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Nat Med. 2019 Mar;25(3):477-486. doi: 10.1038/s41591-018-0337-7. Epub 2019 Feb 11.

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

Author information

1
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. tcloughesy@mednet.ucla.edu.
2
Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. tcloughesy@mednet.ucla.edu.
3
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA. tcloughesy@mednet.ucla.edu.
4
Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
5
Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
6
Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
7
Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
8
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA.
9
Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
10
Adaptive Biotechnologies, Seattle, WA, USA.
11
Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA.
12
Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
13
Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
14
Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
15
Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
16
Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
17
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
18
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
19
Department of Neurology, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
20
Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. rprins@mednet.ucla.edu.
21
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA. rprins@mednet.ucla.edu.
22
Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. rprins@mednet.ucla.edu.
23
Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. rprins@mednet.ucla.edu.

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.

PMID:
30742122
PMCID:
PMC6408961
DOI:
10.1038/s41591-018-0337-7
[Indexed for MEDLINE]
Free PMC Article

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