Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort
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.
Authors
- G. Rees Cosgrove (ORCID: https://orcid.org/0000-0002-6220-5752)
- Lisa Doherty
- Keith Lloyd Ligon (ORCID: https://orcid.org/0000-0002-7733-600X)
- Robert Michael Prins (ORCID: https://orcid.org/0000-0002-6282-6583)
- Pierpaolo Peruzzi (ORCID: https://orcid.org/0000-0001-5034-2963)
- Maria Lavallee
- Richard G. Everson (ORCID: https://orcid.org/0000-0003-2809-3061)
- Kathryn Partridge
- Patrick Yung Wen (ORCID: https://orcid.org/0000-0002-0774-7700)
- Isabel Arrillaga‐Romany (ORCID: https://orcid.org/0000-0001-5951-1225)
- J Ricardo McFaline-Figueroa (ORCID: https://orcid.org/0000-0002-6670-1841)
- E. Antonio Chiocca (ORCID: https://orcid.org/0000-0001-5183-1670)
- Rameen Beroukhim (ORCID: https://orcid.org/0000-0001-6303-3609)
- Omar Arnaout (ORCID: https://orcid.org/0000-0003-3890-8615)
- Wenya Linda Bi (ORCID: https://orcid.org/0000-0002-4635-0247)
- Corey LaForest-Roys
- Jennifer Clarke (ORCID: https://orcid.org/0000-0002-8054-7342)
- Gehad Youssef (ORCID: https://orcid.org/0000-0002-9998-1384)
- Anna Smokovich
- Ugonma Nnenna Chukwueke (ORCID: https://orcid.org/0000-0003-0598-9535)
- Alyssa Russ (ORCID: https://orcid.org/0000-0002-6353-139X)
- David A. Reardon (ORCID: https://orcid.org/0000-0001-6674-0157)
- Alexa Myers
- Timothy F. Cloughesy (ORCID: https://orcid.org/0000-0002-8656-7483)
- Raymond Y. Huang (ORCID: https://orcid.org/0000-0001-7661-797X)
- Tracy T. Batchelor (ORCID: https://orcid.org/0000-0001-7568-6607)
- Lakshmi Nayak
- Amanda Spearman
- Eudocia Q. Lee
- Jennifer Stefanik
- Gang Li (ORCID: https://orcid.org/0000-0002-4753-9420)
- Lu Sun (ORCID: https://orcid.org/0000-0002-6592-1156)
- Jiyoon Kim (ORCID: https://orcid.org/0000-0002-9816-5940)
- Catharina Westergaard
- Christine McCluskey (ORCID: https://orcid.org/0000-0001-5610-8115)
- Rachel Garcia Fox
Institutions
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of California, Los Angeles (US)
- University of California, San Francisco (US)
- NYU Langone Health (US)
- Massachusetts General Hospital (US)
- Center for Neuro-Oncology (US)
- Parker Institute for Cancer Immunotherapy (US)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Harvard Cancer Center (US)
- Neurological Surgery (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-30
- DOI
- https://doi.org/10.1038/s41467-024-54326-7
- Citations
- 26
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 11.39
Funders
- National Brain Tumor Society
- Musella Foundation For Brain Tumor Research and Information
- Ben and Catherine Ivy Foundation
- Ziering Family Foundation
- Parker Institute for Cancer Immunotherapy
- National Institutes of Health
- National Cancer Institute