Development of the novel treatment of idiopathic multicentric Castleman Disease using patientderived cell transplantation in an immunodeficient mouse

Awardee: Takuya Harada

Institution: National Hospital Organization Kyushu Medical Center

Grant Amount: $63,270.00

Funding Period: February 1, 2024 - January 31, 2025

---

Summary:

We have established a patient-derived xenograft (PDX) mouse model of idiopathic multicentric Castleman disease (iMCD). Through preliminary research on these mice, we have discovered the contribution of specific immune cells called peripheral helper T (Tph) cells to the pathophysiology of iMCD. By examining the dynamics of these cells in both patients and the mouse model, we are studying further research to understanding the pathophysiology of iMCD.

Developing a spatiotemporal gene atlas in iMCD lymph node tissue to identify diagnostic biomarkers and therapeutic targets

Awardee: David Fajgenbaum

Institution: University of Pennsylvania

Grant Amount: $60,570.00

Funding Period: February 1, 2023 - January 31, 2024

---

Summary:

Human Herpesvirus (HHV)-8-negative, idiopathic multicentric Castleman disease (iMCD) is a deadly hematologic illness with an unknown etiology that affects individuals of all ages. Although the causes, key immune cell types, signaling pathways, and cytokines involved are poorly understood, a key hallmark of iMCD includes characteristic lymph node features that are used for diagnosis. Despite importance of these lymph node features as diagnostic criteria, the underlying biological mechanisms driving them are not well understood. In the proposed LOI, we will develop a single cell RNAseq/spatial gene expression atlas in iMCD lymph nodes to characterize cell subpopulations, identify cell-type compositional changes, infer intercellular communication networks, and interrogate dysregulated cell types/cell locations within disease tissue. By completing the proposed specific aims we will gain important insights into lymph node biology in iMCD and the thorough characterization of the inflamed tissue will help identify new biomarkers and uncover dysregulated cell types that may be contributing to disease pathogenesis and pathology.

CXCL13 as a novel biomarker and therapeutic target in idiopathic multicentric Castleman disease

Awardee: David Fajgenbaum

Institution: University of Pennsylvania

Grant Amount: $64,205

Funding Period: February 1, 2022 - January 31, 2023

---

Summary:

Idiopathic multicentric Castleman disease (iMCD) is a poorly understood disorder involving lymphoproliferation and multiple organ failure due to a cytokine storm often involving interleukin-6 (IL-6). Its causes, key immune cell types, signaling pathways, and cytokines involved in the disease are poorly understood. Diagnosis is challenging due to lack of a positive diagnostic biomarker and management is suboptimal due to a lack of indicators of response and novel therapeutic approaches. Annual US incidence is ~1000 individuals of all ages, and 5-year survival is estimated at 65-75%. Few treatment options exist beyond cytotoxic chemotherapies for the 50-66% of patients who do not respond to the only FDA-approved therapy, siltuximab, which blocks IL-6. Advances in discovering treatments, diagnostic biomarkers, and indicators of response to siltuximab are critically needed. We recently identified the chemokine CXCL13 as a potential, novel biomarker and therapeutic target in iMCD. CXCL13 is critical to maintaining lymph node morphology as well as developing appropriate adaptive immune responses, both of which are abnormal in iMCD. In a pilot study, we found that CXCL13 is the most elevated circulating cytokine in iMCD patients and that CXCL13 expression is increased in iMCD lymph node tissue (Pierson et al, AJH, 2018). Proteomic profiling of serum from 88 iMCD patients revealed CXCL13 to be the most elevated cytokine compared to healthy controls and, further, it decreases rapidly in siltuximab responders upon administration but remains elevated in siltuximab non-responders (unpublished). The overall goal of this project is to investigate CXCL13 as a possible diagnostic biomarker, indicator of response to therapy, and/or therapeutic target for iMCD. These goals directly align with one of the top priority research questions outlined on the RFA (“What is the role of CXCL13 in iMCD?”). The specific aims of this project are to (1) quantify CXCL13 expression in iMCD lymph node tissue to assess the diagnostic applicability of this test for iMCD and to determine the cellular source of CXCL13, (2) quantify CXCL13 levels in serum to determine a threshold for serum CXCL13 as a potential diagnostic test or a clinical indicator biomarker of response to siltuximab, and (3) assess the in vitro effects of CXCL13 on circulating immune cells from iMCD patients. These studies will improve understanding of iMCD biology and may translate into more effective and personalized therapies and biomarkers that will have a transformative impact. Thank you for your consideration.

JAK1/2 as a Central Regulator of iMCD Pathogenesis and Novel Therapeutic Target

Awardee: David Fajgenbaum

Institution: University of Pennsylvania

Award Amount: $64,590

Funding Period: February 1, 2021 - January 31, 2022

---

Summary: Idiopathic multicentric Castleman disease (iMCD) is a poorly understood disease involving life-threatening immune hyperactivation and cytokine production (a cytokine storm). About 1500 patients of all ages are diagnosed in the US each year and there is a 35% 5-year mortality rate. Siltuximab, which inhibits a key cytokine involved in the immune hyperactivation in iMCD, is the only FDA-approved therapy and is effective in one-third of patients. Dr. Fajgenbaum’s lab in the Center for Cytokine Storm Treatment and Laboratory (CSTL) recently identified another key mechanism of immune hyperactivation in iMCD called JAK/STAT that may be a promising target to direct treatments at. Through the Orphan Disease Center's grant, the CSTL is studying JAK/STAT in iMCD lymph node samples and the role of JAK inhibition as an iMCD treatment.  If promising, the CSTL will develop a protocol for a proof-of-concept clinical trial of a JAK inhibitor (ruxolitinib) in iMCD patients. These studies will improve understanding of iMCD biology and may translate into more effective therapies.

Clonal activation of lymph node stromal cells in unicentric Castleman Disease

Awardee: Ivan Maillard

Institution: University of Pennsylvania

Award Amount: $51,358

Autoantibody Discovery in Castleman Disease Using Multiplexed Assays

Awardee: Paul Utz

Institution: Board of Trustees of the Leland Stanford Junior University

Award Amount: $102,150

Funding Period: February 1, 2019 - January 31, 2020

A longitudinal single cell genomic analysis of HHV8-negative multicentric Castleman Disease

Awardee: Robert Ohgami

Institution: Stanford University

Award Amount: $42,508

Funding Period: January 1, 2018 - December 31, 2018

Genomic analysis of idiopathic multicentric Castleman disease

Awardee: Kojo Elenitoba-Johnson

Institution: University of Pennsylvania

Award Amount: $43,000

Funding Period: January 1, 2017 - December 31, 2017