David Fajgenbaum, MD, MBA, MSc, an associate 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):
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 cstl@pennmedicine.upenn.edu if you're interested in learning more about this study
- Somatic Mutation Search (in process):
We’re working to understand why the immune system becomes overactive in Castleman disease. One possible reason is that Castleman disease cells may undergo somatic mutations—changes in their DNA that develop over time. This study looks for these types of cells in the lymph nodes of Castleman disease patients. By studying these changes, we hope to learn whether they play a role in causing the 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: A Natural History Study of Castleman Disease (now enrolling patients):
Idiopathic multicentric Castleman disease (iMCD) remains poorly understood, and this has significantly slowed the development of effective treatment strategies. Currently, siltuximab is the only FDA-approved treatment for iMCD, but it is only effective in approximately one-third of patients. To address this unmet need, we are conducting ACCELERATE, an international FDA-funded Natural History Study of Castleman Disease (R01FD007632). The study is designed to collect detailed clinical data from patients around the world to better understand disease presentation and identify promising treatment approaches being used off-label.
- Investigator: PI: David Fajgenbaum (University of Pennsylvania)
- Find out more information about the ACCELERATE study cdcn.org/accelerate, including how to register.
- 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 (completed, closed for enrollment):
The Center for Cytokine Storm Treatment and Laboratory partnered with the University of Arkansas for Medical Sciences to conduct a research study of an investigational medicine, sirolimus, for adults who have idiopathic multicentric Castleman disease (iMCD) and are unable to benefit from anti-IL-6 therapies. This trial is now closed to enrollment. Please contact cdtrial@pennmedicine.upenn.edu if you are interested in learning about future upcoming trial information.
- 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.
- SPACE: Serum Proteomic Analysis of Cytokine-Driven Entities (now seeking collaborators)
Cytokine storms, dangerous immune overreactions, play a central role in many inflammatory diseases but remain poorly understood. The SPACE study is an international effort to uncover the biological mechanisms behind these life-threatening conditions and identify new biomarkers and treatment targets. We are currently enrolling collaborators to contribute serum samples from patients with inflammatory diseases and healthy controls.
- Visit https://www.med.upenn.edu/CSTL/space-study.html to learn more about this study.
- Contact Bridget Austin at bridget.austin@pennmedicine.upenn.edu if you are interested in collaborating.
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.
- Dr. Joshua Brandstadter is a hematologist/oncologist at the University of Pennsylvania experienced with treating Castleman disease.