Research

At the Leading Edge of Castleman Disease Research

Scientists at the Center for Cytokine Storm Treatment & Laboratory (CSTL) [pronounced “Castle”] conduct research projects across many subfields of science with the goal of improving the diagnosis, treatment, and management of Castleman Disease and other cytokine storms. Our group is unique in that instead of focusing on one experimental technique, or subfield, our lab uses multiple techniques to study Castleman disease (and related diseases) from multiple angles. To fulfill this goal, the CSTL recruits scientists from different backgrounds and expertise such as basic bench research, biobanking, and data analysis. 

Our interests include elucidating the etiology, dysregulated cell types, signaling pathways, and effector cytokines in idiopathic multicentric Castleman disease (iMCD) and related cytokine storm disorders; identifying effective treatments for iMCD patients; PI3K/Akt/mTOR signaling in iMCD; understanding the role of stromal cells and chemokines in iMCD.

Our research projects are divided into five major broad categories: Defining CD and its clinico-pathology; Etiology of CD; Pathophysiology; Treatment effectiveness studies; and rare-disease sample acquisition methodologies.

Defining CD and Clinico-Pathology

Scientists at the CSTL published the first ever consensus iMCD diagnosis guidelines Link. Our ongoing natural history research (see ACCELERATE below) will allow us to test and improve these guidelines further.

Etiology

The cause of hyper-activation of the immune system in iMCD is still unknown. One of the main hypotheses is that an infectious agent, such as a virus or bacteria, triggers the immune system. In a collaboration with  Robertson's Lab at Penn, scientists are studying lymph node tissue of iMCD patients in order to search for the DNA of viruses, fungi, and bacteria. Robertson's lab PathoChip Array is a leading technology in being able to simultaneously test for all pathogens known to infect humans. CSTL scientists are analyzing PathoChip data to search for potential pathogens. 

In collaboration with Kambayashi's Lab at Penn, we are investigating the role of T cells in Castleman Disease 

Proteomic quantification of serum samples is allowing us to biochemically characterize the heterogeneity of iMCD and how it fits with other related diseases such as rheumatoid arthritis and Hodgkin lymphoma. Serum analytes may also lead to the development of algorithms that predict which patients would respond to specific treatments (such as IL-6 blockade). Furthermore, serum proteins may signal the hyperactivation of certain biochemical pathways and elucidate them as novel therapeutic targets. 

Pathophysiology and Novel Therapeutic Targets

A recent case-series, recently published in JCI, details how three iMCD patients that were refractory to IL-6-blockade responded to mTOR inhibition by sirolimus. The lymph nodes of these patients showed increased mTOR activation LINK. Currently, we are carrying out the largest systematic study of lymph node tissue from Castleman Disease patients. We will study the mTOR pathway in patients from different subtypes of CD and compare it to tissue from related diseases. Using co-immunofluorescence techniques, we are also trying to find out if any specific cell types abnormally express high levels of mTOR.

Quantification of 1,129 plasma proteins in iMCD revealed highly up-regulated acute phase reactants and chemokines (See Full Article). The chemokines that were most upregulated are essential for normal lymph node morphology/function and typically produced by lymph node stromal cells. The most up-regulated chemokine, CXCL13, is responsible for homing B cells into the germinal center. This is interesting, because the pathological hallmark of iMCD is dysmorphic lymph node germinal centers with either too few (atrophic) or too many B cells (hyperplastic). Immunohistochemistry confirmed significantly increased germinal center expression of CXCL13. We are exploring the mechanisms of lymph node stromal cell activation and chemokine signaling.

This study looks for the activated immune cells and cellular pathways in the bone marrow. In collaboration with Penn pathologists, we are examining Castleman Disease bone marrow using immunohistochemistry.

It is still not known which  immune cells or pathways are activated. This study looks for the activated immune cells and cellular pathways by studying both serum samples and lymph node tissue.

Treatment Effectiveness Research

The poor understanding of iMCD pathogenesis has slowed the development of treatment approaches. Currently, there is only one FDA-approved treatment for iMCD, which is effective in approximately one-third or patients. We run an international Natural History Study of Castleman Disease (ACCELERATE) to collect in-depth data on patients around the world to identify effective treatment approaches currently being used off-label.

Find out more information about the ACCELERATE study, including registration.

For contact information: 215-614-0209.

Sample Acquisition

Centralizing data and biospecimens for research is one of the toughest challenges faced by researchers of rare diseases. A lack of samples slows down advancement of research and drug discovery. Researchers at CSTL are continuing to improve methodology on collecting disease characteristic data and identifying individuals interested in contributing biospecimens for research. Data analysts characterize the Biobank and natural history registries of CD to gain insight into research biospecimen acquisition. 

To reach our biobank coordinator: 267-586-9977 or castlebank@uphs.upen.edu

In iMCD we still don't know which immune cells or pathways are activated. This study looks for the activated immune cells and cellular pathways. We are examining iMCD lymph node tissue using multiple cutting-edge technologies, such as TCRb sequencing, BCR sequencing, flow cytometry, Whole Exome Sequencing, 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 cellular pathways. Check out our ASH 2018 abstract.

Current therapeutic options for iMCD are limited and provide benefit for only a subset of patients. Blockade of IL-6 signaling with siltuximab or tocilizumab abrogates symptoms and improves lymphadenopathy only in a portion of patients. Recent research has suggested a key role for the phosphoinositide 3-kinase(PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway in iMCD pathogenesis and off-label administration of sirolimus, an mTOR inhibitor, has shown clinical activity. Based on these experiences, we plan to evaluate the efficacy of sirolimus as a therapy for iMCD patients who are either unable to tolerate anti-IL-6 blockade therapy (siltuximab or tocilizumab), or who fail, relapse, or are refractory to such treatment. See Clinical Trial Registration.