Cancer drug also works for cardiovascular diseases

Recent advances in immuno-oncology could open up new treatment options for cardiovascular diseases in the future. A team from Heidelberg (Germany) and Stanford (USA) has found decisive steps in this direction.

The potential of macrophage checkpoint inhibition for atherosclerosis has been observed

Advances in the field of immuno-oncology could also open up new ways of treating patients with cardiovascular diseases in the future. A team from Heidelberg (Germany) and Stanford (USA) has found decisive steps in this direction.

The research results have already been published in "The New England Journal of Medicine" and have now been awarded the Wilhelm P. Winterstein Prize (10,000 euros). The team led by Dr. med. Kai-Uwe Jarr (Department of Cardiology, Angiology and Pneumology at Heidelberg University Hospital and Stanford University, USA), and Prof. Dr. med. Nicholas J. Leeper (Stanford University) investigated the extent to which an antibody (Magrolimab and Rituximab) directed against the cell surface marker CD47, and already used in cancer therapy for tumour patients can also be used for the treatment of cardiovascular diseases.

"Macrophage checkpoint inhibition", an idea at the heart of the research

"Our work aims to find, and therapeutically influence regulators of immune surveillance to better remove diseased or dying cells," Dr. Jarr emphasises. According to the team, they showed for the first time in humans that blocking CD47 can contribute to a reduction in vascular inflammation and thus potentially have a positive effect on cardiovascular diseases. The first studies in nine patients, each with different risk factors such as diabetes, hypertension, atherosclerosis, coronary heart disease (CHD), and/or heart attack, indicate that "macrophage checkpoint inhibition" can reactivate the removal of inflamed tissue from the vascular plaque.

"Further clinical trials are now necessary to show to what extent this therapy option can reduce the occurrence of plaques and the risk of strokes and heart attacks," explains Dr. Jarr. "The results published by the scientists form an important basis for future work and elegantly demonstrate the successful transfer of findings from immunotherapy to the development of new treatment methods for cardiovascular diseases," emphasises cardiologist Prof. Thomas Voigtländer, MD, Chairman of the Board of the German Heart Foundation (in German: Deutsche Herzstiftung).

Marker CD47: A disruptor in the immune system, on the researchers' focus

The immune system recognises viruses, bacteria, cancer cells, but also dead or dying endogenous cells. Immune cells (macrophages) devour body cells that are not specific to a healthy body. One of the most important surface markers that protects intact body cells from macrophage attack is the molecule CD47 -, a "don't eat me" signal. Theoretically, wherever the cell surface is foreign or altered, the CD47 marker is missing. The cells are therefore devoured and removed by macrophages.

It is known from tumour diseases that this process of the immune system is disturbed: Many cancer cells present too much CD47 on their surface, so that these cells are wrongly assessed as "intact" and are therefore not removed by the immune system. In the field of immuno-oncology, this finding has been used for the development of new therapies. In the meantime, it is known that this disturbance in the immune system can also occur in other chronic diseases such as arteriosclerosis. In coronary heart disease (CHD) as a result of arteriosclerosis, inflammatory changes in the vascular walls occur in a long, gradual process due to plaques containing calcifications, connective tissue and cholesterol. As a result, the coronary vessels narrow and the blood flow to the heart is impeded - depending on the severity, even to the point of a heart attack.

Macrophage checkpoint inhibition: How effective is it against plaque formation?

The removal of diseased cells by macrophages is also disturbed in arteriosclerosis. Studies have already shown that signalling substances of the immune system, which are involved in local and systemic inflammation, contribute to an excessive presentation of the "don't eat me" signal CD47. "Normally, macrophages would clear away diseased and dying cells that promote plaque formation," explains Dr. Jarr. "However, the excessive presentation of the CD47 signal causes the diseased cells to evade the immune system here as well."

Current therapies for atherosclerosis focus on risk factors such as smoking, physical inactivity, unhealthy diet and risk diseases such as dyslipidemia (high cholesterol), hypertension, diabetes and obesity. "But what if it were possible to increase the appetite of macrophages or to therapeutically influence the excessive presentation of "don't eat me" signals and thus reduce plaque formation as well as vascular inflammation? This is exactly the principle of macrophage checkpoint inhibition," explains Dr. Jarr.

Jarr KU, Nakamoto R, Doan BH, Kojima Y, Weissman IL, Advani RH, Iagaru A, Leeper NJ. Effect of CD47 blockade on Vascular Inflammation. New England Journal Medicine. 2021