title: Immunogenicity and efficacy of a rationally designed vaccine against vascular endothelial growth factor in mouse solid tumor models.
abstract: Vascular endothelial growth factor (VEGF) plays an important role in the progression of various cancers. The VEGF-specific antibody bevacizumab combined with chemotherapy was shown to significantly improve progression-free survival in certain cancers. However, repeated administration is necessary for effective suppression of VEGF, thereby making the therapy expensive and cumbersome. Thus, it is urgent to develop alternative reagents such as VEGF vaccines. Here we report that DTT-VEGF, a VEGF-based antigen consisting of the receptor-binding domain of VEGF and diphtheria toxin T domain (DTT), not only stimulated neutralizing antibody response, but also induced type 1 immune response as well as anti-tumor cytotoxic T lymphocytes in mice when administered with aluminum hydroxide adjuvant. The antibodies triggered by DTT-VEGF immunization inhibited the binding of VEGF to VEGF receptor and downregulated the serum VEGF levels in tumor-bearing mice. VEGF-specific IgG2a and IgG2b antibodies as well as type 1 cytokines were stimulated by DTT-VEGF vaccination. The splenocytes from DTT-VEGF-immunized mice showed cytotoxic activity against B16-F10 cells expressing VEGF. Extensive necrosis with severe hemorrhage and enhanced CD8+T cell infiltration were observed in tumors from DTT-VEGF-immunized mice. The percentages of CD31+vascular areas in the tumor sections from DTT-VEGF-immunized mice were significantly lower than those of control mice. DTT-VEGF significantly inhibited tumor growth in preventive and therapeutic vaccination settings in mouse models. Our data suggest that DTT is an effective antigen carrier to break immune self-tolerance and our vaccine design has potential to be used for human cancer therapy.
authors.affiliation: State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.|School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Aizhang
authors.initials: A
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.|School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.|School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.|School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhibing
authors.initials: Z
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China. rxli@sjtu.edu.cn.|School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. rxli@sjtu.edu.cn.|Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China. rxli@sjtu.edu.cn.
authors.forename: Rongxiu
authors.initials: R
authors.lastname: Li
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy; D004168:Diphtheria Toxoid / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000072417:Protein Domains; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D004168:Diphtheria Toxoid; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Cancer vaccine; Cytotoxic T lymphocytes; Diphtheria toxin T domain; Immunotherapy; Type 1 immune response; Vascular endothelial growth factor