Targeting IL-12 and IL-23 in immune-related adverse events from checkpoint inhibitors: current evidence and future directions

Immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer therapy, but they come with the risk of adverse events that can impact any organ system. Our current knowledge of the mechanisms of these immune-related adverse events (irAEs), as well as suitable treatment options, is limited. Recent studies suggest a role for interleukins 12 (IL-12) and 23 (IL-23) in the pathogenesis of irAEs and a potential role for biologics targeting this axis in their treatment, but specific indications for IL-12 and/or IL-23 blockade are not clear. We reviewed the current evidence for IL-12/23 and IL-23 blockade to treat irAEs in various organ systems.

This scoping review comprehensively examined literature on the pathogenesis of cutaneous, rheumatic, gastrointestinal, endocrine, neurologic, hematologic, renal, and pulmonary irAEs in cancer patients receiving ICIs and all preclinical and clinical evidence and rationale for the use of IL-12/23 or IL-23 inhibitors in their treatment.

Our understanding of the pathophysiology underlying irAEs is limited, but recent studies have shown that unique pathways are involved in different types of irAEs. The use of IL-12/23 or IL-23 blockade is helpful specifically in cutaneous (psoriasis), rheumatic (psoriatic arthritis), and gastrointestinal (colitis) irAEs, and there is potential application in pulmonary toxicity. More preclinical studies are needed to identify therapeutic targets in different irAEs, as well as case series on the clinical experience with these agents in irAEs, especially IL-23 inhibitors for ICI-related colitis and ICI-related pneumonitis, given the difficulty of conducting clinical trials in this context.