Clinical applications of a peptide-based vaccine for glioblastoma

Abstract

Glioblastoma multiforme is a malignant, relentless brain cancer with no known cure, and standard therapies leave significant room for the development of better, more effective treatments. Immunotherapy is a promising approach to the treatment of solid tumors that directs the patient's own immune system to destroy tumor cells. The most successful immunologically based cancer therapy to date involves the passive administration of monoclonal antibodies, but significant antitumor responses have also been generated with active vaccination strategies and cell-transfer therapies. This article summarizes the important components of the immune system, discusses the specific difficulty of immunologic privilege in the central nervous system, and reviews treatment approaches that are being attempted, with an emphasis on active immunotherapy using peptide vaccines.

Figure 1. Schematic of the two main immunotherapy strategies

Vaccine therapy attempts to generate an antitumor response by activating the immune system of the patient in vivo. Cell-Transfer Therapy removes lymphocytes from the patient, activates them in vitro against the tumor, then infuses them back into the patient. From Rosenberg SA. Shedding light on immunotherapy for cancer. N Engl J Med. Apr 1 2004;350(14):1462, with permission. Copyright © 2004 Massachusetts Medical Society. All rights reserved.

Figure 2. Localization of a radiolabeled, tumor-specific monoclonal antibody against a CNS glioma

A monoclonal antibody, ch806, which recognizes a tumor-specific mutation in the epidermal growth factor receptor (EGFRvIII) was radiolabeled with Indium-111 and infused into a patient with an anaplastic astrocytoma. A–C all depict gamma camera images of the head, with A representing day 0 of infusion, B representing day 3, and C representing day 7 after infusion. Over time, increased radioactivity at the right temporal tumor site can be seen. Black arrowhead in B illustrates the first visualization of radiolabeled antibody at the tumor site. D is SPECT imaging that demonstrates antibody uptake at the right temporal tumor site. E demonstrates tumor localization with FDG-PET, and F is an axial MRI slice at the equivalent level that demonstrates that the right temporal tumor is in the same location as the antibody uptake. White arrowheads in D–F point to the tumor region. From Scott AM, Lee FT, Tebbutt N, et al. A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors. Proc Natl Acad Sci U S A. Mar 6 2007;104(10):4073, with permission. Copyright 2007 National Academy of Sciences, U.S.A.

Figure 3. Depiction of wild-type EGFR and the formation of EGFRvIII

Drawing illustrates the 801 base pair region that is deleted to form EGFRvIII. The inframe deletion occurs in the extracellular portion of the protein, and at the fusion site a novel glycine amino acid codon is created. The peptide used for vaccination studies, PEPvIII, is the 13 amino acid sequence that spans across this fusion region, which contains a tumor-specific epitope including the novel glycine, and is linked to a terminal cysteine which permits conjugation of the peptide to the adjuvant KLH molecule. Reprinted from Semin Immunol, 20(5), Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Bigner DD, Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma, page 268, copyright 2008, with permission from Elsevier.