In studies in mice, it is much easier to show a slowing of atherosclerotic plaque growth over time than it is to show regression of existing plaque. Only a tiny number of approaches have shown any robust ability to regress obstructive plaque in the arteries once it has formed. Thus one should suspect that any new approach presented with data to show a slowing of plaque growth may not actually have the capacity to regress plaque – otherwise the researchers would have presented that much more desirable outcome instead.
Here, researchers turn the well established approach of engineering T cells to have chimeric antigen receptors to the problem of oxidized LDL particles. LDL particles carry cholesterol from the liver out into the body, and when they become oxidized they cause additional stress to cells and accelerate the development of plaque by worsening an already toxic plaque environment in blood vessel walls. Engineering T cells to target and clear oxidized LDL particles is clearly beneficial, producing a sizable slowing of plaque growth. This reinforces other lines of research indicating that oxidized LDL is an important mechanism in these mouse models.
CAR T cell therapy has revolutionized treatment for blood cancers. It works by engineering a patient’s own T cells in the lab and training them to recognize a marker found on cancer cells, creating an immune response that destroys the cancer. Scientists have been exploring the potential of this powerful technology to treat other diseases. Researchers have now engineered a CAR regulatory T cell (Treg) that targets oxidized LDL (OxLDL), the main inflammation-stoking form of LDL cholesterol that drives plaque buildup in atherosclerosis.
Initial lab-dish tests with human cells confirmed that the anti-OxLDL CAR Tregs suppress inflammation in response to OxLDL, greatly reducing the buildup of the cells that are a central feature of atherosclerotic plaques. The team then engineered a mouse version of the anti-OxLDL CAR-Treg and tested it in mice that were genetically predisposed to high cholesterol and atherosclerosis. After about twelve weeks of treatment, the treated mice’s hearts and aortas showed a roughly 70 percent lower atherosclerotic plaque burden compared to control mice – indicating a clear preventive effect of the CAR-Tregs. Despite this effect, there was no disruption of general immune function in the treated mice.
