Abstract
Glioblastoma (GBM) is the most common, and aggressive, primary brain tumor in adults. With a median patient survival of less than two years, GBM represents one of the biggest therapeutic challenges of the modern era. Even with the best available treatment, recurrence rates are nearly 100% and therapeutic options at the time of relapse are extremely limited. Nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody, has provided significant clinical benefits in the treatment of various advanced cancers and represented a promising therapy for primary and recurrent GBM. CheckMate 143 (NCT 02017717) was the first large randomized clinical trial of PD pathway inhibition in the setting of GBM, including a comparison of nivolumab and the anti-VEGF antibody, bevacizumab, in the treatment of recurrent disease. However, preliminary results, recently announced in a WFNOS 2017 abstract, demonstrated a failure of nivolumab to prolong overall survival of patients with recurrent GBM, and this arm of the trial was prematurely closed. In this review, we discuss the basic concepts underlying the rational to target PD pathway in GBM, address implications of using immune checkpoint inhibitors in central nervous system malignancies, provide a rationale for possible reasons contributing to the failure of nivolumab to prolong survival in patients with recurrent disease, and analyze the future role of immune checkpoint inhibitors in the treatment of GBM.
Highlights
Glioblastoma (GBM) is the most commonly diagnosed primary brain tumor in adults
We discuss the basic concepts underlying the rational to target programmed cell death (PD) pathway in GBM, address implications of using immune checkpoint inhibitors in central nervous system malignancies, provide a rationale for possible reasons contributing to the failure of nivolumab to prolong survival in patients with recurrent disease, and analyze the future role of immune checkpoint inhibitors in the treatment of GBM
Tumors are further protected by the blood brain barrier (BBB), a semipermeable membrane of endothelial cells connected by tight junctions, which prevents the passage of most conventional drugs to tumor sites [3, 4]
Summary
Glioblastoma (GBM) is the most commonly diagnosed primary brain tumor in adults These tumors are highly aggressive and the prognosis for patients is extremely poor, with median overall survival of 14.6 months and 5-year survival rates less than 10% following standard of care treatment [1, 2]. In phase III clinical trials, anti-PD pathway therapies have produced substantial clinical responses in a subset of patients with variety of cancers [9,10,11,12, 54,55,56], culminating in FDA approval of two immune checkpoint inhibitors, pembrolizumab and nivolumab, both anti-PD-1 monoclonal antibodies, in the treatment of unresectable or metastatic melanoma (pembrolizumab and nivolumab) and NSCLC (nivolumab) [57, 58]. Irradiation (HFSRT) Pembrolizumab, 46* With Pembrolizumab bevacizumab, and Bevacizumab for hfSRT
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