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

Abstract

The tumor microenvironment (TME) plays an important role in cancer and plays a role in resistance to therapy. In Waldenstrom 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.