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; Patrick Y Wen

doi:10.1038/s41467-024-54326-7

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

Nat Commun. 2024 Dec 30;15(1):10757. doi: 10.1038/s41467-024-54326-7.

Authors

J Ricardo McFaline-Figueroa^#^{1

2}, Lu Sun^#³, Gilbert C Youssef^{1

4}, Raymond Huang⁵, Gang Li⁶, Jiyoon Kim⁶, Eudocia Q Lee^{1

4}, Lakshmi Nayak^{1

4}, Ugonma Chukwueke^{1

4}, Rameen Beroukhim¹, Tracy T Batchelor^{1

4}, E Antonio Chiocca⁷, Richard G Everson^{3

8}, Lisa Doherty¹, Jennifer Stefanik¹, Kathryn Partridge¹, Amanda Spearman¹, Alexa Myers¹, Catharina Westergaard¹, Alyssa Russ¹, Maria Lavallee¹, Anna Smokovich¹, Corey LaForest-Roys¹, Rachel Garcia Fox¹, Christine McCluskey¹, Wenya Linda Bi⁷, Omar Arnaout⁷, PierPaolo Peruzzi⁷, G Rees Cosgrove⁷, Keith L Ligon⁹, Isabel Arrillaga-Romany¹⁰, Jennifer L Clarke¹¹, David A Reardon¹, Timothy F Cloughesy^{8

12

13}, Robert M Prins^{3

8

13

14}, Patrick Y Wen^{15

16}

Affiliations

¹ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Brain & Spine Tumor Center, Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
³ Department of Neurosurgery, University of California Los Angeles, Los Angeles, CA, USA.
⁴ Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Biostatistics, Jonathan and Karin Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USA.
⁷ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.
⁹ Division of Neuropathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ Division of Neuro-Oncology, Mass General Cancer Center, Harvard Medical School, Boston, MA, USA.
¹¹ Departments of Neurology and Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
¹² Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
¹³ Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
¹⁴ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
¹⁵ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
¹⁶ Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].

^# Contributed equally.

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.

Publication types

Clinical Trial, Phase I

MeSH terms

Adult
Aged
Antibodies, Monoclonal, Humanized* / therapeutic use
Brain Neoplasms* / drug therapy
Brain Neoplasms* / genetics
Brain Neoplasms* / immunology
Brain Neoplasms* / pathology
Cohort Studies
Female
Gene Expression Regulation, Neoplastic
Glioblastoma* / drug therapy
Glioblastoma* / genetics
Glioblastoma* / immunology
Glioblastoma* / pathology
Humans
Immune Checkpoint Inhibitors* / therapeutic use
Immunotherapy / methods
Male
Middle Aged
Neoadjuvant Therapy* / methods
Neoplasm Recurrence, Local*
Programmed Cell Death 1 Receptor* / antagonists & inhibitors
Programmed Cell Death 1 Receptor* / metabolism
Treatment Outcome

Substances

Antibodies, Monoclonal, Humanized
Immune Checkpoint Inhibitors
PDCD1 protein, human
pembrolizumab
Programmed Cell Death 1 Receptor