title: A pan-inhibitor of DASH family enzymes induces immune-mediated regression of murine sarcoma and is a potent adjuvant to dendritic cell vaccination and adoptive T-cell therapy.
abstract: Multimodality therapy consisting of surgery, chemotherapy, and radiation will fail in approximately 40% of patients with pediatric sarcomas and result in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid tumors typically generate antigen-specific responses too weak to overcome considerable tumor burden and tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (dipeptidyl peptidase IV activity and/or structural homologs) enzymes can mediate tumor regression by immune-mediated mechanisms. Herein, we demonstrate that the DASH inhibitor, ARI-4175, can induce regression and eradication of well-established solid tumors, both as a single agent and as an adjuvant to a dendritic cell (DC) vaccine and adoptive cell therapy (ACT) in mice implanted with the M3-9-M rhabdomyosarcoma cell line. Treatment with effective doses of ARI-4175 correlated with recruitment of myeloid (CD11b) cells, particularly myeloid DCs, to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11bLy6-CLy6-G) myeloid-derived suppressor cells. In immunocompetent mice, combining ARI-4175 with a DC vaccine or ACT with tumor-primed T cells produced significant improvements in tumor responses against well-established M3-9-M tumors. In M3-9-M-bearing immunodeficient (Rag1) mice, ACT combined with ARI-4175 produced greater tumor responses and significantly improved survival compared with either treatment alone. These studies warrant the clinical investigation of ARI-4175 for treatment of sarcomas and other malignancies, particularly as an adjuvant to tumor vaccines and ACT.
authors.affiliation: *Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD †Department of Pediatrics, Division of Pediatric Hematology/Oncology, MedStar Georgetown University Hospital, Washington, DC ‡Department of Biochemistry, Tufts University School of Medicine, Boston, MA.
authors.forename: Brynn B
authors.initials: BB
authors.lastname: Duncan
authors.forename: Steven L
authors.initials: SL
authors.lastname: Highfill
authors.forename: Haiying
authors.initials: H
authors.lastname: Qin
authors.forename: Najat
authors.initials: N
authors.lastname: Bouchkouj
authors.forename: Shannon
authors.initials: S
authors.lastname: Larabee
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Iwona
authors.initials: I
authors.lastname: Woznica
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Liu
authors.forename: Youhua
authors.initials: Y
authors.lastname: Li
authors.forename: Wengen
authors.initials: W
authors.lastname: Wu
authors.forename: Jack H
authors.initials: JH
authors.lastname: Lai
authors.forename: Barry
authors.initials: B
authors.lastname: Jones
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
authors.forename: William W
authors.initials: WW
authors.lastname: Bachovchin
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Fry
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D019264:Adoptive Transfer; D000818:Animals; D001896:Boron Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D004151:Dipeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D012208:Rhabdomyosarcoma / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D047368:Tumor Burden / Q000187:drug effects
chemical_list: C587601:ARI-4175; D000276:Adjuvants, Immunologic; D001896:Boron Compounds; D019496:Cancer Vaccines; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors