Monoclonal Antibody-Based Immunotherapy and Its Role in the Development of Cardiac Toxicity

Abstract

Immunotherapy is one of the most effective therapeutic options for cancer patients. Five specific classes of immunotherapies, which includes cell-based chimeric antigenic receptor T-cells, checkpoint inhibitors, cancer vaccines, antibody-based targeted therapies, and oncolytic viruses. Immunotherapies can improve survival rates among cancer patients. At the same time, however, they can cause inflammation and promote adverse cardiac immune modulation and cardiac failure among some cancer patients as late as five to ten years following immunotherapy. In this review, we discuss cardiotoxicity associated with immunotherapy. We also propose using human-induced pluripotent stem cell-derived cardiomyocytes/ cardiac-stromal progenitor cells and cardiac organoid cultures as innovative experimental model systems to (1) mimic clinical treatment, resulting in reproducible data, and (2) promote the identification of immunotherapy-induced biomarkers of both early and late cardiotoxicity. Finally, we introduce the integration of omics-derived high-volume data and cardiac biology as a pathway toward the discovery of new and efficient non-toxic immunotherapy.

Keywords: cardiomyocyte; cardiotoxicity; heart failure; heart failure with preserved ejection fraction (HFpEF); immune checkpoint inhibitors.

Figure 1

Molecular pathogenesis of immunotherapy-induced cardiac toxicity. Schematics describe how the ICIs such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 promote myocarditis via cardiac inflammation, causing myocyte damage. Cardiac myocyte dysfunction impairs systolic and diastolic function and causes failure and death.

Figure 2

Programmed death ligand-1 signaling and CTLA-4 deregulation facilitates tumor growth. Cartoon illustrates how PD-L1 interacts with PD-1 to inhibit T-cell activation and promote tumor cell proliferation (top panel). Working model of ICIs and promotion of cardiotoxicity (bottom panel). Cartoon illustrates how monoclonal anti-PD-1, anti-PDL-1, and anti-CTLA-4 activate T-cells following their binding to respective ligands. The activated T-cells kill/destroy the tumor cells by producing cytotoxic effects on cancer cells. In addition to tumor suppression, ICIs also promote cardiac myocyte damage, impairing function.

Figure 3

Development of preclinical models and determination of cardiac-safe ICIs. Diagram illustrates the use of hiPSC to develop in vitro human cardiomyocytes and cardiac organoids. These in vitro models can be used to screen monoclonal antibody-based ICIs for their cardiac toxicity. Further in vitro cardiac-safe ICIs can now be tested for toxicity in mouse tumor models and in cancer patients.