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. 2023 Apr;12(8):9373-9383.
doi: 10.1002/cam4.5695. Epub 2023 Feb 16.

Monocyte chemoattractant protein 1 as a potential biomarker for immune checkpoint inhibitor-associated neurotoxicity

Nora Möhn  1 , Susann Mahjoub  1 , Laura Duzzi  1 , Emily Narten  1 , Lea Grote-Levi  1 , Gudrun Körner  1 , Tabea Seeliger  1 , Gernot Beutel  2 , Benjamin-Alexander Bollmann  3 , Thomas Wirth  4 , André Huss  5 , Hayrettin Tumani  5 , Imke Grimmelmann  6 , Ralf Gutzmer  6   7 , Philipp Ivanyi  2 , Thomas Skripuletz  1 ; ICOG-CCCH (Immune Cooperative Oncology Group; Comprehensive Cancer Center Hannover)
Affiliations

Monocyte chemoattractant protein 1 as a potential biomarker for immune checkpoint inhibitor-associated neurotoxicity

Nora Möhn et al. Cancer Med. 2023 Apr.

Abstract

Background: Oncological patients can benefit substantially from treatment with immune checkpoint inhibitors (ICI). However, there is a growing awareness of immune-related adverse events (irAE). Especially ICI-mediated neurological adverse events (nAE(+)), are tough to diagnose and biomarkers to identify patients at risk are missing.

Methods: A prospective register with prespecified examinations was established for ICI treated patients in December 2019. At the time of data cut-off, 110 patients were enrolled and completed the clinical protocol. Herein, cytokines and serum neurofilament light chain (sNFL) from 21 patients were analyzed.

Results: nAE of any grade were observed in 31% of the patients (n = 34/110). In nAE(+) patients a significant increase in sNFL concentrations over time was observed. Patients with higher-grade nAE had significantly elevated serum-concentrations of monocyte chemoattractant protein 1 (MCP-1) and brain-derived neurotrophic factor (BDNF) at baseline compared to individuals without any nAE (p < 0.01 and p < 0.05).

Conclusion: Here, we identified nAE to occur more frequently than previously reported. Increase of sNFL during nAE confirms the clinical diagnosis of neurotoxicity and might be a suitable marker for neuronal damage associated with ICI therapy. Furthermore, MCP-1 and BDNF are potentially the first clinical-class nAE predictors for patients under ICI therapy.

Keywords: biomarker; immune-related adverse events; immunotherapy; neurotoxicity; serum neurofilament light chains.

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Conflict of interest statement

All authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

FIGURE 1
FIGURE 1
Illustration of specific immune‐related adverse events (irAE) including neurological adverse events (nAE) within the total cohort (n = 58/110, 52.7%). Displayed are specific ICI‐induced autoimmune adverse events of ≥CTCAE grade 2 including specific nAE. CTCAE, common criteria terminology for adverse events. Version 6.0 CTCAE was used.
FIGURE 2
FIGURE 2
Illustration of neurological adverse events (nAE) of the total cohort (n = 36/110, 32.7%). Displayed are neurological adverse events of varying severity (CTCAE grades 1 – 4). Sensory deficits include hypesthesias, dysesthesias, and paresthesias. CTCAE, common criteria terminology for adverse events; RLS, restless‐legs‐syndrome. Version 6.0 CTCAE was used.
FIGURE 3
FIGURE 3
Comparison of neurofilament light chain in serum in patients without nAE and those with nAE grade 3. EOS, end‐of‐study; FU, follow‐up; nAE, neurological adverse events; ns, not significant. ** p < 0.01. At each time point/study visit, n = 5 patients from each group were studied. None of the patients with nAE showed neurological symptoms at baseline.
FIGURE 4
FIGURE 4
Cytokine measurement in patients with and without ICI‐associated neurotoxicity CTCAE grade 3. (A) Serum monocyte chemoattractant protein 1 (MCP‐1) concentrations, comparison of patients without nAE and those with nAE grade 3. (B) Serum levels of brain derived neurotrophic factor (BDNF), comparison of patients without nAE and those with nAE grade 3. EOS, end‐of‐study; FU, follow‐up; nAE, neurological adverse events; ns, not significant. ** p < 0.01, * p < 0.05. At each time point/study visit, n = 5 patients from each group were studied. None of the patients with nAE showed neurological symptoms at baseline.
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