Tumoricidal effects of macrophage-activating immunotherapy in a murine model of relapsed/refractory multiple myeloma

Jeffrey Lee Jensen, Alexander Rakhmilevich, Erika Heninger, Aimee Teo Broman, Chelsea Hope, Funita Phan, Shigeki Miyamoto, Ioanna Maroulakou, Natalie Callander, Peiman Hematti, Marta Chesi, P. Leif Bergsagel, Paul Sondel, Fotis Asimakopoulos

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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-VκMYC). 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.

Original languageEnglish (US)
Pages (from-to)881-890
Number of pages10
JournalCancer Immunology Research
Volume3
Issue number8
DOIs
StatePublished - Aug 2015

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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    Jensen, J. L., Rakhmilevich, A., Heninger, E., Broman, A. T., Hope, C., Phan, F., Miyamoto, S., Maroulakou, I., Callander, N., Hematti, P., Chesi, M., Bergsagel, P. L., Sondel, P., & Asimakopoulos, F. (2015). Tumoricidal effects of macrophage-activating immunotherapy in a murine model of relapsed/refractory multiple myeloma. Cancer Immunology Research, 3(8), 881-890. https://doi.org/10.1158/2326-6066.CIR-15-0025-T