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Developmental Biology - Castleman Disease

Self-Testing For A Fatal Disease

A therapy for Castleman disease, self-tested on a doctor with the disorder, now begins clinical trials...

Five years ago, David C. Fajgenbaum MD MBA MSc and a Penn Medicine researcher, became a patient with Castleman Disease. Deadly, Castleman's isn't actually a single disease, but a group of inflammatory disorders sharing a common appearance under the microscope. It is diagnosed in about 5,000 people of all ages each year in the United States, making it roughly as common as Lou Gehrig's disease, also known as ALS.

Patients experience a range of symptoms — from a single abnormal lymph node with mild flu-like symptoms — to abnormal lymph nodes throughout their entire body, abnormal blood cell counts and life-threatening failure of multiple organ systems such as kidneys, liver, heart, and lungs.
The most severe subtype, idiopathic multicentric Castleman disease (iMCD), is similar to auto-immune conditions as well as cancers. About 35 percent of patients with iMCD die within five years of diagnosis. In 2014, the FDA approved the drug siltuximab to treat iMCD when studies showed it can send between one-third and one-half of patients into remission, generally lasting years.

Fajgenbaum is both director of the Center for Study & Treatment of Castleman's & Inflammatory Lymphadenopathies (CSTL) in the Perelman School of Medicine at the University of Pennsylvania — and Patient #1 in the study. His findings reveal patients who do not respond to siltuximab, may have another option targeting the specific pathway called PI3K/Akt/mTOR. The research is published in the Journal of Clinical Investigation.
"Patients who don't respond to siltuximab have limited options. They typically receive chemotherapy but often relapse..."

David C. Fajgenbaum MD MBA MSc, Assistant Professor, Translational Medicine & Human Genetics, University of Pennsylvania, and executive director the Castleman Disease Collaborative Network.

The study's senior authors are Thomas S. Uldrick MD MS, deputy head of Global Oncology at Fred Hutchinson Cancer Research Center and formerly Fajgenbaum's treating physician while practicing at the National Institutes of Health; and Frits van Rhee MD PhD, clinical director of the Myeloma Center at the University of Arkansas for Medical Sciences.

A med student, former Division I quarterback, and state-champion weight lifter, Fajgenbaum suddenly became sick in July 2010. In 2012, after failing to respond to other therapies and having relapsed multiple times following chemo, Fajgenbaum's research on his own condition suggested an inhibitor drug called sirolimus (which blocks the PI3K/Akt/mTOR pathway) could be effective. Sirolimus is already available for treatment of other conditions, particularly to prevent organ rejection after kidney transplant.

Fajgenbaum's decision to test it on himself, was based on his own research and made in consultation with Uldrick as his treating physician. It has kept him in remission ever since. Two additional patients also treated with the same approach also have achieved sustained remission. Research shows all three patients saw an increase in two aspects of their immune system. (1) Increased numbers of activated T cells and (2) elevated levels of a protein called VEGF-A, which causes blood vessel growth - before a flare up, then a return to normal levels once remission began.
"Our findings are the first to link T cells, VEGF-A, and the PI3K/Akt/mTOR pathway to iMCD. Most importantly, these patients improved when we inhibited mTOR. This is crucial as it gives us a therapeutic target for patients who don't respond to siltuximab."

David C. Fajgenbaum MD MBA MSc.

Fajgenbaum and his team will test the treatment in a clinical trial (NCT03933904) set to open in the coming weeks at the University of Pennsylvania, with Sunita Nasta MD FACP, associate professor of Hematology-Oncology, along with Adam Cohen MD and assistant professor of Hematology-Oncology, enrolling and treating patients. The University of Arkansas for Medical Sciences will also serve as a trial site under the direction of Frits van Rhee MD PhD, clinical director of the Myeloma Center at the University of Arkansas for Medical Science.

Fajgenbaum also points out the larger implications this research has for the rare disease community: "This highlights the potential for the approximately 1,500 drugs already approved for one condition to also be treatments or cures for the 7,000 diseases with no or insufficient treatment options like ALS and many pediatric cancers."

Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype.

We analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus.

Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months.

This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904).

David C. Fajgenbaum, Ruth-Anne Langan, Alberto Sada Japp, Helen L. Partridge, Sheila K. Pierson, Amrit Singh, Daniel J. Arenas, Jason R. Ruth, Christopher S. Nabel, Katie Stone, Mariko Okumura, Anthony Schwarer, Fábio Freire Jose, Nelson Hamerschlak, Gerald B. Wertheim, Michael B. Jordan, Adam D. Cohen, Vera Krymskaya, Arthur Rubenstein, Michael R. Betts, Taku Kambayashi, Frits van Rhee, and Thomas S. Uldrick.

This study was supported by the Castleman's Awareness & Research Effort, the Penn Center for Precision Medicine, the University of Pennsylvania University Research Foundation, and the National Institutes of Health (ZIA BC 011700, R01-HL141408).

Castleman’s Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute. 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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Aug 23 2019   Fetal Timeline   Maternal Timeline   News  

David C. Fajgenbaum MD MBA MSc, tried an experimental treatment on himself after conducting laboratory research hoping to save his own life — and has been in remission ever since. Now his research is shedding new light on why this treatment is working for him and paving the way
for others to test his new treatment approach. CREDIT Penn Medicine

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