Soluble biomarkers for immune checkpoint inhibitor-related encephalitis: A mini-review

Immune checkpoint inhibitors lead to effective antitumour responses but also to immune-related adverse events (irAEs), which affect the nervous system in 1–5% of patients. Encephalitis is the most frequent central nervous system irAE and is clinically relevant due to its high severity and mortality. Early diagnosis is crucial but is hampered by the broad list of alternative diagnoses, the lack of established diagnostic criteria, and the need of extensive diagnostic procedures (e.g., spinal tap, brain MRI) alongside expert neurological evaluation. Additionally, the response to corticosteroids is inconsistent, and the management of corticosteroid-refractory patients remains poorly defined. This mini-review discusses the role of various soluble biomarkers in the diagnosis, prognostication, and management of ICI-encephalitis. Neural antibodies, which are well-established biomarkers of autoimmune and paraneoplastic encephalitis, are found in only a subset of ICI-encephalitis, in which they can aid to establish the diagnosis. The most prevalent are paraneoplastic neurological syndromes (PNS)-associated antibodies, which are found almost exclusively in focal ICI-encephalitis syndromes and are associated with poor outcomes, possibly due to predominantly cytotoxic T cell involvement leading to irreversible neuronal loss. Beside antibodies, serum brain injury biomarkers such as NfL and S100B are elevated in ICI-encephalitis and, even if non-specific, may be useful as a routine test to quickly identify patients in whom neurological evaluation and second-level diagnostic procedures should be prioritized. Additionally, higher serum and CSF NfL levels have been associated with lack of treatment response in ICI-encephalitis, suggesting they may have a prognostic role. Among cytokines, elevated interleukin 6 (IL6) levels have been observed in serum and/or CSF samples of some patients with ICI-encephalitis, but the role of IL6 as a biomarker for response to IL6-directed therapies requires further investigation. Likewise, the value of other biomarkers, including T cells markers and HLA haplotypes, still needs to be evaluated in large cohorts. Overall, neural antibodies are important diagnostic and prognostic biomarkers in ICI-encephalitis, and other soluble biomarkers, especially NfL, deserve further investigation since they have a promising application in clinical practice.