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Studies to Help us Answer Questions about Castleman Disease and Find a Cure

In patients with Castleman disease, the immune system becomes activated and releases inflammatory proteins called cytokines. In healthy individuals, cytokines are used by the immune system to help fight off infections. In Castleman disease, the levels are very high and no one knows why they're being released. These elevated cytokines cause immune cells to multiply and patients to experience flu-like symptoms and organ failure. This framework was uncovered by members of the CDCN and published in a medical journal (click here to read). With input from physicians, researchers, and patients from around the world, the CDCN is studying Castleman disease to help find the answers to the following questions: 

  1. What causes Castleman disease and the immune system to become activated and release cytokines?
  2. What immune cells are responsible for releasing these cytokines?
  3. What cellular pathways are activated that send a signal for the release of these cytokines?
  4. What are all of the cytokines released (in addition to IL-6) in patients?
  5. What current treatments are the most effective for patients?
  6. Research infrastructure
  7. How can physicians, researchers, and patients contribute to finding the answers to these questions?
  8. How can the CDCN's innovative approach be spread to other diseases to serve as a blueprint for how to cure a disease? 

The studies listed below are currently being conducted or will be conducted in the near future.  These studies will help us find the answers to the questions we have about Castleman Disease and will help us find a cure.


1) What causes Castleman disease and the immune system to become activated and release cytokines?

"HUNT" (Hunting for an Unknown, Novel Trigger) - Study E-100
DESCRIPTION:

We need to understand why the immune system becomes activated in Castleman disease. One hypothesis (idea) about the cause is that a virus or other pathogen triggers the immune system (the body's defense system against infections) to become activated. The activated immune system releases inflammatory proteins that can cause flu-like symptoms and organ failure. The HUNT study looks at Castleman disease patients' lymph node samples to "hunt" for the RNA (like a fingerprint) of pathogens. If a virus is cause Castleman disease, we'll find it. This is also called "viral hunting" or "pathogen discovery."  

STATUS: Funded. Samples have been collected and the study has been performed. Data is currently being analyzed.
COST: $57,000
INVESTIGATORS: Dr. Ian Lipkin (PI, Columbia University); co-Investigators: Drs. David Fajgenbaum (UPenn), Jason Ruth (Harvard), & Chris Nabel (Harvard)
See Map of Collaborators 
"Castleman Genome Project" - Sponsored by the Wharton Class of 2015 and the Penn Orphan Disease Center (Penn ODC) - Study E-200
DESCRIPTION: We need to understand why the immune system becomes activated in Castleman disease. One hypothesis (idea) is that Castleman disease patients may have a genetic defect that causes the immune system to be uncontrolled and to not turn off. A genome is the complete set of DNA (genetic material) that contains all the information for a person to develop and grow.  This study looks at the complete set of genetic material of 14 patients to see if there is a common genetic defect among patients with Castleman disease. This is also called "Whole Genome Sequencing." 
STATUS: Funded. Samples have been collected and the study has been performed. Data is currently being analyzed. 
COST: $63,000 ($28,000 from Castleman Disease Collaborative Network and $35,000 from the Penn Orphan Disease Center)
INVESTIGATORS:

Dr. Minji Byun (PI, Washington University in St. Louis); collaborators: Drs. David Fajgenbaum (UPenn) & Jason Ruth (Harvard)

Watch a video featuring Mike Guo, lead researcher of the donor-funded, Castleman Genome Project:

"Castleman Genome Project II" - Sponsored by attendees and donors at the 2016 Quest for a Cure Gala - Study E-201
DESCRIPTION: We need to understand why the immune system becomes activated in Castleman disease. One hypothesis (idea) is that Castleman disease patients may have a genetic defect that causes the immune system to be uncontrolled and to not turn off. A genome is the complete set of DNA (genetic material) that contains all the information for a person to develop and grow. The exome is the 3% of the genome that is responsible for all human proteins.  This study looks at the complete set of genetic material in the exome of 100 patients to see if there is a common genetic defect among patients with Castleman disease. This is also called "Whole Exome Sequencing." 
STATUS:

Funded. We are currently searching for samples. Patients: let us know if you're interested in contributing samples for research here.

