Oncological therapies have advanced rapidly, significantly improving cancer patient survival. One of the key breakthroughs in oncology is immune checkpoint inhibitors (ICIs). By blocking interactions between programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) or targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), ICIs enhance the immune system's ability to identify and eliminate cancer cells. ICIs have proven effective in treating an ever-increasing range of otherwise incurable malignancies. The overall survival benefit of immunotherapy over conventional therapies has been demonstrated in multiple large-scale phase III clinical trials, particularly in malignancies such as melanoma and PD-L1-positive lung cancer. Despite being an effective cancer treatment, ICI-related toxicities are not uncommon. One rare but potentially lethal side effect is ICI-induced myocarditis, which may occur in isolation or alongside other immune-related adverse events (IRAEs), such as the “3M” syndrome—myocarditis, myositis, and myasthenia (1). Some combinations of immunotherapies and specific dosing intervals carry a higher risk of ICI-myocarditis than others (2). While clinical characteristics and treatment responses to ICI-induced myocarditis are becoming clearer, the precise pathogenic mechanism remains elusive despite previous patient case-control studies and animal models (3, 4).
In a recently published study, Quagliariello et al. used an in vitro model involving co-culturing of cardiomyocytes and peripheral blood mononuclear cells (PBMC), to investigate the inflammatory response to ICI monotherapy and combinational therapies, consisting of PD-L1, PD-1, CTLA-4, and Lymphocyte-activation gene 3 (LAG-3) inhibitors. It was found that co-culture systems that were treated with combinational ICI therapy resulted in higher level of cardiac biomarkers, including troponin and brain natriuretic peptide, than those treated with monotherapy. They found that co-culture systems treated with combination ICI therapy resulted in higher levels of cardiac biomarkers, including troponin and brain natriuretic peptide, than those treated with monotherapy. Further evaluation to investigate potential mechanisms demonstrated heightened inflammatory responses with increased expression of inflammasome and cytokines. The authors also performed additional evaluation to delineate changes in mitochondrial and epigenetic domains. Altogether, the report by Quagliariello et al. provided novel insights into the potential pathogenic mechanism of ICI-induced myocarditis.
In addition to potentially causing myocarditis, ICI therapies have also been linked to other cardiovascular adverse events (CVAE). Overall, 0.80%–1.07% patients treated with ICI therapy experience CVAE (5), which potentially include myocardial infarction, stroke, arrhythmia, heart failure, myocarditis, pericardial disease, vasculitis, and hyperlipidemia (6, 7). Currently, real-world data related to ICI-associated CVAE is still scarce, and it is unclear which groups of patients are more susceptible to developing CVAE. To investigate the potential cardiotoxicities combination therapies, Inno et al. performed a meta-analysis involving 12 trials and 8,124 patients, assessing the cardiovascular toxicity of ICI plus angiogenesis inhibitors (AIs) compared to AIs alone Inno et al. It was found that patients with additional treatment with ICI had higher risk of developing severe hypertension. Reassuringly, the other analyzed CVAE, including stroke, myocardial infarction and pulmonary embolisms, were not significantly increased. Furthermore, patients treated with combination ICI and AI had superior 1-year progression free survival.
The expanding use of ICIs necessitates better understanding of their cardiovascular risks. As research priorities continue to evolve, emphasis must be placed on large-scale prospective studies to identify risk factors and biomarkers, mechanistic investigations to elucidate pathogenic pathways, clinical trials evaluating preventive and therapeutic interventions, and development of standardized monitoring protocols. As our understanding evolves, the goal remains to maximize the therapeutic benefits of ICIs while effectively managing their cardiovascular complications. This requires continued collaboration between oncologists, cardiologists, and basic scientists in the emerging field of cardio-oncology.
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Author contributions
IH: Writing – original draft, Writing – review & editing. Y-TL: Writing – original draft, Writing – review & editing. T-HL: Writing – original draft, Writing – review & editing. C-KW: Writing – original draft, Writing – review & editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declare that no Generative AI was used in the creation of this manuscript.
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References
1.
LamT-HWongJS-LWongC-KKwokGGWZhowMSoBY-Fet alFrom bad to worse: the clinical Spectrum of immune checkpoint inhibitor myocarditis and associated 3M syndrome with concomitant myositis and myasthenia. J Hong Kong Coll Cardiol. (2022) 29(3):135–42. 10.55503/2790-6744.1484
2.
ChangCYParkHMaloneDCWangCYWilsonDLYehYMet alImmune checkpoint inhibitors and immune-related adverse events in patients with advanced melanoma: a systematic review and network meta-analysis. JAMA Netw Open. (2020) 3(3):e201611. 10.1001/jamanetworkopen.2020.1611
3.
ZhuHGaldosFXLeeDWalianySHuangYVRyanJet alIdentification of pathogenic immune cell subsets associated with checkpoint inhibitor-induced myocarditis. Circulation. (2022) 146(4):316–35. 10.1161/CIRCULATIONAHA.121.056730
4.
WongCKLamTHLiaoSYLauYMTseHFSoBYF. Immunopathogenesis of immune checkpoint inhibitor induced myocarditis: insights from experimental models and treatment implications. Biomedicines. (2023) 11(1):107. 10.3390/biomedicines11010107
5.
NielsenDLJuhlCBNielsenOHChenIMHerrmannJ. Immune checkpoint inhibitor-induced cardiotoxicity: a systematic review and meta-analysis. JAMA Oncol. (2024) 10(10):1390–9. 10.1001/jamaoncol.2024.3065
6.
DolladilleCAkrounJMoricePMDompmartinAEzineESassierMet alCardiovascular immunotoxicities associated with immune checkpoint inhibitors: a safety meta-analysis. Eur Heart J. (2021) 42(48):4964–77. 10.1093/eurheartj/ehab618
7.
JainPGutierrez BugarinJGuhaAJainCPatilNShenTet alCardiovascular adverse events are associated with usage of immune checkpoint inhibitors in real-world clinical data across the United States. ESMO Open. (2021) 6(5):100252. 10.1016/j.esmoop.2021.100252
Summary
Keywords
immune checkpoint inhibitor, myocarditis, hypertension, cardiovascular adverse event, cardio-oncology
Citation
Ho I, Lee Y-T, Lam T-H and Wong C-K (2024) Editorial: Cardiovascular complications of emerging oncological therapies. Front. Cardiovasc. Med. 11:1530705. doi: 10.3389/fcvm.2024.1530705
Received
19 November 2024
Accepted
06 December 2024
Published
16 December 2024
Volume
11 - 2024
Edited and reviewed by
Junjie Xiao, Shanghai University, China
Updates
Copyright
© 2024 Ho, Lee, Lam and Wong.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Chun-Ka Wong wongeck@hku.hk
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.