Adverse Events Following Cancer Immunotherapy: Obstacles and Opportunities

Abstract

Oncology has recently undergone a revolutionary change with widespread adoption of immunotherapy for many cancers. Immunotherapy using monoclonal antibodies against checkpoint molecules, including programmed death (PD)-1, PD ligand (PD-L)1, and cytotoxic T lymphocyte-associated antigen (CTLA)-4, is effective in a significant subset of patients. However, immune-related adverse events (irAEs) have emerged as frequent complications of checkpoint blockade, likely due to the physiological role of checkpoint pathways in regulating adaptive immunity and preventing autoimmunity. As immunotherapy becomes more common, a better understanding of the etiology of irAEs and ways to limit these events is needed. At the same time, studying these new therapy-related disorders provides an opportunity to better understand naturally occurring human autoimmune and inflammatory disorders, with the potential to improve therapies for cancer and autoimmune diseases.

Keywords: autoimmunity; cancer immunotherapy; checkpoint blockade; immune-related adverse events; tolerance.

Key Figure, Figure 1:. Pathogenic immune responses and the onset of autoimmunity or immune-relative adverse events.

Perturbed immune homeostasis can provoke pathogenic immune responses and the onset of autoimmunity or immune-relative adverse events (IrAE). (Top) Immune homeostasis involves major contributions from both central and peripheral tolerance mechanisms, acting as fail safes to limit aberrant immune activation against self tissues. (Bottom Left) Autoimmunity manifests when there is a natural breakdown of immune tolerance. While the underlying mechanisms contributing to autoimmunity remain elusive, they are thought to involve a complex interplay between host genetics, environmental factors, and some element of probability. Some autoimmune diseases can be caused by single gene mutations/loss of function, but generally, autoimmunity is caused by perturbations in a number of pathways. (Bottom Right) IrAE can occur following therapy-induced loss of tolerance. The mechanisms may share some overlap with natural autoimmunity in different organ systems, and may also operate via distinct mechanisms. Unlike spontaneous autoimmunity, therapy-induced loss of tolerance occurs following a sudden, widespread inhibition of either a single pathway (e.g. anti-PD-1 or anti-CTLA-4 monotherapy) or several pathways (e.g. combination therapy with anti-PD-1 plus anti-CTLA-4), and in a way not commonly found in the natural breakdown of tolerance.