COST: $115,000 
INVESTIGATORS:

TBD

"FAST (Flow cytometry And Studies of T-cells) I," "FAST II," & "FAST III" - Study E-202

DESCRIPTION:

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 will also investigate the role of a key immune cell called a T-cell.

STATUS:

Funded. Collecting samples and conducting the study.

Patients: let us know if you're interested in contributing samples for research here.

COST: $110,000
INVESTIGATORS: Drs. David Fajgenbaum (co-PI, UPenn) and Taku Kambayashi (co-PI, UPenn)
"Somatic Mutation Search" Study E-300
DESCRIPTION: 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. The techniques used in this study will be "Whole Genome Sequencing" or "Whole Exome Sequencing."
STATUS:

Funded Currently searching for patient samples.

Patients: let us know if you're interested in contributing samples for research here.

COST: $40,000 
INVESTIGATORS: Kojo Elenitoba-Johnson (PI, UPenn), Megan Lim (co-I, UPenn), & David Fajgenbaum (co-I, UPenn)
"Autoantibodies in Castleman disease" - Study E-400
DESCRIPTION: We need to understand why the immune system becomes activated in Castleman disease. Antibodies are secreted by immune cells to fight infection. Sometimes those antibodies attack healthy cells in the body and are called auto-antibodies. One hypothesis is that auto-antibodies are responsible for activating the immune system in patients with Castleman disease. Previous studies have shown that at least 20% of Castleman disease patients have auto-antibodies in their blood. This study will look for auto-antibodies in the blood of patients to see if they are causing the immune system to attack healthy cells. 
STATUS: NEEDS FUNDINGClick here to donate to enable this study.
COST: ~$60,000 
INVESTIGATORS: To be determined. NEED an investigator with expertise in auto-immunity to lead this.

2) What immune cells and 3) cellular pathways are activated and responsible for releasing cytokines in Castleman disease?

"Path to a Cure" & "Unlock the Cell" - Sponsored by Castleman Warriors - Study C-100 & P-100
DESCRIPTION:

In Castleman disease, the immune system becomes activated and releases inflammatory proteins called cytokines. These cytokines cause vital organs (liver, kidneys, bone marrow) to not work well and to shut down. We don't know which immune cells or pathways are activated. This study looks for the activated immune cells and cellular pathways. Researchers will examine Castleman Disease lymph nodes using immunohistochemistry, a process that causes certain cellular markers to light up. A process called flow cytometry will help determine the active cell types and the cell pathways.

STATUS:

Funded. Currently searching for patient samples.

Patients: let us know if you're interested in contributing blood samples for research here.

COST: $20,000
INVESTIGATORS: Dr. Vera Krymskaya (co-PI, UPenn); Dr. David Fajgenbaum (co-PI, UPenn); Dr. Evgeniy Eruslanov (co-PI, UPenn)

"HUNT II/Path to a Cure II" - Study P-200

DESCRIPTION:

In Castleman disease, the immune system becomes activated and releases inflammatory proteins called cytokines. These cytokines cause vital organs (liver, kidneys, bone marrow) to not work well and to shut down. We don't know which immune cells or pathways are activated. This study looks for the pathways that are activated in the cells of lymph node samples by telling us which genes are turned on. This technique is called RNA sequencing. Samples will be used from Study P-100.

STATUS: Funded. Currently searching for patient samples. 
COST: $75,000
INVESTIGATORS: Drs. David Fajgenbaum (co-PI, UPenn), Jason Ruth (co-PI, Harvard), Chris Nabel (co-PI, Harvard), and Ian Lipkin (Columbia)
See Map of Collaborators 
“Next-Gen Cellular and Molecular Study" - C-300
DESCRIPTION:

In Castleman disease, the immune system becomes activated and releases inflammatory proteins called cytokines. These cytokines cause vital organs (liver, kidneys, bone marrow) to not work well and to shut down. We don't know which immune cells or pathways are activated. This study looks for the activated immune cells and cellular pathways. Researchers will examine Castleman Disease lymph nodes using one of the following cutting-edge technologies: CyTOF, MIBI, CODEX, and/or single-cell RNASeq. These new technologies will investigate dozens and hundreds of markers to help determine the active cell types and the cell pathways.

