Nav: Home

CAR T-cell therapy may be harnessed to treat heart disease

September 11, 2019

PHILADELPHIA -- CAR T-cell therapy, a rapidly emerging form of immunotherapy using patients' own cells to treat certain types of cancers, may be a viable treatment option for another life-threatening condition: heart disease. In a first-of-its-kind study, published today in Nature, researchers at Penn Medicine used genetically modified T cells to target and remove activated fibroblasts that contribute to the development of cardiac fibrosis--a scarring process found in most forms of heart disease that results in heart stiffness and decreased function of the heart. The team found the approach significantly reduced cardiac fibrosis and restored heart function in mice with heart disease caused by high blood pressure.

"The ability to harness patients' own cells to fight cancer has been one of the most promising research breakthroughs of the past decade, and we are excited to find ways to leverage this same type of technology to address other common illnesses," said the study's corresponding author Jonathan A. Epstein, MD, executive vice dean, chief scientific officer and the William Wikoff Smith Professor of Cardiovascular Research. "While much more research is needed before we can introduce this approach into the clinical setting, this marks a significant step forward in our efforts to treat - and potentially reverse - a condition that accelerates the progression of heart failure."

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.

CAR T-cell therapy, which involves genetically modifying a patient's own T cells to fight disease, is primarily used to treat blood cancers, including types of lymphoma and leukemia. Penn Medicine's Abramson Cancer Center developed what became the world's first approved CAR T-cell therapy, Kymriah. Driven by the recent breakthroughs in the treatment of cancers, researchers sought to determine the viability of using the CAR T-cell approach to target and attack the activated cardiac fibroblasts that contribute to fibrosis.

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 cognate 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.

Researchers note additional studies are needed to confirm FAP as the optimal target and to ensure safety risks are minimized.

"We've seen enormous progress in the treatment of certain cancers via the use of engineered T cells. Our findings suggest that this approach may extend beyond cancer and serve as an effective treatment for heart disease," said first author Haig Aghajanian, PhD, a member in Epstein's lab.
-end-
The work was supported in part by grants from the National Institutes of Health (R35 HL140018 and T32 HL007843-22), as well as the Cotswold Foundation and the William Wikoff Smith endowed chair.

Additional Penn Medicine authors include Toru Kimura, Ellen Puré, Tao Wang, Kendra McDaid, Joel Rurik, Li Li, Aidan Hancock, Kenneth Bedi, Cheryl Smith, Wei Han, Albert Lo, Rajan Jain, Ricardo Linares Saldana, Michael Morley, Nikhita Bolar, Michael Leibowitz, Carl June, James Monslow, Kenneth Margulies, John Scholler and Steven Albelda.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $425 million awarded in the 2018 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center--which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report--Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation's first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Home Care and Hospice Services, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 40,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2018, Penn Medicine provided more than $525 million to benefit our community.

University of Pennsylvania School of Medicine

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
More Cancer News and Cancer Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#534 Bacteria are Coming for Your OJ
What makes breakfast, breakfast? Well, according to every movie and TV show we've ever seen, a big glass of orange juice is basically required. But our morning grapefruit might be in danger. Why? Citrus greening, a bacteria carried by a bug, has infected 90% of the citrus groves in Florida. It's coming for your OJ. We'll talk with University of Maryland plant virologist Anne Simon about ways to stop the citrus killer, and with science writer and journalist Maryn McKenna about why throwing antibiotics at the problem is probably not the solution. Related links: A Review of the Citrus Greening...