David Fajgenbaum, MD, MBA, MSc, an assistant professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania and associate director of patient impact in the Penn Orphan Disease Center, leads the Center for Cytokine Storm Treatment & Laboratory (CSTL) which includes the Castleman Disease Research Program at Penn, to answer the many remaining questions about Castleman disease and other cytokine storm disorders, including the following:
- What causes the immune system to become activated and release inflammatory molecules (cytokines) in UCD and iMCD?
- What immune cells are responsible for secreting these cytokines?
- What cellular pathways are activated that signal for these cytokines?
- What are all of the cytokines released (beyond IL-6)?
- What existing therapies are most effective at interrupting this disease?
- What research infrastructure should be built to facilitate the most efficient research?
Current research pipeline
- HUNT I (completed, published):
A virus or other pathogen has been hypothesized to be the cause of iMCD. This study searched for RNA sequences (like fingerprints) of pathogens, so if one of them was driving this disease, we'd find it.
- Investigators: PI: Dr. Ian Lipkin (Columbia University); co-Investigators: Drs. David Fajgenbaum (UPenn), Jason Ruth (Harvard), & Chris Nabel (Harvard)
- Castleman Genome Project (completed, published):
Another hypothesis is that a genetic defect in the ability to turn off the immune system could explain why iMCD occurs.
- Investigators: PI: Dr. Minji Byun (Mount Sinai Medical Center); co-Investigators: Drs. David Fajgenbaum (UPenn) & Jason Ruth (Harvard)
- FAST I-III (in process, seeking patient samples):
Defects in a gene, which are called mutations, may cause the gene to no longer function correctly. For example, a mutation in a gene that controls the immune system could cause the immune system to become uncontrollable. These gene mutations may be passed along in families from generation to generation. This study will help us find out if there is a common change in an inflammatory gene among patients with Castleman disease and will help us know if this is a genetic disease. It also investigates the role of a key immune cell called a T-cell.
- Investigators: co-PI: Drs. David Fajgenbaum (UPenn) & Taku Kambayashi (UPenn)
- Contact davidfa@pennmedicine.upenn.edu if you're interested in learning more about this study
- Somatic Mutation Search (in process, seeking patient samples):
We need to understand why the immune system becomes activated in Castleman disease. One hypothesis is that Castleman disease is caused by cancer cells. Cancer cells are just normal cells which have acquired mutations (changes in their DNA) over the course of life. These mutations are called somatic mutations. This study looks for cancer cells in patients' lymph nodes and will help us find out if cancer cells with somatic mutations cause Castleman disease.
- SPEED I (completed, published):
In CD, the immune system becomes activated and releases inflammatory proteins called cytokines that stimulate the immune system further and cause multiple organ systems to shut down. We know a few of these proteins play an important role, but no one has ever measured a large number of the proteins to understand exactly what is happening. In this study, we measured 1000+ proteins from patients during active disease and remission.
- Investigators: Drs. David Fajgenbaum (UPenn), Ruth (Harvard), & van Rhee (UAMS)
- SPEED II (completed, published):
We performed a similar study to SPEED I on more than 300 samples.
- Investigators: PI: Drs. David Fajgenbaum (UPenn) & Jason Ruth (Harvard)
- ACCELERATE (in process, seeking patients to enroll):
We don't have much clinical data on how CD starts and progresses. Lots of different treatments are used for patients with CD, but there is no data on what works for what kinds of patients. In this study, we collect clinical data from CD patients from around the world to better understand the clinical course and the best treatments for CD.
- Penn BioBank (in process, seeking patient samples):
One of the greatest hurdles to progress for CD research is access to the tissue samples needed for research. A few doctors have all the samples available and it is difficult/slow for them to be transferred to other institutions. This biobank will enable quick access to tissue samples.
- Clinical Trial of Sirolimus (in process, seeking patient enrollment):
A Sirolimus clinical trial for iMCD patients who do not respond to siltuximab is underway. Researchers in the CDCN have identified a treatment that may be effective for HHV-8-negative/idiopathic multicentric Castleman disease (iMCD) patients who do not respond to the only FDA-approved treatment, siltuximab. Sirolimus inhibits four aspects of iMCD that CDCN research has identified: T cell activation, B cell activation, VEGF production, and mTOR activation. Check out a case series describing sirolimus for the treatment of three anti-IL-6 refractory iMCD patients.
- Investigator: PI: Dr. David Fajgenbaum (UPenn), Dr. Frits van Rhee (UAMS), Dr. Adam Cohen (UPenn), and Dr. Sunita Nasta (UPenn)
- Contact cdtrial@pennmedicine.upenn.edu if you are interested in learning more about this study.
How patients can get involved
Patients can contribute blood samples or excess samples from previous clinical procedures (example: lymph node biopsy) for research. These can go to one of the above studies or for future research studies that have not even been conceptualized as of yet. Contact castlebank@pennmedicine.upenn.edu if you're interested in learning more about opportunities to enroll in a Castleman disease study and contribute samples for research.
How patients can be treated at Penn
- Dr. Sunita Nasta is a hematologist/oncologist at the University of Pennsylvania experienced with treating Castleman disease.
- Dr. Adam Cohen is a hematologist/oncologist at the University of Pennsylvania experienced with treating Castleman disease.