title: Potent antitumor immunity generated by a CD40-targeted adenoviral vaccine.
abstract: In situ delivery of tumor-associated antigen (TAA) genes into dendritic cells (DC) has great potential as a generally applicable tumor vaccination approach. Although adenoviruses (Ad) are an attractive vaccine vehicle in this regard, Ad-mediated transduction of DCs is hampered by the lack of expression of the Ad receptor CAR on the DC surface. DC activation also requires interaction of CD40 with its ligand CD40L to generate protective T-cell-mediated tumor immunity. Therefore, to create a strategy to target Ads to DCs in vivo, we constructed a bispecific adaptor molecule with the CAR ectodomain linked to the CD40L extracellular domain via a trimerization motif (CFm40L). By targeting Ad to CD40 with the use of CFm40L, we enhanced both transduction and maturation of cultured bone marrow-derived DCs. Moreover, we improved transduction efficiency of DCs in lymph node and splenic cell suspensions in vitro and in skin and vaccination site-draining lymph nodes in vivo. Furthermore, CD40 targeting improved the induction of specific CD8(+) T cells along with therapeutic efficacy in a mouse model of melanoma. Taken together, our findings support the use of CD40-targeted Ad vectors encoding full-length TAA for in vivo targeting of DCs and high-efficacy induction of antitumor immunity.
authors: Department of Medical Oncology and Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Basav N
authors: BN
authors: Hangalapura
authors: Dinja
authors: D
authors: Oosterhoff
authors: Jan
authors: J
authors: de Groot
authors: Louis
authors: L
authors: Boon
authors: Thomas
authors: T
authors: Tüting
authors: Alfons J
authors: AJ
authors: van den Eertwegh
authors: Winald R
authors: WR
authors: Gerritsen
authors: Victor W
authors: VW
authors: van Beusechem
authors: Alexander
authors: A
authors: Pereboev
authors: David T
authors: DT
authors: Curiel
authors: Rik J
authors: RJ
authors: Scheper
authors: Tanja D
authors: TD
authors: de Gruijl
mesh_terms: D000256:Adenoviridae; D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000235:genetics / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D012878:Skin Neoplasms / Q000276:immunology / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D019013:CD40 Antigens; D019496:Cancer Vaccines; D023201:CD40 Ligand