Division of Translational Medicine and Human Genetics

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 Castleman Disease Research Program at Penn to answer the many remaining questions about Castleman disease, including the following:

1) What causes the immune system to become activated and release inflammatory molecules (cytokines) in UCD and iMCD?

2) What immune cells are responsible for secreting these cytokines?

3) What cellular pathways are activated that signal for these cytokines?

4) What are all of the cytokines released (beyond IL-6)?

5) What existing therapies are most effective at interrupting this disease?

6) What research Infrastructure should be built to facilitate the most efficient research?

Current research pipeline:

HUNT I (completed, manuscript in process): A virus or other pathogen has been hypothesized to be the cause of iMCD. This study searches for RNA sequences (like fingerprints) of pathogens, so if one of them is driving this disease, we'll find it. Investigators: PI: Dr. Ian Lipkin (Columbia University); co-Investigators: Drs. David Fajgenbaum (UPenn), Jason Ruth (Harvard), & Chris Nabel (Harvard)

Castleman Genome Project (in process, seeking patient samples): 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) – contact davidfa@mail.med.upenn.edu if you’re interested in learning more about this study

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@mail.med.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 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. Investigators: PI: Kojo Elenitoba-Johnson (UPenn), co-I: Drs. Megan Lim (UPenn) & David Fajgenbaum (UPenn) – contact davidfa@mail.med.upenn.edu if you’re interested in learning more about this study

Path to a Cure/Unlock the Cell (in process, seeking patient samples): We don't know which immune cells are driving the disease or the activated intracellular pathways.  In this study, we will determine which pathways and cell types are active. Investigators: PI: Dr. Vera Krymskaya (UPenn); co-Investigators: Dr. David Fajgenbaum (UPenn) & Evgeniy Eruslanov (UPenn) – contact davidfa@mail.med.upenn.edu if you’re interested in learning more about this study

HUNT II (in process, seeking patient samples): We will sequence RNA from CD lymph node samples to understand which genes are turned on in CD. Investigators: Drs. David Fajgenbaum (UPenn), Jason Ruth (Harvard), Chris Nabel (Harvard), & Ian Lipkin (Columbia)

SPEED I (completed, manuscript in process): 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 (analyses in process): We will perform a similar study to SPEED I on more than 300 samples. Investigators: PI: Drs. David Fajgenbaum (UPenn) & Jason Ruth (Harvard) – contact davidfa@mail.med.upenn.edu if you’re interested in learning more about this study

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. Investigator: PI: David Fajgenbaum (UPenn) — visit www.cdcn.org/accelerate to enroll

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. Investigator: PI: Dr. David Fajgenbaum (UPenn) – contact davidfa@mail.med.upenn.edu if you’re 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 davidfa@mail.med.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. Click here for a link to set up an appointment with Dr. Sunita Nasta.

Dr. Adam Cohen is a hematologist/oncologist at the University of Pennsylvania experienced with treating Castleman disease. Click here for a link to set up an appointment with Dr. Adam Cohen.

 

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