Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma

By T. Cloughesy, A. Mochizuki, J. Orpilla, Willy Hugo, Alexander H. Lee, T. Davidson, Anthony C. Wang, B. Ellingson, J. Rytlewski, C. Sanders and 20 more. Nature Medicine, 2018

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Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell– and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor. Neoadjuvant pembrolizumab promotes a survival benefit with intratumoral and systemic immune responses in patients with recurrent glioblastoma.

Subfields: Genetics, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/645cd65285e90fb7cccb19bae79f72a1355f281f

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Citations in the corpus

Neoadjuvant checkpoint blockade for cancer immunotherapy (2020, methodology): “Similarly, a randomized trial of neoadjuvant versus adjuvant anti–PD-1 (pembrolizumab) in recurrent glioblastoma showed significantly improved RFS and OS in the neoadjuvant group, whose resection specimens were characterized by enhanced IFN-g–related gene expression profiles and PD-L1 expression and”
Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “…research has discovered that tumors maintain a state of T cell exhaustion through PD1 signaling, blocking the PD-1 signaling pathway restores or reverses the activity and immune function of exhausted T cells to some extent, enhancing the effectiveness of cancer immunotherapy [77, 166, 167].”