Integrative Development of a TLR8 Agonist for Ovarian Cancer Chemo-immunotherapy

 Motolimod (formerly VTX-2337)

abstract

Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.