Immunotherapy of tumors with vaccine based on quail homologous vascular endothelial growth factor receptor-2

Blood. 2003 Sep 1;102(5):1815-23. doi: 10.1182/blood-2002-12-3772. Epub 2003 May 15.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Heterophile / immunology
  • Autoantibodies / immunology
  • Cancer Vaccines / pharmacology*
  • Cancer Vaccines / toxicity
  • Carcinoma, Lewis Lung / immunology
  • Carcinoma, Lewis Lung / therapy*
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / therapy*
  • Fibrosarcoma / immunology
  • Fibrosarcoma / therapy
  • Immunotherapy
  • Lung Neoplasms / immunology
  • Lung Neoplasms / therapy*
  • Lymphoma / immunology
  • Lymphoma / therapy
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / immunology
  • Neovascularization, Pathologic / therapy
  • Plasmacytoma / immunology
  • Plasmacytoma / therapy
  • Quail
  • T-Lymphocyte Subsets / immunology
  • Vascular Endothelial Growth Factor Receptor-2 / immunology*

Substances

  • Antigens, Heterophile
  • Autoantibodies
  • Cancer Vaccines
  • Vascular Endothelial Growth Factor Receptor-2