The epidermal growth factor receptor (EGFR) is overexpressed in a significant number of human malignancies and is thought to play a role in oncogenesis in these tumors. Overexpression of the receptor precedes deletional mutation of the gene or the production of aberrant transcripts for the receptor. One of these deletional mutants, EGFRvIII, is oncogenic and constitutes a tumor specific antigen. EGFRvIII is expressed in 15-75% of high grade astrocytomas, ovarian and gastric cancers and therefore represents a potential target for immunotherapy in patients with these malignancies. Patients with tumors which express EGFRvIII have evidence of antibody and T cell immunity specific to the deletional mutant and are therefore capable of recognizing the receptor as a foreign antigen. Preclinical data in a murine model demonstrates that a peptide vaccine incorporating the unique amino acid sequence of the EGFRvIII can augment an immune response of cytotoxic T lymphocytes and antibodies specific for the mutant receptor. In these animals, the induction of cytotoxic T lymphocytes and antibodies prevents tumor implantation and can induce regression of tumors expressing the receptor. Peptide vaccines targeted to another closely related EGFR family member, the HER2 oncoprotein, effectively induce T cell and humoral immunity against HER2, demonstrating feasibility of this approach. No adjuvant therapy has been found to significantly prolong the survival of patients who present with the tumor histologies which express EGFRvIII, and as a group they are at a very high risk of relapse after initial therapy. Innovative approaches to prevention and treatment of these malignancies is warranted. The objective of this proposal is to synthesize and. test peptide vaccine, followed by use of this vaccine in a phase I study in patients with EGTFRvII1 expressing malignancies. The study of this peptide vaccine will examine both the ability to induce T cell and humoral immunity to this peptide and the effect of humoral immunity on expression and signaling by EGFRvIII.
The specific aims of this proposal are; 1. To evaluate the safety and define the potential toxicity of immunizing patients with an EGFRvIII based peptide vaccine. 2. To determine the level of EGFR specific antibody response after immunization with EGFRvIII peptide 3. To characterize effects of human anti-EGFRvIII antibodies on EGFRvIII signaling. 4. To determine the level of EGFR specific T cell response after immunization with EGFRvIII peptide.
| Montgomery, R Bruce; Makary, Ekram; Schiffman, Kathy et al. (2005) Endogenous anti-HER2 antibodies block HER2 phosphorylation and signaling through extracellular signal-regulated kinase. Cancer Res 65:650-6 |