STATUS: NEEDS FUNDINGClick here to donate funds to enable this study. 
COST: ~$100,000
INVESTIGATORS: TBD

 


4) What are all of the cytokines released in Castleman disease?

"SPEED I" (Serum Proteomics Evaluation for Etiology and Pathogenesis Data) - Sponsored by The Jayanthan Family & Friends - S-100
DESCRIPTION: In Castleman disease, the immune system becomes activated and releases inflammatory proteins called cytokines. These cytokines cause vital organs (liver, kidneys, bone marrow) to not work well and to shut down. We know a few of these cytokines that play an important role, but no one has ever measured a large number of them. In this study, we measure 1129 proteins from 7 patients during a disease flare and during remission to find out which proteins play a role in Castleman disease.
STATUS: FundedData received, currently analyzing
COST: $23,000
INVESTIGATORS: Drs. David Fajgenbaum (co-PI, UPenn), Ruth (co-PI, Harvard), & van Rhee (co-PI, UAMS); Somalogic, MyriadRBM
“SPEED II” (Serum Proteomics Evaluation for Etiology and Pathogenesis Data) - S-200
DESCRIPTION:

In Castleman disease, the immune system becomes activated and releases inflammatory proteins called cytokines. These cytokines cause vital organs (liver, kidneys, bone marrow) to not work well and to shut down. We know a few of these cytokines that play an important role, but no one has ever measured a large number of them. In this study, we will measure 1300 proteins in the blood of 80 Castleman disease patients at various time points as well as patients with other diseases that exhibit similar features to Castleman disease (e.g., rheumatoid arthritis, HHV8-positive MCD, Hodgkin's Lymphoma). Seven institutions from around the world will contribute samples. Identifying these proteins released in Castleman disease is important.  If we know which proteins are involved, we can use treatments to target those particular proteins. Also, identifying proteins involved can provide us with new ways to diagnose Castleman disease.

STATUS: FundedCollecting samples. 
COST: $350,000
INVESTIGATORS: Drs. David Fajgenbaum (co-PI, UPenn) & Jason Ruth (co-PI, Harvard); Platform: Somalogic
See Map of Collaborators 

5) What current treatments are the most effective for patients with Castleman disease?

Systematic Literature Review of Patients and Treatments - T-100
DESCRIPTION:

There are many different treatments that have been used in Castleman disease patients, but no one has ever tracked what works and what does not work. We need to know more about which types of treatments work and in which types of people. This study, called a systematic literature review, looked at how well treatments work in different types of people.  This study also looked at how Castleman disease starts and progresses over time in patients. In this study, the authors also collected clinical data from Castleman disease patients around the world.

The key findings included: one-third to one-half of MCD cases are HHV-8-negative, 2) commonly observed features of iMCD are lymphadenopathy, anemia, elevated CRP, hypergammaglobulinemia, hypoalbuminemia, elevated IL6, enlarged liver and/or spleen, fever, fluid accumulation, elevated sIL2R, and elevated VEGF, 3) a variety of treatments (corticosteroids, cytotoxic chemotherapy, anti-IL-6 therapy, immunomodulatory) are used with variable effectiveness, and 4) iMCD patients have a 3-fold increased rate of cancer than age-matched controls. These results were published in a top hematology journal, Lancet Haematology. Click here for the article.

STATUS: Published! 
COST: $2,500
INVESTIGATORS: Dr. David Fajgenbaum (PI, UPenn)
“ACCELERATE” (Global Patient Registry)In collaboration with the University of Pennsylvania (sponsor) and Janssen Pharmaceuticals - T-200
DESCRIPTION:

There are many different treatments that have been used in Castleman disease patients, but no one has ever tracked what works and what does not work. We need to know more about which types of treatments work and in which types of people. This study, called a natural history study, looks at how well treatments work in different types of people.  This study also looks at how Castleman disease starts and progresses over time in patients. In this study, the CDCN will collect clinical data from Castleman disease patients around the world. More information at: www.cdcn.org/accelerate 

STATUS: Funded. Launched in October 2016. See press release here.
COST: $4.8M
INVESTIGATORS: Dr. David Fajgenbaum (PI, UPenn)

6) Research Infrastructure

Systematic Literature Review of CD research and understanding in 2012 - I-001
DESCRIPTION:

