Department of Neurology, Christian-Doppler University Hospital, Paracelsus Medical University, Center for Cognitive Neuroscience, member of EpiCARE, Salzburg, Austria.
Department of Neuroradiology, Christian-Doppler University Hospital, Paracelsus Medical University, Salzburg, Austria.
Eur J Neurol. 2024 Jul;31(7):e16279. doi: 10.1111/ene.16279. Epub 2024 Mar 31.
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).
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.
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.
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.
本研究旨在提高人们对 B 细胞在免疫检查点抑制剂（ICI）相关神经免疫相关不良事件（nirAE）中的作用的认识。
进行了系统的文献回顾，并观察了一例黑色素瘤和一例非小细胞肺癌（NSCLC）患者的病例，他们发生了 ICI 相关的 nirAE，脑脊液（CSF）检查结果表明存在 B 细胞参与。
两名接受伊匹单抗/纳武单抗治疗黑色素瘤和化疗/帕博利珠单抗治疗 NSCLC 的患者分别发展为免疫性心肌炎/肌炎/重症肌无力重叠综合征（三重 M）和小脑炎合并纵向横贯性脊髓炎（c-LETM）形式的 nirAE。两名患者均存在鞘内炎症和趋化因子 C-X-C 基序配体（CXCL13）升高；三重 M 病例存在乙酰胆碱受体抗体、抗肌联蛋白反应、血液中 CD4/CD8 T 细胞比值改变以及 CSF T 细胞程序性死亡-1（PD-1）表达降低；c-LETM 病例显示鞘内抗体产生和浆细胞。两名患者对一线治疗反应不足。NSCLC 患者接受利妥昔单抗的 B 细胞耗竭治疗后病情改善，而黑色素瘤患者在开始升级治疗前死亡。文献研究还发现了一例与 ICI 相关 LETM 相关的 CSF 中 CXCL13 升高的病例，三例与 ICI 相关水通道蛋白-4 抗体神经脊髓炎谱障碍的病例，以及基于 ICI 相关免疫相关不良事件中抗体介导的免疫病理学的 B 细胞介导毒性的证据。
病例观察突出了 ICI 相关 nirAE 诊断和治疗中的诸多不确定性，说明了所涉及的免疫机制的异质性，并提示 B 细胞可能被误诊。鞘内 CXCL13 可能作为 nirAE 中 B 细胞参与的生物标志物，支持鞘内免疫球蛋白合成、浆细胞存在和/或同源免疫细胞募集。
