Inhibition of Tumor Growth with Antiangiogenic Cancer Vaccine Using Epitope Peptides Derived from Human Vascular Endothelial Growth Factor Receptor 1

Abstract

Purpose: Antiangiogenic therapy is now considered to be one of promising approaches to treat various types of cancer. In this study, we examined the possibility of developing antiangiogenic cancer vaccine targeting vascular endothelial growth factor receptor 1 (VEGFR1) overexpressed on endothelial cells of newly formed vessels in the tumor. Experimental Design: Epitope-candidate peptides were predicted from the amino acid sequence of VEGFR1 based on their theoretical binding affinities to the corresponding HLAs. The A2/Kb transgenic mice, which express the a1and a2 domains of human HLA-A*0201, were immunized with the epitope candidates to examine their effects. We also examined whether these peptides could induce human CTLs specific to the target cells in vitro.Results: The CTL responses in A2/Kb transgenic mice were induced with vaccination using identified epitope peptides restricted to HLA-A*0201. Peptide-specific CTL clones were also induced in vitro with these identified epitope peptides from peripheral blood mononuclear cells donated by healthy volunteers with HLA-A*0201. We established CTL clones in vitro from human peripheral blood mononuclear cells with HLA-A*2402 as well. These CTL clones were shown to have potent cytotoxicities in a HLA class I^restricted manner not only against peptide-pulsed target cells but also against target cells endogenously expressing VEGFR1. Furthermore, immunization of A2/Kb transgenic mice with identified epitope peptides restricted to HLA-A*0201 was associated with significant suppression of tumor-induced angiogenesis and tumor growth without showing apparent adverse effects. Conclusions:These results strongly suggest thatVEGFR1is a promising target for antiangiogenic cancer vaccine and warrants further clinical development of this strategy.

RACK1 Regulates VEGF/Flt1-mediated Cell Migration via Activation of a PI3K/Akt Pathway

“…Generation of AG1-G1-Neo and AG1-G1-Flt1 Cell Lines-AG1-G1-Flt1 cells were established from a human angioma with the permission of the Ethics Committee for scientific research at the Institute of Medical Science, University of Tokyo (28). Briefly, an adult benign angioma was excised surgically, and the pEF1␣-SV40 large T antigen plasmid was introduced into the cells.…”

P53, hTERT, WT-1, and VEGFR2 are the most suitable targets for cancer vaccine therapy in HLA-A24 positive pancreatic adenocarcinoma

“…Recent technical advances have enabled the identification of various tumor-associated antigens (TAAs) [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]; however, few of their epitopes are inducers of cytotoxic T lymphocyte (CTL) responses against tumors [22]. Several kinds of epitope have also been identified in patients with pancreatic adenocarcinoma [23,24].…”

Vaccination with xenogeneic tumor endothelial proteins isolated in situ inhibits tumor angiogenesis and spontaneous metastasis

“…[8][9][10] Other endothelial membrane proteins involved in angiogenesis such as integrin b3, Tie-2, endoglin and fibroblast growth factor receptor-1 (FGFR-1) have been under preclinical studies and shown therapeutic potential in cancer treatment. 11 Dendritic cells pulsed with angiogenesis-associated antigens [12][13][14][15] and endothelial-dendritic cell hybrids 16 have also proved effective in angiogenesis inhibition. Because of the fact that angiogenic endothelial antigens remain largely unrevealed, fixed human umbilical vascular endothelial cells (HUVECs), 17 murine hepatic sinusoidal endothelial cells 18 or viable HUVECs 19 were used as vaccines to elicit autoimmunity that attacked tumor endothelium and hence inhibited tumor growth.…”