CAR Treg Cell Therapy Achieves 70% Plaque Reduction in Atherosclerosis Model

Researchers at the Perelman School of Medicine at the University of Pennsylvania (UPenn) have achieved a significant preclinical breakthrough by developing an experimental chimeric antigen receptor regulatory T cell (CAR Treg) therapy to treat coronary artery disease (CAD) driven by atherosclerosis. The findings, published in Circulation, demonstrate that redirecting regulatory T cells (Tregs) to suppress inflammation associated with oxidized low-density lipoprotein (OxLDL) may substantially reduce the development of arterial plaque.

“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 Dr. Avery Posey.

Engineering CAR Tregs to Target OxLDL

The researchers focused on OxLDL because it is a known pro-inflammatory driver that initiates plaque formation (atherosclerosis) in arteries. The team’s approach was to harness the power of CAR technology, typically used in cancer immunotherapy, but apply it to anti-inflammatory immune cells:

• Targeting the Driver: The team engineered both human and mouse regulatory T cells to express a CAR that specifically recognizes an oxidation-specific epitope found on OxLDL.

• Lentiviral Delivery: The CAR and the Treg-defining transcription factor, FoxP3, were delivered to CD4 T cells using a lentiviral vector. This step ensured that all CAR-expressing cells adopted a stable, regulatory T cell phenotype.

• Anti-Inflammatory Response: The engineered cells maintained their anti-inflammatory Treg properties, secreted anti-inflammatory cytokines upon stimulation, and successfully reduced foam-cell formation in in vitro tests.

Lead author Dr. Robert Schwab noted, “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.”

Preclinical Efficacy Shows Significant Plaque Reduction

To assess the therapeutic potential, the investigators administered the engineered mouse CAR Tregs into an immunocompetent hyperlipidemic mouse model that closely mimics human OxLDL biology.

• Plaque Reduction: Twelve weeks after treatment, mice receiving the engineered Tregs showed approximately 70% less plaque burden compared to control mice.

• Immune Function: The treatment demonstrated this significant benefit without disrupting the animals’ overall immune function.

Based on these successful preclinical findings, UPenn and the researchers have launched Cartio Therapeutics to advance the anti-OxLDL CAR Treg toward clinical testing.

Next steps for the team include determining if the CAR Tregs can eliminate established plaques, rather than just slowing new development, and developing a humanized atherosclerosis model to fully assess the safety and long-term activity of the human CAR Tregs.