Adverse events induced by immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors have revolutionized the treatments of cancers but are also associated with immune related adverse events that can interfere with their use. The types and severity of adverse events vary with checkpoint inhibitors. A single mechanism of pathogenesis has not emerged: postulated mechanisms involve direct effects of the checkpoint inhibitor, emergence of autoantibodies or autoreactive T cells, and destruction by toxic effects of activated T cells. Several host factors such as genotypes, preexisting autoimmune disease, inflammatory responses and others may have predictive value. Ongoing investigations seek to identify ways of modulating the autoimmunity without affecting the anti-tumor response with agents that are specific for the autoimmune mechanisms.

Figure 1.. Potential mechanisms of CPI-induced immune related adverse events.

Mechanisms of irAEs vary depending on the organ system affected and type of CPI. The pathophysiology of irAEs remains largely unknown but postulated mechanism are shown. Although frequency of autoantibodies is lower than in spontaneous autoimmune disease, autoantibodies may paly a role in some autoimmune complications, including thyroid dysfunction where presence of autoantibodies at baseline increases risk of this complication. Direct CTLA-4 mAb binding to pituitary cells and complement activation may lead to hypophysitis. Inflammatory cytokines also seem to play a role in the development of certain irAEs. T cell mediated processes, in particular autoreactive T cells, may be involved in the development of myocarditis and skin toxicities. The microbiome may impact risk of developing irAEs, such as colitis, and may also be mechanistically important.