title: Co-expression of tumor antigen and interleukin-2 from an adenoviral vector augments the efficiency of therapeutic tumor vaccination.
abstract: We have previously shown that for the majority of antigens, adenoviral vaccines expressing the target antigen fused to the MHC associated invariant chain (Ii) induce an accelerated, augmented, and prolonged transgene-specific CD8(+) T-cell response. Here we describe a new adenoviral vaccine vector approach where the target antigen fused to Ii is expressed from the adenoviral E1 region and IL-2 is expressed from the E3 region. Immunization of mice with this new vector construct resulted in an augmented primary effector CD8(+) T-cell response. Furthermore, in a melanoma model we observed significantly prolonged tumor control in vaccinated wild type (WT) mice. The improved tumor control required antigen-specific cells, since no tumor control was observed, unless the melanoma cells expressed the vaccine targeted antigen. We also tested our new vaccine in immunodeficient (CD80/86 deficient) mice. Following vaccination with the IL-2 expressing construct, these mice were able to raise a delayed but substantial CD8(+) T-cell response, and to control melanoma growth nearly as efficaciously as similarly vaccinated WT mice. Taken together, these results demonstrate that current vaccine vectors can be improved and even tailored to meet specific demands: in the context of therapeutic vaccination, the capacity to promote an augmented effector T-cell response.
authors.affiliation: Department of International Health, Immunology and Microbiology, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark; Current addresses: Department of Biology, Faculty of Science, University of Copenhagen, Laboratory for Genomics and Molecular Biomedicine, Copenhagen, Denmark.
authors.forename: Benjamin Anderschou Holbech
authors.initials: BAH
authors.lastname: Jensen
authors.affiliation: Department of International Health, Immunology and Microbiology, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.
authors.forename: Maria Abildgaard
authors.initials: MA
authors.lastname: Steffensen
authors.affiliation: Department of International Health, Immunology and Microbiology, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark; Novo Nordisk, Copenhagen, Denmark.
authors.forename: Karen Nørgaard
authors.initials: KN
authors.lastname: Nielsen
authors.affiliation: Department of International Health, Immunology and Microbiology, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.
authors.forename: Jan Pravsgaard
authors.initials: JP
authors.lastname: Christensen
authors.affiliation: Department of International Health, Immunology and Microbiology, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark. Electronic address: athomsen@sund.ku.dk.
authors.forename: Allan Randrup
authors.initials: AR
authors.lastname: Thomsen
authors.affiliation: Department of International Health, Immunology and Microbiology, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark; Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Laboratory for Experimental Vaccinology CSS, Copenhagen, Denmark.
authors.forename: Peter Johannes
authors.initials: PJ
authors.lastname: Holst
mesh_terms: D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D019496:Cancer Vaccines / Q000008:administration & dosage; D045744:Cell Line, Tumor; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000235:genetics* / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D013154:Spleen / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology
chemical_list: D000957:Antigens, Viral, Tumor; D019496:Cancer Vaccines; D007376:Interleukin-2