Myeloma remains a virtually incurable malignancy. The inevitable evolution of multi-drug resistant clones and widespread clonal heterogeneity limit the potential of traditional and novel therapies to eliminate minimal residual disease, 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 and overall survival in an immunocompetent, preclinically validated, transplant-based model of multi-drug resistant, relapsed/refractory myeloma (t-Vκ*MYC). αCD40+CpG was effective in vivo in the absence of cytolytic NK, 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 (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 the powerful anti-tumor cytokine IL12 in vitro and in vivo and synergized with αCD40+CpG to further prolong progression-free and overall survival in vivo. Our results support the innovative combination of αCD40-based macrophage activation and TPL2 inhibition for myeloma immunotherapy. We propose that αCD40-mediated activation of innate anti-tumor immunity may be a promising approach to control/eradicate minimal residual disease following cytoreduction with traditional or novel anti-myeloma therapies.
- Received January 20, 2015.
- Revision received April 8, 2015.
- Accepted April 22, 2015.
- Copyright © 2015, American Association for Cancer Research.