Harnessing the Immune System to Treat Vascular Inflammation

By Amanda Chase, PhD
January 27, 2021

We all know the immune system works hard to keep us healthy. It is a complex system with processes capable of detecting and responding to anything that is “non-self”: viruses, cancer cells, dead or dying cells, or even splinters, among many other things. One of the major players in this process is a type of blood cell called a ‘macrophage’ (Greek: Big Eater) that engulfs anything that is not marked as being specific to a healthy body. One of the special markers that prevents removal of intrinsic cells from the body is CD47, a so-called ‘don’t eat me’ molecule. In theory, anything non-self lacks the CD47 marker, and is thus engulfed by macrophages and removed. Sometimes, the immune system does not work properly, which results in disease. For example, in a wide variety of cancers, CD47 is known to be overexpressed, meaning that the cancer cells are incorrectly recognized as “self” and not removed. Atherosclerosis is another example of a condition where there is defect in the removal of diseased cells by macrophages, due in part to an upregulation of the CD47 ‘don’t eat me’ signal.

Atherosclerosis is the process that leads to heart attacks and stroke, and is the leading cause of death worldwide for both men and women. Atherosclerosis involves narrowed or blocked blood vessels that decrease blood flow as a result of a build-up of fats and cholesterol, as well as diseased and dying macrophages. Normally, the diseased and dying macrophages that promote plaque formation would be removed. However, just like in most cancers, there is an upregulation of the CD47 ‘don’t eat me’ marker which allows the diseased cells to evade clearance and permit plaque growth. Currently, there are no therapies directly targeting plaque build-up, with treatments instead focused on reducing risk-factors (e.g., recommendations to stop smoking and suggestions to maintain a healthy lifestyle). But what if there is the potential to directly target the macrophages that lead to plaque formation to treat atherosclerosis and reduce the rates of heart attack and stroke?  This is the concept behind the emerging field of ‘macrophage checkpoint inhibition’.

A team from Stanford, led by first author Kai-Uwe Jarr, MD, and senior author Nicholas Leeper, MD, Professor of Surgery, sought to leverage advances from the field of immuno-oncology, and the fact that CD47 is overexpressed in atherosclerosis, to find a treatment for patients with cardiovascular disease.

Mechanism of how removal of diseased cells by macrophages may be impaired at sites of atherosclerosis. Overexpression of CD47 ‘don’t eat me’ signal allows cells to evade proper clearance. The resulting plaque build-up leads to heart attacks and stroke, a leading cause of death worldwide. Figure from Kojima Y, et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature. 2016 Aug 4;536(7614):86-90. PMID: 27437576; PMCID: PMC4980260.

In their recent New England Journal of Medicine letter, the team explored the possibility of magrolimab, an anti-CD47 antibody, being used to treat cardiovascular disease. The immuno-oncology field seeks to target macrophage regulators to help restore immune surveillance (i.e., removing diseased and dying cells) with treatments such as magrolimab, targeting CD47. The team showed for the first time in humans that blockade of CD47 by treatment with magrolimab led to decreased vascular inflammation, potentially favorably impacting cardiovascular disease. Their initial studies suggest that using magrolimab may reactivate clearance of inflamed tissues from the plaque, potentially decreasing lesion vulnerability and risk of stroke and heart attack. This critical study provides a rationale for necessary prospective cardiovascular trials to determine if therapies such as magrolimab could become a new therapy for patients with cardiovascular disease, and, for the first time, target plaque formation instead of reducing risk factors. Such an improvement in treatment would have profound implications for rates of death resulting from atherosclerotic cardiovascular disease.

Other Stanford investigators include Ryukuke Nakamoto, MD; Brandon Doan; Yoko Kojima, MD, PhD; Irving Weissman, MD; Ranjana Advani, MD; and Andrei Iagaru, MD.

Dr. Kai-Uwe Jarr

Dr. Nicholas Leeper