Immune Checkpoint Inhibitors and Cardiac Toxicity: An Emerging Issue

Abstract

Although survival of patients with different types of cancer has improved, cardiotoxicity induced by anti-neoplastic drugs remains a critical issue. Cardiac dysfunction after treatment with anthracyclines has historically been a major problem. However, also targeted therapies and biological molecules can induce reversible and irreversible cardiac dysfunction. Over the last years, cancer immunotherapies haverevolutionized the clinical management of a wide spectrum of solid and hematopoietic malignancies previously endowed with poor prognosis. Immune checkpoint inhibitors are at the forefront of immunotherapy: the two most prominent are the targeting of cytotoxic-T-lymphocyte-associated antigen 4 (CTLA- 4) and of programmed cell death 1 (PD-1) and its ligand PD-L1. Ipilimumab (anti-CTLA-4) is the godfather of checkpoint inhibitors, whereas several blocking monoclonal antibodies targeting PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab, durvalumab, avelumab, and BMS-946559) have been developed. Inhibitors of CTLA-4 and PD-1/PD-L1 pathway can unleash anti-tumor immunity and mediate cancer regressions. Although CTLA-4 inhibitors and PD-1 and PD-L1 blocking agents are frequently associated with a wide spectrum of immune-related adverse events, cardiac toxicity has been underestimated. However, early animal studies have demonstrated that after CTLA-4 inhibition and PD-1 deletion autoimmune myocarditis can occur. Moreover, PD-1 and PD-L1 can be expressed in rodent and human cardiomyocytes. During the last years several cases of fatal heart failure have been documented in melanoma patients treated with checkpoint inhibitors. The recent experience with cardiovascular toxic effects associated with checkpoint inhibitors introduces important concepts biologically and clinically relevant for future oncology trials and clinical practice.

Heterogeneity of Liver Disease in Common Variable Immunodeficiency Disorders

“…Cytotoxic T-lymphocyte antigen 4 (CTLA4) is an essential negative immune regulator acting in the suppression of T-cell proliferation and differentiation mediated by regulatory (Treg) cells (101,102). Heterozygous germline mutations in CTLA4 cause an immune dysregulation and immunodeficiency syndrome including hypogammaglobulinemia, lymphoproliferation, recurrent respiratory infections and bronchiectasis, enteropathy, autoimmune cytopenias, atopic dermatitis, endocrinopathy, and neurological features (103,104).…”

Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

“…Thus, serious side effects such as cardiotoxicity are still being documented. Nevertheless, clinical cardiotoxicity induced by ICIs and CART have been reported (Table ).…”

“…ICIs work by blocking inhibitory pathways of T‐cell activation, leading to an immune response directed against tumors; thus, this activation represents a nonspecific immunologic activation that can lead to immune‐related adverse events (IRAEs) . To date, FDA‐approved ICIs include Ipilimumab (CTLA‐4), Pembrolizumab (PD‐1), Nivolumab (PD‐1), Atezolizumab (PD‐L1), Avelumab (PD‐L1), and Durvalumab (PD‐L1). Based on the working principles, ICI‐induced toxicity typically involves autoimmune disorders, including autoimmune myocarditis .…”

“…To date, FDA‐approved ICIs include Ipilimumab (CTLA‐4), Pembrolizumab (PD‐1), Nivolumab (PD‐1), Atezolizumab (PD‐L1), Avelumab (PD‐L1), and Durvalumab (PD‐L1). Based on the working principles, ICI‐induced toxicity typically involves autoimmune disorders, including autoimmune myocarditis . The importance of ICIs in the heart has been addressed in preclinical data, and the data give some mechanistic insights into the clinical observations of autoimmune myocarditis .…”

“…Based on the working principles, ICI-induced toxicity typically involves autoimmune disorders, 28,54,555,557,559 including autoimmune myocarditis. [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]93,550 The importance of ICIs in the heart has been addressed in preclinical data, and the data give some mechanistic insights into the clinical observations of autoimmune myocarditis. 560,561 In addition, although ICIs are an attractive concept in the therapeutic development of cancer treatment, many cancer patients do not respond to treatments with ICIs, partly because of the lack of tumor-infiltrating effector T cells [562][563][564][565] or primary or acquired resistance due to various mechanisms.…”