The University of Pennsylvania’s Abramson Cancer Center is credited with developing the chimeric antigen receptor T-cell (CAR-T) cancer treatment that ultimately became Novartis’ Kymriah, a personalized cell-based therapy for some blood cancers that was approved by the FDA in 2017. Now, researchers at Penn Medicine are adapting the technology to heart disease.
The Penn team targeted cardiac fibrosis, a type of scarring that’s common in heart disease and that impedes the proper functioning of the heart. They genetically modified T cells to remove the fibroblasts that cause the condition and showed the therapy could reduce cardiac scarring in mouse models of heart disease. They published the research in the journal Nature.
In order to program the T cells to recognize and attack the problematic fibroblasts, the researchers first had to identify a specific protein associated with the scarring process. So they analyzed gene expression patterns in patients with heart disease. That helped them uncover their target: fibroblast activation protein (FAP), which sits on the cell surface.
After they engineered CAR-T cells to target FAP, they transferred them into the mice, first at one week and then at two. After a month, the mice showed a reduction in cardiac fibrosis and improvements in heart functioning, the researchers reported.
“Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure. However, clinical interventions and therapies that target fibrosis remain limited,” the Penn team wrote in the study. “These results provide proof-of-principle for the development of immunotherapeutic drugs for the treatment of cardiac disease.”
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Heart disease remains the leading cause of death in both men and women, accounting for one in every four deaths, according to the Centers for Disease Control and Prevention. Therapies are mainly aimed at symptom relief and largely ineffective at reversing heart damage, which is why cardiac researchers are focused on developing new regenerative strategies.
Several groups are investigating the potential of stem cells to repair heart damage. Last month, for example, scientists at the University of Washington and the University of Cambridge reported a combination of heart muscle cells and epicardial cells—both derived from human stem cells—restored damaged heart muscle and blood vessels in rat models.
Some companies are pursuing gene-based strategies for fighting heart disease. Renovacor recently raised $11 million to develop therapies targeted at mutations related to dilated cardiomyopathy. Novartis’ venture group led that funding round. And Verve Therapeutics hauled in $58.5 million to investigate the potential of using gene editing to lower the risk of coronary artery disease.
The next step for the Penn team is to run additional studies to determine whether FAP is the ideal target for CAR-T therapies in heart disease. The researchers are also considering adding a “kill switch” to the CAR-T treatment they developed to minimize side effects, they wrote in the study.
But they are confident the results from this mouse study show the potential of applying immunotherapy to cardiology. “Here we suggest that the ‘immunorevolution’ may extend beyond oncology to affect one of the most common forms of human morbidity and mortality—heart disease,” they wrote.