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  • Review Article
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Vaccine-based immunotherapeutic approaches to gliomas and beyond

Nature Reviews Neurology volume 13, pages 363–374 (2017)Cite this article

Subjects

Key Points

  • Glioblastoma is the paradigm of tumour-associated immunosuppression

  • Several glioma-specific peptide vaccines, with or without dendritic cell support, are in late clinical development

  • Vaccines can be combined with agents that nonspecifically boost immune responses, such as immune checkpoint inhibitors or TGFβ pathway inhibitors

  • Standardization of clinical trial conduct might facilitate progress in this challenging field of oncology

Abstract

Astrocytic and oligodendroglial gliomas are intrinsic brain tumours characterized by infiltrative growth and resistance to classic cancer therapies, which renders them inevitably lethal. Glioblastoma, the most common type of glioma, also exhibits neoangiogenesis and profound immunosuppressive properties. Accordingly, strategies to revert glioma-associated immunosuppression and promote tumour-directed immune responses have been extensively explored in rodent models and in large clinical trials of tumour immunotherapy. This Review describes vaccination approaches investigated for the treatment of glioma. Several strategies have reached phase III clinical trials, including vaccines targeting epidermal growth factor receptor variant III, and the use of either immunogenic peptides or tumour lysates to stimulate autologous dendritic cells. Other approaches in early phases of clinical development employ multipeptide vaccines such as IMA-950, cytomegalovirus-derived peptides, or tumour-derived peptides such as heat shock protein-96 peptide complexes and the Arg132His mutant form of isocitrate dehydrogenase. However, some preclinical trial data suggest that addition of immunomodulatory reagents such as immune checkpoint inhibitors, transforming growth factor-β inhibitors, signal transducer and activator of transcription 3 inhibitors, or modifiers of tryptophan metabolism could augment the therapeutic activity of vaccination and overcome glioma-associated immunosuppression.

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Figure 1: Glioma-associated pathways of local and systemic immunosuppression.
Figure 2: Logistical requirements for autologous immune or immune cell-based vaccination for glioblastoma.
Figure 3: Putative mode of action for glioblastoma vaccines generated using tumour lysate or peptides.
Figure 4: Facilitating effective vaccination by neutralizing glioma-associated immunosuppression.

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Acknowledgements

The authors' research work is supported by grants from the Canton of Zurich HSM-2 (Hochspezialisierte Medizin 2) programme, the German Research Fund (Deutsche Forschungsgemeinschaft), the Swiss National Science Foundation and the Swiss Cancer League (all to M.W. and P.R.).

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Authors and Affiliations

  1. Department of Neurology and Brain Tumour Centre, University Hospital and University of Zurich, Frauenklinikstrasse 26, Zurich, 8091, Switzerland

    Michael Weller & Patrick Roth

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

    Matthias Preusser

  3. Neurology Clinic, Heidelberg University Medical Centre and Neuro-oncology Programme, National Centre for Tumour Diseases Heidelberg, Im Neuenheimer Feld (INF) 400, Heidelberg, 69120, Germany

    Wolfgang Wick & Michael Platten

  4. Dana-Farber Cancer Institute, 450 Brookline Avenue, D-2134, Boston, 02215–5450, Massachusetts, USA

    David A. Reardon

  5. Neurology Clinic, Mannheim Medical Centre, Heidelberg University and Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumour Immunology, German Cancer Research Centre, Im Neuenheimer Feld (INF) 280, Heidelberg, 69120, Germany

    Michael Platten

  6. Department of Neurosurgery, Duke University Medical Center, 200 Trent Drive, Duke South, Blue Zone, 1st Floor, Room 1554, Durham, 27710, North Carolina, USA

    John H. Sampson

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All authors wrote the manuscript, researched data for the article, undertook review or editing of the manuscript before submission and contributed substantially to discussions of the article content.

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Correspondence to Michael Weller.

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Competing interests

The authors declare that M.W. has received research grants from Acceleron, Actelion, Bayer, Isarna, Merck Sharp & Dohme, Merck EMD (Emanuel Merck, Darmstadt), Novocure, Piqur and Roche and honoraria for lectures, advisory board participation or consulting from Bristol-Myers Squibb, Celldex, Immunocellular Therapeutics, Isarna, Magforce, Merck Sharp & Dohme, Merck EMD, Northwest Biotherapeutics, Novocure, Pfizer, Roche, Teva and Tocagen. M. Preusser has received research support from Böhringer-Ingelheim, GlaxoSmithKline, Merck Sharp & Dohme and Roche, as well as honoraria for lectures, advisory board participation or consulting from Bristol-Myers Squibb, CMC Contrast, Gerson Lehrman Group, GlaxoSmithKline, Mundipharma, Novartis and Roche. D.A.R. has received research grants from Celldex Therapeutics, Incyte and Midatech, as well as honoraria for lectures, advisory board participation or consulting from Abbvie, Amgen, Bristol-Myers Squibb, Cavion, Celldex Therapeutics, EMD Serono, Genentech (Roche), Inovio, Juno Pharmaceuticals, Merck & Co, Midatech, Momenta Pharmaceuticals, Novartis, Novocure, Oxigene, Regeneron, and Stemline Therapeutics. M. Platten has received research support from Merck and Novartis, as well as honoraria for lectures, consultation or advisory board participation from Alexion, Bayer, Genentech (Roche), Merck & Co, Medac, Miltenyi Biotec, Novartis and Teva. M. Platten also holds patents on isocitrate dehydrogenase vaccines and aryl hydrocarbon receptor inhibition. P.R. has received research support from Merck Sharp & Dohme and honoraria for lectures or advisory board participation from Merck Sharp & Dohme, Molecular Partners, Novartis and Roche. W.W. has received research funding from Apogenix, Böhringer-Ingelheim, Genentech (Roche), Merck Sharp & Dohme and Pfizer, as well as honoraria for participating in a speaker's bureau for Merck Sharp & Dohme and consulting for Genentech (Roche). J.H.S. declares that he is an employee of Annias, a shareholder in Annias and Istari, and has received honoraria for consulting from Celldex, BrainLAB and Medicenna, as well as licensing fees from Celldex.

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Weller, M., Roth, P., Preusser, M. et al. Vaccine-based immunotherapeutic approaches to gliomas and beyond. Nat Rev Neurol 13, 363–374 (2017). https://doi.org/10.1038/nrneurol.2017.64

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