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  • Review Article
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Prospects of immune checkpoint modulators in the treatment of glioblastoma

Nature Reviews Neurology volume 11, pages 504–514 (2015)Cite this article

Subjects

Key Points

  • The prognosis for glioblastoma patients is poor, with median overall survival of approximately 15–17 months

  • Immunotherapy has clinical benefits in other advanced tumours, such as melanoma and lung cancer, for which conventional therapies have had limited success

  • The blood–brain barrier prevents macromolecules from entering the CNS, but readily allows traffic of activated lymphocytes; thus, communication occurs between the CNS and the immune system

  • The success of immunotherapy in other cancers, and the current understanding of the interaction between the brain and the immune system provide a rationale for exploration of immune checkpoint inhibitors in glioblastoma

  • Tumour progression could involve multiple immunosuppressive mechanisms, making combination of immunotherapeutic agents that target different pathways a promising approach

  • Clinical trials evaluating immune checkpoint inhibitors in glioblastoma patients are ongoing

Abstract

Glioblastoma is the most common primary brain tumour in adults. Prognosis is poor: even with the current gold-standard first-line treatment—maximal safe resection and combination of radiotherapy with temozolomide chemotherapy—the median overall survival time is only approximately 15–17 months, because the tumour recurs in virtually all patients, and no commonly accepted standard treatment for recurrent disease exists. Several targeted agents have failed to improve patient outcomes in glioblastoma. Immunotherapy with immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab has provided relevant clinical improvements in other advanced tumours for which conventional therapies have had limited success, making immunotherapy an appealing strategy in glioblastoma. This Review summarizes current knowledge on immune checkpoint modulators and evaluates their potential role in glioblastoma on the basis of preclinical studies and emerging clinical data. Furthermore, we discuss challenges that need to be considered in the clinical development of drugs that target immune checkpoint pathways in glioblastoma, such as specific properties of the immune system in the CNS, issues with radiological response assessment, and potential interactions with established and emerging treatment strategies.

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Figure 1: Overview of the immune response and major immune checkpoint molecules in the immune cycle of glioblastoma.
Figure 2: PDL1 expression and tumour-infiltrating lymphocytes in glioblastoma.

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Acknowledgements

M. Daniels from inScience Communications in Philadelphia, PA, USA, provided editorial support for writing this article, comprising compilation of tables, management of the reference database, and editing of the manuscript text before submission. The editorial support was funded by Bristol-Myers Squibb. D.A.H. has received the National Multiple Sclerosis Society Collaborative Research Centre Award CA1061-A-18, NIH grants P01 AI045757, U19 AI046130, U19 AI070352, and P01 AI039671, and research support from the Nancy Taylor Foundation for Chronic Diseases and the Penates Foundation. J.H.S. has received the NIH grants R01-CA177476-02, R01-NS086943-01, P50-CA190991-01, and 2R25-NS065731-06, and research support from the Accelerate Brain Cancer Cure and Pediatric Brain Tumor Foundation.

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Authors and Affiliations

  1. Department of Medicine I and Comprehensive Cancer Centre CNS Tumours Unit, Medical University of Vienna, Waehringer Guertel 18–20, Vienna, 1090, Austria

    Matthias Preusser

  2. Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, 21287, MD, USA

    Michael Lim

  3. Department of Neurology, Yale School of Medicine, Yale New Haven Hospital, 15 York Street, PO Box 208018, New Haven, 06520, CT, USA

    David A. Hafler

  4. Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana 2134, Boston, 02215, MA, USA

    David A. Reardon

  5. Division of Neurosurgery, 220 Sands Building, Research Drive, Duke University School of Medicine, Durham, 27705, NC, USA

    John H. Sampson

Authors
  1. Matthias Preusser
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  2. Michael Lim
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  3. David A. Hafler
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  4. David A. Reardon
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Contributions

All authors contributed to researching data for the article, substantial contribution to discussing of content, writing, editing and reviewing of the article.

Corresponding author

Correspondence to John H. Sampson.

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Competing interests

M.P. has received honoraria, research support (unrestricted grants), and travel support (to scientific meetings) from Bristol-Myers Squibb, Böhringer-Ingelheim, GlaxoSmithKline, Mundipharma and Roche. M.L. has received research support from Agenus, Arbor Pharmaceuticals, Bristol-Myers Squibb, Celldex Therapeutics, and ImmunoCellular Therapeutics, and has served as a consultant for Bristol-Myers Squibb. D.A.H. has consulted for Allergan Pharmaceuticals, Bristol-Myers Squibb, EMD Serono, Genzyme Sanofi-Aventis, MedImmune, Mylan Pharmaceuticals, Novartis Pharmaceuticals, Questcor and Teva Neuroscience, and has received grant support from Bristol-Myers Squibb. D.A.R. has received financial compensation for participation in advisory boards for Amgen, Cavion, Genentech/Roche, Midatech Pharma, Momenta Pharmaceuticals, Novartis and Stemline Therapeutics, served as a member of speakers' bureaus for Genentech/Roche and Merck, and received research support from Celldex Therapeutics and Incyte. J.H.S. declares no competing interests.

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Preusser, M., Lim, M., Hafler, D. et al. Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat Rev Neurol 11, 504–514 (2015). https://doi.org/10.1038/nrneurol.2015.139

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