OxLDL-targeted CAR Treg therapy reduces plaque burden in preclinical atherosclerosis model

A novel CAR T cell–based immunotherapy significantly reduced atherosclerotic plaque burden in a preclinical model, according to new findings published in Circulation. Researchers at the Perelman School of Medicine at the University of Pennsylvania engineered regulatory T cells (Tregs) to target oxidized low-density lipoprotein (OxLDL), a key driver of vascular inflammation and early plaque formation. Given that atherosclerosis accounts for the majority of cardiovascular deaths globally, novel anti-inflammatory strategies are of considerable clinical interest.

During immune surveillance, T cells are central to identifying and removing cells that present abnormal antigens; however, certain pathogenic cells express antigens that escape this recognition and persist. CAR T-cell therapy involves genetically modifying T cells to recognise and target specific disease-associated antigens, with the aim of sparing non-target tissues. While this approach was originally developed for cancer treatment, the same strategy can be applied to Tregs to modulate, rather than intensify, immune activity. In this study, CAR-engineered Tregs were directed against OxLDL to dampen inflammation within the arterial wall and limit atherosclerotic plaque development in a preclinical model.

In mice predisposed to high cholesterol and atherosclerosis, treatment with anti-OxLDL CAR Tregs led to approximately 70% less atherosclerotic plaque after 12 weeks compared to a control group. The therapy did not impair systemic immune function and there were no significant differences in LDL levels across treatment groups. Histological analysis also showed increased collagen deposition within plaques, suggesting greater stability.

These findings highlight the therapeutic potential of targeting inflammation; an aspect of atherosclerosis not directly addressed by LDL-lowering therapies. Despite effective cholesterol management, many patients continue to experience residual cardiovascular risk. By locally suppressing OxLDL-driven inflammation, CAR Treg therapy could offer a complementary approach to current standards of care. While these findings are compelling, translation to clinical practice will require careful consideration. This study demonstrates prevention and not regression of established plaques, while the efficacy, safety and longevity of engineered Tregs in humans remain unknown.

This approach may also have implications for cardio-oncology, with many cancer survivors remaining at elevated risk of atherosclerotic cardiovascular disease. This is often due to the cardiotoxic effects of cancer therapies and the inflammatory environment associated with cancer. In the longer term, an OxLDL-directed CAR Treg strategy could be of particular interest for study in patients with malignancy-associated coronary artery disease.

This research demonstrates how CAR-T technology can be repurposed to modulate inflammation at the core of atherosclerosis. If validated in human studies, CAR Treg therapy may emerge as a new class of cardio-immunotherapy, expanding the therapeutic landscape for atherosclerosis beyond lipid management.

Sources

1. PennMedicine. CAR T cell therapy. Available at: https://www.pennmedicine.org/treatments/car-t-cell-therapy (accessed 8 December 2025).
2. Schwab RD, Degaramo D, Hong SJ, et al. OxLDL-Targeted Chimeric Antigen Receptor T Regulatory Cells Reduce Atherosclerotic Plaque Development. Circulation. 2025; Doi: 10.1161/CIRCULATIONAHA.125.073987.
3. PennMedicine. New CAR T strategy targets most common form of heart disease. 2025. [Press release]. Available at: https://www.pennmedicine.org/news/new-car-t-strategy-targets-most-common-form-of-heart-disease (accessed 8 December 2025).