Clinical characterization and baseline immune correlates of immune checkpoint inhibition-induced neurotoxicity

Immune checkpoint inhibitor (ICI)-induced neurotoxicity (N-Tox) can be associated with severe symptoms, yet it remains grossly understudied compared to other immune related adverse events (irAEs). We analyzed irAEs of melanoma patients enrolled in three phase III clinical trials (Checkmate 238, 915 and 067), treated with ipilimumab, nivolumab, or ipilimumab and nivolumab. N-Tox was classified by its clinical phenotype and severity. In subsets of patients with available biospecimens, baseline serum autoantibody (aAb) profiling and bulk RNA sequencing of peripheral CD4+ and CD8+ T cells were conducted to determine if baseline host immune response is associated with N-Tox development. Overall, grade ≥ 2 N-Tox occurred in 187 of 1,553 (12%) patients (Grade 2 n = 148, Grade 3 n = 35, and Grade 4 n = 4). Majority of the patients (80%) developed N-Tox within the first 6 months, and 59 (32%) developed multiple N-Tox symptoms. Grade ≥ 2 N-Tox was preceded by lower grade neurologic symptoms in 63 (34%) patients, and 23 (12%) patients required hospitalization. In a multivariable logistic regression analysis using nivolumab as reference, ipilimumab was associated with higher odds of N-Tox (OR = 1.67, p = 0.01), while COMBO was not significant (OR = 1, p = 0.98). N-Tox was associated with lower recurrence rates (OR = 0.74, p = 0.02) and greater clinical benefit of treatment (OR = 2.55, p < 0.0001). Baseline serum aAb profiles in patients who developed N-Tox showed enrichment of neuroinflammatory and neurodegenerative pathways compared to patients with other grade ≥ 2 irAEs. Gene expression analyses of CD4+ and CD8+ T cells supported these findings, identifying neurodevelopment, neurotransmitter signaling, and synaptic function pathways associated with grade ≥ 2 N-Tox. These findings underscore the importance of early monitoring of ICI-treated patients for N-Tox, including low grade N-Tox. Our results also point to a pre-existing neurotropic contexture that may predispose some patients to N-Tox.