A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib.
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.
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.
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Ray
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.
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Tian
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.
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Das
Dynavax Technologies, Berkeley, CA, USA.
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Coffman
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.
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Richardson
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.
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Chauhan
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.
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Anderson
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D000077269:Lenalidomide; D008213:Lymphocyte Activation / Q000187:drug effects; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D051217:Toll-Like Receptor 9 / Q000819:agonists*
D000970:Antineoplastic Agents; D001897:Boronic Acids; C000592162:C792 oligodeoxynucleotide; D009838:Oligodeoxyribonucleotides; D011719:Pyrazines; D051217:Toll-Like Receptor 9; D013792:Thalidomide; D000069286:Bortezomib; D000077269:Lenalidomide; D008558:Melphalan