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Research Pipeline: Leading to personalized medicine

  • What is the cause of the immune system hyperactivation in Castleman disease?
  • What type of immune cells are activated?
  • What pathways in the cells are activated?
  • What factors are released by the activated immune cells?
  • What treatments are most effective at stopping Castleman disease?
  • What tests could improve a Castleman disease diagnosis?

In a healthy person’s body, inflammatory proteins called cytokines are released when an infection is detected and return to normal once the infection subsides. In CD patients, there is an excessive release of cytokines that occurs for an unknown cause. The elevated cytokines cause immune cells to multiply which leads to CD symptoms. We suspect immune system hyper-activation is caused by an inherited genetic mutation, a genetic mutation acquired during the course of life, autoimmune mechanisms, and/or unidentified infection.

In CD, immune system hyperactivation leads to the release of cytokines. We do not yet know which immune cells are responsible for prompting the immune hyperactivation. Our early research findings suggest that T lymphocytes, B lymphocytes, and follicular dendritic cells may be playing important roles in the onset of CD.

In order for immune cells to produce cytokines, communication lines called pathways must be activated. We don’t know which cellular pathways are activated in CD, but we are work-ing hard to uncover these dysfunctional cellular pathways.

We know a few cytokines that play an important role in CD, such as Interleukin-6, but we suspect that other cytokines may also be involved. We are striving to uncover the immune factors released in CD to ultimately find better treatments and diagnostic tests in order to save lives.

While we know of a few treatments that are helpful for CD patients, including one FDA- approved drug for idiopathic multicentric CD (siltuximab), these treatments, unfortunately, do not help all patients. We are working to find new and more effective treatments for CD patients that don’t benefit from existing options.

Right now, Castleman disease is diagnosed by clinicians and pathologists who review data and lymph node tissue to determine if a patient likely has Castleman disease. Unfortunately, there are no definitive tests and diagnosis relies on this subjective assessment. We would like to identify a more objective way to diagnose Castleman disease that would involve either specific tests of lymph node tissue or blood.

The CDCN’s ground-breaking Collaborative Network Approach: an 8-step approach to accelerating research

  • Step 1
  • Step 2
  • Step 3
  • Step 4
  • Step 5
  • Step 6
  • Step 7
  • Step 8

Build Community

Since it was first established in 2012, the CDCN has connected the global community of physicians, researchers, patients and loved ones to accelerate CD research, treatment, and patient care. The CDCN started by contacting all of the authors from the 2,000+ papers on PubMed associated with Castleman disease. Then, the CDCN held its first in-person meeting of physicians and researchers at ASH 2012 and webinars to connect the various members of the community. Next, the CDCN established an online forum for patients to connect with one another and an online forum for physicians and researchers to connect with one another.

More recently, a database of the top physicians around the world was created to refer patients to them. This community is always growing, but today, it includes:

  • A Scientific Advisory Board of 30 experts from eight countries on five continents
  • 800+ physicians and researchers
  •  Over 10,000 patients and loved ones that have been connected through our online portal
  • Patients are engaged on the Scientific Advisory Board, Leadership Team and research meetings, and supported through a Patient Summit, online discussion board, physician referrals, and educational materials.

Crowdsource and Prioritize Studies

The traditional way that rare disease research is performed is random, and it can be redundant and slow. Typically, research organizations raise funds, invite researchers to submit applications to use the funds how the researchers see fit, and the research organizations select the best applications to fund. One must hope that the right researcher with the right skill set submits an application with the right idea to perform the right project at the right time. The potential possibilities for what studies will be performed are limited to ideas generated by individuals who can actually perform the studies.

The CDCN takes a radically different approach. It leverages the Community (Step 1) of physicians, researchers, and patients to generate ideas for what studies should be done by using online questionnaires, a crowdsourcing platform (Codigital), social media data, and email submissions. Then, the CDCN Scientific Advisory Board prioritizes these crowdsourced ideas into an “International Research Agenda.”

Patients are at the heart of everything the CDCN does – by engaging patients on various platforms like the leadership team and online discussion board, the CDCN ensures the research priorities will answer questions most important to patients.

