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

The tumor microenvironment (TME) plays an important role in cancer and plays a role in resistance to therapy. In Waldenström macroglobulinemia (WM), a B-cell malignancy characterized by the overproduction of a monoclonal IgM protein, the TME plays an important role in WM biology by secreting cytokines that promote 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 reduction in tumor growth rate in mice injected with RPCI-WM1 cells treated with Tocilizumab (p=0.0394). In mice injected with BCWM.1 + stromal cells, there was a significant reduction in human IgM secretion in mice sera with Tocilizumab treatment (p=0.0099). There was no significant change in mice weight suggesting Tocilizumab induced no toxicities to the mice. Taken together, our data suggests 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.


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The tumor microenvironment (TME) plays an important role in cancer and plays a role in 22 resistance to therapy. In Waldenström macroglobulinemia (WM), a B-cell malignancy 23 characterized by the overproduction of a monoclonal IgM protein, the TME plays an 24 important role in WM biology by secreting cytokines that promote malignant phenotype.

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In previous work, we have shown that TME-IL-6 promotes WM cell growth and IgM 26 secretion in WM. Tocilizumab/Actemra is an anti-IL-6R antibody, which can competitively 27 block IL-6 binding to the IL-6R. We investigated the efficacy of Tocilizumab in a 28 preclinical mouse model of WM that considers the role of the TME in disease biology.

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Hairless SCID mice were subcutaneously implanted with BCWM.1 or RPCI-WM1 and 30 bone marrow stromal cells. Groups of mice were treated with Tocilizumab or control 31 antibody three times/week for 5 weeks and the effect on tumor burden and disease 32 biology were evaluated. Although Tocilizumab had no effect on mice survival, there was 33 a reduction in tumor growth rate in mice injected with RPCI-WM1 cells treated with 34 Tocilizumab (p=0.0394). In mice injected with BCWM.1 + stromal cells, there was a 35 significant reduction in human IgM secretion in mice sera with Tocilizumab treatment 36 (p=0.0099). There was no significant change in mice weight suggesting Tocilizumab 37 induced no toxicities to the mice. Taken together, our data suggests that administration 38 of Tocilizumab to tumor bearing mice, results in a significant reduction in tumor volume 39 and IgM secretion. Therefore, the evaluation of the role of Tocilizumab in WM patients 40 may provide therapeutic efficacy by reducing IgM production and slowing the rate of 41 tumor growth.

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Despite the progress made to understand disease biology, like most other 67 neoplasms, WM remains an incurable disease and ultimately patients succumb to 68 disease progression. The TME plays an important role in the development and 69 progression of WM and has been shown to play a protective role in resistance to 70 therapy [5][6][7]. In fact, the cross-talk between malignant cells and cells in the TME favors 71 disease progression and promotes IgM secretion. In previous studies, we and others 72 4 have shown that IL-6 from the TME promotes IgM secretion and cell growth via binding 73 to the IL-6R on WM cells [8][9][10][11]. Therefore, targeting IL-6/IL-6R signaling may provide 74 therapeutic benefit for WM patients, particularly those with high levels of IgM in their 75 serum.

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In this study, we report the efficacy of targeting the TME with Tocilizumab in a 89 preclinical mouse model of WM that considers the role of the TME in disease biology. [21] and malignant B cells [9][10][11][18][19][20]. We have previously shown that IL-6 promotes 125 IgM secretion in WM [8,9]. Therefore, we examined the effect of IL-6 therapy on human 126 IgM secretion in mice sera. Consistent with our previous reports, we found a significant 127 reduction in human IgM secretion in mice sera in groups of mice xenografted with 128 BCWM.1 cells and stromal cells, treated with Tocilizumab (p=0.0029) (Figure 3). IgM secretion and WM cell growth [8,9]. Consistent with this role, we did find a reduction 164 in tumor growth rate when tumor bearing mice were treated with Tocilizumab (Figure 2).

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These results indicate that targeting IL-6 in the TME in WM may slow the rate of tumor 166 growth. Since WM remains an incurable disease, a reduction in IgM levels may provide 167 a much needed symptomatic relief for patients. Future studies combining targeting of IL-168 6 with therapies that induce apoptosis of WM cells, may prove to be effective; with IL-6 169 therapy slowing tumor growth and another therapy targeting the malignant cells.