Immunology and targeted therapy in Castleman disease

ABSTRACT

Introduction

Castleman disease (CD) is a benign lymphoproliferative disease causing severe systemic inflammation. Interleukin-6 (IL-6) is a major pathogenesis of multicentric CD (MCD), but only 30–60% of patients respond to IL-6 inhibitors. Novel agents for IL-6 inhibitor-refractory cases are needed. Clinical data and samples are being collected on a large scale and the clinical, pathological, and pathogenetic aspects are being elucidated.

Areas covered

The pathological and clinical classification of CD is outlined. Focusing on idiopathic MCD (iMCD), this review identifies therapeutic targets and summarizes currently recommended drugs and promising therapeutic candidates.

Expert opinion

The pathogenesis of MCD has been implicated in the activation of the Janus kinase (JAK)-transcriptional signaling activator (STAT) 3 pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt/mechanical target of rapamycin (mTOR) signaling pathway. iMCD-TAFRO (thrombocytopenia, anasarca, fever/elevated CRP, reticulin myelofibrosis/renal dysfunction, organ enlargement) is resistant to IL-6 inhibitors, and cyclosporine and mTOR inhibitors are sometimes effective. JAK inhibitors and mTOR inhibitors may be therapeutic agents for iMCD. Recently, we have shown that peripheral helper T (Tph) cell abnormalities are at the core of iMCD pathogenesis. Therapies targeting chemokine (C-X-C motif) ligand 13 (CXCL13) produced by Tph cells and blocking the Tph-CXCL13-B cell pathway may satisfy unmet need in refractory cases.

KEYWORDS:

• Castleman disease
• CXCL13
• iMCD
• IL-6
• JAK-STAT
• mTOR
• peripheral helper T cell
• TAFRO

Article highlights

• In 1989, it was established that MCD is not a hematologic malignancy, but a systemic chronic inflammatory disease caused by the overproduction of IL-6 by B cells in the affected lymph nodes.

• Many iMCD-NOS patients have responded to IL-6 inhibitors (siltuximab, tocilizumab). On the other hand, iMCD-TAFRO, a severe form of iMCD, does not respond to IL-6 inhibitors and requires chemotherapy including rituximab, calcineurin inhibitors, mTOR inhibitors and JAK inhibitors. None of these drugs target the underlying etiology.

• Because CD is a rare disease and there have been no effective means to analyze the underlying pathogenesis, it has remained unclear why IL-6 is continuously produced. Analysis of iMCD model mice, created by transplanting lymph node cells from iMCD patients into immunodeficient mice, suggested that the basic pathogenesis of iMCD is an immunoregulatory disorder caused by peripheral helper T (Tph) cells.

• In patients with iMCD, CXCL13 produced by an increasing number of Tph cells not only promotes the differentiation of B cells into plasma cells, resulting in the production of polyclonal immunoglobulins, but also induces of inflammatory cytokines such as IL-6, leading to chronic inflammation. In the future, it is desirable to develop therapeutic agents that can block the Tph-CXCL13-B cell pathway, which is at the core of the pathogenesis.

Declaration of interest

Y Kikushige has received honoraria/lecture fees from Astellas Pharma Inc. and Kyowa Kirin Co., Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.