EGFRvIII-targeted vaccination therapy of malignant glioma

Abstract

Given the highly infiltrative growth pattern of malignant glioma and the lack of specificity associated with currently available treatment regimens, alternative strategies designed to eradicate cancer cells while limiting collateral toxicity in normal tissues remain a high priority. To this end, the development of specific immunotherapies against targeted neoplastic cells represents a promising approach. The epidermal growth factor receptor class III variant (EGFRvIII), a constitutively activated mutant of the wild-type tyrosine kinase, is present in a substantial proportion of malignant gliomas and other human cancers, yet completely absent from normal tissues. This receptor variant consists of an in-frame deletion, the translation of which produces an extracellular junction with a novel glycine residue, flanked by amino acid sequences that are not typically adjacent in the normal protein. In this review, both preclinical and early clinical development of a peptide vaccine directed against this portion of the EGFRvIII antigenic domain are recapitulated. Following vaccination, our group has demonstrated potent, redirected cellular and humoral immunity against cancer cells expressing the mutant receptor without significant toxicity. Additionally, the corresponding therapeutic outcomes observed in these studies lend credence to the potential role of peptide-based vaccination strategies among emerging antitumor immunotherapies in patients with malignant glioma.

Figure 1

Targeting of glioma by radiolabeled chimeric monoclonal antibody directed against the EGFRvIII tumor antigen. (A–C) Planar images of the head and neck obtained on day 0 (A), day 3 (B), and day 7 (C) after infusion of ¹¹¹In‐ch806. Initial blood pool activity is seen on day 0, and uptake of ¹¹¹In‐ch806 in an anaplastic astrocytoma in the right frontal lobe is evident by day 3 (arrow) and increases by day 7. (D–F) Tumor‐specific uptake of ¹¹¹In‐ch806 (arrow) is demonstrated in a SPECT image of the brain (D), ¹⁸F‐FDG (FDG, Fluorodeoxyglucose) positron emission tomography (E) and MRI (F). Figure reproduced with permission from reference (90).

Figure 2

EGFR downstream signaling in cancer cells. Figure reproduced with permission from reference (6).

Figure 3

Schematic diagram of the EGFR wild‐type protein showing the area of in‐frame deletion which forms EGFRvIII. During the deletion, amino acids 6 and 273 are split forming a novel glycine at the junction of amino acids 5 and 274. PEPvIII is a 13 amino acid peptide with a terminal cysteine added to facilitate conjugation to KLH. Figure reproduced with permission from reference (85).

Figure 4

A. High‐grade astrocytoma used in subsequent immunohistochemical assays (hematoxylin–eosin, original magnification ×400). B. Antiepidermal growth factor receptor (anti‐EGFR) wild‐type immunohistochemistry showing strong diffuse cytoplasmic immunoreactivity, a pattern that is frequently associated with EGFR genetic amplification (original magnification ×400). C. Anti‐EGFRvIII immunohistochemical reactivity exhibiting strong cytoplasmic localization. EGFRvIII immunoreactivity is most commonly encountered in tumors also exhibiting amplification of the EGFR locus (original magnification ×400). D. Antiphosphatase and tensin homolog (anti‐PTEN) immunoreactivity demonstrating 80% of tumor cells with cytoplasmic reactivity, a pattern associated with an intact PTEN status in the tumor (original magnification ×400). E. Anti‐phospho‐S6 immunohistochemistry revealing approximately 20% of tumor cells labeling, indicating this messenger is activated in this tumor (original magnification ×400). F. Anti‐phospho‐Akt immunohistochemistry demonstrating approximately 80% of tumor cells labeling, indicating this messenger is activated in this tumor (original magnification ×400). Figure reproduced with permission from reference (63).