title: Selective Targeting of Myeloid-Derived Suppressor Cells in Cancer Patients Using DS-8273a, an Agonistic TRAIL-R2 Antibody.
abstract: Purpose:Myeloid-derived suppressor cells (MDSC) are one of the major contributors to immune suppression in cancer. We recently have demonstrated in preclinical study that MDSCs are sensitive to TRAIL receptor 2 (TRAIL-R2) agonist. The goal of this study was to clinically test the hypothesis that targeting TRAIL-R2 can selectively eliminate MDSCs.Experimental Design:The TRAIL-R2 agonistic antibody (DS-8273a) has been tested in 16 patients with advanced cancers enrolled in a phase I trial. The antibody (24 mg/kg) was administered intravenously once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated.Results:The treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Treatment with DS-8273a resulted in reduction of the elevated numbers of MDSCs in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSCs rebounded back to the pretreatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells. Decrease in MDSCs inversely correlated with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSCs in 50% of the patients who were able to provide pre- and on-treatment biopsies.Conclusions:Targeting TRAIL-R2 resulted in elimination of different populations of MDSCs without affecting mature myeloid or lymphoid cells. These data support the use of this antibody in combination immmunotherapy of cancer.Clin Cancer Res; 23(12); 2942-50. ©2016 AACR.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: George A
authors.initials: GA
authors.lastname: Dominguez
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Thomas
authors.initials: T
authors.lastname: Condamine
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Sridevi
authors.initials: S
authors.lastname: Mony
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama.
authors.forename: Andres
authors.initials: A
authors.lastname: Forero
authors.affiliation: Sarah Cannon Research Institute Tennessee Oncology, Nashville, Tennessee.
authors.forename: Johanna
authors.initials: J
authors.lastname: Bendell
authors.affiliation: Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, Delaware.
authors.forename: Robert
authors.initials: R
authors.lastname: Witt
authors.affiliation: Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, Delaware.
authors.forename: Neil
authors.initials: N
authors.lastname: Hockstein
authors.affiliation: Daiichi-Sankyo Inc., Parsippany, New Jersey.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Kumar
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania. dgabrilovich@wistar.org.
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Gabrilovich
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D018572:Disease-Free Survival; D006801:Humans; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects* / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human