Novel Immunogenic HLA-A*0201-restricted Epidermal Growth Factor Receptor-specific T-cell Epitope in Head and Neck Cancer Patients

Therapeutic targeting or the epidermal growth factor receptor (EGFR), which is highly overexpressed and correlated with poor prognosis in colorectal and head and neck squamous cell carcinoma (SCCHN), has shown clinical efficacy using the blocking mAbs, cetuximab or panitumumab, but only in 10% to 20% of patients. Clinical responsiveness is correlated with certain Fey receptor genotypes, suggesting immune activity may contribute to therapeutic efficacy. In addition, cetuximab-resistant tumor cells exhibit ubiquitination and degradation of EGFR, which would increase its processing as a tumor antigen for cytotoxic T lymphocyte (CTL) lysis. Thus, T cell-based immunotherapy might enhance the antitumor efficacy of EGFR-specific mAbs, but CTL epitopes are poorly defined. To permit combinatorial EGFR-targeted immunotherapy, we identified a novel immunogenic wildtype sequence peptide, EGFR(853-861) and modified its anchor sequence to enhance HLA-A*0201 binding and stimulation of cross-reactive anti-wild-type EGFR(853-861)-specific CTL. Cross-reactivity was also observed with HER2(861-869). EGFR(853-861)-specific CTL recognition of SCCHN cells was increased by incubation of tumor cells with cetuximab, which led to EGFR degradation. In addition, EGFR(853-861)-specific CTLs were elevated in the circulation of SCCHN patients Lis compared with healthy control peripheral blood mononuclear cells. Thus, a novel, immunogenic EGFR-encoded CTL epitope may be incorporated into vaccines and would be Useful for combinatorial immunotherapy with EGFR-specific mAbs in cancer patients.