Application of a patient-centered reverse translational systems-based approach to understand mechanisms of an adverse drug reaction of immune checkpoint inhibitors

Abstract

Immunotherapy became a key pillar of cancer therapeutics with the approvals of ipilimumab, nivolumab, and pembrolizumab, which inhibit either cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1) that are negative regulators of T-cell activation. However, boosting T-cell activation is often accompanied by autoimmunity, leading to adverse drug reactions (ADRs), including high grade 3-4 colitis and its severe complications whose prevalence may reach 14% for combination checkpoint inhibitors. In this research, we investigated how mechanistic differences between anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab and pembrolizumab) affect colitis, a general class toxicity. The data analytical platform Molecular Health Effect was utilized to map population ADR data from the US Food and Drug Administration (FDA) Adverse Event Reporting System to chemical and biological databases for hypothesis generation regarding the underlying molecular mechanisms causing colitis. Disproportionality analysis was used to assess the statistical relevance between adverse events of interest and molecular causation. We verified that the anti-CTLA-4 drug is associated with an approximately three-fold higher proportional reporting ratio associated with colitis than those of the anti-PD-1 drugs. The signal of the molecular mechanisms, including signaling pathways of inflammatory cytokines, was statistically insignificant to test the hypothesis that the severer rate of colitis associated with ipilimumab would be due to a greater magnitude of T-cell activation as a result of earlier response of the anti-CTLA-4 drug in the immune response. This patient-centered systems-based approach provides an exploratory process to better understand drug pair adverse events at pathway and target levels through reverse translation from postmarket surveillance safety reports.