This approach means that we don’t just hope that the right study will be conceptualized and applied for by a researcher. We identify the right study and then recruit the right researcher (Step 3) with the right skill set to perform the study and provide the necessary funding and tissue samples. Most importantly, any idea can potentially turn into a study rather than just ideas conceived by the researchers that can perform the studies.

Identify Researchers

With the right studies identified and prioritized (Step 2) on the CDCN’s “International Research Agenda” (IRA, studies listed below), the CDCN actively recruits and engages the

leading expert for a particular kind of study to conduct the high-priority project that the CDCN needs performed. If you are a physician/researcher interested in getting involved, please join the network  here.

Fundraise

With the right study identified and prioritized (Step 2) and the top researcher in the world recruited (Step 3), the CDCN performs targeted fundraising to enable the specific studies. The CDCN maximizes every dollar contributed by maintaining very low operating costs, promoting collaboration among researchers rather than duplication, and strategically funding high-impact research initiatives.

Funds are raised through four main channels:

  1. Events and campaigns (Quest for a Cure Gala!)
  2. Individual donations (donate here!)
  3. The Castleman Warrior Program – The Warrior program was established to connect patients and loved ones around the world. This very dedicated group of patients and loved ones fight back against CD by raising money and awareness for research. Get involved here!
  4. Collaborative partnerships with corporations and foundations

Enroll Patients and Procure Samples

For every study, the CDCN works with patients and physicians around the world to coordinate obtaining the necessary samples (e.g., blood, saliva, left over lymph node tissue, etc). Obtaining high-quality samples is a major challenge in rare disease research.

The CDCN proactively seeks to obtain tissue samples for future studies, because researchers can’t do research without patient samples. The CDCN’s international community of researchers needs samples from Castleman disease patients so that we can continue to drive forward our search for a cure!  These samples help us to better characterize this disease and will lead to greater knowledge about current and potential treatments. If you would like to donate a sample, please click here!

Conduct Studies

After selecting the top priority project (Step 2), recruiting the foremost expert in that field (Step 3), and obtaining the necessary funds (Step 4) and samples (Step 5), the CDCN assists with all aspects of successful execution of the study.

We establish a research agreement, coordinate contracts among collaborators, provide project management support, and contribute scientific advice throughout the process.

Analyze data and search for new treatments based on results

After the data is generated from the study, the CDCN works with collaborators to ensure rapid analysis of the data. Together with the researcher and input from members of the CDCN research community, a paper is generated for a peer-reviewed journal that features the results of the study. Using results from research studies,

the CDCN aims to identify existing drugs that may be effective against Castleman disease. Results from the use of these existing treatments are captured in the ACCELERATE Patient Research Study. The CDCN also advances clinical trials of promising drugs based on these studies.

Disseminate Knowledge

After performing the studies and publishing the data, the CDCN works to ensure these findings are disseminated among researchers, physicians, patients and loved ones around the world as quickly as possible. We accomplish this through physician/researcher meetings, Patient Summits, online portals for patients, physicians and researchers, social media and online CDCN resources.

When battling a rare disease, it is essential new findings are shared with a wide audience as quickly as possible.

Then, the CDCN shares these results with the Community (Step 1) to inspire new ideas for research (Step 2) and the cycle repeats.

What is the cause of the immune system hyperactivation in Castleman disease?

  • Step 1

    Build Community

  • Step 2

    Prioritize Studies

  • Step 3

    Identify Researchers

  • Step 4

    Fundraise

  • Step 5

    Enroll Patients

  • Step 6

    Conduct Studies

  • Step 7

    Analyze Data

  • Step 8

    Disseminate Knowledge

  • HUNT (Hunting for an Unknown, Novel Trigger) I
    CDCN-2015-002-R
         Step 8
    Status Complete

    Cost: $57,000

    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 another 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 causing Castleman disease, we’ll find it. This is also called “viral hunting” or “pathogen discovery”. The full published paper can be found here. 

    INVESTIGATORS

    Dr. Ian Lipkin (PI, Columbia University); co-Investigators: Drs. David Fajgenbaum (UPenn), Jason Ruth (Harvard), & Chris Nabel (Harvard)

  • HUNT II Step 7
    Status Funded

    We need to understand why the immune system becomes activated in Castleman disease. One hypothesis (idea) about the cause is that a virus or another 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 II study looks at Castleman disease patients’ lymph node samples to “hunt” for the RNA (like a fingerprint) of pathogens. If a virus, fungus, or bacteria is causing Castleman disease, we’ll find it. This is also called “pathogen hunting”.

