Author(s): Martha R Neagu aff1 , David A Reardon [*] aff1
bevacizumab; epidermal growth factor receptor variant III; glioblastoma; rindopepimut; vaccine
Glioblastoma (GBM), the most common malignant primary tumor in adults, carries a dismal prognosis. Median overall survival (OS) following currently available standard therapy for newly diagnosed patients, which includes maximal safe resection followed by fractionated radiotherapy plus concurrent and adjuvant temozolomide is under 15 months [1 ] and has failed to improve despite recently reported randomized Phase III studies evaluating dose dense temozolomide [2 ], VEGF blockade [3,4 ] and anti-integrin therapy [5 ]. Effective therapy for patients following recurrence has been even more problematic. Although the genetic complexity of GBM tumors has recently been elegantly articulated [6,7 ], exploitation of this information using targeted molecular therapeutics in multiple clinical studies has been uniformly disappointing to date [ 8 ]. Furthermore, although GBM tumors are highly angiogenic and express high levels of VEGF; VEGF targeting therapeutics such as bevacizumab have modestly improved progression-free survival at best for recurrent patients [ 9 ]. Therapeutics capable of improving OS for GBM have remained elusive, underscoring the critical need for innovative treatment approaches for this major unmet need in oncology.
A variety of immunotherapy approaches, including cancer vaccines, immune checkpoint blockade and chimeric antigen receptor T cells, have recently demonstrated exciting benefit across a spectrum of cancers. Nonetheless, the role of these agents for GBM patients remains undefined [10 ]. Furthermore, many speculate that immunotherapies are unlikely to be of value for GBM patients based on historical dogma supporting immunoprivilege of the CNS. Despite this bias, growing data argues against the concept of CNS immunosanctity, and in fact demonstrates that a dynamic and effective interaction exists between the CNS and systemic immune systems. Accordingly, a wide array of immune-based therapies is currently under clinical evaluation for GBM patients.
The most advanced immunotherapeutic in the clinical arena for GBM patients is rindopepimut, a peptide vaccine targeting EGFRvIII. In contrast to early GBM vaccines utilizing either whole tumor lysate or tumor-associated antigen (TAA) cocktail approaches, rindopepimut was developed to attack EGFRvIII, a target that is exquisitely tumor specific. EGFRvIII is present in approximately 30% of GBM tumors and can be readily detected by available immunohistochemistry or RT-PCR assays. EGFRvIII results from an in-frame deletion of exons 2-7 that leads to the physical approximation of two normally separated portions of the EGFR protein [11 ]. EGFRvIII is ligand-independent and constitutively activated, and confers a poor prognosis among GBM patients in some studies [12 ]. Recognition of EGFRvIII as an ideal tumor-specific antigen inspired the development of EGFRvIII targeting immunotherapeutics including rindopepimut and more recently EGFRvIII-targeting chimeric antigen receptors for GBM patients (clinical trials: NCT02209376 and NCT01454596). Rindopepimut consists of 13 amino acids that span the in-frame EGFRvIII mutation and is covalently linked to the immunoadjuvant keyhole limpet hemocyanin (KLH) plus coadministered GM-CSF to enhance immunogenicity. It was initially developed in the laboratory of John Sampson, MD, PhD, following preclinical studies demonstrating safety and efficacy of an EGFRvIII-specific vaccine...