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 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 drugsin vivoThe 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.
authors.affiliation: Arizona Oncology (US Oncology Network), University of Arizona College of Medicine-Phoenix, Creighton University School of Medicine at St. Joseph's Hospital, Phoenix, Arizona. Bradley.monk@usoncology.com.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Monk
authors.affiliation: University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Andrea
authors.initials: A
authors.lastname: Facciabene
authors.affiliation: NRG Oncology Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: William E
authors.initials: WE
authors.lastname: Brady
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Aghajanian
authors.affiliation: University of Virginia, Charlottesville, Virginia.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Fracasso
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Joan L
authors.initials: JL
authors.lastname: Walker
authors.affiliation: NRG Oncology Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Lankes
authors.affiliation: VentiRx Pharmaceuticals, Seattle, Washington.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Manjarrez
authors.affiliation: University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Gwenn-Äel H
authors.initials: GH
authors.lastname: Danet-Desnoyers
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Bell-McGuinn
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Carolyn K
authors.initials: CK
authors.lastname: McCourt
authors.affiliation: University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Alexander
authors.initials: A
authors.lastname: Malykhin
authors.affiliation: VentiRx Pharmaceuticals, Seattle, Washington.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hershberg
authors.affiliation: University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: George
authors.initials: G
authors.lastname: Coukos
mesh_terms: D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001552:Benzazepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015153:Blotting, Western; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008252:Macaca fascicularis; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D051200:Toll-Like Receptor 8 / Q000819:agonists*
chemical_list: D001552:Benzazepines; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; C573973:VTX-2337; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin