PHILADELPHIA – Five years ago, David C. Fajgenbaum, MD, MBA, MSc, a Penn Medicine researcher and patient, attempted experimental self-medication based on the findings of his lab research in hopes of saving his own life. It has been in remission ever since. Now his research sheds new light on why it works, paving the way for further testing of a new approach to treating Castlemann's disease, a rare and deadly condition with limited options for patients. The work is led by Faygenbaum, who is also director of the Castleman and Inflammatory Lymphadenopathy Research and Treatment Center (CSTL) at Perelman Medical School at the University of Pennsylvania, as well as Patient 1 in the study. The findings show that patients who do not respond to the only drug currently approved by the U.S. Food and Drug Administration (FDA) for disease management may have another option that targets a specific pathway called PI3K / Akt / mTOR. The study was published in Journal of Clinical Research today.
Castleman's disease is not really one disease. The term describes a group of inflammatory disorders that have a common occurrence under a microscope. It is diagnosed in about 5,000 people of all ages each year in the United States, making it about as common as Lou Gehrig's disease, also called ALS. Patients experience a range of symptoms – from one abnormal lymph node with mild flu-like symptoms to abnormal lymph nodes found throughout the 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 multicenter Castleman's disease (iMCD), has similarities with both autoimmune conditions and cancer. About 35 percent of iMCD patients will die within five years of diagnosis. In 2014, the FDA approved siltuximab for the treatment of iMCD, and studies have shown that it can send between one-third and one-half of patients into remission, which generally lasts for years.
"Patients who do not respond to siltuximab have limited options. They usually receive chemotherapy, but recurrences often occur," said Faygenbaum, who is also assistant professor of medicine at Translational Medicine and Human Genetics at Penn and CEO of Castleman's Collaborative Disease Network . Senior authors of the study are Thomas S. Uldrick, Ph.D. Med., Mr. Sc., Deputy Head of Global Oncology at the Fred Hutchinson Center for Cancer Research who also served as Faygenbaum's physician while practicing at the National Institutes of Health, and Frits van Rhee, Ph.D. Med., Dr. Sc. clinical director of the Myeloma Center at the University of Arkansas for Medical Sciences.
A college student, a former Division I champion, weightlifter in the National Champion, Feigenbaum suddenly became ill in July 2010. In 2012, after failing to respond to other therapies and being repeatedly present after chemotherapy, Faygenbaum's own-state research suggested that an inhibitory drug called sirolimus blocking the PI3K / Akt / mTOR pathway could be effective. This drug is already available to treat other conditions, especially to prevent organ rejection after kidney transplantation. Faygenbaum's decision to test him for himself, based on his own research and made in consultation with Uldrick, his doctor, has since kept him in remission. This study also examines two additional patients treated with the same approach who also achieved sustained remission. The study found that all three patients noticed an increase in two aspects of the immune system – an increased number of activated T cells and an elevated level of a protein called VEGF-A that causes blood vessels to grow – before the onset of the flash, then remission once started.
"Our findings are the first to link T cells, VEGF-A and the PI3K / Akt / mTOR pathway to iMCD," Faygenbaum said. "Most importantly, these patients improved when we inhibited mTOR. This is crucial because it gives us a therapeutic goal for patients who do not respond to siltuximab."
Feigenbaum and his team will test treatment in a clinical trial (NCT03933904), which will open in the coming weeks at the University of Pennsylvania, with Sunita Nast, MD. Med., FACP, Associate Professor of Hematology-Oncology, et al. By Adam Cohen, Ph.D. Assistant Professor of Hematology-Oncology, Patient Enrollment and Treatment. The University of Arkansas for Medical Sciences will also serve as a test site under van Rhee's leadership.
Faygenbaum also points to the larger implications this research has for the rare disease community.
"This indicates the potential for about 1500 medicines already approved for a single condition to be medicines or medicines for 7000 diseases without any or insufficient treatment options like ALS and many childhood cancers," Faygenbaum said.
This study was supported by Castleman Consciousness and Research Effort, Penn Center for Precision Medicine, University of Pennsylvania Research Foundation, and National Institutes of Health (ZIA BC 011700, R01-HL141408).
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