knitted pink heart with a mended hole
knitted pink heart with a mended hole

CAR T Cells Mend Broken Mouse Hearts

Specialized immune cells generated in vivo reduce cardiac scar tissue in mice, a new study shows.

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Sophie Fessl

Sophie Fessl is a freelance science journalist. She has a PhD in developmental neurobiology from King’s College London and a degree in biology from the University of Oxford.

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Jan 6, 2022

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In the cutting-edge cancer treatment known as CAR T cell therapy, some of a patient’s immune cells are removed and engineered to express a synthetic CAR receptor that allows the cells to latch onto and destroy cancer cells. With a new method developed in mice, CAR T cells can now be made in vivo, without removing and re-transfusing cells—and then used to treat a very different condition. In the mice, the CAR T cells targeted wound-healing cells called fibroblasts and thus reduced the formation of scar tissue on the heart. The results are reported today (January 6) in Science

The ability to generate CAR T cells in vivo “now makes every center in the United States that can handle a syringe a potential treatment place,” Jeffery Molkentin, a molecular biologist at Cincinnati Children’s Hospital who was not involved in the study, tells The Scientist. “If this is used for cancer therapeutics or other disease types, you now no longer need a cellular manufacturing GMP facility,” he says, referring to the regulatory requirements involved in making CAR T treatments outside the body.

As hearts can’t regenerate lost cells, scar formation is critical after a heart attack or other cardiac injury to maintain the organ’s structure and its ability to pump blood. However, scars stiffen the heart and worsen heart function, and can lead to heart failure. In a previous study, Haig Aghajanian and Jonathan Epstein at the University of Pennsylvania engineered CAR T cells outside the body, the traditional way, to target fibroblast activating protein (FAP), a surface antigen on activated fibroblasts. In mice with cardiac injury, the CAR T cells targeted activated fibroblasts and reduced cardiac fibrosis. However, CAR T cells generated ex vivo can persist for months after being transferred into patients. Activated fibroblasts are needed for wound healing, so “if you have persistent anti-fibroblast CAR T cells, that could become a risk in case of future injuries,” says Hamideh Parhiz, a coauthor on the present study and molecular biologist at the University of Pennsylvania

The present study aimed to produce CAR T cells that are only transiently active, so Aghajanian and Epstein teamed up with Parhiz, who specializes in targeted delivery of nanomedicine, and Penn Medicine’s Drew Weissman, a coinventor of the mRNA technology used in the Pfizer/BioNTech and Moderna COVID-19 vaccines. The team’s approach uses injected mRNA to get T cells in mice to produce their own CAR, or chimeric antigen receptor,  which targets the FAP on fibroblasts. Similar to mRNA-based COVID-19 vaccines, the mRNA is encapsulated in lipid nanoparticles. The researchers targeted these nanoparticles toward T cells by decorating the particles with antibodies against CD5, a receptor naturally expressed by T cells. The T cells took up the mRNA and translated it to produce the FAPCAR. But because mRNA is unstable, this CAR production was only transient. “About 24 to 48 hours after [lipid nanoparticle] injection, we could find between 15 to 22 percent of FAPCAR-positive T cells in mice that received the treatment. . . . Then it gradually goes down and a week after injection, you don’t see any FAPCAR expression,” says Parhiz. 

To test how well the in vivo–generated CAR T cells work, the researchers infused mice with angiotensin II and phenylephrine to induce high blood pressure. After waiting a week for fibrosis to occur, the team injected the mice with lipid nanoparticles containing the mRNA. When the mice were assessed two weeks later, their cardiac functions had improved compared to control mice in which cardiac fibrosis was induced, but that were not treated with CAR T cells, as assessed by echocardiography. Looking at the mice’s heart tissue, the researchers found that scar tissue in the ventricles was reduced—in some treated mice, to the point where they were indistinguishable from healthy controls. Only scar tissue around blood vessels persisted, as this fibrosis is caused by fibroblasts that do not express the FAP  targeted by T cells. 

“Using this approach to target and reprogram immune cells represents an innovative application for cardiovascular medicine and opens up exciting opportunities for developing novel therapeutics,” Ronald Vagnozzi and Timothy McKinsey, heart researchers at the University of Colorado Anschutz Medical Campus who were not involved in the study, write in a joint email to The Scientist. 

Molkentin adds that this approach “is ground-breaking because it’s a whole new way of thinking about a therapeutic application, redirecting the T cell to control other aberrant cells. Obviously that makes huge sense in cancer, but that’s just the start of things.” Parhiz and her coauthors have founded a company to develop a platform for reprogramming immune cells, with the goal of developing off-the-shelf therapeutics that—unlike current CAR T cell therapies—wouldn’t have to be tailored to individual patients. In the long run, Parhiz says mRNA may be used to also reprogram other cell types for a broader spectrum of applications. For example, she says, mRNA could be targeted to reprogram endothelial cells, which could be used for treating injuries such as acute respiratory distress syndrome, a life-threatening lung condition. 

When it comes to using CAR T cells to treat cardiac disease, Molkentin cautions that “it is not clear in the human context if the mouse can teach us what the long-term ramifications could be,” including potential off-target effects of the CAR. Vagnozzi and McKinsey point out that in this study, CAR T cell therapy was applied early in the disease process. “It will be important to see whether this approach can be used to treat hearts with severe, stable scars, or other forms of heart disease where fibrosis can persist for years before treatment,” they write. One question raised, they point out, is how removing fibroblasts from the heart alters scar tissue and heart function, since “Subtle changes in the extracellular matrix can have a major impact on contraction and relaxation of the heart. Thus, future studies to explore how CAR-T removal of fibroblasts affects the biophysical and biochemical properties of cardiac scar tissue would be valuable.” 

However, Molkentin underlines that this approach is “precedent-setting,” allowing for temporary therapy with CAR cells. “This would still behave like a drug, for a finite period of time. Its [effects] wouldn’t be irreversible, but it could be used multiple times.” 

He adds, “to me, it is groundbreaking, and I think it is the start of a whole new era, potentially, in how we treat human diseases more selectively.”