    INVESTIGATORS

    Dr. Erle Robertson (PI, Columbia University); co-Investigator: Drs. David Fajgenbaum (UPenn)

  • HUNT III Step 7
    Status Funded

    We need to understand why the immune system becomes activated in Castleman disease. One hypothesis (idea) about the cause is that a virus or another 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 II study looks at Castleman disease patients’ blood samples to “hunt” for the RNA (like a fingerprint) of pathogens. If a virus, fungus, or bacteria is causing Castleman disease, we’ll find it. This is also called “pathogen hunting”.

    INVESTIGATORS

    Dr. Danny Douek (PI, National Institutes of Health); co-Investigator: Drs. David Fajgenbaum (UPenn)

  • Castleman Genome Project I
    CDCN-2015-004-S
         Step 8
    Status Complete

    Cost: $63,000; $28,000 from CDCN and the Wharton Class of 2015 and $35,000 from the Penn Orphan Disease Center 

    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.” This study found a mutation in the FAS gene in a family with multiple members with Castleman disease. The FAS gene is known to play an important role in maintaining lymphatic organs and mutations in the gene are known to be associated with Autoimmune Lymphoproliferative Syndrome, which can present with similar findings to Castleman disease. Based on this work, Dr. Byun is now performing experiments to understand how the FAS mutation she uncovered may play a role in Castleman disease. The full text of the published paper can be found here. Whole genome sequencing data on iMCD and UCD patients from this study is publicly available here to be used for future research. 

    INVESTIGATORS

    Dr. Minji Byun (PI, Icahn School of Medicine at Mount Sinai); collaborators: Drs. David Fajgenbaum (UPenn) & Jason Ruth (Harvard)

    Castleman Genome Project Video

  • Functional Validation of Genomic Hits I
    CDCN-2018-001-R
         Step 8
    Status Funded

    Cost, $42,000; Sponsored by the Castleman Warriors

    DESCRIPTION

    We need to figure out what is causing immune system hyperactivation in Castleman disease. One hypothesis is that a genetic difference may cause, or increase the risk of developing, Castleman disease in some patients. Prior CDCN-funded research conducted by Dr. Minji Byun identified a genetic difference in a patient with Castleman disease that may be related to the disease. The genetic difference occurred in a gene called DNMT3A but it was only present in a fraction of all cells, suggesting that it occurred during the course of life rather than being inherited from the patient’s parents. Genetic differences often do not cause problems, so the next steps for Dr. Byun was to determine how the genetic difference works and whether it plays a role in Castleman disease.

    The study has been completed, and it found that this mutation in DNMT3A may be contributing to this patient’s Castleman disease. It is published here and full text here!

    More work is needed to determine if the genetic difference is causing Castleman disease in the patient and the potential therapeutic implications.

     

    INVESTIGATORS

    Dr. Minji Byun, PhD; Assistant Professor Department of Medicine, Division of Clinical Immunology Icahn School of Medicine at Mount Sinai, New York, NY

  • Functional Validation of Genomic Hits II
    CDCN-2017-002-S
         Step 6
    Status Funded

    Cost: $42,000; Split between the CDCN and the Penn Orphan Disease Center

    DESCRIPTION

    We need to figure out what is causing immune system hyperactivation in Castleman disease. One hypothesis is that a genetic difference may cause or increase the risk of developing Castleman disease in some patients. Prior research conducted by Dr. Robert Ohgami identified a genetic difference in a patient with Castleman disease that may be related to the disease. The genetic difference occurred in a gene called DNMT3A but it was only present in a fraction of all cells, suggesting that it occurred during the course of life rather than being inherited from the patient’s parents. Genetic differences often do not cause problems, so the next step for Dr. Ohgami is to determine the significance of the original finding by combining laser microdissection with genetic sequencing to pinpoint cells in lymph node tissue that express the genetic difference. Identifying a genetic cause could lead to new diagnostic tools and point us in the direction of new treatments. This work is still in progress.

