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it decreases rapidly in siltuximab responders upon administration but remains elevated in siltuximab non-responders (unpublished).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.