Therapeutic targeting of 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 Fcgamma 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 wild-type sequence
peptide, EGFR853-861 and modified its anchor sequence to enhance
HLA-A*0201 binding and stimulation of cross-reactive anti-wild-type EGFR853-861-specific CTL. Cross-reactivity was also observed with HER2861-869. EGFR853-861-specific CTL recognition of SCCHN cells was increased by incubation of
tumor cells with
cetuximab, which led to EGFR degradation. In addition, EGFR853-861-specific CTLs were elevated in the circulation of SCCHN patients as 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.