A team led by Washington University School of Medicine in St. Louis has adapted a cancer-style immunotherapy to strip away dangerous plaque in mouse arteries. The approach could one day complement cholesterol drugs and help people already living with advanced heart disease.
Heart disease remains the world’s leading killer, even in people who take cholesterol-lowering drugs and follow heart-healthy diets. Now, in a study led by Washington University School of Medicine in St. Louis, researchers have shown that a new kind of immunotherapy can actually shrink and stabilize artery-clogging plaque in mice, opening a potential new front in the fight against heart attacks.
The experimental treatment, described in an article published in the journal Science, uses a lab-made antibody to hunt down and destroy a specific type of harmful cell hiding in the walls of blood vessels. By clearing out these cells, the therapy reduced the amount of plaque, calmed inflammation inside the arteries and made the remaining plaque less likely to rupture — a key trigger of heart attacks.
The strategy is designed to complement, not replace, standard care such as statins and other cholesterol-lowering medications. Those drugs are highly effective at preventing plaque from forming, but they do not reliably erase dangerous buildup that is already there.
“Cholesterol-lowering medications are mainly preventive, which does not substantially reduce plaques that are already there. An immunotherapy that can reduce inflammation and dangerous plaque in patients with more advanced atherosclerosis is an exciting prospect,” senior author Kory J. Lavine, a professor of medicine in WashU Medicine’s Cardiovascular Division, said in a news release.
Atherosclerosis, the underlying process behind most heart attacks and strokes, is a chronic inflammatory disease of the arteries. Over years, high blood pressure, high cholesterol, high blood sugar and other stresses damage the inner lining of blood vessels. Fat, immune cells and scar-like tissue accumulate, forming plaques that narrow the arteries and can suddenly rupture, causing a clot that blocks blood flow to the heart.
Inside these plaques, a group of structural cells called vascular smooth muscle cells can go rogue. Instead of staying in their usual position and helping blood vessels contract and relax, they migrate into new areas of the artery wall and transform into so-called modulated smooth muscle cells. In this altered state, they send out signals that attract and activate inflammatory immune cells, feeding a vicious cycle of plaque growth and instability.
Lavine’s team set out to design a precision therapy that would selectively eliminate these troublemaking cells without harming the rest of the artery.
To do that, the researchers first needed a detailed map of what is happening inside diseased human coronary arteries. They analyzed 27 coronary arteries from patients undergoing heart transplantation, using a cutting-edge technique called single-cell profiling. This method allowed them to examine more than 150,000 individual cells, identifying which genes and proteins were active in each one.
They then combined this molecular information with spatial data showing exactly where each cell type sits within the three-dimensional structure of the artery and its plaque. The result was a high-resolution cellular “atlas” of human coronary artery disease.
Using this atlas, the team identified a protein called fibroblast activation protein on the surface of modulated smooth muscle cells. Because this protein was present on the harmful cells in vulnerable areas of plaque, it offered a promising target for therapy.
The researchers then partnered with scientists at the biotech company Amgen to test an antibody-based molecule designed to latch onto fibroblast activation protein and call in the immune system’s T cells to kill the marked cells. This type of engineered molecule is known as a bispecific T cell engager, or BiTE.
“This type of antibody therapy was originally designed to target cancers, such as lymphoma, and we imagine a similar precision medicine approach for cardiovascular disease,” Lavine added.
When the team used the BiTE molecule in mouse models of atherosclerosis, they saw a significant reduction in plaque compared with untreated animals. The plaques that remained were less inflamed and structurally more stable — changes that, in people, would be expected to lower the risk of a sudden, life-threatening rupture.
“We found that these cells are located in areas of the plaque that are particularly vulnerable to rupture, which is the primary cause of heart attacks,” added Lavine. “What this BiTE molecule seems to be doing in removing these damaging cells is leading to an improved wound healing process, reducing inflammation and the amount of plaque, and increasing the stability of any plaque that remains.”
In addition to the treatment itself, the researchers developed a way to see these dangerous cells inside living patients. They created an imaging tracer that also targets fibroblast activation protein and used it with PET/CT scans to visualize coronary plaques.
In early tests in people with coronary artery disease, conducted in collaboration with an international team of resarchers, the tracer lit up plaque in the heart’s arteries, suggesting it could eventually help doctors identify which plaques are most dangerous. The team hopes to refine this imaging tool to distinguish between relatively stable plaques and those at high risk of rupture, so clinicians can better predict and prevent heart attacks.
The work is still in its early stages. The BiTE therapy has so far been tested only in mice, and any treatment for people would need to go through extensive safety and effectiveness studies. The researchers are now optimizing the BiTE molecule and planning additional imaging studies to better understand how and where it acts in the body.
If the approach translates to humans, it could mark a shift in how doctors think about treating advanced coronary artery disease. Instead of focusing solely on lowering cholesterol and managing risk factors, future therapies might also directly remodel dangerous plaques from the inside out.
For patients who already live with significant plaque despite doing everything right, that possibility is especially compelling. While much more work lies ahead, the study points toward a future in which tools originally built to fight cancer, like BiTE molecules, are repurposed to heal damaged arteries and reduce the toll of heart disease.
Source: Washington University School of Medicine in St. Louis