Tumoricidal Effects of Macrophage-Activating Immunotherapy in a Murine Model of Relapsed/Refractory Multiple Myeloma.
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.
Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin. University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Jeffrey Lee
JL
Jensen
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin.
Alexander
A
Rakhmilevich
Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin. University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Erika
E
Heninger
Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin.
Aimee Teo
AT
Broman
Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin. University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Chelsea
C
Hope
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin.
Funita
F
Phan
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin.
Shigeki
S
Miyamoto
Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.
Ioanna
I
Maroulakou
Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin. University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Natalie
N
Callander
Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin. University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Peiman
P
Hematti
Mayo Clinic-Scottsdale, Scottsdale, Arizona.
Marta
M
Chesi
Mayo Clinic-Scottsdale, Scottsdale, Arizona.
P Leif
PL
Bergsagel
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin. Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin.
Paul
P
Sondel
Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin. University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. fasimako@medicine.wisc.edu.
Fotis
F
Asimakopoulos
D000818:Animals; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009364:Neoplasm Recurrence, Local; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
D019013:CD40 Antigens; D052002:NF-kappa B p50 Subunit; D009838:Oligodeoxyribonucleotides; D011518:Proto-Oncogene Proteins; C073701:Nfkb1 protein, mouse; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse