Chimeric Antigen Receptor T Cells as a Treatment for Fibrosis

Chimeric antigen receptor (CAR) T cell therapies are used to treat cancer, engineering T cells to be more aggressive towards cancer cells. The approach has proven quite effective in comparison to past treatments for a number of cancer types. In principle this CAR-T immunotherapy can be used to target any cell population that has distinct surface markers, not just cancer cells. Here, researchers demonstrate the ability to destroy the fibroblasts responsible for generating fibrosis in the aging heart. Fibrosis is a form of dysregulated tissue maintenance, in which cells build up scar-like deposits of collagen that degrade tissue structure and function. It is interesting to compare this with work on clearing senescent cells in heart tissue, which also reverses fibrosis. Senescence is clearly one of the factors driving fibroblasts to become overactive, most likely via the inflammatory, pro-growth signaling produced by senescent cells, rather than via fibroblasts becoming senescent in large numbers.

Heart disease is the leading cause of death in the United States, and excessive cardiac fibrosis is an important factor in the progression of many forms of heart disease. It develops after chronic inflammation or cardiac injury, when cardiac fibroblasts - cells that play an important role in the structure of the myocardium, the muscular middle layer of the heart's wall - become activated and begin to remodel the myocardium via extracellular matrix deposition. Research has shown that the removal of activated cardiac fibroblasts can reduce heart stiffness, making it easier for the ventricles to relax. However, there are no therapies that directly target excessive fibrosis, and very few interventions have shown the ability to improve heart function and outcomes among patients with impaired cardiac compliance.

As a first step, researchers launched a genetic proof-of-concept experiment using mice that can express an artificial antigen (OVA) on cardiac fibroblasts. The mice were treated with agents to model hypertensive heart disease, a condition associated with left ventricular hypertrophy (enlargement or thickening of the heart walls), systolic and diastolic dysfunction (pumping of blood in and out of the heart), and widespread cardiac fibrosis. To selectively target the OVA proteins expressing cardiac fibroblasts, the team treated one cohort of mice with engineered CD8+ T cells that express a T-cell receptor against the OVA peptide. At the four-week mark, the mice who were treated with the reengineered cells had significantly less cardiac fibrosis, whereas the mice in the control groups still had widespread fibrosis.

After establishing the feasibility of this approach, researchers sought to identify a protein specifically expressed by activated fibroblasts that they could program the genetically modified T cells to recognize and attack. Using an RNA sequence database, the team analyzed gene expression data of patients with heart disease and identified the target: fibroblast activation protein (FAP), a cell surface glycoprotein. Researchers then transferred engineered FAP CAR T-cells into mice at the one and two week marks, aiming to target and deplete FAP-expressing cardiac fibroblasts. Within a month, researchers saw a significant reduction of cardiac fibrosis in the mice that were treated with the engineered cells, as well as improvements in diastolic and systolic function.



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