title: A randomized phase II trial of multiepitope vaccination with melanoma peptides for cytotoxic T cells and helper T cells for patients with metastatic melanoma (E1602).
abstract: OBJECTIVE
  This multicenter randomized trial was designed to evaluate whether melanoma helper peptides augment cytotoxic T lymphocyte (CTL) responses to a melanoma vaccine and improve clinical outcome in patients with advanced melanoma.
  
  
  METHODS
  One hundred seventy-five patients with measurable stage IV melanoma were enrolled into 4 treatment groups, vaccinated with 12 MHC class I-restricted melanoma peptides to stimulate CTL (12 MP, group A), plus a tetanus peptide (group B), or a mixture of 6 melanoma helper peptides (6 MHP, group C) to stimulate helper T lymphocytes (HTL), or with 6 melanoma helper peptide (6 MHP) alone (group D), in incomplete Freund's adjuvant plus granulocyte macrophage colony-stimulating factor. CTL responses were assessed using an in vitro-stimulated IFN-γ ELIspot assay, and HTL responses were assessed using a proliferation assay.
  
  
  RESULTS
  In groups A to D, respectively, CTL response rates to 12 melanoma peptides were 43%, 47%, 28%, and 5%, and HTL response rates to 6 MHP were in 3%, 0%, 40%, and 41%. Best clinical response was partial response in 7 of 148 evaluable patients (4.7%) without significant difference among study arms. Median overall survival (OS) was 11.8 months. Immune response to 6 MHP was significantly associated with both clinical response (P = 0.036) and OS (P = 0.004).
  
  
  CONCLUSIONS
  Each vaccine regimen was immunogenic, but MHPs did not augment CTL responses to 12 melanoma peptides. The association of survival and immune response to 6 MHP supports further investigation of helper peptide vaccines. For patients with advanced melanoma, multipeptide vaccines should be studied in combination with other potentially synergistic active therapies.
authors: Department of Surgery, Human Immune Therapy Center, University of Virginia, Charlottesville, Virginia, USA. cls8h@virginia.edu
authors: Craig L
authors: CL
authors: Slingluff
authors: Sandra
authors: S
authors: Lee
authors: Fengmin
authors: F
authors: Zhao
authors: Kimberly A
authors: KA
authors: Chianese-Bullock
authors: Walter C
authors: WC
authors: Olson
authors: Lisa H
authors: LH
authors: Butterfield
authors: Theresa L
authors: TL
authors: Whiteside
authors: Philip D
authors: PD
authors: Leming
authors: John M
authors: JM
authors: Kirkwood
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D005260:Female; D005620:Freund's Adjuvant; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008055:Lipids; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000276:immunology; D009367:Neoplasm Staging; D010455:Peptides / Q000008:administration & dosage*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D013742:Tetanus / Q000378:metabolism; D016896:Treatment Outcome; D014611:Vaccination; D022223:Vaccines, Subunit / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D008055:Lipids; D010455:Peptides; D022223:Vaccines, Subunit; C114843:incomplete Freund's adjuvant; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005620:Freund's Adjuvant
references: Nat Med. 2004 Sep;10(9):909-15
references: 15340416
references: Clin Cancer Res. 2012 Mar 1;18(5):1386-94
references: 22156613
references: Int J Cancer. 1995 Nov 3;63(3):375-80
references: 7591235
references: Am J Pathol. 1997 Dec;151(6):1549-53
references: 9403705
references: J Infect Dis. 1996 Jan;173(1):24-31
references: 8537666
references: Cancer Res. 2010 Jul 1;70(13):5213-9
references: 20551059
references: Clin Cancer Res. 2009 Nov 15;15(22):7036-44
references: 19903780
references: Ann Surg. 1989 Aug;210(2):194-202
references: 2787972
references: J Exp Med. 2004 Sep 20;200(6):701-12
references: 15381726
references: J Clin Oncol. 2008 Oct 20;26(30):4973-80
references: 18809608
references: J Immunol. 1989 May 1;142(9):3329-35
references: 2785141
references: J Natl Cancer Inst. 1988 Sep 7;80(13):1016-26
references: 3261800
references: J Cutan Pathol. 1998 Apr;25(4):204-9
references: 9609139
references: Blood. 2009 Jun 25;113(26):6658-68
references: 19282460
references: J Immunol. 2007 Oct 15;179(8):5033-40
references: 17911588
references: J Clin Oncol. 2013 Jan 20;31(3):373-9
references: 23248256
references: AIDS Res Hum Retroviruses. 1996 Mar 1;12(4):259-72
references: 8906986
references: Cancer. 2009 Aug 15;115(16):3670-9
references: 19536890
references: J Clin Oncol. 2006 Jul 1;24(19):3089-94
references: 16809734
references: Nat Med. 2012 Aug;18(8):1254-61
references: 22842478
references: J Pathol. 2001 Jan;193(1):13-20
references: 11169510
references: N Engl J Med. 2011 Jun 2;364(22):2119-27
references: 21631324
references: J Clin Oncol. 2008 Feb 1;26(4):527-34
references: 18235113
references: Cancer Res. 2009 Apr 1;69(7):3077-85
references: 19293190
references: J Immunother (1991). 1992 Oct;12(3):203-6
references: 1445813
references: Ann Surg Oncol. 2008 Dec;15(12):3538-49
references: 18923873
references: J Clin Oncol. 1983 Nov;1(11):710-9
references: 6668489
references: Vaccine. 2009 Mar 10;27(11):1764-70
references: 19185050
references: Cancer Immunol Immunother. 2000 Mar;48(12):661-72
references: 10752474
references: J Immunol. 1994 Jan 15;152(2):549-56
references: 8283036
references: Clin Cancer Res. 2009 Feb 15;15(4):1443-51
references: 19228745
references: Clin Cancer Res. 2007 Nov 1;13(21):6386-95
references: 17975151
references: Cancer. 2012 May 15;118(10):2594-602
references: 21989902
references: J Immunother. 2010 Nov-Dec;33(9):965-74
references: 20948440
references: Cancer Immunol Immunother. 2001 Mar;50(1):3-15
references: 11315507
references: Curr Opin Oncol. 2000 Mar;12(2):163-73
references: 10750729
references: Clin Cancer Res. 2001 Oct;7(10):3012-24
references: 11595689
references: Science. 1991 Dec 13;254(5038):1643-7
references: 1840703
references: J Immunother. 1998 Jan;21(1):27-31
references: 9456433
references: J Clin Oncol. 2011 Jul 20;29(21):2924-32
references: 21690475
references: Drugs R D. 2006;7(3):197-201
references: 16752945
references: Science. 1994 Apr 29;264(5159):716-9
references: 7513441
references: Clin Cancer Res. 2009 Nov 15;15(22):7029-35
references: 19903777
references: Clin Cancer Res. 2013 Mar 1;19(5):1225-31
references: 23307859