title: Results of the first phase 1 clinical trial of the HER-2/neu peptide (GP2) vaccine in disease-free breast cancer patients: United States Military Cancer Institute Clinical Trials Group Study I-04.
abstract: BACKGROUND
  HER-2/neu, overexpressed in breast cancer, is a source of immunogenic peptides that include GP2 and E75. Phase 2 testing of E75 as an adjuvant vaccine has suggested a clinical benefit. GP2, derived from the transmembrane portion of HER-2/neu, has differing binding characteristics and may be more immunogenic than E75. Results of the first phase 1 trial of GP2 peptide vaccine are presented.
  
  
  METHODS
  Disease-free, lymph node-negative, human leukocyte antigen (HLA)-A2(+) breast cancer patients were enrolled. This dose escalation trial included 4 groups to determine safety and optimal GP2 peptide/granulocyte-macrophage colony-stimulating factor (GM-CSF) dose. Toxicities were monitored. Immunologic response was assessed ex vivo via the HLA-A2:immunoglobulin dimer assay to detect GP2-specific CD8(+) T cells (and E75-specific CD8(+) T cells to assess epitope spreading) and in vivo via delayed type hypersensitivity (DTH) reaction (medians/ranges).
  
  
  RESULTS
  Eighteen patients were enrolled. All toxicities were grade < or =2. Eight (88.9%) of 9 patients in the first 3 dose groups required GM-CSF dose reductions for local reactions > or =100 mm or grade > or =2 systemic toxicity. GM-CSF dose was reduced to 125 microg for the final dose group. All patients responded immunologically ex vivo (GP2-specific CD8(+) T cells from prevaccination to maximum, 0.4% [0.0%-2.0%] to 1.1% [0.4%-3.6%], P < .001) and in vivo (GP2 pre- to postvaccination DTH, 0 mm [0.0-19.5 mm] to 27.5 mm [0.0-114.5 mm, P < .001). E75-specific CD8(+) T cells also increased in response to GP2 from prevaccination to maximum (0.8% [0.0%-2.41%] to 1.6% [0.86%-3.72%], P < .001).
  
  
  CONCLUSIONS
  The GP2 peptide vaccine appears safe and well tolerated with minimal local/systemic toxicity. GP2 elicited HER-2/neu-specific immune responses, including epitope spreading, in high-risk, lymph node-negative breast cancer patients. These findings support further investigation of the GP2 vaccine for the prevention of breast cancer recurrence.
authors.affiliation: Cancer Vaccine Development Program, United States Military Cancer Institute, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Carmichael
authors.forename: Linda C
authors.initials: LC
authors.lastname: Benavides
authors.forename: Jarrod P
authors.initials: JP
authors.lastname: Holmes
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Gates
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mittendorf
authors.forename: Sathibalan
authors.initials: S
authors.lastname: Ponniah
authors.forename: George E
authors.initials: GE
authors.lastname: Peoples
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000628:therapy*; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000939:Epitopes / Q000032:analysis; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D022223:Vaccines, Subunit / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use
chemical_list: D019496:Cancer Vaccines; D000939:Epitopes; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D022223:Vaccines, Subunit; C091577:HER2-neu-derived peptide (654-662)