Angiogenesis is a critical mechanism for
tumor progression. Multiple studies have suggested that
tumor growth can be suppressed if
tumor angiogenesis can be inhibited using various types of
antiangiogenic agents. Recent studies in mouse systems have shown that
tumor angiogenesis can also be inhibited if cellular immune response could be induced against
vascular endothelial growth factor receptor 2 (VEGFR2), which is one of the key factors in
tumor angiogenesis. In this study, we examined the possibility of developing this novel
immunotherapy in clinical setting. We first identified the
epitope peptides of VEGFR2 and showed that stimulation using these
peptides induces CTLs with potent cytotoxicity in the HLA class I-restricted fashion against not only
peptide-pulsed target cells but also endothelial cells endogenously expressing VEGFR2. In A2/Kb transgenic mice that express alpha1 and alpha2 domains of human
HLA-A*0201, vaccination using these
epitope peptides in vivo was associated with significant suppression of the
tumor growth and prolongation of the animal survival without fatal adverse effects. In antiangiogenesis assay,
tumor-induced angiogenesis was significantly suppressed with the vaccination using these
epitope peptides. Furthermore, CTLs specific to the
epitope peptides were successfully induced in
cancer patients, and the specificities of the CTLs were confirmed using functional and HLA-tetramer analysis. These results in vitro and in vivo strongly suggest that the
epitope peptides derived from VEGFR2 could be used as the agents for antiangiogenic
immunotherapy against
cancer in clinical settings.