A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study

Autor: Thomas A. Davis, David A. Reardon, John H. Sampson, Nina Paleologos, Darell D. Bigner, James M. Schuster, Morris D. Groves, Lawrence Recht, Gary E. Archer, Randy L. Jensen, Scott Cruickshank, Amy B. Heimberger, Maciej M. Mrugala, Jennifer Green, Joachim M. Baehring, Andrew E. Sloan, Rose Lai, Tibor Keler
Rok vydání: 2015
Předmět:
Zdroj: Neuro-Oncology. 17:854-861
ISSN: 1523-5866
1522-8517
Popis: The epidermal growth factor receptor variant III deletion mutation, EGFRvIII, results in a constitutively activated receptor with a novel, highly immunogenic extracelluar epitope. EGFRvIII is present in 25%–30% of glioblastomas1 but is not significantly expressed in healthy tissue. Expression of EGFRvIII correlates with increased tumorigenicity in mouse models.2 In glioblastoma, EGFRvIII has been associated with poor long-term survival, independent of other known significant prognostic factors, such as gross total resection (GTR).3–6 EGFRvIII expression is often heterogeneous in glioblastoma specimens, but EGFRvIII+ cells may influence neighboring EGFRvIII–tumor cells through cytokines and microvesicles, providing a proliferative signal even to nonexpressing cells.7–9 EGFRvIII is also frequently expressed in glioblastoma tumor stem cells.10,11 EGFRvIII and isocitrate dehydrogenase (IDH) 1/2 mutations, the latter associated with long-term survival, rarely coexist in the same patient.12,13 Rindopepimut vaccine consists of the unique 13 amino acid sequence created by the in-frame deletion of EGFRvIII, chemically conjugated to keyhole limpet hemocyanin (KLH) as described by Heimberger and colleagues.14 Rindopepimut is designed to generate a specific immune response against EGFRvIII+ tumor cells, an approach which may be particularly relevant for glioblastoma, where diffuse infiltration of tumor into healthy white matter presents a treatment challenge. Preclinical models have demonstrated that induction of humoral and cellular anti-EGFRvIII immune responses can be effective against EGFRvIII+ intracranial tumors.14 In 2 small single-arm phase II trials conducted at MD Anderson and Duke University (“ACTIVATE” and “ACT II”),6,15 rindopepimut was well tolerated in patients with resected, EGFRvIII+ glioblastoma with promising progression-free survival (PFS) and overall survival (OS) compared with a contemporary cohort of patients matched for major study eligibility. In addition, the vaccine elicited robust anti-EGFRvIII immune responses despite concurrent temozolomide chemotherapy, and EGFRvIII was routinely eliminated in posttreatment tumor samples obtained at recurrence. The current study (“ACT III”) was performed to confirm these results in a larger, multicenter trial.
Databáze: OpenAIRE
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