Clinical and biological correlates of immune-related adverse events

Abstract

Introduction: Immune checkpoint inhibitors (ICI) have revolutionised modern cancer treatment. However, they may cause toxicities known as immune-related adverse events (irAE), which are unpredictable and potentially severe. We therefore evaluated systemic immune markers, cytokines and antibodies, in a cohort of patients receiving ICI.

Methods: We identified clinical outcomes including overall survival (OS) and development of irAE in a cohort of patients enrolled in a prospective biospecimen collection protocol. Multiplex panels of 40 serum cytokines and 124 serum autoantibodies at baseline and 6 weeks after ICI initiation were analysed. For differences in immune parameters, P < 0.05 and false discovery rate (FDR) < 0.2 were considered significant.

Results: A total of 327 patients were included in the cohort, of whom 205 (63%) developed an irAE. Development of irAE was associated with improved OS (HR 0.67; 95% CI, 0.49-0.93; P = 0.015). In multivariate models, grade 1 irAE were associated with improved OS with HR 0.63 (95% CI 0.45-0.89; P < 0.01). Dermatological irAEs (HR 0.58; P = 0.012) and hyperthyroidism (HR 0.40; P = 0.013) were also associated with improved OS. Levels of several cytokines were reduced at baseline (CXCL8, CXCL9, CXCL10, CCL20, IL-4, CXCL13, interferon-gamma, and CCL1; all P < 0.05 and FDR < 0.2) and increased at 6 weeks (CXCL10; FDR = 0.1) in those that developed an irAE. Levels of cytokines between different irAE grades were similar.

Conclusions: Development of an irAE is associated with improved outcomes, with strongest correlation noted for grade 1, dermatological, and thyroid irAE. A characteristic pattern of dynamic changes including lower baseline levels of interferon gamma-inducible cytokines and greater increases in CXCL10 at 6 weeks is associated with development of irAE, regardless of irAE grade.