Abstract 193: The tumor microenvironment protects against ibrutinib but not rituximab-mediated control of Waldenström macroglobulinemia (WM) in vivo
Authors: Han Weiguo , Sklavanitis Brandon L. , Jackson David A. , Matissek Stephan J. , Elsawa Sherine F. 
Published: August 2018

Abstract
The tumor microenvironment (TME) plays an important role in the development and progression of cancer. It has also been shown to play a protective role in resistance to therapy. Therefore, understanding the role of the TME is a vital component of our understanding of malignant cell biology. In Waldenström macroglobulinemia (WM), a B cell malignancy characterized by the overproduction of a monoclonal IgM protein, several studies have shown that the TME plays an important role in malignant disease. Therefore, the goal of this study was to investigate the efficacy of combined targeting of the TME with either Ibrutinib or Rituximab therapy in WM in vivo. SCID mice were injected with RPCI-WM1 + HS-5 stromal cells (5:1 ratio) and upon tumor development, mice were treatment with Ibrutinib (αBTK), Actemra (αIL-6), or a combination of Ibrutinib+Actemra or vehicle controls. An additional group of mice were injected with BCWM.1 + HS-5 cells (5:1 ratio) subcutaneously followed by treatment with Rituxmab (αCD20), Actemra (αIL-6) or both Rituximab+Actemra or controls. There was no improvement in survival of mice treated with Ibrutinib or Actemra as single therapy and combined treatment did not improve survival compared to controls. We also found a reduction in tumor growth rate in mice treated with Ibrutinib + Actemra compared with mice treated with Ibrutinib alone. There was no difference in human IgM secretion among different groups when examining serum samples by ELISA. In the cohort of mice treated with Rituximab, we found that the TME did not provide a protective effect on Rituximab therapy as Rituximab significantly enhanced the survival of mice (p&lt;0.0001). Combined treatment with Rituximab and Actemra did not significantly improve survival compared with Rituximab alone. We also found that mice treated with Rituximab alone had a significant reduction in tumor growth rate and combined therapy did not reduce tumor growth rate beyond that of Rituximab alone. Furthermore, we found a significant reduction in human IgM secretion in mice serum in mice treated with Rituximab alone (p=0.005) or combined therapy (p=0.0007) compared with control mice. However, there was no difference between Rituximab alone and combined therapy. There was no significant change in mice weight over the course of the treatment suggesting that none of these therapies had toxic effects. Taken together, our data suggests that the TME provided a protective effect against Ibrutinib, but not Rituximab therapy and inhibition of IL-6, a cytokine known to modulate the TME in WM did not enhance either therapy.
Citation Format: Weiguo Han, Brandon L. Sklavanitis, David A. Jackson, Stephan J. Matissek, Sherine F. Elsawa. The tumor microenvironment protects against ibrutinib but not rituximab-mediated control of Waldenström macroglobulinemia (WM) in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 193.