Tumoricidal Effects of Macrophage-Activating Immunotherapy in a Murine Model of Relapsed/Refractory Multiple Myeloma

Cancer Immunol Res. 2015 Aug;3(8):881-90. doi: 10.1158/2326-6066.CIR-15-0025-T. Epub 2015 May 4.


Myeloma remains a virtually incurable malignancy. The inevitable evolution of multidrug-resistant clones and widespread clonal heterogeneity limit the potential of traditional and novel therapies to eliminate minimal residual disease (MRD), a reliable harbinger of relapse. Here, we show potent anti-myeloma activity of macrophage-activating immunotherapy (αCD40+CpG) that resulted in prolongation of progression-free survival (PFS) and overall survival (OS) in an immunocompetent, preclinically validated, transplant-based model of multidrug-resistant, relapsed/refractory myeloma (t-Vκ*MYC). αCD40+CpG was effective in vivo in the absence of cytolytic natural killer, T, or B cells and resulted in expansion of M1-polarized (cytolytic/tumoricidal) macrophages in the bone marrow. Moreover, we show that concurrent loss/inhibition of Tpl2 kinase (Cot, Map3k8), a MAP3K that is recruited to activated CD40 complex and regulates macrophage activation/cytokine production, potentiated direct, ex vivo anti-myeloma tumoricidal activity of αCD40+CpG-activated macrophages, promoted production of antitumor cytokine IL12 in vitro and in vivo, and synergized with αCD40+CpG to further prolong PFS and OS in vivo. Our results support the combination of αCD40-based macrophage activation and TPL2 inhibition for myeloma immunotherapy. We propose that αCD40-mediated activation of innate antitumor immunity may be a promising approach to control/eradicate MRD following cytoreduction with traditional or novel anti-myeloma therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism
  • Cytotoxicity, Immunologic*
  • Disease Models, Animal
  • Gene Knockout Techniques
  • Humans
  • Immunotherapy
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Macrophage Activation / immunology*
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • Multiple Myeloma / genetics
  • Multiple Myeloma / immunology*
  • Multiple Myeloma / mortality
  • Multiple Myeloma / pathology
  • Multiple Myeloma / therapy
  • NF-kappa B p50 Subunit / metabolism
  • Neoplasm Recurrence, Local
  • Oligodeoxyribonucleotides / immunology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism


  • CD40 Antigens
  • NF-kappa B p50 Subunit
  • Oligodeoxyribonucleotides
  • Proto-Oncogene Proteins
  • Nfkb1 protein, mouse
  • MAP Kinase Kinase Kinases
  • Map3k8 protein, mouse