News Release 

Penn researchers discover key mechanism of cytokine storm in Castleman disease

Findings could have implications for COVID-19 patients experiencing same symptoms

University of Pennsylvania School of Medicine

PHILADELPHIA - When Castleman Disease patients have a flare of their symptoms, they experience a cytokine storm inside their bodies - a hyper-response from the immune system that can cause a fever, organ failure, and even death. Now researchers at the Perelman School of Medicine at the University of Pennsylvania say they know what's happening at the cellular level of the immune system when these cytokine storms occur, and the answer not only informs future potential Castleman therapies but may also provide new insight into why similar events take place in COVID-19 patients. The researchers published their findings today in the Journal of Clinical Investigation Insight. Castleman Disease isn't actually a single disease. The term describes a group of inflammatory disorders that share a common appearance under the microscope. It's diagnosed in about 5,000 people of all ages each year in the United States, which makes it roughly as common as Lou Gehrig's disease, also called Amyotrophic Lateral Sclerosis or ALS. Patients experience a range of symptoms - from a single abnormal lymph node with mild flu-like symptoms to abnormal lymph nodes located throughout their entire body, abnormal blood cell counts, and life-threatening failure of multiple organ systems, such as the kidneys, liver, heart, and lungs. The most severe subtype, idiopathic multicentric Castleman disease (iMCD), has similarities to autoimmune conditions, viral illnesses, and cancer. About 35 percent of patients with iMCD will die within five years of diagnosis.

"With iMCD, just as with COVID-19, it is the body's hyper-response that's deadly rather than the disease itself, and this study gives us new clues about why the immune cells are out of control and what we can do to rein them in," said the study's senior author David C. Fajgenbaum, MD, MBA, MSc, an assistant professor of Translational Medicine and Human Genetics, director of the Center for Study & Treatment of Lymphadenopathies & Cytokine Storms, executive director of the Castleman Disease Collaborative Network (CDCN), and a Castleman patient himself.

For this study, researchers took blood samples from iMCD patients who were asymptomatic and from those who were in flare to examine the differences in their immune cells. Previous research has shown the cytokine storm is tied to a cytokine, or inflammatory mediator, called interleukin-6 (IL-6), which in turn is connected to another pathway called mTOR. This study advanced these findings further and discovered a particular group of cytokines called Type-I Interferons are highly active when patients are in flare. They also found that another pathway called JAK seems to be a critical mediator of the cytokine storm.

"This deeper understanding of exactly what's causing the immune system's hyper-response strengthens the link between mTOR activation and cytokine storms, suggesting new treatment approaches for the patients in flare," said the study's lead author Ruth-Anne Langan Pai, a PhD candidate in Immunology and a member of the CDCN. Langan Pai performed the work as her doctoral thesis in Fajgenbaum's lab.

This alternative approach could address a vital clinical need. In 2014, the U.S Food and Drug Administration approved the drug siltuximab to treat iMCD, and studies have shown it can send between one-third and one-half of patients into a remission that generally lasts for years. However, patients who don't respond have limited options. They typically receive chemotherapy but often relapse.

Fajgenbaum and his team are currently testing treatment with mTOR inhibitors in a clinical trial (NCT03933904) at the University of Pennsylvania, with Sunita Nasta, MD, FACP, an associate professor of Hematology-Oncology, and Adam Cohen, MD, an assistant professor of Hematology-Oncology, enrolling and treating patients.

Fajgenbaum also says he hopes this work will prompt others in the field to consider different ways to approach the cytokine storms COVID-19 patients are experiencing. A provisional patent has been filed for a new treatment approach involving inhibition of JAK based on this work.

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This study was funded by the CDCN, the National Heart, Lung, and Blood Institute (1R01HL141408-01), the Hematologic Malignancies Translational Center of Excellence of the Abramson Cancer Center, and Uplifting Athletes.

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.

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