Anti-tumoral effect of active immunotherapy in C57BL/6 mice using a recombinant human VEGF protein as antigen and three chemically unrelated adjuvants

• Published in: Angiogenesis (London) 2008-12, Vol.11 (4), p.381-393
• Main Authors: Morera, Yanelys, Bequet-Romero, Mónica, Ayala, Marta, Lamdán, Humberto, Agger, Else-Marie, Andersen, Peter, Gavilondo, Jorge V.
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - pharmacology; Animals; Antibodies; Antigens - immunology; Behavior, Animal - drug effects; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blood and lymphatic vessels; Cancer Research; Cardiology; Cardiology. Vascular system; Cardiovascular system; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - cytology; Endothelial Cells - drug effects; Escherichia coli; Humans; Immune Sera; Immunotherapy, Active; Lymphocyte Depletion; Medical sciences; Mice; Mice, Inbred C57BL; Mutant Proteins - isolation & purification; Mutant Proteins - metabolism; Neoplasm Transplantation; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; Oncology; Ophthalmology; Original Paper; Pharmacology. Drug treatments; Recombinant Proteins - immunology; Recombinant Proteins - pharmacology; Vascular Endothelial Growth Factor A - immunology; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vasodilator agents. Cerebral vasodilators
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1007/s10456-008-9121-5

Following the clinical success of Bevacizumab, a humanized monoclonal antibody that affects the interaction between vascular endothelial growth factor (VEGF) and its receptors, blocking tumor-induced angiogenesis has become one of the most important targets for the development of new cancer therapeutic drugs and procedures. Among the latter, therapeutic vaccination using VEGF as antigen presents itself as very attractive, with the potential of generating not only a growth factor blocking antibody response but also a cellular response against tumor cells and stromal elements, which appear to be a major source of tumor VEGF. In this paper, we report the development of a protein vaccine candidate, based on a human modified VEGF antigen that is expressed at high levels in E. coli . With respect to controls, immunization experiments in C57BL/6 mice using weekly doses of this antigen and three adjuvants of different chemical natures show that time for tumor development after subcutaneous injection of Melanoma B16-F10 cells increases, tumors that develop grow slower, and overall animal survival is higher. Immunization also prevents tumor development in some mice, making them resistant to second tumor challenges. Vaccination of mice with the human modified VEGF recombinant antigen produces antibodies against the human antigen and the homologous mouse VEGF molecule. We also show that sera from immunized mice block human VEGF-induced HUVEC proliferation. Finally, a possible contribution of T cell cytotoxicity to the overall anti-tumor effect is suggested from the results of vaccination experiments where CD8+ lymphocytes were impaired using neutralizing rat antibodies.