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

Elevated epidermal growth factor receptor (EGFR) expression in colorectal,1 and head and neck squamous cell carcinomas (SCCHNs, Ref. (2) is a powerful indicator of poor prognosis,3 suggesting that this tumor antigen may be a promising immunotherapeutic target. Indeed, clinically efficacious targeting of EGFR using the blocking mAbs cetuximab,4,5 or panitumumab,6,7 has been achieved. However, clinical responses are seen in only 10% to 20% of patients, do not correlate with level of EGFR expression,8,9 but correlate with Fcγ receptor genotypes. Several studies have demonstrated the ability of cetuximab to mediate antibody-mediated cellular cytotoxicity against SCCHN,10 esophageal,11 breast,12 and nonsmall cell lung carcinoma cells.13 In colorectal carcinoma, clinical response to single agent cetuximab therapy correlated with Fcγ receptor polymorphisms expressed by patients’ lymphocytes, supporting an immune mechanism in clinical activity.14 In addition, some cetuximab-treated tumors acquire resistance, due to internalization and degradation of EGFR.15,16 This form of tumor cell escape from cetuximab treatment could increase EGFR-derived peptide presentation to EGFR-specific cytotoxic T lymphocytes (CTLs), as proteasomal degradation is the first step in the HLA class 1 antigen processing pathway for transmembrane proteins.17,18 Thus, novel combination approaches may increase the number of SCCHN patient responses and avoid treatment escape by tumor cells, through combination EGFR-specific mAb and T cell-based immunotherapeutic strategies. In breast carcinoma, the anti-HER2–specific mAb, trastuzumab (Herceptin), increases tumor cell lysis in combination with HER2-specific CTL.19,20 Although there is significant homology between EGFR (HER1) and HER2, an analogous effect has not been shown with SCCHN. In part this may be due to a lack of identification of EGFR-specific CTL epitope(s) and the resulting paucity of T-cell immunotherapeutic trials targeting EGFR. However, due to recent widespread use of the clinically efficacious EGFR-specific mAbs,1,8,21 increasing cetuximab resistance is being observed. HER2 upregulation is also observed in aero-digestive tract malignancies as an escape mechanism from anti-EGFR therapies.16 This presents a compelling need for more efficacious combinatorial immunotherapeutic approaches, to expand the number of patients experiencing clinical responses and to obviate tumor escape from mAb therapy.