Epidermal growth factor receptor (EGFR) mutations and tumor-specific targeting of malignant glioma by vaccine-based immunotherapeutic approaches.

摘要

Epidermal growth factor receptor (EGFR) is amplified and rearranged in malignant gliomas. In addition to the most common mutation, EGFRvIII, we found other EGFR-reactive species in gliomas containing tandem duplication of exons. Mutation of EGFR results in unique exon recombination junctions encoding novel epitopes that could be used for vaccine based targeted immunotherapy.; We used a multiple antigenic peptide (MAP) to EGFRvIII as a tumor vaccine against rat F98 glioma cells expressing EGFRvIII. Rats vaccinated with MAP alone have median survival time (MeST) 3.5 days longer than non-vaccinated rats. The addition of GM-CSF to the MAP added 13 days to MeST. A DNA vaccine encoding the EGFRvIII extracellular domain was used to expand the immunogenic epitopes. This DNA vaccine was delivered in polyethylenimine through micro-osmotic pumps into brain parenchyma. The DNA vaccine alone had a MeST of 6–9 days longer than controls. Vaccine plus GM-CSF extended the MeST by 24 days beyond nonvaccinated rats. With the DNA vaccine, we also found an increase in immunized cervical lymph node cells secreting IFNγ, a decrease in infiltrative CD4+ T cells, and a marked increase in tumor infiltrating CD8+ T cells compared to MAP vaccination.; Glioma cells may create novel antigens from EGFR through intron recombination. Both multiple antigenic peptide and DNA vaccination generate a local immune response capable of tumor destruction. This project has provided a greater understanding of the immune response to intracranial tumor antigens and may aid in developing more effective vaccination strategies towards malignant glioma.