Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort

Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort

Abstract Glioblastoma is immunologically “cold” and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrol...

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Main Authors: J. Ricardo McFaline-Figueroa, Lu Sun, Gilbert C. Youssef, Raymond Huang, Gang Li, Jiyoon Kim, Eudocia Q. Lee, Lakshmi Nayak, Ugonma Chukwueke, Rameen Beroukhim, Tracy T. Batchelor, E. Antonio Chiocca, Richard G. Everson, Lisa Doherty, Jennifer Stefanik, Kathryn Partridge, Amanda Spearman, Alexa Myers, Catharina Westergaard, Alyssa Russ, Maria Lavallee, Anna Smokovich, Corey LaForest-Roys, Rachel Garcia Fox, Christine McCluskey, Wenya Linda Bi, Omar Arnaout, PierPaolo Peruzzi, G. Rees Cosgrove, Keith L. Ligon, Isabel Arrillaga-Romany, Jennifer L. Clarke, David A. Reardon, Timothy F. Cloughesy, Robert M. Prins, Patrick Y. Wen
Format: Article
Language:English
Published: Nature Portfolio 2024-12-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-024-54326-7
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Summary:Abstract Glioblastoma is immunologically “cold” and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we enrolled an additional 25 patients with a primary endpoint of evaluating the cell cycle gene signature associated with neoadjuvant pembrolizumab and performed bulk-RNA seq on resected tumor tissue (NCT02852655). Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent positive risk factor for survival. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not confirm a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma and our secondary endpoint of PFS-6 was 19.5% (95% CI: 9.29-41.2%) for the pooled neoadjuvant cohorts. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively.
ISSN:2041-1723

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