The EGFR variant III mutant as a target for immunotherapy of glioblastoma multiforme

Abstract

In epithelial tumors, the epidermal growth factor receptor (EGFR) controls key signaling pathways responsible for growth, proliferation, migration, and survival of tumor cells. The epidermal growth factor receptor variant III (EGFRvIII) is the most common EGFR mutation that occurs in up to 30% of high-grade gliomas especially glioblastoma multiforme (GBM). EGFRvIII arises from the deletion of exon 2–7 that leads to the formation of the constitutively activated mutant receptor incapable of binding any known ligand. EGFRvIII-expressing cells are resistant to EGFR inhibitors and therefore take advantage in survival. Furthermore, EGFRvIII expression in tumors is often correlates with poor prognosis. Indeed, EGFRvIII targeting is of great therapeutic value in order to inhibit GBM progression and invasion. The presence of the unique glycine site in EGFRvIII provides an option to develop EGFRvIII-specific monoclonal antibodies (MAbs). These antibodies are used for detection of EGFRvIII and immunotherapy. Peptide CDX-110 derived from EGFRvIII has high immunogenicity. This peptide was used for the development of anti-EGFRvIII MAbs with improved specificity to the mutant receptor, EGFRvIII-specific dendritic cell vaccine, and CDX-110-KLH peptide vaccine. These immune reagents were successfully tested in preclinical and clinical studies for GBM treatment.