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

Daan C.H.van Dorst, Leni van Doorn, Katrina M. Mirabito Colafella, Olivier C. Manintveld, H. Carlijne Hassing, A. H.Jan Danser, Ron H.J. Mathijssen, Jorie Versmissen

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5 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1649-1668
Number of pages20
JournalClinical science (London, England : 1979)
Issue number14
Publication statusPublished - 20 Jul 2021

Bibliographical note

Funding Information:
This work was supported by the National Health and Medical Research Council (NHMRC) of Australia CJ Martin Fellowship [grant number GNT1112125 (to K.M.M.C.)]; consultation fees from Servier (to R.H.J.M.); the Astellas (to R.H.J.M.); the Mayer (to R.H.J.M.); the Boehringer Ingelheim (to R.H.J.M.); the Cristal Therapeutics (to R.H.J.M.); the Pamgene (to R.H.J.M.); the Pfizer (to R.H.J.M.); the Novartis (to R.H.J.M.); the Roche (to R.H.J.M.); the Servier (to R.H.J.M.); and the Sanofi (to R.H.J.M.).

© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.


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