EGFRvIII vaccine in glioblastoma—InACT-IVe or not ReACTive enough?

Variant III of the epidermal growth factor receptor (EGFRvIII) fulfills many criteria of a suitable target for a glioblastoma vaccine. Unlike many tumor-associated self antigens currently targeted in vaccine trials, it is specifically expressed by tumor cells but not in healthy tissue, thus representing a so-called neoantigen. The in-frame deletion of the extracellular domain in EGFRvIII results in the fusion of exons 1 and 8 and thus generates a peptide sequence encompassing the fusion point, which is foreign to the immune system. EGFRvIII is the most common gain-of-function mutation in glioblastoma shown to contribute to the malignant phenotype by complex cytokine network alterations.¹ Preclinical studies have shown immunogenicity and efficacy in several tumor models.² In the clinical development the vaccine (rindopepimut) has early on been tested in patients with newly diagnosed glioblastoma to ensure low tumor burden and a sufficient time window to achieve a meaningful immune response. The single-arm ACTIVATE, ACT II, and ACT III trials in patients with newly diagnosed, resected, EGFRvIII+ glioblastoma demonstrated a median survival of 20–22 months, comparing favorably to historical matched controls.³