Dovepress Rindopepimut for the treatment of glioblastoma AAs 1 to 621 (extracellular domain) AAs 622 to 644 (trans-membrane domain) AAs 645 to 1186 (intracellular domain) Ligand binding domain Tyrosine phosphorylation sites Deletion of AAs 6 to 273 Novel glycine residue Wild-type EGFR EGFRvIII Figure 1 Schematic showing a deletion of amino acids 6 to 273 and an insertion of a novel glycine residue in the extracellular domain of wild-type EGFR, forming EGFRvIII. Abbreviations: EGFR, epidermal growth factor receptor; vIII, variant III. ligand-independent mutant enhances tumorigenicity, tumor cell migration, and resistance to chemoradiotherapy.22–27 As it is not expressed on normal cells, EGFRvIII is an effective target for immunotherapies.10,14 One such therapy is rindopepimut (PEPvIII-KLH; CDX-110; Celldex Therapeutics, Phillipsburg, NJ), an EGFRvIII-specific, 14-mer peptide which when coupled with keyhole limpet hemocyanin (KLH) elicits humoral and cellular immune responses.28,29 Currently, rindopepimut is undergoing clinical testing in a Phase III trial for newly diagnosed GBM (NCT01480479), a Phase II trial with granulocyte- macrophage colony-stimulating factor (GM-CSF) for relapsed GBM (NCT01498328), and a Phase I trial for use in children with diffuse intrinsic pontine gliomas (NCT01058850). This review summarizes the current evidence for the use of rindopepimut in GBM. Barriers to immunotherapy for brain tumors For immunotherapies to initiate immune responses, CD4+ (helper) and CD8+ (cytotoxic) T cells must be activated by the recognition of antigens on the class I or II major histocompat- ibility complexes (MHCs) found on antigen-presenting cells (APCs).30 However, full activation only occurs following a co-stimulatory signal between T cells and APCs. The absence of this signal, which is necessary for T cell proliferation and differentiation, results in anergy or cell death. Several challenges are present for the use of immunotherapy for intracerebral tumors. Firstly, the brain is considered to be Core Evidence 2012:7 immunologically isolated compared to other organs. This was suggested by studies showing that intracranially implanted tissue grafts in animals did not result in rejection.31 This is thought to be due to the absence of lymphatic architecture, the presence of the blood–brain barrier (BBB), and paucity of APCs within the brain.32,33 However, more recent studies have shown that the brain is not as isolated as previously thought. While there are no draining lymph nodes in the brain, antigens within the central nervous system (CNS) can drain in the cerebrospinal fluid (CSF) through Virchow–Robin spaces to cervical and nasal lymph nodes.34–36 Also though the BBB was thought to limit leukocyte movement into the CNS, numerous studies have demonstrated lymphocyte BBB penetration.37–39 Activated T cells highly express molecules such as leukocyte- function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) which allow for their migration across the BBB.40–42 The production of inflammatory mediators by the peripheral immune system can also increase the permeability of the BBB, allowing for activated macrophages and dendritic cells (DCs) to enter the CNS. Other mechanisms of leukocyte entry into the CNS include transmigration via transient pore-like structures within the endothelial cells of the BBB, and extravasation across the fenestrated endothelium of the choroid plexuses.43–46 Additionally, BBB composition has been shown to vary between different brain regions, resulting in various degrees of cellular immune surveillance.47 Finally, while there is not an abundance of APCs within the CNS, macrophages, DCs, and microglia can act as effective APCs to stimulate T-cell responses.48–50 As studies have demonstrated submit your manuscript | www.dovepress.com Dovepress 95