TY - JOUR
T1 - Tumoricidal effects of macrophage-activating immunotherapy in a murine model of relapsed/refractory multiple myeloma
AU - Jensen, Jeffrey Lee
AU - Rakhmilevich, Alexander
AU - Heninger, Erika
AU - Broman, Aimee Teo
AU - Hope, Chelsea
AU - Phan, Funita
AU - Miyamoto, Shigeki
AU - Maroulakou, Ioanna
AU - Callander, Natalie
AU - Hematti, Peiman
AU - Chesi, Marta
AU - Bergsagel, P. Leif
AU - Sondel, Paul
AU - Asimakopoulos, Fotis
N1 - Publisher Copyright:
© 2015 AACR.
PY - 2015/8
Y1 - 2015/8
N2 - 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.
AB - 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.
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U2 - 10.1158/2326-6066.CIR-15-0025-T
DO - 10.1158/2326-6066.CIR-15-0025-T
M3 - Article
C2 - 25941352
AN - SCOPUS:84962018269
SN - 2326-6066
VL - 3
SP - 881
EP - 890
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 8
ER -