Cardiotoxicity of T-Cell Antineoplastic Therapies: JACC: CardioOncology Primer

Abstract

T-cell therapies, such as chimeric antigen receptor (CAR) T-cell, bispecific T-cell engager (BiTE) and tumor-infiltrating lymphocyte (TIL) therapies, fight cancer cells harboring specific tumor antigens. However, activation of the immune response by these therapies can lead to a systemic inflammatory response, termed cytokine release syndrome (CRS), that can result in adverse events, including cardiotoxicity. Retrospective studies have shown that cardiovascular complications occur in 10% to 20% of patients who develop high-grade CRS after CAR T-cell therapy and can include cardiomyopathy, heart failure, arrhythmias, and myocardial infarction. While cardiotoxicities have been less commonly reported with BiTE and TIL therapies, systematic surveillance for cardiotoxicity has not been performed. Patients undergoing T-cell therapies should be screened for cardiovascular conditions that may not be able to withstand the hemodynamic perturbations imposed by CRS. Generalized management of CRS, including the use of the interleukin-6 antagonist, tocilizumab, for high-grade CRS, is used to mitigate the risk of cardiotoxicity.

Keywords: BCMA, B-cell maturation antigen; BiTE therapy; BiTE, bispecific T-cell engager; CAR T-cell therapy; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; HF, heart failure; ICSR, individual case safety report; IL, interleukin; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular event(s); TIL, tumor-infiltrating lymphocyte; arrhythmia; cardiomyopathy; cardiotoxicity; heart failure; tumor-infiltrating lymphocytes.

Graphical abstract

Figure 1

Mechanisms of T-Cell Therapies and Manifestations of Cardiotoxicity Mechanism of (A) chimeric antigen receptor (CAR) T-cell, (B) bispecific T-cell engager (BiTE), and (C) tumor-infiltrating lymphocyte (TIL) therapy. With these therapies, T-cell activation leads to tumor-cell lysis and initiates a cascade of cytokine release, including interleukin (IL)-1, IL-6, interferon (IFN)–γ, and tumor necrosis factor (TNF)–α. This inflammatory response can trigger cytokine release syndrome (CRS), which has been associated with hypotension, heart failure, arrhythmias, acute coronary syndrome, and cardiac arrest. CRS is most commonly treated with tocilizumab, an anti-IL-6 monoclonal antibody (Ab), and steroids are used in refractory cases. Partly adapted Stein-Merlob AF, Ganatra S, Yan EH. T-cell immunotherapy and cardiovascular disease: chimeric antigen receptor T-cell and bispecific T-cell engager therapies. Heart Fail Clin. 2022;18(3):443-454. Created using BioRender.com. MAGE-A3 = melanoma-associated antigen 3; TCR = T-cell receptor.