    INVESTIGATORS

    Robert Ohgami, MD, PhD; Assistant Professor of Pathology, Stanford University, Stanford, CA

    Matthew van de Rijn, MD, PhD; Professor of Pathology, Stanford University, Stanford, CA

  • Functional Validation of Genomic Hits III
    CDCN-2018-002-R
         Step 8
    Status Complete

    Cost: $42,000; Funded by the CDCN

    DESCRIPTION

    We need to figure out what is causing immune system hyperactivation in Castleman disease. One hypothesis is that a genetic difference may cause or increase the risk of developing Castleman disease in some patients. Prior research conducted by Dr. Wenbin Xiao identified patients with Castleman disease who had differences in their genetic code that may be related to the disease. One genetic difference is in a gene called MAP2K2 and another in a gene called RUNX1. Genetic differences often do not cause harm, so the next step for Dr. Xiao was to determine whether these genetic differences play a role in Castleman disease by investigating the activity of associated cellular pathways and products. Validating a genetic cause could lead to new diagnostic tools and point us in the direction of new treatments.

    The study has been completed and published here and full text here!

    INVESTIGATORS

    Wenbin Xiao, MD, PhD; Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York City, NY

    Omar Abdel-Wahab, MD; Human Oncology and Pathogenesis Program/Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY

    Ahmet Dogan, MD, PhD; Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York City, NY

  • Functional Validation of Genomic Hits IV
    CDCN-2019-001-S
         Step 6
    Status Funded

    Cost: $42,000; Split between the CDCN and the Penn Orphan Disease Center

    DESCRIPTION

    We need to figure out what is causing immune system hyperactivation in Castleman disease. One hypothesis is that a genetic difference may cause or increase the risk of developing Castleman disease in some patients. Prior research identified a a genetic difference in lymph node tissue from a large proportion of unicentric Castleman disease (UCD) patients that may be related to the disease. The genetic difference was found in a gene called PDGFRb. Now, Dr. Maillard is advancing this research to understand the role of this mutation and the implications for treatment of UCD. Identifying a genetic cause could lead to new diagnostic tools and point us in the direction of new treatments. This work is still in progress.

    INVESTIGATORS

    Ivan Maillard, MD, PhD; Professor of Medicine, University of Pennsylvania, Philadelphia, PA

    Josh Brandstadter, MD, PhD; Hematology-Oncology Specialist, University of Pennsylvania, Philadelphia, PA

    David Fajgenbaum, MD, MBA, MSc; Assistant Professor of Medicine, University of Pennsylvania, Philadelphia, PA

  • Functional Validation of Genomic Hits V
    CDCN-2020-004-S
         Step 6
    Status Funded

    Cost, $50,000; Sponsor TBD

    DESCRIPTION

    One hypothesis is that a genetic difference may cause or increase the risk of developing Castleman disease in some patients. Prior research identified a a genetic difference in lymph node tissue from a large proportion of unicentric Castleman disease (UCD) patients that may be related to the disease. Now, Dr. Boutboul is advancing this research to understand the role of this mutation in PDGFRb and the implications for treatment of UCD. Identifying a genetic cause could lead to new diagnostic tools and point us in the direction of new treatments. This work is still in progress.

    INVESTIGATORS

    Dr. David Boutboul, MD (PI), Dr. Eric Oksenhendler, MD (co-I), Hopital Saint Loui, Paris, France

  • Castleman Genome Project II
    TBD
         Step 5
    Status Seeking Funding & Samples

    Cost: $375,000: $250,000 covered by the Broad Institute and the remaining $125,000 will need to be raised by the CDCN

    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 300 patients to see if there is a common genetic defect among patients with Castleman disease. This is also called “Whole Exome Sequencing.” This will be fully paid for by the Broad Institute. The CDCN will also pay to perform HLA typing on all of these patients.

    INVESTIGATORS

    TBD

    Blood samples are urgently needed from iMCD patients. Click here for more information.

    Castleman Genome Project Video

  • FAST (Flow Cytometry And Studies of T-cells) I, FAST II, FAST III, & FAST IV
    CDCN-2016-001,002,003-R
    CDCN-2018-005-R         Step 6
    Status Funded

    Cost: $160,000

    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.

