Pathophysiology of Immune Checkpoint Inhibitor-Induced Myocarditis

Abstract

Immune checkpoint inhibitors (ICIs) have recently emerged as strong therapies for a broad spectrum of cancers being the first-line treatment for many of them, even improving the prognosis of malignancies that were considered untreatable. This therapy is based on the administration of monoclonal antibodies targeting inhibitory T-cell receptors, which boost the immune system and prevent immune evasion. However, non-specific T-cell de-repression can result in a wide variety of immune-related adverse events (irAEs), including gastrointestinal, endocrine, and dermatologic, with a smaller proportion of these having the potential for fatal outcomes such as neurotoxicity, pulmonary toxicity, and cardiotoxicity. In recent years, alarm has been raised about cardiotoxicity as it has the highest mortality rate when myocarditis develops. However, due to the difficulty in diagnosing this cardiac condition and the lack of clinical guidelines for the management of cardiovascular disease in patients on therapy with ICIs, early detection of myocarditis has become a challenge in these patients. In this review we outline the mechanisms of tolerance by which this fatal cardiomyopathy may develop in selected cancer patients treated with ICIs, summarize preclinical models of the disease that will allow the development of more accurate strategies for its detection and treatment, and discuss the challenges in the future to decrease the risks of its development with better decision making in susceptible patients.

Rare Immune-Related Adverse Events (irAEs): Approach to Diagnosis and Management

“…Given such a wide-ranging spectrum of possible presentations, recognition and diagnosis is often poor and the reported frequency likely under-represents the true incidence of this condition. In addition, a mortality rate as high as 50% has been reported, underscoring the need to define risk factors, improve diagnostic tools and develop effective management strategies [ 19 , 20 ]. While combination immunotherapy approaches have been associated with higher rates of myocarditis, there are minimal data to inform further predisposing factors [ 2 , 3 ].…”

“…The median time to the development of myocarditis is reported to be 30 days, indicating that it tends to arise early in the treatment course [ 21 ]. Tumour-related factors may also influence the development of toxicity, either through alterations in the tumour microenvironment or through the presence of a shared antigen to specific tissues [ 3 , 20 ]. It is clear from mouse models and post-mortem analyses that the pathogenesis of ICI-myocarditis is distinct, and involves immune-cell infiltrates rich in T cells and macrophages, with minimal antibody-mediated inflammation.…”

“…Syndromes involving inflammation of smooth muscle have not been reported. This adds weight to the theory of a shared antigen between the tumour and striated muscle [ 20 ].…”

“…Current evidence suggests that initiation of high-dose corticosteroids or additional immunosuppression within 24 hours of development of myocarditis yields the best outcomes [ 5 ]. However, due to the rarity and sometimes minimally or atypically symptomatic nature of ICI-myocarditis, there can be delays in recognition, diagnosis and subsequent treatment [ 20 ]. The optimal duration of corticosteroid treatment is unknown but guidelines suggest patients are weaned off these medications slowly, often over a period of 4–6 weeks [ 5 , 23 ].…”

“…These were observed more commonly with anti-PD-1/PD-L1 agents than anti-CTLA-4 or combination therapy. Co-existing myopathy is common [ 20 ]. Interestingly, 58% of patients demonstrated positive AChR antibodies but anti-muscle–specific kinase (MusK) was not demonstrated [ 25 ].…”