Targeting IL-6 receptor reduces IgM levels and tumor growth in Waldenström macroglobulinemia

Weiguo Han,Brandon Sklavanitis,Stephan J Matissek,Sherine F Elsawa,David A Jackson

doi:10.18632/oncotarget.26946

Weiguo Han, Brandon Sklavanitis + Show 3 more

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https://doi.org/10.18632/oncotarget.26946

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Abstract

ABSTRACTThe tumor microenvironment (TME) plays an important role in cancer cell biology and is implicated in resistance to therapy. In Waldenström macroglobulinemia (WM), a subtype of Non-Hodgkin lymphoma, the TME modulates WM biology by secreting cytokines that promote the malignant phenotype. In previous work, we have shown that TME-IL-6 promotes WM cell growth and IgM secretion in WM. Tocilizumab/Actemra is an anti-IL-6R antibody, which can competitively block IL-6 binding to the IL-6R. We investigated the efficacy of Tocilizumab in a preclinical mouse model of WM that considers the role of the TME in disease biology. Hairless SCID mice were subcutaneously implanted with BCWM.1 or RPCI-WM1 and bone marrow stromal cells. Groups of mice were treated with Tocilizumab or control antibody three times/week for 5 weeks and the effect on tumor burden and disease biology were evaluated. Although Tocilizumab had no effect on mice survival, there was a significant reduction in tumor growth rate in mice injected with RPCI-WM1 cells treated with Tocilizumab. In mice injected with BCWM.1 cells, there was a significant reduction in human IgM secretion in mice sera with Tocilizumab treatment. There was no significant change in mice weight suggesting Tocilizumab induced no toxicities to the mice. Taken together, our data found that administration of Tocilizumab to tumor bearing mice, results in a significant reduction in tumor volume and IgM secretion. Therefore, the evaluation of the role of Tocilizumab in WM patients may provide therapeutic efficacy by reducing IgM production and slowing the rate of tumor growth.

Highlights

Waldenström macroglobulinemia (WM) is a subtype of non-Hodgkin lymphoma (NHL) characterized by infiltration of the bone marrow with lymphoplasmacytic cells [1]
This allowed us to examine the role of paracrine IL-6 from bone marrow stromal cells, which have been shown to play an important role in malignant B cells in WM [5, 8, 9, 16, 17], on WM cells in vivo
We found that Tocilizumab treatment did not affect overall survival in mice xenografted with BCWM.1 or RPCI-WM1 and stromal cells (Figure 1B)

Summary

Introduction

Waldenström macroglobulinemia (WM) is a subtype of non-Hodgkin lymphoma (NHL) characterized by infiltration of the bone marrow with lymphoplasmacytic cells [1]. Despite WM being an indolent lymphoma, WM cells secrete very high levels of a monoclonal immunoglobulin M (IgM) protein, which is associated with symptoms such as anemia, serum hyperviscosity syndrome and peripheral neuropathy [2]. Several significant enhancements were made in our understanding of WM biology This has led to the evaluation and introduction of several new therapeutic options for WM patients. A BTK inhibitor, is the only FDA approved therapy for WM It is administered indefinitely and can cause adverse reactions such diarrhea, thrombocytopenia, rash, atypical bleeding, among other symptoms [4]. Despite evidence for a role of the tumor microenvironment (TME) in promoting WM cell growth, survival and IgM www.oncotarget.com secretion [5], there have been little studies investigating targeting the TME as a therapeutic strategy for WM patients

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