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Neurologische Nebenwirkungen von Checkpoint-Inhibitoren

Neurological side effects of checkpoint inhibitors

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Zusammenfassung

Hintergrund

In den letzten Jahren wurde die Therapie zahlreicher Tumorentitäten durch den Einsatz moderner Immuntherapien mit Checkpoint-Inhibitoren revolutioniert. Guten Ansprechraten stehen jedoch zahlreiche immunvermittelte Nebenwirkungen gegenüber. Neurologische immunvermittelte Nebenwirkungen gehören zu den seltenen, jedoch häufig schwer verlaufenden Komplikationen einer Checkpoint-Inhibitor-Therapie.

Methode

Es wurde eine systematische Suche in den Datenbanken PubMed und Web of Science nach Fallberichten und Studien zu neurologischen Nebenwirkungen unter Checkpoint-Inhibitor-Therapie durchgeführt.

Ergebnisse

Insgesamt 42 Arbeiten zu neurologischen Nebenwirkungen von Checkpoint-Inhibitoren mit insgesamt 85 berichteten Fällen wurden identifiziert. Die häufigsten berichteten neurologischen Nebenwirkungen waren Myopathien, Neuropathien, Erkrankungen der neuromuskulären Endplatte und Enzephalitiden. Die höchste Morbidität und Mortalität wiesen Enzephalopathien und Myopathien mit begleitender Myokarditis auf.

Schlussfolgerung

Vor dem Hintergrund eines rasch zunehmenden Einsatzes von Checkpoint-Inhibitoren gibt diese Arbeit einen Überblick über bislang berichtete klinische Verlaufsformen neurologischer Nebenwirkungen. Kontrollierte Studien zur Therapie neurologischer Nebenwirkungen fehlen. Fallberichte lassen vermuten, dass eine frühzeitige Steroidtherapie die Wahrscheinlichkeit einer kompletten Remission der neurologischen Symptome erhöht. Typische Symptomkonstellationen müssen daher schnell erkannt und eine immunsuppressive Therapie eingeleitet werden.

Abstract

Background

In recent years the treatment of many tumor entities has been revolutionized by the use of modern immunotherapies with checkpoint inhibitors; however, good response rates are contrasted by many immune-mediated side effects. Neurological immune-mediated side effects are rare but often severe complications of checkpoint inhibitor treatment.

Method

A systematic search in the PubMed and Web of Sciences databases was carried out for case reports and studies on neurological side effects during checkpoint inhibitor treatment.

Results

A total of 42 articles on neurological side effects of checkpoint inhibitors with a total of 85 reported cases could be identified. The most frequently reported neurological side effects were myopathies, neuropathies, diseases of the neuromuscular endplates and encephalitides. Among those, encephalitides and myopathies with accompanying myocarditis were associated with the highest morbidity and mortality.

Conclusion

Against the background of a rapidly increasing use of checkpoint inhibitors, this article provides an overview of currently available reports on the clinical courses of neurological side effects. Controlled studies on the treatment of neurological side effects are lacking. From case studies it can be assumed that early steroid treatment increases the probability of a complete remission of neurological symptoms. Typical symptom constellations must therefore be rapidly recognized and an immunosuppressive treatment must be initiated.

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Abb. 1

Abbreviations

AChR:

Acetylcholin-Rezeptor

CD28:

„Cluster of differentation 28“

CD80:

„Cluster of differentiation 80“

CD86:

„Cluster of differentiation 86“

CIDP:

Chronisch inflammatorische demyelinisierende Polyneuropathie

CK:

Kreatinkinase

CTLA-4:

„Cytotoxic T‑lymphocyte-associated protein 4, cytotoxic T lymphocyte antigen 4“

DMMR:

„Mismatch repair deficient“

EMG:

Elektromyographie

FDA:

Food and Drug Administration

GBS:

Guillain-Barré-Syndrom

irAE:

„Immune related adverse events“

IVIg:

Intravenöse Gabe von Immunglobulinen

MERS:

„Mild encephalopathy with a reversible splenial lesion“

MRT:

Magnetresonanztomographie

MSI-H:

„Microsatellite instability-high“

NK-Zellen:

Natürliche Killerzellen

NMDA:

N-Methyl-D-Aspartat

PD-1:

„Programmed cell death-1“

PD-L1:

„Programmed cell death-ligand 1“

PD-L2:

„Programmed cell death-ligand 2“

PNS:

Peripheres Nervensystem

PPH:

Plasmapherese

PRES:

Posterior reversible encephalopathy syndrome

SREAT:

Steroid responsive encephalopathy associated with autoimmune thyroiditis

ZNS:

Zentrales Nervensystem

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Authors and Affiliations

  1. Klinik für Neurologie mit Experimenteller Neurologie, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charité Platz 1, 10117, Berlin, Deutschland

    S. Knauss, L. Ginesta Roque, P. Hühnchen,  W. Böhmerle & M. Endres

  2. Hautklinik, Universitätsklinikum Erlangen, Erlangen, Deutschland

    L. Heinzerling

  3. Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Deutschland

    M. Endres

  4. Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Berlin, Deutschland

    M. Endres

  5. Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Berlin, Deutschland

    M. Endres

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Caption Electronic Supplementary Material

Anhang

Anhang

Die häufigsten Checkpoint-Inhibitoren

CTLA-4-Antikörper

Ipilimumab.

