Cardiovascular toxicity of angiogenesis inhibitors and immune checkpoint inhibitors: synergistic anti-tumour effects at the cost of increased cardiovascular risk?

Abstract

In the past two decades, treatment outcomes for a wide range of malignancies have improved remarkably due to the development of novel anti-cancer therapies, including vascular endothelial growth factor inhibitors (VEGFIs) and immune checkpoint inhibitors (ICIs). Despite their unprecedented anti-tumour effects, it is becoming increasingly clear that both types of agents are associated with specific cardiovascular toxicity, including hypertension, congestive heart failure, myocarditis and acceleration of atherosclerosis. Currently, VEGFI and ICI combination therapy is recommended for the treatment of advanced renal cell carcinoma (RCC) and has shown promising treatment efficacy in other tumour types as well. Consequently, VEGFI and ICI combination therapy will most likely become an important therapeutic strategy for various malignancies. However, this combinatory approach is expected to be accompanied by a substantial increase in cardiovascular risk, as both types of agents could act synergistically to induce cardiovascular sequelae. Therefore, a comprehensive baseline assessment and adequate monitoring by specialised cardio-oncology teams is essential in case these agents are used in combination, particularly in high-risk patients. This review summarises the mechanisms of action and treatment indications for currently registered VEGFIs and ICIs, and discusses their main vascular and cardiac toxicity. Subsequently, we provide the biological rationales for the observed promising synergistic anti-tumour effects of combined VEGFI/ICI administration. Lastly, we speculate on the increased risk for cardiovascular toxicity in case these agents are used in combination and its implications and future directions for the clinical situation.

Cardiovascular toxicity associated with angiogenesis inhibitors: A comprehensive pharmacovigilance analysis based on the FDA Adverse Event Reporting System database from 2014 to 2021

“…Although the application of angiogenesis inhibitors has revolutionized the therapy and substantially improved the outcomes for patients with a variety of malignancies, their side effects, especially cardiovascular toxicity, have been increasingly recognized along with their curative effects (1,2,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Nevertheless, the real profiles of cardiovascular toxicity associated with angiogenesis inhibitors are still unclear due to scarce evidence in the real-world setting (20).…”

“…Despite the remarkable anti-tumor effects of angiogenesis inhibitors in a variety of cancer cases, emerging evidence has shown cardiovascular toxicity associated with angiogenesis inhibitors (6)(7)(8). Although hypertension has received the most attention, a wider range of cardiovascular toxicity, including left ventricular systolic dysfunction, heart failure, myocardial ischemia, thromboembolic events, QT interval prolongation, and arrhythmia, has also been increasingly recognized (1,2,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). However, the majority of these data were from clinical trials, conducted in selected populations, which may underestimate the real burden of cardiovascular toxicity.…”

“…Angiogenesis plays a critical role in tumor growth and metastasis, and vascular endothelial growth factor (VEGF) has been confirmed to be the main proangiogenetic factor ( 1 , 2 ). Targeting VEGF-induced angiogenesis to establish an anti-neoplastic effect was first proposed by Folkman in 1971 ( 3 ).…”

The Diagnosis and Management of Immune Checkpoint Inhibitor Cardiovascular Toxicity: Myocarditis and Beyond

“…Some examples include engineering high affinity PD-1 variants for immune-PET imaging and a humanized antibody for imaging immune checkpoint ligand PD-L1 expression in tumors [50,51]. In principle, the toxicities can involve various organs, including cardiovascular, where imaging of this type may be of potential assistance in monitoring and diagnosis [52,53].…”

Mechanistic science in cardiovascular-oncology: the way forward to maximise anti-cancer drug effects and minimise cardiovascular toxicity

“…The cardiovascular consequences of more prolonged exposure to angiogenesis inhibition remain unknown, although these are a concern and require careful prospective ascertainment via longer term trial follow-up with appropriately defined cardiovascular endpoints and via dedicated cardio-oncology registries. Whether angiogenesis inhibition potentiates the cardiovascular toxic effects of immunotherapy, particularly atherogenesis and plaque inflammation remains unclear [ 13 ]. In more general terms, there is great potential for interaction between cardiovascular therapies and anti-cancer agents, especially via cytochrome p450 effects [ 14 ].…”