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

• Published in: Cancer immunology research Vol. 3; no. 8; p. 881
• Main Authors: Jensen, Jeffrey Lee, Rakhmilevich, Alexander, Heninger, Erika, Broman, Aimee Teo, Hope, Chelsea, Phan, Funita, Miyamoto, Shigeki, Maroulakou, Ioanna, Callander, Natalie, Hematti, Peiman, Chesi, Marta, Bergsagel, P Leif, Sondel, Paul, Asimakopoulos, Fotis
• Format: Journal Article
• Language: English
• Published: United States 01.08.2015
• Subjects: 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; Macrophage Activation - immunology; Macrophages - immunology; Macrophages - metabolism; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Mice; Multiple Myeloma - genetics; Multiple Myeloma - immunology; Multiple Myeloma - mortality; Multiple Myeloma - pathology; Multiple Myeloma - therapy; Neoplasm Recurrence, Local; NF-kappa B p50 Subunit - metabolism; Oligodeoxyribonucleotides - immunology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.CIR-15-0025-T

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.