Management of Immune-Related Adverse Events for Patients Undergoing Treatment with Checkpoint Inhibitors

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Background

Programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are immune checkpoints that are expressed on the surface of antigen-presenting cells in the initiator and effector phase of T-cell activation respectively. These immune checkpoints are responsible for “switching off” the T-cell. Inhibition of these checkpoints allows for overexpression of the immune system. This immune system over-activation may result in side effects in healthy body tissues, which is how toxicities possible arise; however, the precise mechanism is unknown. These side effects are referred to as immune-related adverse events (irAEs). The overall incidence of grade 3 or 4 irAEs is higher with CTLA-4 blockers, compared to PD-1 and PDL-1 inhibitors, which are better tolerated. The combination of PD-1 inhibitor with a CTLA-4 inhibitor was recently approved for melanoma. The combination was associated with a greater overall response rate; however, more adverse reactions were seen with the two antibodies used together, especially grade 3 or 4 irAEs (55%).

Fatigue is a very common irAE seen in patients treated with checkpoint inhibitors in approximately half of the patients. Other common irAEs seen includes colitis in a third of the patients and dermatological irAEs in 44%. The incidence of hepatic and endocrine system (hypophysitis, adrenal insufficiency, and hypothyroidism) involvement follows with about 5–6%. Pulmonary irAEs are more prevalent with PD-1 blockers, with an incidence of approximately 1% and develops far later during the course of treatment.

The neurological system is less commonly affected (sensory and motor neuropathies, Guillain-Barre syndrome, posterior reversible encephalopathy syndrome, aseptic meningitis, enteric neuropathy, and transverse myelitis). Additionally, ophthalmologic (episcleritis, conjunctivitis, and uveitis), renal (renal insufficiency and nephritis), hematological (red cell aplasia, neutropenia, acquired hemophilia A, thrombocytopenia, hemolytic-uremic syndrome) cardiovascular, and musculoskeletal irAE’s have been reported.

Most IrAEs commonly develop within 6–12 weeks of initial dose and resolve within 12 weeks of onset, but in some patients, it could appear after the first treatment. The optimal management of irAEs includes early recognition (by far the most important), proper assessment of severity, and early initiation of therapy (either supportive or immunosuppressive). In general mild irAEs can be observed and treated symptomatically with supportive care. Moderate irAEs, usually require stopping the offending agent, treatment with oral corticosteroid and resuming the checkpoint inhibitor once the irAE have resolved. Severe irAEs warrant permanent discontinuation of the checkpoint inhibitor, patient hospitalization, and treatment with high-dose intravenous corticosteroids. In very severe cases other immunosuppressive agents such as infliximab or mycophenolate mofetil may be needed. When managed correctly, promptly and with close monitoring, most irAEs are reversible.

This Research Topic will focus on broad aspects in the understanding of the pathogenesis, incidence and management of irAE associated with cancer immunotherapy and checkpoint inhibitors alone or in combination with other types of treatment such as kinase inhibitors, radiation therapy, chemotherapy as well as immunomodulatory agents and cancer vaccines. We welcome high-quality original articles, meta-analyses, short reviews as well as full-length review contributions related to the above topic.

Keywords: Immune-Related Adverse Events, Checkpoint Inhibitors, Pneumonitis, Colitis, Nephritis, Anti-PD1, Anti-PDL1, Anti-CTLA4

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