Table 4.

Outstanding pathophysiological and therapeutic questions relevant to immune-related adverse events (irAEs) associated with immune checkpoint inhibitors.

What are the immunological bases of different irAEs? Is there a genetic predisposition to explain why irAEs occur in some patients and not in others? Are genetic or epigenetic alterations linked to different irAEs? Are irAEs the new face of primary autoimmune disorders or rather a new disease entity? Why do some irAEs occur early whereas others occur late during ICI therapy? Can late-onset irAEs (i.e., accelerated atherosclerosis) up to several years after starting treatment occur? Are we accelerating atherosclerosis in cancer patients by releasing the brakes with ICIs? What is the long-term safety of cancer patients with pre-existing autoimmune disorders treated with ICIs? Are specific gut microbiota associated with different irAEs? Can gut microbiome be used to identify cancer patients who may develop irAEs? Is there a possibility of preventing irAEs with biological therapies (e.g., anti-TNF-α, anti-IL-1R)? Can gut microbiome engineering (e.g., fecal microbiota transplantation) lead to treatment of irAEs?