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Prepublished online as a Blood First Edition Paper on May 15, 2003; DOI 10.1182/blood-2002-12-3772.
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Blood, 1 September 2003, Vol. 102, No. 5, pp. 1815-1823
IMMUNOBIOLOGY
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
From the Key Laboratory of Biotherapy of Human Diseases, Ministry of
Education, People's Republic of China and Cancer Center, West China Hospital,
West China Medical School, Sichuan University, Chengdu; and the Department of
Gynecology and Obstetrics, Second West China Hospital, West China Medical
School, Sichuan University, Chengdu, China.
The breaking of immune tolerance of "self-antigens" associated
with angiogenesis is an attractive approach to cancer therapy by active
immunity. We used vascular endothelial growth factor 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, a protein vaccine based on the corresponding ligand-binding
domain of mouse self-VEGFR-2 (mVEGFR) was also prepared and used as a control.
We found that immunotherapy with qVEGFR was effective at 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 enzyme-linked immunosorbent assay (ELISA).
Anti-VEGFR antibody-producing B cells were detectable by ELISPOT. Endothelial
deposition of immunoglobulins developed within tumor. VEGF-mediated
endothelial cell proliferation was inhibited in vitro by immunoglobulins from
qVEGFR-immunized mice. Antitumor activity was caused by the adoptive transfer
of the purified immunoglobulins. Antitumor activity and production of
autoantibodies against Flk-1 could be abrogated by the 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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