title: A Novel DNA Vaccine Platform Enhances Neo-antigen-like T Cell Responses against WT1 to Break Tolerance and Induce Anti-tumor Immunity.
abstract: Tumor-associated antigens have emerged as important immunotherapeutic targets in the fight against cancer. Germline tumor antigens, such as WT1, Wilms' tumor gene 1, are overexpressed in many human malignancies but have low expression in somatic tissues. Recent vaccination approaches to target WT1 have been hampered by poor in vivo immune potency, likely due to the conserved self-antigen nature of WT1. In this study, we use a novel synthetic micro-consensus SynCon DNA vaccine approach with the goal of breaking tolerance and increasing vaccine immune potency. This approach induced new, neo-antigen-like responses that were superior to those induced by native WT1 DNA immunogens for driving T cell immunity and breaking tolerance. Non-human primates (NHPs) vaccinated with SynCon WT1 antigens elicited immune responses against native rhesus WT1 peptides. When delivered by electroporation (EP) in mice, SynCon-based WT1 constructs elicited strong CD4 and CD8 T cell responses (including IFN-γ, CD107a, and TNF-α) to both native and consensus peptides. In addition, SynCon WT1 vaccine-induced antibodies recognized native WT1 in vitro. Vaccination with the SynCon WT1 immunogens was capable of slowing tumor growth in therapeutic models in vivo. These data support the further study of synthetic consensus DNA vaccines for breaking tolerance to important germline antigens.
authors.affiliation: Inovio Pharmaceuticals, Inc., 660 West Germantown Pike, Suite 110, Plymouth Meeting, PA 19462, USA.
authors.forename: Jewell N
authors.initials: JN
authors.lastname: Walters
authors.affiliation: Inovio Pharmaceuticals, Inc., 660 West Germantown Pike, Suite 110, Plymouth Meeting, PA 19462, USA.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Ferraro
authors.affiliation: The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104, USA.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Duperret
authors.affiliation: Inovio Pharmaceuticals, Inc., 660 West Germantown Pike, Suite 110, Plymouth Meeting, PA 19462, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Kraynyak
authors.affiliation: The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104, USA.
authors.forename: Jaemi
authors.initials: J
authors.lastname: Chu
authors.affiliation: The Johns Hopkins University, Baltimore, MD 21231, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Saint-Fleur
authors.affiliation: Inovio Pharmaceuticals, Inc., 660 West Germantown Pike, Suite 110, Plymouth Meeting, PA 19462, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.affiliation: The Johns Hopkins University, Baltimore, MD 21231, USA.
authors.forename: Hy
authors.initials: H
authors.lastname: Levitsky
authors.affiliation: Inovio Pharmaceuticals, Inc., 660 West Germantown Pike, Suite 110, Plymouth Meeting, PA 19462, USA.
authors.forename: Amir S
authors.initials: AS
authors.lastname: Khan
authors.affiliation: Inovio Pharmaceuticals, Inc., 660 West Germantown Pike, Suite 110, Plymouth Meeting, PA 19462, USA.
authors.forename: Niranjan Y
authors.initials: NY
authors.lastname: Sardesai
authors.affiliation: The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104, USA. Electronic address: dweiner@wistar.org.
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007108:Immune Tolerance; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D010455:Peptides / Q000276:immunology; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*; D025721:WT1 Proteins / Q000276:immunology*
chemical_list: D000906:Antibodies; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D010455:Peptides; D019444:Vaccines, DNA; D025721:WT1 Proteins
keywords: DNA vaccines; WT1; immune tolerance; leukemia; neo-antigen