A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth.
Tumor cells are elusive targets for immunotherapy due to their heterogeneity and genetic instability. Here we describe a novel, oral DNA vaccine that targets stable, proliferating endothelial cells in the tumor vasculature rather than tumor cells. Targeting occurs through upregulated vascular-endothelial growth factor receptor 2 (FLK-1) of proliferating endothelial cells in the tumor vasculature. This vaccine effectively protected mice from lethal challenges with melanoma, colon carcinoma and lung carcinoma cells and reduced growth of established metastases in a therapeutic setting. CTL-mediated killing of endothelial cells indicated breaking of peripheral immune tolerance against this self antigen, resulting in markedly reduced dissemination of spontaneous and experimental pulmonary metastases. Angiogenesis in the tumor vasculature was suppressed without impairment of fertility, neuromuscular performance or hematopoiesis, albeit with a slight delay in wound healing. Our strategy circumvents problems in targeting of genetically unstable tumor cells. This approach may provide a new strategy for the rational design of cancer therapies.
Niethammer
Andreas G
AG
Department of Immunology, Scripps Research Institute, La Jolla, California, USA.
Xiang
Rong
R
Becker
Jürgen C
JC
Wodrich
Harald
H
Pertl
Ursula
U
Karsten
Gabriele
G
Eliceiri
Brian P
BP
Reisfeld
Ralph A
RA
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology*; D014945:Wound Healing
D019444:Vaccines, DNA; D040301:Vascular Endothelial Growth Factor Receptor-2