title: Results of the first phase I clinical trial of the novel II-key hybrid preventive HER-2/neu peptide (AE37) vaccine.
abstract: OBJECTIVE
  HER-2/neu is overexpressed in breast cancer and is the source of immunogenic peptides. CD4(+) T-helper peptides for HER-2/neu are being evaluated in vaccine trials. The addition of Ii-Key, a four-amino-acid LRMK modification, increases vaccine potency when compared with unmodified class II epitopes. We present the results of the first human phase I trial of the Ii-Key hybrid HER-2/neu peptide (AE37) vaccine in disease-free, node-negative breast cancer patients.
  
  
  METHODS
  The dose escalation trial included five dose groups, to determine safety and optimal dose of the hybrid peptide (100 microg, 500 microg, 1,000 microg) and granulocyte-macrophage colony-stimulating factor (GM-CSF; range, 0 to 250 microg). In the event of significant local toxicity, GM-CSF (or peptide in absence of GM-CSF) was reduced by 50%. Immunologic response was monitored by delayed-type hypersensitivity and [(3)H]thymidine proliferative assays for both the hybrid AE37 (LRMK-positive HER-2/neu:776-790) and AE36 (unmodified HER-2/neu:776-790).
  
  
  RESULTS
  All 15 patients completed the trial with no grade 3 to 5 toxicities. Dose reductions occurred in 47% of patients. In the second group (peptide, 500 microg; GM-CSF, 250 microg), all patients required dose reductions, prompting peptide-only inoculations in the third group. The vaccine induced dose-dependent immunologic responses in vitro and in vivo to AE37, as well as AE36.
  
  
  CONCLUSIONS
  The hybrid AE37 vaccine seems safe and well tolerated with minimal toxicity if properly dosed. AE37 is capable of eliciting HER-2/neu-specific immune responses, even without the use of an adjuvant. This trial represents the first human experience with the Ii-Key modification, and to our knowledge, AE37 is the first peptide vaccine to show potency in the absence of an immunoadjuvant.
authors.affiliation: Department of Surgery, General Surgery Service, Brooke Army Medical Center, 3851 Roger Brooke Dr, Fort Sam Houston, TX, 78234, USA.
authors.forename: Jarrod P
authors.initials: JP
authors.lastname: Holmes
authors.forename: Linda C
authors.initials: LC
authors.lastname: Benavides
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Gates
authors.forename: Mark G
authors.initials: MG
authors.lastname: Carmichael
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Hueman
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mittendorf
authors.forename: James L
authors.initials: JL
authors.lastname: Murray
authors.forename: Asna
authors.initials: A
authors.lastname: Amin
authors.forename: Dianna
authors.initials: D
authors.lastname: Craig
authors.forename: Eric
authors.initials: E
authors.lastname: von Hofe
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 / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007111:Immunity, Cellular; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D009367:Neoplasm Staging; D010446:Peptide Fragments; D011336:Probability; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000627:therapeutic use*; D018570:Risk Assessment; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D016896:Treatment Outcome; D014611:Vaccination / Q000379:methods
chemical_list: D019496:Cancer Vaccines; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; C530655:AE37 vaccine