A Degenerate HLA-DR Epitope Pool of HER-2/neu Reveals a Novel In vivo Immunodominant Epitope, HER-2/neu(88-102)

作者：Karyampudi Lavakumar; Formicola Courtney; Erskine Courtney L; Maurer Matthew J; Ingle James N; Krco Christopher J; Wettstein Peter J; Kalli Kimberly R; Fikes John D; Beebe Melanie; Hartmann Lynn C; Disis Mary L; Ferrone Soldano; Ishioka Glenn; Knutson Keith L^*

来源：Clinical Cancer Research, 2010, 16(3): 825-834.

DOI：10.1158/1078-0432.CCR-09-2781

Purpose: Over the past two decades, there has been significant interest in targeting HER-2/neu in immune-based approaches for the treatment of HER-2/neu+ cancers. For example, peptide vaccination using a CD8 T cell-activating HER-2/neu epitope (amino acids 369-377) is an approach that is being considered in advanced phase clinical trials. Studies have suggested that the persistence of HER-2/neu-specific CD8 T cells could be improved by incorporating human leukocyte antigen (HLA) class II epitopes in the vaccine. Our goal in this study was to identify broad coverage HLA-DR epitopes of HER-2/neu, an antigen that is highly expressed in a variety of carcinomas.
Experimental Design: A combination of algorithms and HLA-DR-binding assays was used to identify HLA-DR epitopes of HER-2/neu antigen. Evidence of preexistent immunity in cancer patients against the identified epitopes was determined using IFN-gamma enzyme-linked immunosorbent spot (ELIspot) assay.
Results: Eighty-four HLA-DR epitopes of HER-2/neu were predicted, 15 of which had high binding affinity for >= 11 common HLA-DR molecules. A degenerate pool of four HLA-DR-restricted 15-amino acid epitopes (p59, p88, p422, and p885) was identified, against which >58% of breast and ovarian cancer patients had preexistent T-cell immunity. All four epitopes are naturally processed by antigen-presenting cells. Hardy-Weinberg analysis showed that the pool is useful in similar to 84% of population. Lastly, in this degenerate pool, we identified a novel in vivo immunodominant HLA-DR epitope, HER-2/neu(88-102) (p88).
Conclusion: The broad coverage and natural immunity to this epitope pool suggests potential usefulness in HER-2/neu-targeting, immune-based therapies such as vaccines. Clin Cancer Res; 16(3); 825-34.

• 出版日期2010-2-1