Evaluation of the HER2/neu-derived peptide GP2 for use in a peptide-based breast cancer vaccine trial.
BACKGROUND
E75 and GP2 are human leukocyte antigen (HLA)-A2-restricted immunogenic peptides derived from the HER2/neu protein. In a E75 peptide-based vaccine trial, preexisting immunity and epitope spreading to GP2 was detected. The purpose of this study was to further investigate GP2 for potential use in vaccination strategies. Importantly, a naturally occurring polymorphism (I-->V at position 2, 2VGP2) associated with increased breast cancer risk was addressed.


METHODS
Prevaccination peripheral blood samples (PBMC) from HLA-A2 breast cancer patients and CD8+ T cells from HLA-A2 healthy donors were stimulated with autologous dendritic cells (DC) pulsed with GP2 and tested in standard cytotoxicity assays with HER2/neu+ tumor cells or GP2- or 2VGP2-loaded T2 targets. Additional cytotoxicity experiments used effectors stimulated with DC pulsed with E75, GP2, or the combination of E75+GP2.


RESULTS
GP2-stimulated prevaccination PBMC from 28 patients demonstrated killing of MCF-7, SKOV3-A2, and the HLA-A2- control target SKOV3 of 28.8+/-3.7% (P<.01), 29.5+/-4.0% (P<.01), and 16.9+/-2.7%, respectively. When compared with E75, GP2-stimulated CD8+ T cells lysed HER2/neu+ targets at 43.8+/-5.2% versus 44.2+/-5.7% for E75 (P=.87). When combined, an additive effect was noted with 58.6+/-5.4% lysis (P=.05). GP2-stimulated CD8+ T cells specifically recognized both GP2-loaded (19.6+/-5.7%) and 2VGP2-loaded T2 targets (17.7+/-5.2%).


CONCLUSIONS
GP2 is a clinically relevant HER2/neu-derived peptide with immunogenicity comparable to that of E75. Importantly, GP2-specific effectors recognize 2VGP2-expressing targets; therefore, a GP2 vaccine should be effective in patients carrying this polymorphism. GP2 may be most beneficial used in a multiepitope vaccine.
Mittendorf
Elizabeth A
EA
Clinical Breast Care Project, Department of Surgery, Walter Reed Army Medical Center, Washington, DC, USA.
Storrer
Catherine E
CE
Foley
Rebecca J
RJ
Harris
Katie
K
Jama
Yusuf
Y
Shriver
Craig D
CD
Ponniah
Sathibalan
S
Peoples
George E
GE
D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002857:Chromium / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy; D010446:Peptide Fragments / Q000276:immunology* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014019:Tissue Donors; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; D002857:Chromium; D000939:Epitopes; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; C474513:HER-2 peptide E75 (369-377), human; C091577:HER2-neu-derived peptide (654-662)