Identification and characterization of a HER-2/neu epitope as a potential target for cancer immunotherapy.
Our aim is to develop peptide vaccines that stimulate tumor antigen-specific T-lymphocyte responses against frequently detected cancers. We describe herein a novel HLA-A*0201-restricted epitope, encompassing amino acids 828-836 (residues QIAKGMSYL), which is naturally presented by various HER-2/neu (+) tumor cell lines. HER-2/neu(828-836), [HER-2(9(828))], possesses two anchor residues and stabilized HLA-A*0201 on T2 cells in a concentration-dependent Class I binding assay. This peptide was stable for 3.5 h in an off-kinetic assay. HER-2(9(828)) was found to be immunogenic in HLA-A*0201 transgenic (HHD) mice inducing peptide-specific and functionally potent CTL and long-lasting anti-tumor immunity. Most important, using HLA-A*0201 pentamer analysis we could detect increased ex vivo frequencies of CD8(+) T-lymphocytes specifically recognizing HER-2(9(828)) in 8 out of 20 HLA-A*0201(+) HER-2/neu (+) breast cancer patients. Moreover, HER-2(9(828))-specific human CTL recognized the tumor cell line SKOV3.A2 as well as the primary RS.A2.1.DR1 tumor cell line both expressing HER-2/neu and HLA-A*0201. Finally, therapeutic vaccination with HER-2(9(828)) in HHD mice was proven effective against established transplantable ALC.A2.1.HER tumors, inducing complete tumor regression in 50% of mice. Our data encourage further exploitation of HER-2(9(828)) as a promising candidate for peptide-based cancer vaccines.
Lekka
Eftychia
E
Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece. lekka@ciic.gr
Gritzapis
Angelos D
AD
Perez
Sonia A
SA
Tsavaris
Nikolaos
N
Missitzis
Ioannis
I
Mamalaki
Avgi
A
Papamichail
Michael
M
Baxevanis
Constantin N
CN
D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D002469:Cell Separation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005434:Flow Cytometry; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D010446:Peptide Fragments / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; C435939:HLA-A*02:01 antigen