P06.19.A BEYOND T CELL TOXICITY - INTRATHECAL CXCL13 ELEVATION INDICATES B-CELL INVOLVEMENT IN NEUROLOGICAL IMMUNE-RELATED ADVERSE EVENTS FOLLOWING IMMUNE CHECKPOINT INHIBITION: 2 CASE OBSERVATIONS AND COMPREHENSIVE REVIEW
Authors: Bieler L , Otto F , Seiberl M , Moser T , Kleindienst W , Wipfler P , Kölblinger P , Harrer A 
Published: September 2023

Abstract

BACKGROUND
Neurological immune-related adverse events (nirAE) can occur following cancer treatment with immune checkpoint inhibitors (ICI). Mainly attributed to autoreactive T-cells, nirAE usually respond to first line therapy with high-dose steroids (GC). Severe or fatal outcomes are rare & most frequently reported in clinically overlapping syndromes with accumulating evidence of B cell autoimmunity.

MATERIAL AND METHODS
We present 2 patients who developed grade 3-4 nirAE with evidence suggestive for B cell involvement.

RESULTS
Case 1: A 75y female with metastatic melanoma developed double vision & general weakness 2 weeks after the 1st cycle of ipilimumab & nivolumab. Diagnostic workup showed pleocytosis (27 cells/µl) with elevated CXCL13 (316 pg/ml) in cerebrospinal fluid (CSF). Increases of creatine kinase, troponin T, elevated levels of anti-acetylcholine receptor antibodies & positive anti-titin antibodies led to the diagnosis of myocarditis & myositis/myasthenia gravis overlap syndrome. The patient received pulsed high-dose GC with tapering. CSF flow cytometry revealed intrathecal recruitment of CXCL13-responsive B cell helper T cells of a predominant inflammatory phenotype & a highly increased pathological CD4/CD8 T cell ratio in peripheral blood. Clinically non-responding to GC, the patient received additional therapy with immunoglobulins (IVIG). 2 weeks later she was readmitted due to generalized myopathy with dropped head & received a second cycle of high-dose GC since she refused plasmapheresis. Further escalation with rituximab could not be realized because the patient rapidly deteriorated & deceased. Case 2: A 75y female with metastatic invasive enteric adenocarcinoma of the lung developed gait ataxia & ataxia of the lower limbs 5 months after pembrolizumab therapy. CSF analysis showed a pleocytosis (248 cells/µl) with plasma cells, pronounced CXCL13 elevation (&gt;488 pg/ml) & positive screening for anti-neuronal cerebellar antibodies, suggesting ICI-mediated cerebellitis. The patient received high-dose GC & IVIG for 5 days each, was discharged but readmitted 5 months later due to subacute onset of spastic paraparesis. Magnetic resonance imaging of the spine revealed thoracic myelopathy & CSF showed mild pleocytosis (5 cells/µl), intrathecal immunoglobulin synthesis & mild CXCL13 elevation (33 pg/ml). The patient completed a second cycle of steroids followed by rituximab targeting B-cell involvement & currently 4 months later is clinically stable.

CONCLUSION
Intrathecal CXCL13 may serve as diagnostic tool of B cell involvement, here supported by intrathecal immunoglobulin synthesis, presence of plasma cells and/or severely altered immune cell compositions. Early treatment escalation with B cell depleting agents such as rituximab may help prevent fatal clinical courses.