Immune Checkpoint Inhibitor Therapy Aggravates T Cell–Driven Plaque Inflammation in Atherosclerosis

Poels, Kikkie; Leent, Mandy M. T. van; Boutros, Céline; Tissot, Hervé; Roy, Séverine Le; Meerwaldt, Anu E.; Toner, Yohana C.; Reiche, Myrthe E.; Kusters, Pascal; Malinova, Tsveta S.; Huveneers, Stephan; Kaufman, A.A.; Mani, Venkatesh; Fayad, Zahi A.; Winther, Menno P.J. de; Marabelle, Aurélien; Mulder, Willem J. M.; Robert, Caroline; Seijkens, Tom; Lutgens, Esther

doi:10.1016/j.jaccao.2020.08.007

Cited by 82 publications

(62 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…53 As combined inhibition of CTLA4 and PD1 is a therapeutic strategy for several malignancies, we recently investigated the effects of dual antibody-mediated inhibition of CTLA4 and PD1 on atherosclerosis in Ldlr −/− mice. 36 Short-term (5 weeks) antibody treatment did not affect atherosclerotic lesion size. However, morphological analysis of the plaque phenotype demonstrated that inhibition of CTLA4 and PD1 resulted in a more advanced, clinically unfavorable plaque phenotype.…”

Section: Pathophysiology Of Ici-related Atherosclerotic Cvdmentioning

confidence: 96%

“…We previously investigated the effects of short-term ICI therapy on vascular inflammation in a small cohort of 10 ICI-treated patients with melanoma with a mean age of 53 years and without a history of CVD. 36 The majority of patients was treated with ipilimumab (intratumoral or intravenously) and nivolumab (intravenously), one patient received pembrolizumab (intravenously). FDG uptake was measured in the thoracic aorta and carotid arteries before and 6 weeks after initiation of ICI treatment.…”

Section: Insights From Imaging Studies: Ici Therapy Increases Vascular Inflammation and Plaque Progressionmentioning

confidence: 99%

“…No differences in arterial FDG maximum standardized uptake values (SUV max ) were observed, indicating that short-term ICI treatment did not affect vascular inflammation in this small cohort of patients with melanoma. 36 Another recent study investigated the effects of ICIs on vascular inflammation in a group of 20 patients with melanoma, a mean age of 74 years, and unknown history of CVD, who were treated for a longer period. 37 In this study, in which 80% of the patients received PD1 inhibitors, 5% received CTLA4 inhibitors, and 15% received dual therapy with PD1 and CTLA4 inhibitors, FDG uptake was measured in six arterial regions (ascending aorta, aortic arch, descending aorta, abdominal aorta, and both iliac arteries) before and 4.4 months after initiation of ICI treatment.…”

Section: Insights From Imaging Studies: Ici Therapy Increases Vascular Inflammation and Plaque Progressionmentioning

confidence: 99%

“…However, morphological analysis of the plaque phenotype demonstrated that inhibition of CTLA4 and PD1 resulted in a more advanced, clinically unfavorable plaque phenotype. 36 Antibody treatment also induced endothelial activation, characterized by increased expression of adhesion molecules, including VCAM1 and ICAM1, which may enhance immune cell migration into the plaque. 36 Accordingly, CD8 + T-cell abundance in the plaque increased by 2.7-fold, which increased the T cell:macrophage ratio (figure 1).…”

Section: Pathophysiology Of Ici-related Atherosclerotic Cvdmentioning

confidence: 99%

See 3 more Smart Citations

Immune checkpoint inhibitor treatment and atherosclerotic cardiovascular disease: an emerging clinical problem

