CAR-T against myocardial fibrosis

GM lymphocytes cured mice of heart fibrosis

Ekaterina Kharybina, N+1

Researchers have shown the possibility of treating myocardial fibrosis in mice by injecting CAR-T lymphocytes that attacked activated cardiac fibroblasts. As targets for immune cells, the authors of an article in Nature (Aghajanian et al., Targeting cardiac fibrosis with engineered T cells) tested ovalbumin artificially injected into fibroblasts and the fibroblast-activating protein (FAP) synthesized by them.

The myocardium is the middle layer of the heart wall, which consists of muscle tissue. It is damaged in diseases of the cardiovascular system. These injuries lead to the activation of fibroblasts in the wall, they begin to synthesize a lot of extracellular matrix – this process is called fibrosis. As a result, the heart muscle loses elasticity, which negatively affects the work of the heart and the patient's condition. At the same time, there is no treatment for myocardial fibrosis.

An international group of researchers led by Jonathan Epstein from The University of Pennsylvania suggested that it is possible to try to destroy activated fibroblasts in the heart using CAR-T cells. GM lymphocytes have modified receptors consisting of a variable site recognizing the antigen and domains transmitting a signal into the cell. After recognizing the antigen on the target cell, the CAR-T lymphocyte destroys it. Such therapy is effective against some oncological diseases – leukemia and lymphomas. 

To test the hypothesis, the scientists used mice whose myocardial fibroblasts began to express an uncharacteristic ovalbumin protein upon activation. Mice were injected with an osmotic mini-pump with angiotensin II and phenylephrine, which led to the development of myocardial damage and fibrosis. A week after the pump was injected, the animals were injected with CAR-T cells that recognize ovalbumin (experimental group). After assessing the condition of the myocardium four weeks after the start of the experiment, the scientists observed a low degree of fibrosis and a reduced heart mass in an experimental group of mice.

a, experimental scheme: mice were injected with a mini-pump with drugs (AngII/PE) that cause myocardial damage and fibrosis, a week later they were injected with CAR-T recognizing ovalbumin (CD8+ OT-I T cells). b, assessment of the degree of fibrosis: the first section is normal mice, the second is mice that did not express ovalbumin and were injected with CAR–T, the third is mice with ovalbumin expression that were not injected with CAR–T, the fourth is an experimental group.
The fibrosis area is red, the color is picrosirius red. Drawings from an article in Nature.

Having confirmed the possibility of CAR-T fibrosis therapy, the authors of the article found a protein specific to the studied fibroblasts. They evaluated the activity of myocardial fibroblast genes taken from patients with cardiomyopathy and identified those whose expression increases in the case of fibrosis, in particular, the FAP gene. In mice injected with CAR-T recognizing FAP, the fibrosis area was reduced and myocardial functions were restored in comparison with the control group.

a, experimental scheme, CAR-T cells recognizing FAP were injected twice. b-c, assessment of the degree of fibrosis, the left section and column – the group that was injected with saline, the middle – mice that were injected with a mixture of AngII/PE, on the right – the experimental group that was injected with AngII/PE and CAR-T.
The fibrosis area is red, stained with picrosirius.

The therapy had no effect on the condition of other mouse tissues and was non-toxic to the heart. Although human testing is still a long way off, the authors hope that CAR-T will be able to treat not only cancer, but also diseases of the cardiovascular system.

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