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Myeloma

A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib

Leukemia volume 28, pages 1716–1724 (2014)Cite this article

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Abstract

Our prior study in multiple myeloma (MM) patients showed increased numbers of plasmacytoid dendritic cells (pDCs) in the bone marrow (BM), which both contribute to immune dysfunction as well as promote tumor cell growth, survival and drug resistance. Here we show that a novel Toll-like receptor (TLR-9) agonist C792 restores the ability of MM patient-pDCs to stimulate T-cell proliferation. Coculture of pDCs with MM cells induces MM cell growth; and importantly, C792 inhibits pDC-induced MM cell growth and triggers apoptosis. In contrast, treatment of either MM cells or pDCs alone with C792 does not affect the viability of either cell type. In agreement with our in vitro data, C792 inhibits pDC-induced MM cell growth in vivo in a murine xenograft model of human MM. Mechanistic studies show that C792 triggers maturation of pDCs, enhances interferon-α and interferon-λ secretion and activates TLR-9/MyD88 signaling axis. Finally, C792 enhances the anti-MM activity of bortezomib, lenalidomide, SAHA or melphalan. Collectively, our preclinical studies provide the basis for clinical trials of C792, either alone or in combination, to both improve immune function and overcome drug resistance in MM.

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Acknowledgements

This investigation was supported by National Institutes of Health Specialized Programs of Research Excellence (SPORE) grants P50100707, PO1-CA078378, and RO1 CA050947. KCA is an American Cancer Society Clinical Research Professor.

Author contributions

DC designed research, analyzed data and wrote the manuscript; AR performed the experiments, analyzed data and wrote the manuscript; ZT and DSD helped in flow cytometry; RLC provided technical advice, analyzed data and reviewed the manuscript; PR provided clinical samples; and KCA analyzed data and wrote the manuscript.

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  1. D Chauhan and K C Anderson: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    A Ray, Z Tian, D S Das, P Richardson, D Chauhan & K C Anderson

  2. Dynavax Technologies, Berkeley, CA, USA

    R L Coffman

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  1. A Ray
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Correspondence to D Chauhan or K C Anderson.

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RLC is an employee of Dynavax Technologies. The remaining authors declare no conflict of interest.

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Ray, A., Tian, Z., Das, D. et al. A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib. Leukemia 28, 1716–1724 (2014). https://doi.org/10.1038/leu.2014.46

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