title: DNA fusion vaccines enter the clinic.
abstract: Induction of effective immune attack on cancer cells in patients requires conversion of weak tumor antigens into strong immunogens. Our strategy employs genetic technology to create DNA vaccines containing tumor antigen sequences fused to microbial genes. The fused microbial protein engages local CD4+ T cells to provide help for anti-tumor immunity, and to reverse potential regulation. In this review, we focus on induction of CD8+ T cells able to kill target tumor cells. The DNA vaccines incorporate tumor-derived peptide sequences fused to an engineered domain of tetanus toxin. In multiple models, this design induces strong CD8+ T-cell responses, able to suppress tumor growth. For clinical relevance, we have used "humanized" mice expressing HLA-A2, successfully inducing cytolytic T-cell responses against a range of candidate human peptides. To overcome physical restriction in translating to patients, we have used electroporation. Clinical trials of patients with cancer are showing induction of responses, with preliminary indications of suppression of tumor growth and evidence for clinically manageable concomitant autoimmunity.
authors.affiliation: Molecular Immunology Group, Cancer Sciences Division, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK. fs@soton.ac.uk
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
authors.forename: Ann
authors.initials: A
authors.lastname: Mander
authors.forename: Lindsey
authors.initials: L
authors.lastname: Chudley
authors.forename: Christian H
authors.initials: CH
authors.lastname: Ottensmeier
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020811:Biomedical Technology / Q000639:trends; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines; D002986:Clinical Trials as Topic; D003602:Cytotoxicity, Immunologic; D015789:HLA-A2 Antigen / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019139:Tumor Escape; D019444:Vaccines, DNA
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA