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 
tumor-bearing NSG-HIS mice closely mimicked those in patients with ovarian 
cancer treated in a phase Ib trial (NCT01294293). The NSG-HIS mouse helped 
elucidate the mechanism 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. Clin Cancer Res; 
23(8); 1955-66. ©2016 AACR.