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Prepublished online as a Blood First Edition Paper on May 15, 2003; DOI 10.1182/blood-2002-12-3772.
Submitted December 13, 2002
Accepted May 9, 2003
Immunotherapy of tumors with vaccine based on quail homologous vascular endothelial growth factor receptor-2
Ji-yan Liu, Yu-quan Wei*, Li Yang, Xia Zhao, Ling Tian, Jian-mei Hou, Ting Niu, Fen Liu, Yu Jiang, Bing Hu, Yang Wu, Jing-mei Su, Yan-yan Lou, Qiu-ming He, Yan-jun Wen, Jin-liang Yang, Bing Kan, Yong-qiu Mao, Feng Luo, and Feng Peng
Key Laboratory of Biotherapy of Human Diseases, Ministry of Education, P.R. China and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
Department of Gynecology and Obstetrics, Second West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
* Corresponding author; email: yuquawei{at}vip.sina.com.
The breaking of immune tolerance of "self antigens" associated with angiogenesis is an attractive approach to cancer therapy by active immunity. We used VEGF receptor-2 (VEGFR-2) as a model antigen to explore the feasibility of the immunotherapy with a vaccine based on a xenogeneic homologous protein. To test this concept, we prepared a quail homologous VEGFR-2 protein vaccine (qVEGFR) based on quail VEGFR-2, at the same time, the protein vaccine based on the corresponding ligand binding domain of mouse self-VEGFR-2 (mVEGFR) were also prepared and used as a control. We found that immunotherapy with qVEGFR was effective at both protective and therapeutic antitumor immunity in several solid and hematopoietic tumor models in mice. Autoantibodies against mouse VEGFR-2 (Flk-1) were identified by Western blot analysis and ELISA. Anti-VEGFR antibody-producing B cells were detectable by ELISPOT. There was endothelial deposition of immunoglobulins within tumor. VEGF-mediated endothelial cell proliferation was inhibited in vitro by immunoglobulins from qVEGFR-immunized mice. The anti-tumor activity was caused by the adoptive transfer of the purified immunoglobulins. The anti-tumor activity and production of autoantibodies against Flk-1 could be abrogated by depletion of CD4+ T lymphocytes. Angiogenesis was apparently inhibited within the tumors, and the vascularization of alginate beads was also reduced. No marked toxicity was found in the immunized mice. The observations may provide a vaccine strategy for cancer therapy through the induction of autoimmunity against the growth factor receptor associated with angiogenesis in a cross reaction with single xenogeneic homologous protein.
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