A Novel DNA Vaccine Platform Enhances Neo-antigen-like T Cell Responses against WT1 to Break Tolerance and Induce Anti-tumor Immunity

• Published in: Molecular therapy 2017-04, Vol.25 (4), p.976-988
• Main Authors: Walters, Jewell N., Ferraro, Bernadette, Duperret, Elizabeth K., Kraynyak, Kimberly A., Chu, Jaemi, Saint-Fleur, Ashley, Yan, Jian, Levitsky, Hy, Khan, Amir S., Sardesai, Niranjan Y., Weiner, David B.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animal models; Animals; Antibodies - immunology; Antigen (tumor-associated); Antigens; Antigens, Neoplasm - immunology; Autoantigens; Cancer; Cancer Vaccines - immunology; CD4 antigen; CD8 antigen; Cell Line, Tumor; Cytokines - metabolism; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA damage; DNA vaccines; Electroporation; Epitopes, T-Lymphocyte - immunology; Female; Gene Expression; Growth factors; Humans; Immune Tolerance; Immunity; Immunodominant Epitopes - chemistry; Immunodominant Epitopes - immunology; Immunological tolerance; Leukemia; Lymphocyte Subsets - immunology; Lymphocyte Subsets - metabolism; Lymphocytes; Lymphocytes T; Macaca mulatta; Male; Mesothelioma; Mice; Mutation; neo-antigen; Neoplasms - immunology; Neoplasms - mortality; Neoplasms - pathology; Neoplasms - therapy; Original; Patients; Peptides; Peptides - immunology; Pharmaceutical industry; Proteins; Stock options; Studies; T cell receptors; Tumor necrosis factor-α; Tumors; Vaccination; Vaccines; Vaccines, DNA - immunology; WT1; WT1 Proteins - immunology; γ-Interferon
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2017.01.022

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. Breaking tolerance to tumor-associated self-antigens is a major challenge for cancer immune therapy. Here, Walters et al. report a novel DNA vaccine design strategy using consensus sequences to help break tolerance and induce a neo-antigen-like response to the germline antigen WT1.