe adjuvant.
Perales
Miguel-Angel
MA
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Yuan
Jianda
J
Powel
Sarah
S
Gallardo
Humilidad F
HF
Rasalan
Teresa S
TS
Gonzalez
Christina
C
Manukian
Gregor
G
Wang
Jian
J
Zhang
Yan
Y
Chapman
Paul B
PB
Krown
Susan E
SE
Livingston
Philip O
PO
Ejadi
Samuel
S
Panageas
Katherine S
KS
Engelhorn
Manuel E
ME
Terzulli
Stephanie L
SL
Houghton
Alan N
AN
Wolchok
Jedd D
JD
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D009367:Neoplasm Staging; D010455:Peptides / Q000009:adverse effects / Q000276:immunology; D010641:Phenotype; D011994:Recombinant Proteins; D019444:Vaccines, DNA / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D022223:Vaccines, Subunit / Q000009:adverse effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D010455:Peptides; D011994:Recombinant Proteins; D019444:Vaccines, DNA; D022223:Vaccines, Subunit; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
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