Inhibition of tumor growth with antiangiogenic cancer vaccine using epitope peptides derived from human vascular endothelial growth factor receptor 1
Inhibition of tumor growth with antiangiogenic cancer vaccine using epitope peptides derived from human vascular endothelial growth factor receptor 1
复制标题
DOI：
10.1158/1078-0432.ccr-06-0750
复制
发表时间：
2006-10-01
影响因子：
11.5
通讯作者：
Tahara, Hideaki
中科院分区：
文献类型：
--
作者：
Ishizaki, Hidenobu;Tsunoda, Takuya;Tahara, Hideaki
目的：抗血管生成治疗目前被认为是治疗各种类型癌症的有前途的方法之一。在这项研究中，我们研究了针对肿瘤新生血管内皮细胞过度表达的血管内皮生长因子受体1(VEGFR1)的抗血管生成癌症疫苗的可能性。实验设计：根据VEGFR1的氨基酸序列预测其与相应HLA的理论结合亲和力。将表达人HLA-A*0201α1和α2结构域的A2/KB转基因小鼠免疫，检测其免疫效果。结果：利用已鉴定的人类白细胞抗原A 0201表位多肽免疫A2/KB转基因小鼠，可诱导产生CTL反应。从健康志愿者捐献的外周血单个核细胞中提取的表位多肽，在体外也能诱导出多肽特异性CTL克隆。我们也从人类外周血单个核细胞中建立了具有人类白细胞抗原-A*2402的CTL克隆。这些CTL克隆不仅对多肽冲击的靶细胞具有强大的细胞毒作用，而且对内源性表达VEGFR1的靶细胞也具有强烈的细胞毒作用。此外，用已鉴定的HLA-A*0201表位多肽免疫A2/KB转基因小鼠，可显著抑制肿瘤诱导的血管生成和肿瘤生长，且无明显不良反应。结论：VEGFR1是一种很有前途的抗血管生成肿瘤疫苗靶点，值得临床进一步研究。
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 alpha 1 and alpha 2 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 that VEGFR1 is a promising target for antiangiogenic cancer vaccine and warrants further clinical development of this strategy.