Der gegen das CTLA-4-Protein gerichtete Antikörper Ipilimumab war im Jahr 2011 der erste von der Food and Drug Administration (FDA) zugelassene Checkpoint-Inhibitor [40]. Er wird für die primäre Therapie des nichtresezierbaren oder metastasierten Melanoms und für die adjuvante Therapie des Melanoms eingesetzt.

CTLA-4 ist ein auf aktivierten T‑Lymphozyten exprimierter Rezeptor, der nach Bindung seines Liganden CD80/CD86 zu einer Inhibierung der T‑Zell-Aktivierung führt [10]. Ipilimumab blockiert die Interaktion von CTLA-4 mit seinen Liganden und verstärkt somit die T‑Zell-Aktivierung und -proliferation [53]. Insgesamt wurden bislang 40 Fälle von neurologischen Nebenwirkungen einer Ipilimumabtherapie publiziert.

PD-1-Antikörper

Nivolumab.

Nivolumab ist ein von der FDA seit 2015 zugelassener gegen PD-1 gerichteter Antikörper, der aktuell für die Therapie des nichtresezierbaren oder metastasierten Melanoms, metastasierten nichtkleinzelligen Lungenkarzinoms, Nierenzellkarzinoms, klassischen Hodgkin-Lymphoms, Plattenepithelkarzinoms im Kopf-Hals-Bereich, Urothelkarzinoms, metastasierten kolorektalen Karzinoms mit hoher Mikrosatelliteninstabilität („microsatellite instability-high“, MSI-H) oder Mismatch-Reparatur-Defizienz („mismatch repair deficient“, dMMR) und des hepatozellulären Karzinoms eingesetzt wird [53].

PD-1 ist ein Rezeptor, der auf aktivierten T‑Zellen, B‑Zellen, Monozyten und natürlichen Killer(NK)-Zellen exprimiert wird [20]. Einige Tumoren besitzen die Fähigkeit, seine Liganden zu exprimieren. Durch Bindung dieser Liganden (PD-L1, PD-L2) an den PD-1-Rezeptor wird die T‑Zell-Proliferation und Zytokinproduktion gehemmt. Nivolumab blockiert diese Interaktion und wirkt somit einer Hemmung der T‑Zell-Aktivierung entgegen [53].

Pembrolizumab.

Pembrolizumab ist ein weiterer PD-1-Antikörper, der für die Therapie des nichtresezierbaren oder metastasierten Melanoms, metastasierten nichtkleinzelligen Lungenkarzinoms und wiederkehrenden oder metastasierten Plattenepithelkarzinoms im Kopf-Hals-Bereich eingesetzt wird und seit 2014 von der FDA zugelassen ist [54].

Avelumab und Atezolizumab.

Avelumab und Atezolizumab sind gegen PD-L1, den Hauptliganden des PD-1-Rezeptors, gerichtet und hemmen so eine Aktivierung des PD-1. Avelumab wurde 2017 zur Behandlung von Merkelzellkarzinomen und Urothelkarzinomen zugelassen. Atezolizumab ist seit 2016 zur Behandlung des Urothelkarzinoms und der metastasierten nichtkleinzelligen Lungentumoren zugelassen [53, 54].

Kombinationstherapie

Nivolumab und Ipilimumab.

Checkpoint-Inhibitoren werden auch in Form einer Kombinationstherapie eingesetzt. In einer doppelblinden Phase-III-Studie mit zuvor unbehandelten Melanompatienten konnte gezeigt werden, dass eine Kombinationstherapie aus Nivolumab und Ipilimumab Überlebensvorteile im Vergleich zur Monotherapie mit jeweils einer der beiden Substanzklassen bietet [23]. Aus den bereits beschriebenen Wirkmechanismen der Therapeutika lässt sich eine komplementäre Aktivität zwischen PD-1- und CTLA-4-Inhibitoren annehmen, die womöglich für ein besseres Ansprechen verantwortlich ist [10, 20, 23, 53, 55]. Die verbesserte Wirksamkeit ging in dieser Studie jedoch auch mit insgesamt häufigeren immunvermittelten Nebenwirkungen bei der Kombinationstherapie (55 %) im Vergleich zur Monotherapie mit Nivolumab (16,3 %) und Ipilimumab (27.3 %) einher (s. Supplementary Material 4).

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Knauss, S., Ginesta Roque, L., Hühnchen, P. et al. Neurologische Nebenwirkungen von Checkpoint-Inhibitoren. Nervenarzt 90, 138–147 (2019). https://doi.org/10.1007/s00115-018-0571-8

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