title: Effective cancer vaccine platform based on attenuated salmonella and a type III secretion system.
abstract: Vaccines explored for cancer therapy have been based generally on injectable vector systems used to control foreign infectious pathogens, to which the immune system evolved to respond naturally. However, these vectors may not be effective at presenting tumor-associated antigens (TAA) to the immune system in a manner that is sufficient to engender antitumor responses. We addressed this issue with a novel orally administered Salmonella-based vector that exploits a type III secretion system to deliver selected TAA in the cytosol of professional antigen-presenting cells in situ. A systematic comparison of candidate genes from the Salmonella Pathogenicity Island 2 (SPI2) locus was conducted in the vaccine design, using model antigens and a codon-optimized form of the human TAA survivin (coSVN), an oncoprotein that is overexpressed in most human cancers. In a screen of 20 SPI2 promoter:effector combinations, a PsifB::sseJ combination exhibited maximal potency for antigen translocation into the APC cytosol, presentation to CD8 T cells, and murine immunogenicity. In the CT26 mouse model of colon carcinoma, therapeutic vaccination with a lead PsifB::sseJ-coSVN construct (p8032) produced CXCR3-dependent infiltration of tumors by CD8 T cells, reversed the CD8:Treg ratio at the tumor site, and triggered potent antitumor activity. Vaccine immunogenicity and antitumor potency were enhanced by coadministration of the natural killer T-cell ligand 7DW8-5, which heightened the production of IL12 and IFNγ. Furthermore, combined treatment with p8032 and 7DW8-5 resulted in complete tumor regression in A20 lymphoma-bearing mice, where protective memory was demonstrated. Taken together, our results demonstrate how antigen delivery using an oral Salmonella vector can provide an effective platform for the development of cancer vaccines.
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Division of Microbiology, University of Osnabrück, Osnabrück, Germany.
authors.forename: Wael A H
authors.initials: WA
authors.lastname: Hegazy
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors.forename: Linjie
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors.forename: Amy N
authors.initials: AN
authors.lastname: Courtney
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors.forename: Suhrab
authors.initials: S
authors.lastname: Kurbanov
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors.forename: Daofeng
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors.forename: Gengwen
authors.initials: G
authors.lastname: Tian
authors.affiliation: Division of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Manuel
authors.affiliation: Division of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California.
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
authors.affiliation: Division of Microbiology, University of Osnabrück, Osnabrück, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hensel
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas. lsmeteli@txch.org.
authors.forename: Leonid S
authors.initials: LS
authors.lastname: Metelitsa
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000008:administration & dosage*; D001426:Bacterial Proteins / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D001426:Bacterial Proteins; D019496:Cancer Vaccines; D008565:Membrane Proteins; C440638:SPI-2 protein, Salmonella; D014613:Vaccines, Attenuated