title: Off-the-shelf adenoviral-mediated immunotherapy via bicistronic expression of tumor antigen and iMyD88/CD40 adjuvant.
abstract: Recent modest successes in ex vivo dendritic cell (DC) immunotherapy have motivated continued innovation in the area of DC manipulation and activation. Although ex vivo vaccine approaches continue to be proving grounds for new DC manipulation techniques, the intrinsic limits of ex vivo therapy, including high cost, minimal standardization, cumbersome delivery, and poor accessibility, incentivizes the development of vaccines compatible with in vivo DC targeting. We describe here a method to co-deliver both tumor-specific antigen (TSA) and an iMyD88/CD40 adjuvant (iMC), to DCs that combines toll-like receptor (TLR) and CD40 signaling. In this study, we demonstrate that simple TSA delivery via adenoviral vectors results in strong antitumor immunity. Addition of iMC delivered in a separate vector is insufficient to enhance this effect. However, when delivered simultaneously with TSA in a single bicistronic vector (BV), iMC is able to significantly enhance antigen-specific cytotoxic T-cell (CTL) responses and inhibit established tumor growth. This study demonstrates the spatial-temporal importance of concurrent DC activation and TSA presentation. Further, it demonstrates the feasibility of in vivo molecular enhancement of DCs necessary for effective antitumor immune responses.
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jan Ole
authors.initials: JO
authors.lastname: Kemnade
authors.forename: Mamatha
authors.initials: M
authors.lastname: Seethammagari
authors.forename: Priya
authors.initials: P
authors.lastname: Narayanan
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Levitt
authors.forename: Alison A
authors.initials: AA
authors.lastname: McCormick
authors.forename: David M
authors.initials: DM
authors.lastname: Spencer
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D000229:Dependovirus; D005260:Female; D007167:Immunotherapy; D018664:Interleukin-12 / Q000378:metabolism; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000096:biosynthesis / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019013:CD40 Antigens; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D018664:Interleukin-12