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.
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 cancer patients to test the effects of motolimod and to assess the combination of motolimod with PLD for the treatment of ovarian cancer.
The pharmacodynamic effects of motolimod monotherapy in NSG-HIS mice closely mimicked those in non-human primates and healthy human subjects, while 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 1b 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 ovarian cancer patients. Two subjects (15%) had complete responses and 7 subjects (53%) had disease stabilization. A phase 2 study was consequently initiated.
These results are the first to demonstrate the value of pharmacologic approaches integrating the NSG-HIS mouse, non-human primates, and cancer patients for the development of novel immunomodulatory anticancer agents with human specificity.
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