When the CDCN was established in 2012, the first priority was to perform a systematic literature review of all published research on Castleman disease (CD). The results from review of over 2,000 papers were synthesized into the following key findings: 1) CD should be subdivided into unicentric CD, HHV-8-associated multicentric CD, and HHV-8-negative/idiopathic multicentric CD (iMCD), 2) CD should be thought of, researched, and treated less like a cancer and more like a disoder of the immune system, and 3) there are three potential hypotheses that could explain why the immune system becomes hyperactivated in iMCD that require further investigation. These results were published in the top hematology journal in the world, Blood. Click here for the article.

STATUS: Complete. Results published. Click here for the article.
COST: $0, research was performed by David Fajgenbaum while in medical school
INVESTIGATORS: Dr. David Fajgenbaum (PI, UPenn) and CDCN Scientific Advisory Board  

 

Establish a unique ICD-10 code for CD - I-002
DESCRIPTION:

When the CDCN was established in 2012, there was not a unique code in the US health care system for Castleman disease. The code for Castleman disease also included any other cause of enlarged lymph nodes. Therefore, patients with CD often had their treatments denied by insurers who didn't realize they had CD and research could not be done to identify patients with CD around the US. The CDCN put together an application and advocated for a unique code in 2014. In October 2016, CD received a unique code: D47.Z2

STATUS: ICD-10 code created. 
COST: $0, research that supported this project came from I-001.
INVESTIGATORS: Dr. David Fajgenbaum (PI, UPenn) and CDCN Scientific Advisory Board 

 

“CastleBank” (Castleman disease biobank)I-100
DESCRIPTION:

Studying Castleman disease is difficult because it is difficult to get samples of blood, saliva, and lymph nodes for research. Samples may be stored in various places all over the world with no way of other researchers being able to obtain them. In order to find out what causes Castleman disease, researchers need access to these samples so they can study them. The CastleBank will provide a central location for all samples. Researchers studying Castleman disease will then have access to these samples, making it much easier to study the disease.

STATUS: Funded for 2016. Click here to donate to support this biobank in future years.
COST: $40,000 per year
INVESTIGATORS: Dr. David Fajgenbaum (PI, UPenn) and CDCN Scientific Advisory Board 
Establishment of an International Diagnostic Criteria - I-200
DESCRIPTION:

Diagnosing Castleman disease can be very challenging because there is not an established diagnostic criteria for physicians to check. Diagnostic criteria provide a consistent standard that doctors can use based on signs, symptoms, and laboratory findings of the disease to make a diagnosis. Having diagnostic criteria make diagnosing the disease easier. The CDCN co-hosted a meeting with the Penn Orphan Disease Center (ODC) to establish an international diagnostic criteria. 

STATUS: Results published. Click here for the article.
COST: $17,000 from CDCN, $17,000 from ODC
INVESTIGATORS: Dr. David Fajgenbaum (UPenn) and CDCN Scientific Advisory Board

7) How can physicians, researchers, and patients contribute to finding the answers to these questions?

Physicians: we need physicians to conduct clinical research, help with identifying and prioritizing patient-focused research projects, contribute patient samples to research, and give patients the opportunity to contribute data and samples for research. Email info@castlemannetwork.org for more information about contributing in the above ways.
 
Researchers: we need researchers to conduct basic, translational, and clinical research and help with identifying and prioritizing high-impact research projects. Email info@castlemannetwork.org for more information about contributing in the above ways.
 
Patients: we need patients to help with identifying and prioritizing patient-focused research projects, contribute samples and data to research, and help with raising the funds to conduct these high-impact, patient-focused studies. Click here for more information. Email info@castlemannetwork.org for more information about contributing in the above ways.
 

Among several other projects, the CDCN is currently working on the following non-research priorities:

Dr. David Fajgenbaum leads physicians and researchers through a discussion on the current status of Castleman disease research, resources for patients and unmet needs at an ASH meeting:


8) How can the CDCN's innovative approach be spread to other diseases to serve as a blueprint for how to cure a diseases?

The CDCN has made ground breaking progress in a very short period of time. The CDCN's innovative approach has been written up in The Lancet Haematology. You can read about the approach here.