CAR T Cell Therapy Shows 70% Reduction in Atherosclerotic Plaque in Preclinical Study
核心洞察
University of Pennsylvania researchers demonstrated that CAR T cell therapy (搜索) using regulatory T cells (Tregs) targeting oxidized LDL (搜索) reduced atherosclerotic plaque burden by approximately 70% in mice after twelve weeks of treatment.
The study represents the first application of CAR T technology to target the underlying inflammatory cause of atherosclerosis (搜索), the leading cause of heart disease and death worldwide.
The anti-OxLDL CAR Tregs (搜索) suppressed arterial inflammation without disrupting general immune function, offering a potential complementary treatment for patients on cholesterol-lowering therapy.
A groundbreaking preclinical study from the University of Pennsylvania has demonstrated that CAR T cell therapy (搜索), traditionally used to treat blood cancers (搜索), could offer a revolutionary approach to combating atherosclerosis (搜索). The research, published in Circulation, showed that experimental CAR T cells blocked arterial inflammation and prevented more than two-thirds of plaque buildup in mice compared to untreated controls.
"Our study shows for the first time how CAR T cell technology could be used to treat the underlying cause of the most common form of heart disease, which is the leading cause of death worldwide," said senior author Avery Posey, PhD, an assistant professor of Pharmacology at the Perelman School of Medicine (搜索). "This preclinical finding represents an important step forward for continuing to expand the impact of CAR T cell therapy (搜索) to common diseases beyond cancer."
Novel Approach Targets Inflammatory Root Cause
Atherosclerosis (搜索) underlies ischemic heart disease (搜索) and stroke (搜索), which together kill tens of millions globally each year. While current treatments include medications to reduce low-density lipoprotein (LDL) cholesterol and lifestyle modifications, no approved therapies specifically target atherosclerotic inflammation, and previous clinical trials of anti-inflammatory drugs have failed to show benefit.
The Penn researchers took a unique approach by engineering regulatory T cells (Tregs) - immune cells that dampen rather than activate immune responses - to target oxidized LDL (搜索) (OxLDL (搜索)), the main inflammation-promoting form of LDL cholesterol (搜索) that drives plaque formation.
"OxLDL (搜索) is a pro-inflammatory molecule, and that inflammation is what starts atherosclerosis (搜索)," explained lead author Robert Schwab, MD, an instructor of Hematology-Oncology. "The idea was, if we can get the immune system to see OxLDL and provoke an anti-inflammatory response, it would reduce inflammation and essentially stop the pathogenesis in its tracks."
Dramatic Plaque Reduction in Animal Models
Initial laboratory tests with human cells confirmed that the anti-OxLDL CAR Tregs (搜索) suppress inflammation in response to OxLDL (搜索), greatly reducing the buildup of cells that characterize atherosclerotic plaques. The team then engineered a mouse version and tested it in mice genetically predisposed to high cholesterol and atherosclerosis (搜索).
After approximately twelve weeks of treatment, the treated mice's hearts and aortas showed roughly 70% lower atherosclerotic plaque burden compared to control mice, indicating a clear preventive effect. Importantly, this dramatic reduction occurred without disrupting general immune function in the treated animals.
Complementary Treatment Strategy
Co-author Daniel J. Rader, MD, an expert on lipids and atherosclerosis (搜索) and chair of the Department of Genetics, emphasized the potential clinical application: "The use of a CAR T approach to target the proinflammatory molecule oxLDL (搜索) could provide an important complementary treatment approach to reducing the high residual risk of atherosclerotic cardiovascular disease in patients on effective cholesterol-lowering therapy."
The researchers do not envision CAR T cell therapy (搜索) replacing existing treatments when they work well for patients. Instead, it could serve as an additional tool for patients requiring alternative or supplementary treatment options.
From Cancer to Cardiovascular Disease
Both Posey and Schwab trained under CAR T cell therapy (搜索) pioneer Carl June, MD, who led the development of the first CAR T cell therapy approved by the FDA in 2017. Their work builds on the revolutionary success of CAR T therapy in blood cancers (搜索), where patients' T cells are engineered to recognize and destroy cancer cells.
The connection between cancer and cardiovascular disease motivated their research direction. "Cancer, inflammation, and heart disease go hand-in-hand," Schwab noted. "It's a real shame to see a patient cured of cancer die from a heart attack a year or two later."
For many cancer survivors, heart disease becomes their primary health risk, partly due to treatment side effects and the inflammatory environment created by cancer itself, which can promote atherosclerosis (搜索) development.
Path to Clinical Translation
The researchers and Penn have founded a spinout company, Cartio Therapeutics (搜索), to advance the OxLDL (搜索) CAR Tregs toward human clinical trials. This commercialization effort represents a critical step in translating the promising preclinical results into potential patient treatments.
"We're inspired by the potential that this technology developed for cancer could have to help so many people, cancer survivors included," Posey said.
The study received funding from the Hematology Research Training Program, the American Society of Hematology Research Training Award for Fellows, and the Department of Veterans Affairs, highlighting the multi-institutional support for this innovative cardiovascular research approach.