Successful cancer vaccine therapy for carcinoembryonic antigen (CEA)-expressing colon cancer using genetically modified dendritic cells that express CEA and T helper-type I cytokines in CEA transgenic mice
Successful cancer vaccine therapy for carcinoembryonic antigen (CEA)-expressing colon cancer using genetically modified dendritic cells that express CEA and T helper-type I cytokines in CEA transgenic mice
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DOI：
10.1002/ijc.22298
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发表时间：
2007-02-01
影响因子：
6.4
通讯作者：
Yamaue, Hiroki
中科院分区：
文献类型：
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作者：
Ojima, Toshiyasu;Iwahashi, Makoto;Yamaue, Hiroki
本研究旨在确定接种同时表达癌胚抗原（CEA）、粒细胞巨噬细胞集落刺激因子（GM-CSF）和白细胞介素12 （IL-12）的转基因树突状细胞（DCs）是否能克服外周t细胞对CEA的耐受性，从而在CEA转基因小鼠中引起治疗反应。用CEA和T辅助型I型细胞因子基因腺病毒转导的dc皮下注射CEA转基因小鼠一次免疫。表达CEA的dc （DC-AxCACEA）免疫小鼠脾脏细胞对表达CEA的肿瘤MC38-CEA的细胞毒活性高于dc - axcalacz免疫小鼠（p < 0.0001），并通过与GM-CSF/IL-12基因的共转导而增强（p < 0.05）。在皮下肿瘤模型中，接种DC-AxCACEA/GM-CSF/IL-12能比接种DC-AxCACEA产生更强的治疗性免疫（p < 0.0001）， 5只小鼠中有4只显示皮下肿瘤完全根除。即使在一个大的肿瘤模型中，这种疫苗治疗也完全消除了所有小鼠的皮下肿瘤。这种抗肿瘤活性在体内随着CD8(+) T细胞和NK细胞的消耗而基本消失，随着CD4(+) T细胞的消耗而完全消失。组织病理学检查未发现自身免疫反应。未观察到其他不良反应。这种疫苗接种策略导致在没有自身免疫反应的情况下产生针对MC38-CEA的高效治疗性免疫反应，并且没有不良反应，因此可能在未来的临床应用中作为癌症疫苗治疗有用。(c) 2006年威利利斯。公司。
This study was designed to determine whether the vaccination of genetically modified dendritic cells (DCs) simultaneously expressing carcinoembryonic antigen (CEA), granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin 12 (IL-12) can overcome the peripheral T-cell tolerance to CEA and thereby elicit a therapeutic response in CEA transgenic mice. CEA transgenic mice were immunized once by subcutaneous injection with DCs adenovirally transduced with CEA and T helper-type I cytokine genes. The cytotoxic activity of spleen cells against CEA-expressing tumors, MC38-CEA, in the mice immunized with DCs expressing CEA (DC-AxCACEA) was higher than that in those immunized with DCs-AxCALacZ (p < 0.0001), and was augmented by the cotransduction with the GM-CSF/IL-12 gene (p < 0.05). The vaccination with DC-AxCACEA/GM-CSF/IL-12 could elicit a more potent therapeutic immunity than the vaccination with DC-AxCACEA in subcutaneous tumor models (p < 0.0001), and 4 of 5 mice showed a complete eradication of the subcutaneous tumors in these vaccination groups. Even in a large tumor model, this vaccination therapy completely eliminated the subcutaneous tumors in all mice. This antitumor activity mostly vanished with the depletion of CD8(+) T cells and NK cells in vivo and was completely abrogated with the depletion of CD4(+) T cells. A histopathological examination showed no evidence of an autoimmune reaction. No other adverse effects were observed. This vaccination strategy resulted in the generation of highly efficient therapeutic immune responses against MC38-CEA in the absence of autoimmune responses and demonstrated no adverse effects, and may therefore be useful for future clinical applications as a cancer vaccine therapy. (c) 2006 Wiley-Liss. Inc.