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

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 and Patrick Y. Wen ()
Additional contact information
J. Ricardo McFaline-Figueroa: Dana-Farber Cancer Institute
Lu Sun: University of California Los Angeles
Gilbert C. Youssef: Dana-Farber Cancer Institute
Raymond Huang: Harvard Medical School
Gang Li: University of California Los Angeles
Jiyoon Kim: University of California Los Angeles
Eudocia Q. Lee: Dana-Farber Cancer Institute
Lakshmi Nayak: Dana-Farber Cancer Institute
Ugonma Chukwueke: Dana-Farber Cancer Institute
Rameen Beroukhim: Dana-Farber Cancer Institute
Tracy T. Batchelor: Dana-Farber Cancer Institute
E. Antonio Chiocca: Harvard Medical School
Richard G. Everson: University of California Los Angeles
Lisa Doherty: Dana-Farber Cancer Institute
Jennifer Stefanik: Dana-Farber Cancer Institute
Kathryn Partridge: Dana-Farber Cancer Institute
Amanda Spearman: Dana-Farber Cancer Institute
Alexa Myers: Dana-Farber Cancer Institute
Catharina Westergaard: Dana-Farber Cancer Institute
Alyssa Russ: Dana-Farber Cancer Institute
Maria Lavallee: Dana-Farber Cancer Institute
Anna Smokovich: Dana-Farber Cancer Institute
Corey LaForest-Roys: Dana-Farber Cancer Institute
Rachel Garcia Fox: Dana-Farber Cancer Institute
Christine McCluskey: Dana-Farber Cancer Institute
Wenya Linda Bi: Harvard Medical School
Omar Arnaout: Harvard Medical School
PierPaolo Peruzzi: Harvard Medical School
G. Rees Cosgrove: Harvard Medical School
Keith L. Ligon: Harvard Medical School
Isabel Arrillaga-Romany: Harvard Medical School
Jennifer L. Clarke: University of California San Francisco
David A. Reardon: Dana-Farber Cancer Institute
Timothy F. Cloughesy: University of California Los Angeles
Robert M. Prins: University of California Los Angeles
Patrick Y. Wen: Dana-Farber Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54326-7

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