    INVESTIGATORS

    Drs. David Fajgenbaum (co-PI, UPenn) and Taku Kambayashi (co-PI, UPenn)

  • Somatic Mutation Search
    CDCN-2016-004-S
         Step 6
    Status Funded

    Cost: $40,000; Funded through the Penn Orphan Disease Center and the 2016 Quest for a Cure gala

    DESCRIPTION

    We need to understand why the immune system becomes activated in Castleman disease. One hypothesis (idea) 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. The techniques used in this study will be “Whole Genome Sequencing” or “Whole Exome Sequencing.” This work is still in progress.

    INVESTIGATORS

    Drs. Kojo Elenitoba-Johnson (PI, UPenn), Megan Lim (co-I, UPenn), & David Fajgenbaum (co-I, UPenn)

  • Clonal activation of lymph node stromal cells in unicentric Castleman Disease
    CDCN-2019-001-S
         Step 6
    Status Funded

    Cost: $20,000; Funded in partnership between Uplifting Athletes and CDCN

    DESCRIPTION

    We need to understand why the immune system becomes activated in Castleman disease. One hypothesis (idea) 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 specific mutations in patients’ lymph nodes and will help us find out if these somatic mutations cause Castleman disease. This work is still in progress.

    INVESTIGATORS

    Drs. Joshua Brandstadter (co-PI, UPenn), Ivan Maillard (co-PI, UPenn) & David Fajgenbaum (co-I, UPenn)

  • Autoantibodies in Castleman Disease
    CDCN-2018-006-S
         Step 7
    Status Funded

    Cost: $100,000

    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. This work is still in progress.

    INVESTIGATORS

    PJ Utz, MD, Stanford University, Palo Alto, CA

  • Autoantibodies in Castleman Disease: Validation
    CDCN-2020
         Step 6
    Status Seeking Funding & Samples

    Cost: $40,000

    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 follow up on the exciting finding from “Autoantibodies in Castleman Disease” and look to further investigate a potential auto-antibody in the blood of patients to see if is are causing the immune system to attack healthy cells.

    INVESTIGATORS

    PJ Utz, MD, Stanford University, Palo Alto, CA

What type of immune cells are activated?

  • Step 1

    Build Community

  • Step 2

    Prioritize Studies

  • Step 3

    Identify Researchers

  • Step 4

    Fundraise

  • Step 5

    Enroll Patients

  • Step 6

    Conduct Studies

  • Step 7

    Analyze Data

  • Step 8

    Disseminate Knowledge

  • Unlock the Cell
    CDCN-2015-001-R
         Step 8
    Status Funded

    Cost: $25,000; Sponsored by Castleman Warriors and the University of Pennsylvania Hematologic Malignancies Bank

    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.

    A poster was presented from this work at the American Society of Hematology annual meeting.

    INVESTIGATORS

    Dr. Vera Krymskaya (co-PI, UPenn); Dr. David Fajgenbaum (co-PI, UPenn); Dr. Evgeniy Eruslanov (co-PI, UPenn)

  • PACE-LN (Pathology Analysis for Castleman Cell Type and Etiology-Lymph Node)
    CDCN-2018-BLF
         Step 6
    Status Funded

    Cost: $20,000

    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 in the lymph node. Researchers will examine Castleman Disease lymph nodes using immunohistochemistry, a process that causes certain cellular markers to light up. We also plan to apply machine learning algorithms to identify patterns within the samples and across patients.

    INVESTIGATORS

    Dr. David Fajgenbaum (PI, UPenn)

  • Identification of Cytokine Producing Cells
    CDCN-2017-004-R
         Step 7
    Status Funded

    Cost: $42,000; Funded by the CDCN

    DESCRIPTION

    We know that the immune system becomes activated in Castleman disease and releases proteins called cytokines which can increase inflammation in the body. These cytokines and the high levels of inflammation they promote can cause damage to vital organs (liver, kidney, bone marrow) and impair their function. Prior research has identified specific cytokines (IL-6, VEGF) that are important in Castleman disease, but we need to figure out which cells are producing them and whether other cytokines are involved. Dr. Pillai will use a technique called in situ hybridization to look at lymph node tissue taken from patients with Castleman disease to pinpoint the cells responsible for producing specific cytokines. Identifying these cells will help us with targeted treatments in the future.

