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Cited by 1,382Glioma Diagnosis and TreatmentCancer Immunotherapy and BiomarkersFerroptosis and cancer prognosis

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

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Cloughesy, Timothy F., Mochizuki, Aaron Y., Orpilla, Joey R., Hugo, Willy, Lee, Alexander H., Davidson, Tom B., Wang, Anthony C., Ellingson, Benjamin M. +22 more·2019·Nature Medicine
DOI 10.1038/s41591-018-0337-7PMC PMC6408961
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Abstract

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.

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  • ICB, especially targeting PD-1 expressed on CD8+ T cells, is a highly effective immunotherapy for various cancers.

    “Immune checkpoint blockade (ICB), especially targeting the inhibitory receptor programmed cell death 1 (PD-1) expressed on CD8+ T cells, is a highly effective immunotherapy for various cancers.”

    From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [1]

    The Introduction (page unavailable) says PD-1 blockade has yielded promising results in metastatic cancer and that pembrolizumab has demonstrated benefit in multiple cancer types. It does not characterize the treatment as highly effective across various cancers; the Introduction also notes limited efficacy in glioblastoma. The paper discusses CD8+ T cells, but the cited passages do not directly establish the claim that PD-1 is expressed on them. (LLM, conf=0.84)

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Authors
Cloughesy, T. F., Mochizuki, A. Y., Orpilla, J. R., Hugo, W., Lee, A. H., Davidson, T. B., Wang, A. C., Ellingson, B. M., Rytlewski, J. A., Sanders, C. M., Kawaguchi, E. S., Du, L., Li, G., Yong, W. H., Gaffey, S. C., Cohen, A. L., Mellinghoff, I. K., Lee, E. Q., Reardon, D. A., O’Brien, B. J., Butowski, N. A., Nghiemphu, P. L., Clarke, J. L., Arrillaga-Romany, I. C., Colman, H., Kaley, T. J., de Groot, J. F., Liau, L. M., Wen, P. Y., & Prins, R. M.
Affiliations
  • University of California, Los Angeles (US)
  • Adaptive Biotechnologies (United States) (US)
  • Center for Neuro-Oncology (US)
  • University of Utah (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • University of California, San Francisco (US)
Corresponding author
  • Cloughesy, Timothy F.
  • Prins, Robert M.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2019-02-11
Volume
25
Issue
3
Pages
477-486
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-018-0337-7
PMC
PMC6408961
OpenAlex
W2911752971
Cited by
1,382
References
11
Citations by year
2026: 118 · 2025: 147 · 2024: 200 · 2023: 245 · 2022: 218 · 2021: 218 · 2020: 169 · 2019: 66 · 2018: 1
FWCI
92.80
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (UL1TR000371)
  • National Cancer Institute (R21CA186004, P30CA008748, P50CA211015, P30CA016672, T32CA009120)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
Keywords
recurrent glioblastoma, neoadjuvant immunotherapy, pembrolizumab, anti-PD-1 therapy, PD-L1 upregulation, tumor microenvironment, intratumoral immune response, systemic immune response, T cell clonal expansion, overall survival, adjuvant therapy
MeSH terms
Antineoplastic Agents, Immunological, Adult, Aged, Brain Neoplasms, Female, Glioblastoma, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, T-Lymphocytes, Survival Rate, Chemotherapy, Adjuvant, Neurosurgical Procedures, Neoadjuvant Therapy, Tumor Microenvironment, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized

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