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Tara Fernandez
Originally designed to treat cancer, a new study shows genetically-engineered T-cells could also be a game-changer for treating heart disease.
In a world first, a recent study has uncovered a new use for an approved cancer therapy – for fixing broken hearts. Researchers at the University of Pennsylvania’s Abramson Cancer Center reported how genetically engineered immune cells, designed to target tumor cells, can also be trained to zero in on cells responsible for heart disease. Cardiovascular biology expert Jonathan Epstein and his research team recently published their findings in the journal Nature.
The cells that are responsible for maintaining the structure and function of the heart are cardiac fibroblasts. In response to injury, fibroblasts become activated and start working in overdrive, triggering a process similar to scarring on the heart, called fibrosis. Fibrosis leads to the stiffening of heart tissue, seriously compromising its ability to pump blood. Cardiac fibrosis has no cure and is a major cause of heart failure, creating the need for innovation towards new therapies.
For Epstein’s group, the inspiration came from an FDA-approved personalized immunotherapy against blood cancers, using chimeric antigen receptor T-cells (CAR-T). Here, the patient’s own white blood cells are artificially modified, arming them with a synthetic receptor that unmasks cancer cells from stealth mode, triggering T-cells to attack them, leaving healthy cells completely unscathed. For more on CAR-T in cancer, check out previous articles featured on Onco Bites.
Using this principle, the Penn team hypothesized that a similar tactic could be used to stop activated cardiac fibroblasts in their tracks, as a countermeasure against fibrosis.
For this to work, however, a differentiating factor on the surface of fibrosis-causing activated fibroblasts would have to serve as a docking site for CAR-Ts, ensuring that this therapy is targeted only to disease-causing fibroblasts, and not those that the heart needs to function. To test their theory in mice, scientists genetically inserted ovalbumin, or OVA, a protein found in egg white, onto the surface of activated fibroblasts. This would serve to flag down circulating CAR-Ts, specifically programmed to seek and destroy cells bearing the OVA protein. This is a common tactic for artificially creating models to study; once the method is shown to work, the next step is finding more biologically relevant tags to target.
A month after chemically inducing hypertension, mouse hearts in the untreated group showed the signature patterns of heart disease and imminent failure: stiffness and impaired function due to fibrosis. To their surprise, however, mice treated with anti-OVA CAR-Ts showed virtually none of these classical markers of heart disease.
With their hypothesis showing promise, the scientists started seeking naturally-occurring markers on activated cardiac fibroblasts that CAR-Ts could latch on to. They compared the genetic profiles from the heart tissues of 238 healthy and diseased individuals. The analysis revealed that fibroblast activated protein, or FAP, was selectively present on the surface of activated fibroblasts, but not healthy, unactivated ones.
They knew they were on the right track with this finding. Just this year, German scientists found that screening patients for this FAP marker could identify those most at risk of cardiac fibrosis.
This was a catalyst for repeating their mouse experiment, this time using anti-FAP CAR-Ts. As early as one day after injecting CAR-Ts into mice with heart disease, the cells had already found their way into the fibrotic tissue. A month later, another astounding result: all the mice treated with FAP CAR-Ts had significantly lower levels of fibrosis and improved cardiac function compared to the control group.
Heart disease is the leading cause of death globally, with the American Heart Association estimating over 17 million deaths occurring in 2016 alone from cardiovascular disease.
Given the shortage of viable drug interventions, cell and gene therapies are becoming increasingly attractive options for combating heart disease. Verve Therapeutics, for instance, pocketed $58.5 million in investment dollars this year to develop their one-time gene therapy to prevent coronary artery disease.
With the Penn scientists’ recent breakthrough, repurposing CAR-Ts to thwart fibrosis could be revolutionary. As a byproduct of inflammation, fibrosis is not just limited to the heart, but also occurs in a variety of conditions including arthritis, Crohn’s disease, and chronic liver problems.
Still, despite CAR-Ts being successfully used to treat leukemia, it’s unlikely that it will make its way to the clinic for heart disease patients any time soon. Taking into account cancer patients’ experiences as a predictor, seeking out CAR-T therapies means having to fork out an excess of $1 million. Even with this price tag, supply shortages due to CAR-T manufacturing challenges and severe, potentially life-threatening side effects mean much has yet to be done to make CAR-Ts safe and accessible.
Despite these ongoing hurdles, Penn University joins a surge of pharmaceutical companies, biotechs and research institutions driving the “immunorevolution” and creating new opportunities for T-cell therapies. If Epstein’s study is a sign of things to come, the ability to precisely target any disease-causing cell with CAR-Ts would be truly transformative for millions of hopeful patients.
Edited by: Sara Musetti
Work Discussed:
Aghajanian, H., Kimura, T., Rurik, J. G., Hancock, A. S., Leibowitz, M. S., Li, L., . . . Epstein, J. A. (2019). Targeting cardiac fibrosis with engineered T cells. Nature, 573(7774), 430-433. doi: 10.1038/s41586-019-1546-z
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