ReviewNeurological adverse events associated with immune checkpoint inhibitors: Review of the literature
Introduction
Anti-CTLA4 (ipilimumab, tremelimumab) and anti-PD1 (nivolumab, pembrolizumab, lambrolizumab, pidilizumab) monoclonal antibodies enhance antitumour immunity by targeting T-cells inhibitory receptors. These antibodies, classified as immune checkpoint inhibitors (ICIs), have recently obtained approval for treatment in metastatic melanoma [1], [2], [3], [4], [5], non-small cell lung cancer [6], [7], [8], renal-cell carcinoma [9] and are currently under clinical trials in several other indications. Immune checkpoint inhibitors have undoubtedly been a major step forward in immunotherapy these last years, having significantly increased survival of cancer patients.
As might be expected, adverse effects (AEs) can occur through immunologic activation, that have been termed immune-related adverse events (irAEs) or, occasionally, adverse events of special interest. Grade 3 and 4 adverse events occurred in 13ā55% of ipilimumab-treated patients, in 9ā43% of nivolumab-treated patients, in 11ā14% of pembrolizumab-treated patientsĀ and in 54ā86% in ipilimumab plus nivolumab-treated patients [10]. These irAEs can potentially involve every organ system but gastrointestinal, dermatologic, hepatic, endocrine and pulmonary toxicities predominate [11], [12]. Although rare, neurological adverse effects (nAEs) require prompt recognition and treatment to avoid substantial morbidity.
This review summarises the published data on neurological toxicities reported with immune checkpoint inhibitors, trying to define their incidence, timing patterns, clinical and paraclinical presentation.
Section snippets
Patients and methods
A systematic literature search, up to February 2016, mentioning treatment with immune checkpoint inhibitors on adult human beings and published in English was conducted in PubMed database, using the keywords: āipilimumab or tremelimumab or nivolumab or pembrolizumab or lambrolizumab or pidilizumab or anti-CTLA4 or anti-CTLA-4 or anti-PD1 or anti-PD-1ā and āclinical trialsā. Observational studies were excluded. For the case reports search, the keywords used were āsafety or toxicity or sides
Literature search
The Pubmed search identified 82 relevant publications for the present study: 59 clinical trials (totalling 9208 patients exposed to anti-CTLA4 or anti-PD1 antibodies) and 23 case reports reporting 26 cases. One case seen in our ward was added to the case reports. Among the 59 clinical trials, 37 were investigating anti-CTLA4 antibodies (7 phase I, 24 phase II, 6 phase III), 22 anti-PD1 antibodies (9 phase I, 6 phase II, 7 phase III)Ā and 4 a combination of both (1 phase I, 1 phase II, 2 phase
Discussion
Immune checkpoint inhibitors have shown promising results in cancersĀ but can possibly induce auto-immune disorders. In this study, we reviewed the neurological adverse events occurring under immune checkpoint inhibitors in oncologic patients to more clearly define their incidence and characteristics.
The most striking feature of this literature review is the extremely broad spectrum of possible syndromes, potentially involving all areas of the central and peripheral nervous system. An
Conflict of interest statement
None declared.
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