Incidence and severity of immune-related hepatitis after dual checkpoint therapy is linked to younger age independent of herpes virus immunity

Abstract

Abstract Background and Aims Dual immune checkpoint blockade (ICB) therapy can result in immune-related-adverse events (irAE) such as ICB-hepatitis. An expansion of effector-memory (TEM) CD4 T cells associated with antiviral immunity against herpesviridae was implicated in ICB-hepatitis. Notably, these memory subsets are frequently associated with age. Here, we sought to understand baseline patient, immune and viral biomarkers associated with the development of ICB-hepatitis to identify currently lacking baseline predictors and test if an expansion of TEM or positive serology against herpesviridae can predict ICB-hepatitis. Methods A discovery (n = 39) and validation cohort (n = 67) of patients with advanced melanoma undergoing anti-PD-1&anti-CTLA4 combination therapy (total n = 106) were analyzed for baseline clinical characteristics, occurrence of irAE and oncological outcomes alongside serological status for CMV, EBV and HSV. Immune populations were profiled by high-parametric flow cytometry (n = 29). Results ICB-hepatitis occurred in 59% of patients within 100 days; 35.9% developed severe (CTCAE 3–4) hepatitis. Incidence of ICB-hepatitis was higher in the younger ( = 55y: 27.8%) age group (p = 0.0003), occured earlier in younger patients (p < 0.0001). The association of younger age with ICB-Hepatitis was also observed in the validation cohort (p = 0.0486). Incidence of ICB-hepatitis was also associated with additional non-hepatic irAE (p = 0.018), but neither positive IgG serostatus for CMV, EBV or HSV nor TEM subsets despite an association of T cell subsets with age. Conclusion Younger age more accurately predicts ICB-hepatitis after anti-PD-1&anti-CTLA4 checkpoint therapy at baseline compared to herpes virus serology or TEM subsets. Younger patients should be carefully monitored for the development of ICB-hepatitis.

Keywords

• Checkpoint therapy
• Immune-related adverse effects
• Hepatitis
• Age
• Herpes virus