Peripheral nervous system immune-related adverse events due to checkpoint inhibition

Immune checkpoint inhibitors have revolutionized cancer therapy and are increasingly used to treat a wide range of oncological conditions, with dramatic benefits for many patients. Unfortunately, the resulting increase in T cell effector function often results in immune-related adverse events (irAEs), which can involve any organ system, including the central nervous system (CNS) and peripheral nervous system (PNS). Neurological irAEs involve the PNS in two-thirds of affected patients. Muscle involvement (immune-related myopathy) is the most common PNS irAE and can be associated with neuromuscular junction involvement. Immune-related peripheral neuropathy most commonly takes the form of polyradiculoneuropathy or cranial neuropathies. Immune-related myopathy (with or without neuromuscular junction involvement) often occurs along with immune-related myocarditis, and this overlap syndrome is associated with substantially increased mortality. This Review focuses on PNS adverse events associated with immune checkpoint inhibition. Underlying pathophysiological mechanisms are discussed, including antigen homology between self and tumour, epitope spreading and activation of pre-existing autoreactive T cells. An overview of current approaches to clinical management is provided, including cytokine-directed therapies that aim to decouple anticancer immunity from autoimmunity and emerging treatments for patients with severe (life-threatening) presentations. Some patients who are treated with checkpoint inhibitors experience peripheral nervous system (PNS) immune-related adverse events (irAEs). O'Hare and Guidon describe the spectrum of PNS irAE phenotypes, discuss their underlying mechanisms and outline a consensus-based, pathophysiology-driven approach to their clinical management. Checkpoint inhibitors have improved cancer outcomes but the resultant increase in T cell effector function can result in immune-related adverse events (irAEs).Neurological irAEs occur in 1-2% of all patients treated with checkpoint inhibitors and most frequently (in about two-thirds of individuals) involve the peripheral nervous system (PNS).The most common presentation of PNS irAEs is immune-related myopathy, which can be associated with immune-related neuromuscular junction involvement; immune-related neuropathy most commonly presents as polyradiculoneuropathy or cranial neuropathies.irAEs are largely driven by excessive T cell activity and autoimmunity resulting from factors including antigen homology between self and tumour, epitope spreading and activation of pre-existing autoreactive T cells.Clinical management of PNS irAEs is guided by syndrome subtype, severity and comorbidities, most notably myocarditis; research focuses on prevention, identification of new targeted treatments and strategies for severe, life-threatening PNS irAEs.