Despite advances in our understanding of glioblastoma multiforme (GBM) tumor pathogenesis, the overall survival of patients has not significantly increased over the past 25 years (median 11.3 months to 14.6 months).1,2 This dismal prognosis is due to the near universal recurrence despite treatment with surgery, radiation, and chemotherapy.3 The major limitation of these conventional modalities is their lack of specificity and inherent morbidities.4 Considering that a number of genes are altered in gliomas, including P53, PTEN, CDKN2A, and EGFR,5-11 as well as the fact that a number of allelic losses and alterations have been shown to be predictive of outcome and treatment response,5-12 immunotherapy centered at tumor-specific mutations holds the promise of more precise tumor treatment. To this end, investigations have focused on neoplasm directed vaccines.14-19
A mutation in epidermal growth factor receptor is expressed in one third of GBMs.11,20 This mutation is the result in a frame deletion and produces a novel glycine at the fusion junction encoding a protein with a constitutively active tyrosine kinase.21 This results in increased tumor cell migration, resistance to radiation and chemotherapeutic agents, and is an overall negative prognostic indicator.17,22-26
On the basis of preclinical data supporting the possible benefit of EGFR targeted vaccines,27,28 a phase II study was recently completed by Sampson et al in patients with newly diagnosed GBM.29 Eligible patients for this multicenter, prospective trial included adults with EGFRvIII-positive GBM and a Karnofsky performance status (KPS) greater than 80 who underwent a gross total resection and demonstrated no radiographic evidence of progression after external beam radiation therapy and concurrent temozolomide (TMZ). The results were as follows. Toxicity to the intradermal vaccine was minimal. The median progression-free survival (PFS) from time of histologic diagnosis for the 18 patients receiving the vaccine was 14.2 months as compared to 6.3 months in the 17 patients within the matched cohort. The PFS hazard ratio (HR) comparing the matched cohort with patients receiving the vaccine patients was 2.4. After adjustment for age and KPS, the PFS of vaccinated patients remained significantly greater than that observed in the matched control group. Similarly, overall survival (OS) was greater in patients receiving the vaccine, and after adjustment for age and KPS, the survival of vaccinated patients was significantly better than that observed in the matched control group (HR = 5.1). Notably, in patients who received the vaccine and eventual reoperation for recurrence, reoperative pathology revealed that 82% had lost EGFRvIII expression. In addition, 14 patients had serum samples demonstrating an EGFRvIII-specific humoral response. This subset of patients with a humoral response lived significantly longer than those that did not.
A possible bias in the study was presence of MGMT methylation, which compromises DNA repair and is associated with longer survival in GBM patients receiving alkylating agents such as TMZ.30 Surprisingly, however, the PFS and OS were unexpectedly longer in vaccinated patients with unmethylated MGMT. Moreover, in multivariate analysis after adjusting for age and KPS, patients with unmethylated MGMT had a significantly longer PFS from vaccination and histologic diagnosis than patients with methylated MGMT who did not receive the vaccine. This is consistent with results from Mural et al who found that EGFR signaling confers resistance to TMZ and predicts a poor outcome after standard therapy.31 Certainly, moving forward a phase III study would need to account for and stratify by MGMT status.
This promising study demonstrates that patients with newly diagnosed EGFRvIII-positive GBM may be safely treated with an EGFR vaccine and achieve immunity against EGFR with the elimination of EGFRvIII-expressing cells at recurrence. This study also suggests that the immunologic privilege of the brain may not be absolute in this context. A limitation of the study is that overall survival may not be significantly different from recent studies using different forms of immunotherapy.14-19 In addition, considering that only one third of patients with GBM express EGFRvIII,11,20 the overall target population is restricted. Moreover, inherent differences in patient characteristics may account for variance in outcomes. Regardless, the findings should provide the impetus for a blinded, placebo-controlled, multicenter, randomized phase III study utilizing multiantigenic vaccines.
Ricardo J. Komotar
Robert M. Starke
E. Sander Connolly
Michael B. Sisti
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