Immune Checkpoint Inhibitors: Cardiotoxicity in Pre-clinical Models and Clinical Studies

Abstract

Since the approval of the first immune checkpoint inhibitor (ICI) 9 years ago, ICI-therapy have revolutionized cancer treatment. Lately, antibodies blocking the interaction of programmed cell death protein (PD-1) and ligand (PD-L1) are gaining momentum as a cancer treatment, with multiple agents and cancer types being recently approved for treatment by the US Food and Drug Administration (FDA). Unfortunately, immunotherapy often leads to a wide range of immune related adverse events (IRAEs), including several severe cardiac effects and most notably myocarditis. While increased attention has been drawn to these side effects, including publication of multiple clinical observational data, the underlying mechanisms are unknown. In the event of IRAEs, the most widely utilized clinical solution is administration of high dose corticosteroids and in severe cases, discontinuation of these ICIs. This is detrimental as these therapies are often the last line of treatment options for many types of advanced cancer. In this review, we have systematically described the pathophysiology of the PD-1/PD-L1 axis (including a historical perspective) and cardiac effects in pre-clinical models, clinical trials, autoimmune mechanisms, and immunotherapy in combination with other cancer treatments. We have also reviewed the current challenges in the diagnosis of cardiac events and future directions in the field. In conclusion, this review will delve into this expanding field of cancer immunotherapy and the emerging adverse effects that should be quickly detected and prevented.

Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: A Systematic Review

“…A case described by Martinez-Calle et al showed that the patient did have IgG autoantibodies against cardiac troponin T, but it is unknown if the antibodies were present before initiation of ICI therapy [33]. Two other patients have shown autoantibody deposition in cardiac muscle, suggesting a direct relationship between the antibodies and myocarditis [34]. However, many more cases have stated that no autoantibodies were found on histology or blood tests [11,15,35], leading to the conclusion that autoantibodies are generally not involved in the pathogenesis of cardiotoxicity with ICIs.…”

Comparative Transcriptomics of Immune Checkpoint Inhibitor Myocarditis Identifies Guanylate Binding Protein 5 and 6 Dysregulation

“…Animal models have been used to study the effects of the ICI-associated immune reaction on the heart [14]. Genetic deletion of PD-1 in the BALB/c mouse line resulted in dilated cardiomyopathy (DCM) with accumulation of immunoglobulins on the cardiomyocytes' surface [15].…”

Human Organoids for Predictive Toxicology Research and Drug Development

“…Thus, a novel assay system, such as the co-culture of PSC-CMs and immune cells, may help us to gain a deeper understanding of the crosstalk between CMs and immune cells. Furthermore, efforts to develop such assay systems may help reveal the mechanisms underlying immune checkpoint inhibitor-related cardiotoxicity ( Michel et al, 2019 ; Behravesh et al, 2020 ; Xu et al, 2021 ) and to mimic such adverse effects in vitro . Another limitation of the 3D cardiac organoids/microtissues is that the degree of maturation for the fabricated organoids is not yet sufficient, when compared to adult cardiac tissues, in terms of morphology, function, and gene expression, and this prevents accurate predictions of drug-induced cardiotoxicity.…”