PML-RARA-targeted DNA vaccine induces protective immunity in a mouse model of leukemia
PML-RARA-targeted DNA vaccine induces protective immunity in a mouse model of leukemia
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DOI：
10.1038/nm949
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发表时间：
2003-11-01
期刊：
影响因子：
82.9
通讯作者：
Chomienne, C
中科院分区：
文献类型：
--
作者：
Padua, RA;Larghero, J;Chomienne, C
尽管恶性肿瘤的分子特征有所改善，靶向治疗也得到了发展，但急性白血病是不可治愈的，很少有患者在确诊后存活超过10年。最近，不同治疗策略的组合(基于细胞凋亡、分化和细胞毒性的机制)显著提高了生存率。为了进一步改善结果，我们研究了使用特异性免疫疗法增强患者免疫反应的潜在疗效。在急性早幼粒细胞白血病动物模型中，我们通过融合人早幼粒白血病-维甲酸受体-α(PML-RARA)癌基因和破伤风片段C(FRC)序列，开发了一种基于DNA的疫苗。我们首次表明，专门针对癌蛋白的DNA疫苗可以单独或与全反式维甲酸(ATRA)联合使用，对存活率产生显著影响。生存优势伴随着时间依赖性抗体的产生和干扰素-伽马(干扰素-伽马)的增加。我们还表明，在这个模型中，ATRA治疗本身就会触发免疫反应。当DNA疫苗与传统的全反式维甲酸治疗相结合时，它们可以在小鼠体内诱导针对白血病进展的保护性免疫反应，并可能为改善人类白血病的临床结局提供一种新的途径。
Despite improved molecular characterization of malignancies and development of targeted therapies, acute leukemia is not curable and few patients survive more than 10 years after diagnosis. Recently, combinations of different therapeutic strategies (based on mechanisms of apoptosis, differentiation and cytotoxicity) have significantly increased survival. To further improve outcome, we studied the potential efficacy of boosting the patient's immune response using specific immunotherapy. In an animal model of acute promyelocytic leukemia, we developed a DNA-based vaccine by fusing the human promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) oncogene to tetanus fragment C (FrC) sequences. We show for the first time that a DNA vaccine specifically targeted to an oncoprotein can have a pronounced effect on survival, both alone and when combined with all-trans retinoic acid (ATRA). The survival advantage is concomitant with time-dependent antibody production and an increase in interferon-gamma (IFN-gamma). We also show that ATRA therapy on its own triggers an immune response in this model. When DNA vaccination and conventional ATRA therapy are combined, they induce protective immune responses against leukemia progression in mice and may provide a new approach to improve clinical outcome in human leukemia.