title: Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and antitumor effects.
abstract: We recently demonstrated that Venezuelan equine encephalitis virus-based replicon particle (VRPs) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP-expressing interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and antitumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)), and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12, and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP-IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing antitumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than that of VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted.
authors.affiliation: Department of Surgery, Duke University Medical Center, Box 2606 MSRB1 Rm 433b Research Dr, Durham, NC 27710, USA.
authors.forename: Takuya
authors.initials: T
authors.lastname: Osada
authors.forename: Peter
authors.initials: P
authors.lastname: Berglund
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.forename: Bolyn
authors.initials: B
authors.lastname: Hubby
authors.forename: Whitney
authors.initials: W
authors.lastname: Lewis
authors.forename: Donna
authors.initials: D
authors.lastname: Niedzwiecki
authors.forename: Xiao Yi
authors.initials: XY
authors.lastname: Yang
authors.forename: Amy
authors.initials: A
authors.lastname: Hobeika
authors.forename: Bruce
authors.initials: B
authors.lastname: Burnett
authors.forename: Gayathri R
authors.initials: GR
authors.lastname: Devi
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Clay
authors.forename: Jonathan
authors.initials: J
authors.lastname: Smith
authors.forename: H
authors.initials: H
authors.lastname: Kim Lyerly
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000912:Antibodies, Neoplasm / Q000097:blood / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000628:therapy*; D004666:Encephalitis Virus, Venezuelan Equine; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012093:Replicon; D013601:T-Lymphocytes / Q000276:immunology; D014771:Virion
chemical_list: D000276:Adjuvants, Immunologic; D000912:Antibodies, Neoplasm; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D018664:Interleukin-12