Details

Autor(en) / Beteiligte

• Monk, Bradley J
• Facciabene, Andrea
• Brady, William E
• Aghajanian, Carol A
• Fracasso, Paula M
• Walker, Joan L
• Lankes, Heather A
• Manjarrez, Kristi L
• Danet-Desnoyers, Gwenn-Äel H
• Bell-McGuinn, Katherine M
• McCourt, Carolyn K
• Malykhin, Alexander
• Hershberg, Robert M
• Coukos, George

Titel

Integrative Development of a TLR8 Agonist for Ovarian Cancer Chemoimmunotherapy

Ist Teil von

• Clinical cancer research, 2017-04, Vol.23 (8), p.1955-1966

Ort / Verlag

United States: American Association for Cancer Research Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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 patients with cancer 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, 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 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. 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. .