    A paper from this work is currently under review for publication.

    INVESTIGATORS

    Vinodh Pillai, MD, PhD; Assistant Professor of Pathology and Laboratory Medicine at The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

    Eline Luning Prak, MD, PhD; Associate Professor of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 

    Megan Lim, MD, PhD; Professor of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

    David Fajgenbaum, MD, MBA, MSc, FCPP; Executive Director of the Castleman Disease Collaborative Network, Research Assistant Professor of Medicine in Translational Medicine & Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

  • PACE-BM (Pathology Analysis for Castleman Cell Type and Etiology-Bone Marrow)
    N/A
         Step 8
    Status Complete

    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 in the bone marrow. Researchers will examine Castleman Disease bone marrow using immunohistochemistry, a process that causes certain cellular markers to light up.

    Read full text article here

    INVESTIGATORS

    Drs. Megan Lim (co-PI, UPenn), Dale Frank (co-PI, UPenn), David Fajgenbaum (co-PI, UPenn)

  • CastleBank (Castleman disease biobank)
    CDCN-2016-006-S
    CDCN-2017-003-S         Step 5
    Status Not Funded

    Cost: $100,000 per year

    DESCRIPTION

    Studying Castleman disease is particularly challenging 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. Samples are needed for research about what types of immune cells are activated and much more. Click here to check out a research article about the CDCN’s biobanking processes.

    Click here to learn about how you can donate blood and/or tissue samples towards research.

    INVESTIGATORS

    Dr. David Fajgenbaum (PI, UPenn) and CDCN Scientific Advisory Board 

What pathways in the cells are activated?

  • Step 1

    Build Community

  • Step 2

    Prioritize Studies

  • Step 3

    Identify Researchers

  • Step 4

    Fundraise

  • Step 5

    Enroll Patients

  • Step 6

    Conduct Studies

  • Step 7

    Analyze Data

  • Step 8

    Disseminate Knowledge

  • Investigation of mTOR in Castleman Disease
    URF-2017, PCPM-2017
    R01-HL141408
         Step 6
    Status Funded

    Cost: $125,000; Sponsored by the University of Pennsylvania Research Foundation & Penn Center for Precision Medicine

    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. The CDCN recently discovered that an important communication line in the immune system called the mTOR pathway was activated in a few patients. This study investigates the mTOR pathway in more patients via immunohistochemistry, a process that causes certain cellular markers to light up, and flow cytometry. See early results presented at the American Society of Hematology Meeting in 2017 here! Check out a case series describing the discovery of increased mTOR activation and effective use of an mTOR inhibitor (sirolimus) for the treatment of three anti-IL-6 refractory iMCD patients here.

    Check out a published paper reporting mTOR activation across over 30 CD patients here.

    INVESTIGATORS

    Drs. David Fajgenbaum (PI, UPenn) & Taku Kambayashi (co-I, UPenn)

  • Investigation of JAK/STAT3 in Castleman Disease Step 6

    Cost: $50,000; Split between the CDCN and the Penn Orphan Disease Center

    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. The CDCN recently discovered that an important communication line in the immune system called the JAK/STAT pathway was activated in a cohort of patients. This study investigates the JAK/STAT pathway in more patients via immunohistochemistry, a process that causes certain cellular markers to light up, and flow cytometry. A few patients have already been treated with JAK inhibitors based on the results of these studies. See case report here.

    INVESTIGATORS

    Drs. David Fajgenbaum (PI, UPenn) & Taku Kambayashi (co-I, UPenn)

  • Multi-omic Profiling of iMCD-TAFRO Circulating Immune Cells
    CDCN-2018-003-R
         Step 8
    Status Funded

    Cost: $250,000

    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 examined Castleman Disease circulating immune cells using multiple cutting-edge technologies, such as TCRb sequencing, BCR sequencing, flow cytometry, Whole Exome Sequencing, MIBI, and single-cell RNASeq. These new technologies investigate hundreds of markers to determine the active cell types and cellular pathways.

