Cardiotoxicities of novel cancer immunotherapies

Abstract

Immunotherapy revolutionised oncology by harnessing the native immune system to effectively treat a wide variety of malignancies even at advanced stages. Off-target immune activation leads to immune-related adverse events affecting multiple organ systems, including the cardiovascular system. In this review, we discuss the current literature describing the epidemiology, mechanisms and proposed management of cardiotoxicities related to immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engagers. ICIs are monoclonal antibody antagonists that block a co-inhibitory pathway used by tumour cells to evade a T cell-mediated immune response. ICI-associated cardiotoxicities include myocarditis, pericarditis, atherosclerosis, arrhythmias and vasculitis. ICI-associated myocarditis is the most recognised and potentially fatal cardiotoxicity with mortality approaching 50%. Recently, ICI-associated dysregulation of the atherosclerotic plaque immune response with prolonged use has been linked to early progression of atherosclerosis and myocardial infarction. Treatment strategies include immunosuppression with corticosteroids and supportive care. In CAR T-cell therapy, autologous T cells are genetically engineered to express receptors targeted to cancer cells. While stimulating an effective tumour response, they also elicit a profound immune reaction called cytokine release syndrome (CRS). High-grade CRS causes significant systemic abnormalities, including cardiovascular effects such as arrhythmias, haemodynamic compromise and cardiomyopathy. Treatment with interleukin-6 inhibitors and corticosteroids is associated with improved outcomes. The evidence shows that, although uncommon, immunotherapy-related cardiovascular toxicities confer significant risk of morbidity and mortality and benefit from rapid immunosuppressive treatment. As new immunotherapies are developed and adopted, it will be imperative to closely monitor for cardiotoxicity.

Single-Cell RNA Sequencing Reveals the Altered Landscape of Immune Cells in Immune Checkpoint Inhibitor Related Myocarditis

“…The increased B cell cluster together with substantially different B cell receptor repertoire suggest the innate immunity is of crucial importance during the acute disease onset, consistent with previous assumptions 1, 2 . The B cell receptor repertoire diversity is achieved by somatic recombination of immunoglobulin (Ig) genes centrally and by somatic hypermutation and Ig heavy chain class-switching peripherally 27 .…”

“…With the revolutionized utilization of Immune checkpoint inhibitor (ICI) therapy in various malignancies, myocarditis has emerged as a rare but lethal ICI-associated toxicity, the mortality rate of which approaching 50%. While stimulating an effective tumor response by blocking the co-inhibitory pathway used by tumor cells to evade the T cell-mediated immune response, ICI could also elicit profound immune reaction and cytokine release, causing significant systemic abnormalities, including fulminant myocarditis 1, 2 . However, the exact mechanism for ICI related myocarditis remains underexplored; and the specific therapeutic targets is still lacking.…”

CHA1: A New Combinatorial Therapy That Reciprocally Regulates Wnt and JAK/STAT/Interferon Signaling to Re-program Breast Tumors and the Tumor-Resident Landscape

“…CHA1 is built from compounds with few side effects or with known side effects and that have been use or FDA-approved for other cancer. Similarly, reducing the efficacious dose of ICIs needed for efficacy may lessen the known ICI toxicities (158, 159). Together, we think the evidence is compelling to test CHA1 to improve anti-PD-L1 efficacy.…”

Clinical Characteristics and Outcomes in Immune Checkpoint Inhibitor Therapy-Associated Myocarditis

“…Cardiac magnetic resonance imaging has also been noted as being helpful in evaluation of the myocardium in ICI-associated myocarditis but with overall poor sensitivity. Ultimately, the main determining diagnostic modality is endomyocardial biopsy [81]. Endomyocardial biopsy usually demonstrates a predominance of lymphocytes with myocyte necrosis along with fibrosis and inflammation [82].…”