Prospect of rindopepimut in the treatment of glioblastoma

Abstract

Introduction Rindopepimut (CDX-110) is a peptide vaccine that targets epidermal growth factor receptor variant III (EGFRvIII), a tumor-specific epitope expressed in the most common and lethal primary malignant neoplasm of the brain – glioblastoma (GBM). Areas covered The EGFRvIII mutation introduces an 801 base pair in-frame deletion of the extracellular domain of the transmembrane tyrosine kinase, resulting in constitutive kinase activity, amplification of cell growth, and inhibition of apoptosis. Rindopepimut contains a 14mer amino acid peptide spanning the EGFRvIII mutation site that is conjugated to keyhole limpet hemocyanin (KLH). The EGFRvIII neoantigen is exclusively present on GBM cells, providing rindopepimut tumor-specific activity. The authors review rindopepimut’s clinical efficacy, administration, safety, and prospects in the treatment of GBM. Expert opinion Rindopepimut showed clinical benefit and significant efficacy in phase II clinical trials, including as part of a multi-immunotherapy approach. A phase III clinical trial was terminated early, however, as it was deemed likely the study would fail to meet its primary endpoint. Longer term and sub-group analyses will be necessary to better understand rindopepimut’s future role in GBM therapy.

Single-cell RNA-seq reveals that glioblastoma recapitulates normal brain development

“…More recently, it has been shown that multiple subtypes coexist in different regions 20 and different cells 12 within the same tumour. This interpatient and intratumoural heterogeneity poses a daunting challenge for research programs aimed at developing targeted therapeutic approaches 21 and may explain the failures of such approaches in this disease.…”

Recurrent Malignant Gliomas: Treatment Options and Their Effect on Patient's Quality of Life

“…blood-brain barrier (12). Bev is a humanized monoclonal antibody directed against VEGF that effects dramatic radiographic responses, improved quality of life, decreased dependence on oral steroids, and improved PFS (12).…”

“…Second line chemotherapy is generally in the form of an alkylating agent such as lomustine, or an anti-angiogenic agent such as bevacizumab (Bev) that is FDA approved for this purpose (8)(9)(10)(11)(12). Vascular endothelial growth factor-A (VEGF-A) is a regulator of angiogenesis and the prime driver of endothelial proliferation, a hallmark of GBM.…”

Impact of Immunotherapy in the Treatment of Glioblastoma

“…Such vaccination resulted in prolonged progressionfree and overall survival (OS) with no safety concerns. However, a phase III CT (ACT IV (NCT01480479)) with rindopepimut was discontinued since the study failed to meet its primary OS endpoint [7,17,18]. Another example is a live attenuated Listeria-based vaccine (ADU-623) expressing both EGFRvIII and NY-ESO-1 antigens, which is currently being tested in patients with recurrent GBM through a phase I CT (NCT01967758) [11,18].…”