title: A pan inhibitor of DASH family enzymes induces immunogenic modulation and sensitizes murine and human carcinoma cells to antigen-specific cytotoxic T lymphocyte killing: implications for combination therapy with cancer vaccines.
abstract: Recent studies have suggested that pan inhibitors of dipeptidyl peptidase-4 activity and/or structure homologs (DASH), including ARI-4175, can mediate tumor regression by immune-mediated mechanisms. This study assessed the potential of combining ARI-4175 with cancer vaccines. We evaluated ARI-4175's effect on immunogenic modulation, ability to sensitize tumor cells to antigen-specific CTL killing, effect on immune-cell subsets and function, and antitumor activity in 2 tumor models, both as a monotherapy and in combination with a recombinant viral or dendritic cell (DC)-based tumor-cell vaccine. ARI-4175's effects on the growth, surface phenotype, and antigen-specific CTL-mediated lysis of murine and human carcinoma cell lines were assessed in vitro. In vivo, C57BL-6 mice were treated orally with ARI-4175, after which splenocytes were assessed by flow cytometry and functional assays. Antitumor studies were performed in murine models of colon carcinoma (MC38-CEA(+) in CEA-transgenic C57BL-6 mice) and rhabdomyosarcoma (M3-9-M in C57BL-6 mice). Mice received oral ARI-4175 alone or in combination with a vaccine consisting of recombinant vaccinia/fowlpox CEA-TRICOM (colon model) or a DC-based tumor-cell vaccine (rhabdomyosarcoma model). Exposure to ARI-4175 had no effect on the proliferation or viability of carcinoma cells in vitro; however, it did alter tumor phenotype, making murine and human tumor cells more sensitive to antigen-specific CTL killing. Assessment of immune-cell subsets and function indicated that ARI-4175 increased levels of natural killer cells and DCs. Detrimental immune effects, including reduced T effector cells and increased immunosuppressive cells (Tregs, MDSCs), were normalized when treatment stopped, suggesting that scheduling is critical when combining this agent with vaccine. As a monotherapy, ARI-4175 had potent antitumor activity in both tumor models, and had even greater effects when combined with a vaccine (either DC-based or poxviral vector based). These findings provide the rationale for the combined use of cancer immunotherapy with DASH enzyme inhibitors such as ARI-4175.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: renee.donahue@nih.gov.
authors.forename: Renee N
authors.initials: RN
authors.lastname: Donahue
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: bbd6@georgetown.edu.
authors.forename: Brynn B
authors.initials: BB
authors.lastname: Duncan
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: fryt@mail.nih.gov.
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Fry
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA. Electronic address: Barry.Jones@tufts.edu.
authors.forename: Barry
authors.initials: B
authors.lastname: Jones
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA; Arisaph Pharmaceuticals, Boston, MA, USA. Electronic address: william.bachovchin@tufts.edu.
authors.forename: William W
authors.initials: WW
authors.lastname: Bachovchin
authors.affiliation: Arisaph Pharmaceuticals, Boston, MA, USA. Electronic address: ckiritsy@arisaph.com.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Kiritsy
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA; Arisaph Pharmaceuticals, Boston, MA, USA. Electronic address: Jack.Lai@tufts.edu.
authors.forename: Jack H
authors.initials: JH
authors.lastname: Lai
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA. Electronic address: Wengen.Wu@tufts.edu.
authors.forename: Wengen
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA. Electronic address: Peng.Zhao@tufts.edu.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA. Electronic address: Yu.Liu@tufts.edu.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: tsangkwo@mail.nih.gov.
authors.forename: Kwong-Yok
authors.initials: KY
authors.lastname: Tsang
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: hodgej@mail.nih.gov.
authors.forename: James W
authors.initials: JW
authors.lastname: Hodge
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000517:prevention & control; D004151:Dipeptides / Q000494:pharmacology*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D012208:Rhabdomyosarcoma / Q000517:prevention & control; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: C587601:ARI-4175; D000276:Adjuvants, Immunologic; D001896:Boron Compounds; D019496:Cancer Vaccines; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors
keywords: DASH family enzymes; Immunogenic modulation; Immunotherapy; T-cell response; Vaccine
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