Increased serum NfL and GFAP levels indicate different subtypes of neurologic immune-related adverse events during treatment with immune checkpoint inhibitors

Abstract

Neurologic immune-related adverse events (nirAEs) represent rare, yet severe side effects associated with immune checkpoint inhibitor (ICI) therapy. Given the absence of established diagnostic biomarkers for nirAEs, we aimed to evaluate the diagnostic utility of serum Neurofilament Light Chain (NfL) and Glial Fibrillary Acidic Protein (GFAP). Fifty-three patients were included at three comprehensive cancer centers, of these 20 patients with manifest nirAEs and 11 patients with irHypophysitis. Controls included patients without any irAE (n = 8) and other irAEs (n = 14). Using a single-molecule enzyme-linked immunosorbent assay (Simoa), serum levels were measured prior to, during and after the manifestation of (n)irAEs in 80 samples. Symptom severity of the (n)irAEs was graded according to the Common Criteria for Adverse Events (CTCAE) version 5.0. Serum NfL levels were significantly higher in the nirAE group (n = 20) compared to irHypophysitis (n = 11; p = .0025) and controls (n = 22; p = .0384). Subgroup analysis demonstrated a significant elevation of NfL in nirAEs of the peripheral nerves (PNirAE) in contrast to neuromuscular syndromes (NMirAE) (p = .0260). GFAP levels were highest in patients with nirAE affecting the central nervous system (CNSirAE) compared to PNirAE and NMirAE (p = .0064). Symptom severity of nirAEs was associated with increased levels of NfL and GFAP (p = .0069, .0092). Individuals with elevated NfL levels exhibited less favorable outcomes of the (n)irAEs (p = .0199). Measurement of NfL and GFAP may be helpful for the differentiation of the broad spectrum of nirAEs and may serve as an indicator of symptom severity. Further investigation is needed to evaluate their potential as diagnostic and prognostic biomarkers.