    Read full text article here

    INVESTIGATORS

    Dr. David Fajgenbaum (PI, UPenn), Ruth-Anne Langan Pai (UPenn)

  • Multi-omic Profiling of iMCD Lymph Nodes Step 5
    Status Funded

    Cost: $250,000

    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 in lymph node tissue. Researchers will examine Castleman Disease lymph nodes using multiple cutting-edge technologies, such as TCRb sequencing, BCR sequencing, flow cytometry, Whole Exome Sequencing, MIBI, and single-cell RNASeq. These new technologies will investigate dozens and hundreds of markers to help determine the active cell types and cellular pathways.

     

    INVESTIGATORS

    Dr. David Fajgenbaum (PI, UPenn)

  • Discovering new treatment approaches for treatment refractory patients Step 3
    Status Identify Researchers

    DESCRIPTION

    In this study, which was identified as one of the top 3 priority studies in AIM2021, we plan to continue to investigate potential new treatment approaches for treatment refractory patients, such as anti-CXCL13 therapy by identifying CXCL13-producing cells and pathways involved in CXCL13 production. The data obtained will inform the important decision regarding initiation of an anti-CXCL13 clinical trial in refractory-iMCD patients. 

What factors are released by the activated immune cells?

  • Step 1

    Build Community

  • Step 2

    Prioritize Studies

  • Step 3

    Identify Researchers

  • Step 4

    Fundraise

  • Step 5

    Enroll Patients

  • Step 6

    Conduct Studies

  • Step 7

    Analyze Data

  • Step 8

    Disseminate Knowledge

  • SPEED (Serum Proteomics Evaluation for Etio-pathogenesis Data) I
    CDCN-2014-001-S
         Step 8
    Status Complete

    Cost: $24,000; Sponsored by The Jayanthan Family & Friends

    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. See full text of the paper here!

    INVESTIGATORS

    Drs. David Fajgenbaum (co-PI, UPenn), Ruth (co-PI, Harvard), & van Rhee (co-PI, UAMS); Somalogic, MyriadRBM

    SPEED I Video

  • SPEED II
    CDCN-2016-005-S
         Step 7
    Status Funded

    Cost: $350,000; Sponsored by Janssen Pharmaceuticals; all legal costs provided pro bono by Dechert, LLC

    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 contributed 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.

    INVESTIGATORS

    Drs. David Fajgenbaum (co-PI, UPenn) & Jason Ruth (co-PI, Harvard); Platform: Somalogic

  • SPEED III
    CDCN-2016-005-S
         Step 7
    Status Funded

    Cost of SPEEDII: $350,000; Sponsored by Janssen Pharmaceuticals; all legal costs provided pro bono by Dechert, LLC

    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 contributed samples. Identifying these proteins released in Castleman disease is important. In SPEEDIII, we will look for differences in various proteins after treatment with siltuximab is initiated. If we know which proteins are involved, we can use treatments to target those particular proteins.

    INVESTIGATORS

    Drs. David Fajgenbaum (co-PI, UPenn) & Jason Ruth (co-PI, Harvard); Platform: Somalogic

What treatments are most effective at stopping Castleman disease?

  • Step 1

    Build Community

  • Step 2

    Prioritize Studies

  • Step 3

    Identify Researchers

  • Step 4

    Fundraise

  • Step 5

    Enroll Patients

  • Step 6

    Conduct Studies

  • Step 7

    Analyze Data

  • Step 8

    Disseminate Knowledge

  • Systematic Literature Review of Castleman Disease Treatments and Clinical Data
    N/A
         Step 8
    Status Complete

    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.

    INVESTIGATORS

    Drs. David Fajgenbaum (PI, UPenn), Frits van Rhee (co-I, UAMS), Chris Nabel (co-I, Harvard)

  • ACCELERATE Global Patient Research Study
    CDCN-2015-003-R
         Step 5
    Status Funded

    Cost: $4,780,000; Funded through a collaboration with the University of Pennsylvania (sponsor) and Janssen Pharmaceuticals. Funded until 2021

    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. See the first data from ACCELERATE presented at the American Society of Hematology Meeting in 2017 here! More information about the study and how patients can enroll themselves directly online, go to: www.cdcn.org/accelerate

    Click here for full text of an article describing the impact of the ACCELERATE study.

