Integrative development of a TLR8 agonist for ovarian cancer chemoimmunotherapy Journal Article

Authors: Monk, B. J.; Facciabene, A.; Brady, W. E.; Aghajanian, C. A.; Fracasso, P. M.; Walker, J. L.; Lankes, H. A.; Manjarrez, K. L.; Danet-Desnoyers, G. Ä H.; Bell-McGuinn, K. M.; McCourt, C. K.; Malykhin, A.; Hershberg, R. M.; Coukos, G.
Article Title: Integrative development of a TLR8 agonist for ovarian cancer chemoimmunotherapy
Abstract: Purpose: Immunotherapy is an emerging paradigm for the treatment of cancer, but the potential efficacy of many drugs cannot be sufficiently tested in the mouse. We sought to develop a rational combination of motolimod - a novel Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses in humans but diminished responses in mice - with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death. Experimental Design: We followed an integrative pharmacologic approach including healthy human volunteers, non-human primates, NSG-HIS ("humanized immune system") mice reconstituted with human CD34+ cells, and patients with cancer to test the effects of motolimod and to assess the combination of motolimod with PLD for the treatment of ovarian cancer. Results: The pharmacodynamic effects of motolimod monotherapy in NSG-HIS mice closely mimicked those in non-human primates and healthy human subjects, whereas the effects of the motolimod/PLD combination in tumorbearing NSG-HIS mice closely mimicked those in patients with ovarian cancer treated in a phase Ib trial (NCT01294293). The NSG-HIS mouse helped elucidate themechanism of action of the combination and revealed a positive interaction between the two drugs in vivo. The combination produced no dose-limiting toxicities in patients with ovarian cancer. Two subjects (15%) had complete responses and 7 subjects (53%) had disease stabilization. A phase II study was consequently initiated. Conclusions: These results are the first to demonstrate the value of pharmacologic approaches integrating the NSG-HIS mouse, non-human primates, and patients with cancer for the development of novel immunomodulatory anticancer agents with human specificity. © 2016 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 23
Issue: 8
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2017-04-15
Start Page: 1955
End Page: 1966
Language: English
DOI: 10.1158/1078-0432.ccr-16-1453
PROVIDER: scopus
PMCID: PMC5437973
PUBMED: 27702821
Notes: Article -- Export Date: 2 June 2017 -- Source: Scopus
Altmetric Score
MSK Authors