Cancer Immunology, Immunotherapy

, Volume 66, Issue 2, pp 181–192

Immunogenicity and efficacy of a rationally designed vaccine against vascular endothelial growth factor in mouse solid tumor models

  • Aizhang Xu
  • Li Zhang
  • Yangyang Chen
  • Zhibing Lin
  • Rongxiu Li
Original Article

DOI: 10.1007/s00262-016-1928-0

Cite this article as:
Xu, A., Zhang, L., Chen, Y. et al. Cancer Immunol Immunother (2017) 66: 181. doi:10.1007/s00262-016-1928-0
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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.

Keywords

Cancer vaccine Cytotoxic T lymphocytes Diphtheria toxin T domain Immunotherapy Type 1 immune response Vascular endothelial growth factor 

Abbreviations

Alum

Aluminum hydroxide

CFSE

Carboxyfluorescein succinimidyl ester

CTLs

Cytotoxic T lymphocytes

DCs

Dendritic cells

DTT

Diphtheria toxin T domain

GST

Glutathione S-transferase

H&E

Hematoxylin and eosin

IFA

Incomplete Freund’s adjuvant

LDH

Lactate dehydrogenase

mAbs

Monoclonal antibodies

SEM

Standard error of mean

VEGF

Vascular endothelial growth factor

VEGFR

Vascular endothelial growth factor receptor

Supplementary material

262_2016_1928_MOESM1_ESM.pdf (5.8 mb)
Supplementary material 1 (PDF 5965 kb)

Funding information

Funder NameGrant NumberFunding Note
Shanghai Municipal Science and Technology Program
  • 14431904100
National S and T major projects of China (Key Innovative Drug Development)
  • 2014ZX09101043
Shanghai Industry-Academia-Research Collaboration Program
  • CXY-2013-54
Specialized Research Fund for the Doctoral Program of Higher Education of China
  • 20130073120110
Medicine Science/Engineering Hybrid Project of Shanghai Jiao Tong University
  • YG2013MS09

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Aizhang Xu
    • 1
    • 2
  • Li Zhang
    • 1
    • 2
  • Yangyang Chen
    • 1
    • 2
  • Zhibing Lin
    • 1
    • 2
  • Rongxiu Li
    • 1
    • 2
    • 3
  1. 1.State Key Laboratory of Microbial MetabolismShanghai Jiao Tong UniversityShanghaiChina
  2. 2.School of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghaiChina
  3. 3.Engineering Research Center of Cell and Therapeutic Antibody, Ministry of EducationShanghai Jiao Tong UniversityShanghaiChina

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