Babu and Adamson Limitations While rindopepimut is efficacious and safe for the treatment of GBM, there are several limitations. Firstly, as EGFRvIII is only expressed in a small number of GBMs (∼20%–30%), rindopepimut cannot be used to treat the majority of GBM cases. Therefore, immunotherapy directed toward other tumor-specific targets such as cytomegalovirus antigens may allow for more widespread use. Rindopepimut also has limited utility for the continued treatment of cases with tumor recurrence despite vaccine therapy as most of these tumors lose EGFRvIII expression. Additionally, the performed clinical trials have had several shortcomings. Firstly, all patients did not receive salvage therapy uniformly for tumor progression as the use of additional agents was the discretion of the patient’s neurooncologist. This may introduce bias by affecting OS. The presence of isocitrate dehydrogenase 1/2 (IDH1/2) mutations was not determined in enrolled patients. These mutations which occur most commonly in secondary GBMs significantly predict survival and may confer a survival advantage.96–98 As a result, an overrepresentation of these mutations in the study cohort may artificially improve OS compared to historical controls. However, as EGFRvIII is rarely expressed in secondary GBMs, the effect of IDH1/2 mutations is likely minor as the ACTIVATE, ACTII, and ACTIII trials only enrolled patients with EGFRvIII-expressing tumors. In addition to the small sample sizes in the current studies, only patients with a high performance status and those not having evidence of disease progression following chemoradiotherapy were enrolled. These inclusion criteria result in the selection of patients having an overall better prognosis and thus introduce significant selection bias. Also, all patients underwent image verified gross total resections. This was intended to minimize the immunosuppressive effects of the tumor mass. As a significant percentage of GBM patients do not receive gross total resection, the efficacy of rindopepimut in these cases in unclear. The use of inhibitors to negate the effects of various immunosuppressive cascades such as the signal translation and activator of transcription-3 pathway may improve the efficacy of rindopepimut in cases with significant residual disease. Conclusion Rindopepimut (PEPvIII-KLH/CDX-110) is an effective EGFRvIII-targeted immunotherapy which appeared to improve PFS and OS in Phase I and II clinical trials for patients with EGFRvIII-expressing GBMs. Serious adverse reactions are rare, with patients typically only experiencing 100 submit your manuscript | www.dovepress.com Dovepress Dovepress hypersensitivity reactions at the injection site. Currently, a Phase II trial for relapsed GBM and a Phase III trial for newly diagnosed cases are ongoing and will provide additional data regarding the efficacy of rindopepimut in the near future. While rindopepimut has limitations, it is a promising therapy for patients with EGFRvIII-expressing GBMs and significantly adds to our arsenal for combating this aggressive disease. There remains a paucity of approved immunotherapies in oncology (therapeutic one for prostate cancer and preventive one for cervical cancer), but we are optimistic that studies on therapies like rindopepimut will identify therapies that will prove efficacious in the general population. Disclosure The authors have no financial or institutional interest in any of the drugs, materials, or devices described in this article, or any other type of conflict of interest. References 1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–996. 2. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13(4):1253–1259. 3. Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999;17(8):2572–2578. 4. Narayana A, Gruber D, Kunnakkat S, et al. A clinical trial of bevacizumab, temozolomide, and radiation for newly diagnosed glioblastoma. J Neurosurg. 2012;116(2):341–345. 5. Imperato JP, Paleologos NA, Vick NA. Effects of treatment on long- term survivors with malignant astrocytomas. Ann Neurol. 1990;28(6): 818–822. 6. Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature. 2001;411(6835):380–384. 7. Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. J Clin Oncol. 2011;29(36):4828–4836. 8. Heimberger AB, Hlatky R, Suki D, et al. Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin Cancer Res. 2005;11(4):1462–1466. 9. Wong AJ, Ruppert JM, Bigner SH, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A. 1992;89(7):2965–2969. 10. Wikstrand CJ, Hale LP, Batra SK, et al. Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas. Cancer Res. 1995;55(14): 3140–3148. 11. Sok JC, Coppelli FM, Thomas SM, et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res. 2006;12(17): 5064–5073. 12. Humphrey PA, Wong AJ, Vogelstein B, et al. Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci U S A. 1990;87(11):4207–4211. 13. Okamoto I, Kenyon LC, Emlet DR, et al. Expression of constitutively activated EGFRvIII in non-small cell lung cancer. Cancer Sci. 2003; 94(1):50–56. Core Evidence 2012:7