title: Phase I/II study of GM-CSF DNA as an adjuvant for a multipeptide cancer vaccine in patients with advanced melanoma.
abstract: 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.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Miguel-Angel
authors.initials: MA
authors.lastname: Perales
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.forename: Sarah
authors.initials: S
authors.lastname: Powel
authors.forename: Humilidad F
authors.initials: HF
authors.lastname: Gallardo
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Rasalan
authors.forename: Christina
authors.initials: C
authors.lastname: Gonzalez
authors.forename: Gregor
authors.initials: G
authors.lastname: Manukian
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
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: Samuel
authors.initials: S
authors.lastname: Ejadi
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Panageas
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Engelhorn
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Terzulli
authors.forename: Alan N
authors.initials: AN
authors.lastname: Houghton
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: 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
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D010455:Peptides; D011994:Recombinant Proteins; D019444:Vaccines, DNA; D022223:Vaccines, Subunit; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
references.citation: Blood. 1998 Jan 1;91(1):222-30
references.pmid: 9414288
references.citation: J Virol. 2008 Mar;82(6):2853-66
references.pmid: 18184702
references.citation: Cancer Immunol Immunother. 1999 May-Jun;48(2-3):123-31
references.pmid: 10414466
references.citation: Nat Rev Immunol. 2008 Apr;8(4):247-58
references.pmid: 18323851
references.citation: J Clin Invest. 1998 Sep 15;102(6):1258-64
references.pmid: 9739060
references.citation: J Infect Dis. 1998 Jul;178(1):92-100
references.pmid: 9652427
references.citation: Nat Immunol. 2003 Dec;4(12):1191-8
references.pmid: 14625547
references.citation: J Exp Med. 1992 Jun 1;175(6):1717-28
references.pmid: 1588289
references.citation: Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):540-9
references.pmid: 17255276
references.citation: Blood. 1998 Dec 15;92(12):4491-508
references.pmid: 9845514
references.citation: BMC Immunol. 2008 Apr 11;9:13
references.pmid: 18405363
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3539-43
references.pmid: 8097319
references.citation: J Urol. 1994 Mar;151(3):622-8
references.pmid: 8308972
references.citation: Cytokines Cell Mol Ther. 1999 Dec;5(4):217-25
references.pmid: 10850386
references.citation: Annu Rev Immunol. 1994;12:337-65
references.pmid: 8011285
references.citation: Clin Cancer Res. 2003 Apr;9(4):1284-90
references.pmid: 12684396
references.citation: Hematol Oncol Clin North Am. 2006 Jun;20(3):613-36
references.pmid: 16762727
references.citation: Clin Cancer Res. 2005 Nov 15;11(22):8114-21
references.pmid: 16299244
references.citation: J Clin Oncol. 2001 May 1;19(9):2370-80
references.pmid: 11331315
references.citation: J Clin Oncol. 1996 Jan;14(1):7-17
references.pmid: 8558223
references.citation: Cytotherapy. 2006;8(5):498-508
references.pmid: 17050255
references.citation: Blood. 2006 Apr 1;107(7):2855-62
references.pmid: 16357322
references.citation: Infect Immun. 2005 May;73(5):2863-72
references.pmid: 15845492
references.citation: J Immunol. 2000 Mar 1;164(5):2728-37
references.pmid: 10679114
references.citation: Clin Cancer Res. 2002 May;8(5):967-72
references.pmid: 12006508
references.citation: J Immunol Methods. 2003 Oct 1;281(1-2):65-78
references.pmid: 14580882
references.citation: Clin Cancer Res. 2006 Sep 15;12(18):5511-9
references.pmid: 17000687
references.citation: Hematology. 2004 Jun;9(3):207-15
references.pmid: 15204102
references.citation: Nat Immunol. 2000 Nov;1(5):426-32
references.pmid: 11062503
references.citation: Nat Med. 2007 Jul;13(7):843-50
references.pmid: 17558415
references.citation: Cancer Res. 2002 Oct 15;62(20):5845-52
references.pmid: 12384547
references.citation: Vaccine. 2005 Jan 26;23(10):1273-83
references.pmid: 15652670
references.citation: J Exp Med. 2007 Oct 1;204(10):2473-85
references.pmid: 17893201
references.citation: Cytokines Cell Mol Ther. 2002;7(3):125-33
references.pmid: 12850812
references.citation: J Exp Med. 2007 Jun 11;204(6):1405-16
references.pmid: 17535971
references.citation: J Immunol. 1996 Sep 15;157(6):2539-48
references.pmid: 8805655
references.citation: J Immunol. 1996 May 15;156(10):3858-65
references.pmid: 8621924
references.citation: J Clin Oncol. 2000 Jun;18(12):2444-58
references.pmid: 10856105
references.citation: Annu Rev Immunol. 2004;22:745-63
references.pmid: 15032595
references.citation: Mol Ther. 2007 Nov;15(11):2044-50
references.pmid: 17726460
references.citation: Eur J Immunol. 1994 Mar;24(3):759-64
references.pmid: 8125142
references.citation: Vaccine. 2006 May 22;24(21):4582-5
references.pmid: 16188351