UCLA team engineers 'triple-threat' immune cells to fight plaque buildup behind heart attacks, strokes

Findings

A UCLA research team has engineered a new type of immune cell that attacks atherosclerotic plaques - the fatty buildup inside artery walls that drives most heart attacks and strokes. These engineered cells work by recognizing three harmful cell types within plaques. In a mouse model, a lab-grown mini blood vessel and artery tissue from patients with severe heart disease, these "triple-threat" cells outperformed a single-target version, clearing out more of the cell types that keep plaques active and dangerous.

Background

Atherosclerosis is the underlying driver of most cardiovascular disease, which continues to be the leading cause of death worldwide. It remains difficult to treat even with cholesterol-lowering and anti-inflammatory drugs, largely because plaques aren't a uniform mass of fat but complex environments packed with different cell types that reinforce each other's damage. Rogue smooth muscle cells transform into a more aggressive, scar tissue-producing state, while immune cells called macrophages become overloaded with cholesterol and swell into foam cells that pump out inflammatory signals - provoking the smooth muscle cells even further and creating a vicious cycle.

One emerging approach adapts CAR-T cell therapy, which has already shown promise in scarring-related diseases, to create engineered FAP.CAR-T cells that target fibroblast activation protein, or FAP. FAP is found on rogue smooth muscle cells, making it a useful marker for this approach. However, this strategy has a key limitation: CAR-T cells targeting only FAP leave inflamed macrophages and foam cells untouched. One troublemaker is removed, but the others keep causing damage.

Method

To address this, UCLA scientists built FAP.CAR-NKT cells. Rather than starting with a standard T cell, they used a rarer, more versatile immune cell called an invariant natural killer T cell, or NKT cell, and added the FAP-targeting mechanism on top. FAP.CAR-NKT cells have three separate ways to detect plaque threats: the engineered targeting system for rogue smooth muscle cells, a natural receptor that recognizes fat-related molecules on macrophages and foam cells, and built-in sensors that detect stress markers given off by unhealthy foam cells.

The team tested FAP.CAR-NKT cells across three settings: a mouse model of atherosclerosis, a lab-grown "vessel-on-a-chip" built from human artery cells, and artery tissue donated by patients with severe heart disease. FAP.CAR-NKT cells consistently outperformed FAP.CAR-T cells in each one. In a mouse model of atherosclerosis, FAP.CAR-NKT cells produced smaller, less fatty plaques than FAP.CAR-T cells, which barely slowed disease progression. The pattern held in a lab-grown mini blood vessel: The single-target cells killed rogue smooth muscle cells but missed nearby foam cells, while the new cells cleared both. In artery tissue from patients with severe heart disease, FAP.CAR-NKT cells killed rogue smooth muscle cells, macrophages and foam cells, while FAP.CAR-T cells fell short. Notably, FAP.CAR-NKT cells showed no signs of toxicity in mice. This is likely because FAP is rare in healthy tissue, leaving little healthy tissue for the cells to mistakenly attack.

Impact

Cell-based immunotherapies have so far struggled to make a meaningful impact in treating atherosclerosis. In these preclinical tests, FAP.CAR-NKT cells outperformed single-target approaches by recognizing a broader range of plaque cell types - a different strategy for a stubborn problem. Next, researchers will work to pin down how long the treatment effects last and the right dosing to sustain them. This study marks an early but meaningful step toward a new kind of atherosclerosis treatment: one that fights plaque on multiple fronts at once.

Journal

The study was published in the journal Circulation Research.

Authors

The study's corresponding authors are Lili Yang, a professor of microbiology, immunology and molecular genetics and a member of the UCLA Broad Stem Cell Research Center and the UCLA Health Jonsson Comprehensive Cancer Center; and Tzung Hsiai, a professor of medicine and bioengineering. The first authors on the study are Yanruide Li, a postdoctoral scholar in the Yang lab; Enbo Zhu, an assistant project scientist in the Hsiai lab; and Jae Min Cho, a postdoctoral scholar in the Hsiai lab. Other co-authors are Robert Kropp, Yunpei Zhang, Yas Sanaiha, Oh Jin Kwon, Yichen Zhu, Seul-Ki Park, Brian Arianpour, Melissa Justo, Peng Zhao, Shaolei Wang, Mingxia Gu and Peyman Benharash.

Disclosures

The technology described in this study is covered by a provisional patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Yang, Hsiai, Li and Zhu listed as inventors.

Funding

The research was supported by the American Heart Association and the National Institutes of Health.