Opinion | Published:

Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives

Nature Reviews Neurology volume 13, pages 755763 (2017) | Download Citation

Abstract

Cancer treatment strategies based on immune stimulation have recently entered the clinical arena, with unprecedented success. Immune checkpoint inhibitors (ICIs) work by indiscriminately promoting immune responses, which target tumour-associated antigens or tumour-specific mutations. However, the augmented immune response, most notably the T cell response, can cause either direct neurotoxicity or, more commonly, indirect neurotoxic effects through systemic or local inflammatory mechanisms or autoimmune mechanisms. Consequently, patients treated with ICIs are susceptible to CNS disease, including paraneoplastic neurological syndromes, encephalitis, multiple sclerosis and hypophysitis. In this Opinion article, we introduce the mechanisms of action of ICIs and review their adverse effects on the CNS. We highlight the importance of early detection of these neurotoxic effects, which should be distinguished from brain metastasis, and the need for early detection of neurotoxicity. It is crucial that physicians are well informed of these neurological adverse effects, given the anticipated increase in the use of immunotherapies to treat cancer.

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Acknowledgements

The authors' work is supported by INSERM, the French National Centre for Scientific Research (CNRS) and Toulouse III University. R.S.L. is supported by grants from Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques (ARSEP), Midi-Pyrénées Region, Agence Nationale de la Recherche (ANR) T cell-Mig, FP7-PEOPLE-2012-ITN NeuroKine, European Research Area Network (ERA-NET) Meltra-BBB, L'Association pour la Recherche sur le Cancer (ARC) Cancer Research Foundation and Ligue Régionale Contre le Cancer. R.H. is supported by the German Research Foundation (DFG; SFB-TRR128; SyNergy, EXC 1010), German Ministry for Education and Research (BMBF; German Competence Network Multiple Sclerosis), Werner Reichenberger Stiftung, Cyliax Stiftung and Verein Therapieforschung für Multiple Sklerose Kranke. The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. We thank C. Robert, A. Dejean, D. Dunia, G. Martin-Blondel and S. Valitutti for insightful comments on the manuscript.

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  1. INSERM U1043 — CNRS UMR 5282, Centre de Physiopathologie Toulouse-Purpan, Purpan Hospital, Place du Docteur Baylac TSA 40031, 31059 Toulouse Cedex 9, France.

    • Lidia M. Yshii
  2. Institute of Clinical Neuroimmunology, Biomedical Centre and University Hospital, Ludwig Maximilian University, Munich 80539, Germany, and Munich Cluster for Systems Neurology (SyNergy), Munich D-81377, Germany.

    • Reinhard Hohlfeld
  3. INSERM U1043 — CNRS UMR 5282, Centre de Physiopathologie Toulouse-Purpan, Purpan Hospital, Place du Docteur Baylac TSA 40031, 31059 Toulouse Cedex 9, France, and the Department of Immunology, Hôpital Rangueil, 1, Avenue du Professeur Jean Poulhès — TSA 50032 — 31059 Toulouse Cedex 9, France.

    • Roland S. Liblau

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L.M.Y., R.H. and R.S.L. wrote the article. All authors made substantial contributions to discussion of the content and reviewed and/or edited the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Roland S. Liblau.

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    Ongoing or completed immune checkpoint molecule clinical trials

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https://doi.org/10.1038/nrneurol.2017.144

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