Exploiting the central role of IL6 signalling in MCD

Transcription

1 Exploiting the central role of IL6 signalling in MCD Mark Bower 1 & Justin Stebbing 2 1 National Centre for HIV Malignancy Chelsea & Westminster Hospital London SW10 9NH, UK. 2 Department of Oncology Charing Cross Hospital London W6 8RF *Address for correspondence: Professor Mark Bower PhD FRCP FRCPath Department of Oncology Chelsea & Westminster Hospital 369 Fulham Road London SW10 9NH Tel: Fax: m.bower@imperial.ac.uk

2 Rare diseases often provide insights into pathology and sometimes yield unforeseen therapeutic surprises. Although Benjamin Castleman first described a case of unicentric hyaline vascular Castleman s disease (CD) in 1954 (1), none of the subtypes of the disease (unicentric or multicentric, hyaline vascular or plasmblastic, KSHV-associated or idiopathic) have yet been granted an ICD-10 code. The original descriptions were of unicentric hyaline vascular CD presenting as asymptomatic mediastinal masses (2). In the 1980s multicentric forms of CD were described that coexisted with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes), a vascular endothelial growth factor (VEGF) driven proliferative disorder of plasma cells, also known as both Crow-Fukase syndrome and Takatsuki disease (3). This plasma cell type of CD is usually multisite disease and associated with systemic symptoms (4, 5). A third histologic subtype is characterised by large abnormal plasma cells named plasmablasts that occasionally coalesce into aggregates of microlymphoma and may evolve into plasmablastic lymphoma (6). It is this form of plasmablastic multicentric CD (MCD) that occurs in people living with HIV. Following the discovery of the Kaposi sarcoma-associated herpesvirus (KSHV) also known as human herpesvirus 8 (HHV8), this virus was detected in the plasmablasts in all cases of HIVassociated MCD, and is now known to not only be associated with MCD, but be causative (7). KSHV encodes a viral homologue of interleukin-6 (IL6) and it was this clue that ultimately led to the recognition that IL6 signalling plays a central role in the pathogenesis of MCD, both the KSHVassociated form and the rarer KSHV negative, HIV negative idiopathic plasmablastic form of MCD (8) that is the subject of the trial in this edition of Lancet Oncology (**). The pro-inflammatory cytokine IL6 is involved in immune regulation, haematopoiesis, bone metabolism and the acute phase reaction, (9). Human (h)il6 promotes B cell development, differentiation and antibody secretion (10) and pathologically the development of B cell malignancies (11). Serum levels of IL6 are raised in MCD and correlate with disease activity in both HIV-positive and -negative individuals (12, 13). Mice overexpressing IL6 or lacking C/EBP beta, an important regulatory element of IL6 signalling, develop an MCD-like phenotype (14, 15). Moreover, the MCD-like syndrome in transgenic mice that overexpress IL6 is prevented by administration of an anti-il6 receptor antibody (16). There are two hil6 signalling pathways. The classical IL6 pathway involves binding of IL6 to plasma membrane bound IL6 receptor (IL6R) leading to the recruitment and activation of gp130, a signal transducing component that activates the JAK1/JAK2-STAT3 (Janus Kinase 1/2-Signal Transducer and Activator of Transcription 3) and MAPK (Mitogen-Activated Protein Kinase) downstream pathways (17). The second pathway is the trans activating pathway that sees IL6 binding to soluble IL6R and the subsequent binding of this soluble IL6/IL6R complex to membrane bound gp130. This trans pathway can activate a broader range of cell types, because membrane-bound IL6R is confined to lymphoid cells, whilst gp130 is expressed ubiquitously (18). The KSHV viral (v)il6 homologue or virokine shares only 25% amino acid sequence with hil6 including the receptor binding domain (19). Viral IL6 however possesses many of the biologic

3 characteristics of hil6 including stimulating the growth of IL6-dependent mouse hybridoma cell lines (20, 21). Similarly, overexpression of vil6 in mice induces a phenotype resembling MCD (22) just as hil6 does (14). In addition to activating both classical and trans IL6 signalling pathways, vil6 can directly activate gp130 without recruiting IL6R (23-25). The recognition that vil6 plays an important part in the pathology of KSHV associated MCD lead to genetic studies of hil6, IL6R and gp130 in idiopathic KSHV negative MCD. Two single nucleotide polymorphisms (SNPs) of IL6R gene were found to be over represented in patients with KSHV negative CD and these were associated with a highly significant increase in plasma sil6r levels in these patients (26). These findings further implicate a role for IL6R, particularly in its soluble form, in the pathogenesis of idiopathic MCD, and indicatde that this may be a suitable therapeutic target. The monoclonal antibody rituximab has revolutionised the treatment and outcomes in KSHV associated MCD in people living with HIV (27). Two open-label trials and numerous case reports have confirmed its efficacy (28, 29) although the mechanism of action of rituximab in MCD is uncertain, particularly as plasmablasts do not usually express CD20. Now van Rhee et al. report the benefit of siltuximab, an antibody to IL6R in KSHV negative idiopathic MCD in randomised controlled study. The study of MCD is still held back by difficulties in disease definition and response criteria. Whilst the diagnosis of KSHV-associated MCD has become easier with immunohistochemical staining for the KSHV latent nuclear antigen-1 (LANA-1) and the monotypic expression of IgM lambda immunoglobulin, the precise diagnosis of idiopathic MCD remains challenging. Similarly the definitions of disease activity and response to therapy remain unclear. Two separate but similar schemes are employed to assess disease activity in HIV-associated MCD (30, 31) and they do not always concur (32). Likewise there is no validated method to establish response to therapy in MCD; the NCI attempted to define response in terms of shrinkage of lymphadenopathy, resolution of systemic symptoms and normalisation of blood tests (33). However, these have not yet been used in published studies making it impossible to compare responses between different treatments. The encouraging results published in this issue hopefully will galvanise the field to set up validated diagnostic and response criteria for idiopathic MCD. One of the benefits of this study is the establishment of the Castleman Disease Collaborative Network (CDCN) which includes not only clinicians and researchers but also patients. We think it is remarkable and rewarding to hear patients voices in rare diseases and to read their views (8).

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