Checkpoint inhibitor-induced adverse events in the CNS - T-cell characteristics and biomarkers

Abstract

Immune checkpoint inhibitors (ICI) activate T cells to kill cancer cells by blocking inhibitory receptors PD-1 (nivolumab; nivo) or CTLA-4 (ipilimumab; ipi). Activated T cells can also attack any healthy organ, causing unpredictable immune related adverse events (irAE). The risk of irAE is highest when treating with ipi and nivo simultaneously. An adverse event of the central nervous system (CNS irAE) can cause paralysis and even death. CNS irAE is difficult to diagnose because of unspecific symptoms and no known blood tests that indicate CNS irAE. In addition, the immune mechanisms behind CNS irAE are unknown but T cells are likely to have a central role.

The aim of this thesis is to identify blood tests (biomarkers) to facilitate early diagnosis of CNS irAE. The second aim is to identify which T cell subsets are associated with CNS irAE. We also wanted to establish the frequency of CNS irAE in a cohort of ipi+nivo treated patients. In paper I we describe how brain damage markers S100B and NfL in blood was high in a patient with severe CNS irAE. In paper II we investigated a cohort of 9 ipi+nivo treated patients with CNS irAE. In this cohort, S100B and NfL in blood increased significantly during CNS irAE and normalized during immunosuppression. CNS irAE was detected with a sensitivity of 100% (S100B) and 79% (NfL) and a specificity of 89% (S100B) and 74% (NfL). Interestingly, patients with CNS irAE had increased concentration of C-reactive protein (CRP) and liver enzymes (ALT/AST) in blood. In papers I and III , flow cytometry analysis demonstrated high proportion of T cells expressing costimulatory receptor ICOS in patients with CNS irAE. Finally, the frequency of CNS irAE in a cohort of 197 ipi+nivo treated patients was 4,6%, which is considerably higher than previously reported.

In conclusion, our findings support that combined analysis of S100B and NfL in blood facilitates diagnosis and monitoring of CNS irAE. Increased CRP and liver enzymes in blood during CNS irAE may suggest shared immune mechanisms between CNS and hepatitis irAE. Also, our observations identify ICOS as a potential mediator of CNS irAE. Finally, CNS irAE may be more common than previously reported.