Abstract
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. Despite significant efforts, no therapies have demonstrated valuable survival benefit beyond the current standard of care. Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape and improved patient survival in many advanced malignancies. Unfortunately, these clinical successes have not been replicated in the neuro-oncology field so far. This review summarizes the status of ICI investigation in high-grade gliomas, critically presenting the available data from preclinical models and clinical trials. Moreover, we explore new approaches to increase ICI efficacy, with a particular focus on combinatorial strategies, and the potential biomarkers to identify patients most likely to benefit from immune checkpoint blockade.
Highlights
Given these encouraging preclinical results and durable responses observed in brain metastases from other cancer types, such as melanoma and lung carcinoma, an intensive clinical investigation has been undertaken to explore the potential effectiveness of immune checkpoint modulation as a treatment strategy for GBM patients
Other two small early-phase trials demonstrated the safety of adding programmed death-ligand 1 (PD-L1) blockade to the standard of care (SOC) in newly diagnosed GBM
Preliminary results of the Checkmate 143 mentioned above led to the opening of a large randomized open-label phase III study directly comparing the efficacy and safety of nivolumab monotherapy versus the anti-vascular endothelial growth factor A (VEGF-A) monoclonal antibodies (mAb) bevacizumab in GBM patients at first recurrence after standard chemoradiation
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Neutrophils are the most prevalent immune population, comprising up to 70% of total leukocytes in the body In glioma, they support progression, invasiveness, and angiogenesis through the secretion of elastase and metalloproteases. TAMs expressing T-cell immunoglobulin and mucin domain-containing molecule-4 and DCs producing indoleamine 2,3 dioxygenase (IDO) play a direct role in Tregs induction. Approval of ipilimumab (anti-CTLA-4 mAb) in 2011, PD-1 inhibitors nivolumab, pembrolizumab, cemiplimab, and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab have entered clinical use. These remarkable successes have raised great expectations in whether these agents could be such effective in the context of neuro-oncology, and an intensive clinical investigation has been undertaken. We will further discuss the current landscape of biomarkers and potential novel insights to be explored to raise the bar beyond current disappointing results and make significant progress in this field
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