Poels

Neppelenbroek

Kersten

et al. 2021

J Immunother Cancer

Self Cite

View full text Add to dashboard Cite

Antibody-mediated blockade of co-inhibitory molecules such as cytotoxic T lymphocyte-associated protein 4, PD1 and PDL1 elicits potent antitumor responses and improves the prognosis of many patients with cancer. As these immune checkpoint inhibitors (ICIs) are increasingly prescribed to a diverse patient population, a broad range of adverse effects is emerging. Atherosclerosis, a lipid-driven chronic inflammatory disease of the large arteries, may be aggravated by ICI treatment. In this review, we discuss recent clinical studies that analyze the correlation between ICI use and atherosclerotic cardiovascular disease (CVD). Indeed, several studies report an increased incidence of atherosclerotic CVD after ICI administration, with the occurrence of pathologies such as myocardial infarction, ischemic stroke and coronary artery disease significantly higher after ICI use. Increased awareness and better monitoring of ICI-treated patients can elucidate risk factors that contribute to ICI-induced aggravation of atherosclerosis and identify promising treatment strategies. For now, optimal cardiovascular risk assessment is required to protect ICI-receiving patients and long-term survivors of cancer from the detrimental effects of ICI therapy on atherosclerotic CVD.

show abstract

Section: Pathophysiology Of Ici-related Atherosclerotic Cvdmentioning

confidence: 96%

Section: Insights From Imaging Studies: Ici Therapy Increases Vascular Inflammation and Plaque Progressionmentioning

confidence: 99%

Section: Insights From Imaging Studies: Ici Therapy Increases Vascular Inflammation and Plaque Progressionmentioning

confidence: 99%

Section: Pathophysiology Of Ici-related Atherosclerotic Cvdmentioning

confidence: 99%

See 2 more Smart Citations

Immune checkpoint inhibitor treatment and atherosclerotic cardiovascular disease: an emerging clinical problem

Poels

Neppelenbroek

Kersten

et al. 2021

J Immunother Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, the intraplaque immune response shifted from macrophage to T cell-predominant with increased necrotic core and endothelial activation indicating plaque vulnerability to rupture. 25 Beyond the acute risk of ACS, ICIs lead to atherosclerosis progression and ASCVD risk. 16 PD-1 expression modulates the arterial wall immune response; disruption via PD-1 inhibition leads to atherosclerosis progression.…”

Section: Ici-associated Atherosclerosismentioning

confidence: 99%

Cardiotoxicities of novel cancer immunotherapies

Stein-Merlob

Rothberg

Ribas

et al. 2021

Heart

View full text Add to dashboard Cite

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.

show abstract

Association between immune checkpoint inhibitors and myocardial infarction in Asians: A population‐based self‐controlled case series

Chan¹,

Tang²,

Lee

et al. 2023

Cancer Medicine

View full text Add to dashboard Cite

Background While immune checkpoint inhibitors (ICIs) are associated with elevated cardiovascular risks, evidence of any association between ICIs and myocardial infarction (MI) was scarce, especially in Asians. Methods Using prospectively collected population‐based data, this self‐controlled case series included patients prescribed an ICI between 1/1/2014 and 31/12/2020 in Hong Kong who had MI within January 1, 2013 to December 31, 2021. Incidence rate ratios (IRRs) for MI during and after ICI exposure were estimated, compared to the year before ICI initiation. Results Of 3684 identified ICI users, 24 had MI during the study period. MI incidence increased significantly in the first 90 days of exposure (IRR 3.59 [95% confidence interval: 1.31–9.83], p = 0.013), but not days 91–180 ( p = 0.148) or ≥181 ( p = 0.591) of exposure, nor postexposure ( p = 0.923). Sensitivity analyses excluding patients with MI‐related death and incorporating extended exposure periods produced consistent results separately. Conclusions ICIs were associated with increased MI incidence in Asian Chinese patients during the first 90 days of use, but not later.

show abstract

Immune Checkpoint Inhibitor Therapy Aggravates T Cell–Driven Plaque Inflammation in Atherosclerosis

Cited by 82 publications

References 42 publications

Immune checkpoint inhibitor treatment and atherosclerotic cardiovascular disease: an emerging clinical problem

Immune checkpoint inhibitor treatment and atherosclerotic cardiovascular disease: an emerging clinical problem

Cardiotoxicities of novel cancer immunotherapies

Association between immune checkpoint inhibitors and myocardial infarction in Asians: A population‐based self‐controlled case series

Contact Info

Product

Resources

About