    INVESTIGATORS

    Dr. David Fajgenbaum (PI, UPenn)

  • Clinical Trial of Sirolimus for iMCD Patients who do not Respond to Siltuximab
    R01-HL141408
         Step 5
    Status Funded

    Funded through National Institute of Health Research Grant Program (R01). Enrollment began in September 2019

    DESCRIPTION

    Researchers in the CDCN network 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 here.

    Enrollment began in September 2019.

    For more information about this trial, please visit https://cdcn.org/trial/ or https://clinicaltrials.gov/ct2/show/NCT03933904.

    INVESTIGATORS

    Dr. David Fajgenbaum (PI, UPenn)

    Dr. Frits van Rhee (co-I, UAMS)

    Dr. Adam Cohen (co-I, UPenn)

    Dr. Sunita Nasta (co-I, UPenn)

  • Discovery of Predictive Biomarkers of Response to Siltuximab in iMCD
    CDCN-2017-003-S
         Step 8
    Status Complete

    Cost: $40,000; Tony Ressler provided a generous gift that enabled this study and a portion of another study

    DESCRIPTION

    Siltuximab is the only FDA-approved treatment for HHV-8-negative/idiopathic multicentric Castleman disease (iMCD). Approximately one-third to one-half of iMCD patients do not respond to treatment with siltuximab. A 2017-2018 Ressler Innovation Fellow was chosen by the CDCN to perform in-depth analyses of available clinical trial data to identify characteristics that may predict why someone may respond or not. In-depth analyses of the patients who do not respond to siltuximab identified proteins that could predict responders, guide treatment, and potentially help with identification of new treatments.

    The study has been completed and published here and full text here!

    INVESTIGATORS

    Dr. David Fajgenbaum (PI, UPenn)

  • International Treatment Guidelines
    N/A
         Step 8
    Status Complete

    DESCRIPTION

    There are many different treatments that have been used in Castleman disease patients, but there were no guidelines on what should be tried first, second, third, etc and the specific sub-types that require specific treatments before the CDCN created them for UCD and iMCD. A group of international experts reviewed the existing published data and then made recommendations regarding which types of treatments work and in which types of patients.

    The guidelines have been published:

    Idiopathic multicentric Castleman disease article and full text here.

    Unicentric Castleman disease full-text article here.

    INVESTIGATORS

    Drs. Frits van Rhee (co-PI, UAMS), David Fajgenbaum (co-PI, UPenn), and the CDCN Scientific Advisory Board

  • Understand the role of JAK inhibitors for refractory iMCD patients Step 3
    Status Identify Researchers

    DESCRIPTION

What tests could improve a Castleman disease diagnosis?

  • Step 1

    Build Community

  • Step 2

    Prioritize Studies

  • Step 3

    Identify Researchers

  • Step 4

    Fundraise

  • Step 5

    Enroll Patients

  • Step 6

    Conduct Studies

  • Step 7

    Analyze Data

  • Step 8

    Disseminate Knowledge

  • International Diagnostic Criteria Step 8
    Status Complete

    DESCRIPTION

    Castleman disease (CD) can be difficult to diagnose as it is both a rare disease and an imitator of many other diseases. There were no diagnostic criteria for UCD and iMCD. A group of international experts established the first ever diagnostic criteria for iMCD and UCD.

    The diagnostic criteria have been published:

    Idiopathic multicentric Castleman disease full-text article here.

    Unicentric Castleman disease full-text article here.

    INVESTIGATORS

    Drs. Frits van Rhee (co-PI, UAMS), David Fajgenbaum (co-PI, UPenn), and the CDCN Scientific Advisory Board

  • Identify diagnostic biomarkers and predictive biomarkers of relapse Step 3
    Status Identify Researchers

    DESCRIPTION

    In this study, which was identified as one of the top 3 priority studies in AIM2021, we will pursue a multi-pronged approach to identify potential lymph node and blood-based tests that can help with diagnosing Castleman disease. This effort will involve looking at levels of serum CXCL13 (and other proteins from SPEED2) as well as results from profiling lymph node tissue as potential ways to distinguish CD from other disorders.

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