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- Title
Beyond T cell toxicity – Intrathecal chemokine CXCL13 indicating B cell involvement in immune‐related adverse events following checkpoint inhibition: A two‐case series and literature review.
- Authors
Otto, Ferdinand; Seiberl, Michael; Bieler, Lara; Moser, Tobias; Kleindienst, Waltraud; Wallner‐Essl, Walter; Koelblinger, Peter; Wipfler, Peter; Harrer, Andrea
- Abstract
Background and purpose: This study was undertaken to raise awareness of a role of B cells in immune checkpoint inhibitor (ICI)‐associated neurological immune‐related adverse events (nirAE). Methods: A systematic literature review was made, with case observations of a melanoma and a non‐small cell lung cancer (NSCLC) patient who developed ICI‐associated nirAE with cerebrospinal fluid (CSF) findings indicating B cell involvement. Results: Two patients receiving ipilimumab/nivolumab for melanoma and chemotherapy/pembrolizumab for NSCLC developed nirAE in the form of myocarditis/myositis/myasthenia gravis overlap syndrome (triple M) and cerebellitis plus longitudinal transverse myelitis (c‐LETM), respectively. Intrathecal inflammation with chemokine C‐X‐C motif ligand (CXCL13) elevation was present in both patients; the triple M case had acetylcholine receptor antibodies, antititin reactivity, altered CD4/CD8 T cell ratio in blood, and depressed programmed death‐1 (PD‐1) expression on CSF T cells; the c‐LETM case showed intrathecal antibody production and plasma cells. Both patients insufficiently responded to first‐line treatment. The NSCLC case improved upon administration of B cell‐depleting therapy with rituximab, whereas the melanoma patient died before escalation therapy was initiated. Literature research revealed one additional ICI‐associated LETM case with intrathecal CXCL13 elevation, three cases with ICI‐associated aquaporin‐4 antibody neuromyelitis spectrum disorder, and evidence of B cell‐mediated toxicity based on antibody‐mediated immune pathologies in ICI‐associated immune‐related adverse events. Conclusions: The case observations highlight the plethora of uncertainties in diagnosis and treatment of ICI‐associated nirAE, exemplify the heterogeneity of immune mechanisms involved, and suggest a role of B cells, which may be underdiagnosed. Intrathecal CXCL13 may serve as a biomarker of B cell involvement in nirAE, supported by intrathecal immunoglobulin synthesis, presence of plasma cells, and/or recruitment of cognate immune cells.
- Subjects
DRUG side effects; LITERATURE reviews; B cells; T cells; MYASTHENIA gravis; NEUROMYELITIS optica; CEREBROSPINAL fluid
- Publication
European Journal of Neurology, 2024, Vol 31, Issue 7, p1
- ISSN
1351-5101
- Publication type
Article
- DOI
10.1111/ene.16279