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

Myeloma remains a virtually incurable malignancy. The inev-itable evolution of multidrug-resistant clones and widespread clonal heterogeneity limit the potential of traditional and novel therapies to eliminateminimal residual disease (MRD), a reliable harbinger of relapse. Here, we show potent anti-myeloma acti-vity of macrophage-activating immunotherapy (aCD40þCpG) that resulted in prolongation of progression-free survival (PFS) and overall survival (OS) in an immunocompetent, preclinical-ly validated, transplant-based model of multidrug-resistant, relapsed/refractory myeloma (t-VkMYC). aCD40þCpG was effective in vivo in the absence of cytolytic natural killer, T, or B cells and resulted in expansion ofM1-polarized (cytolytic/tumor-icidal)macrophages in the bonemarrow.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 aCD40þCpG–acti-vated macrophages, promoted production of antitumor cytokine IL12 in vitro and in vivo, and synergized with aCD40þCpG to further prolong PFS and OS in vivo. Our results support the combination of aCD40-based macrophage activation and TPL2 inhibition for myeloma immunotherapy. We propose that aCD40-mediated activation of innate antitumor immunity may be a promising approach to control/eradicate MRD following cytoreduction with traditional or novel anti-myeloma therapies. Cancer Immunol Res; 3(8); 881–90. 2015 AACR