Nat Nanotechnol:重磅!利用纳米颗粒在体内制造CAR-T细胞

2017-04-19 生物谷 生物谷

在一项新的概念验证研究中,来自美国弗雷德-哈金森癌症研究中心和华盛顿大学的研究人员开发出生物可降解的纳米颗粒,这些纳米颗粒能够被用来对T细胞(一种免疫细胞)进行基因编程,使得它们识别和摧毁癌细胞,并且它们仍然停留在体内。 在这项于2017年4月17日在线发表在Nature Nanotechnology期刊上的研究中,这些研究人员证实



在一项新的概念验证研究中,来自美国弗雷德-哈金森癌症研究中心和华盛顿大学的研究人员开发出生物可降解的纳米颗粒,这些纳米颗粒能够被用来对T细胞(一种免疫细胞)进行基因编程,使得它们识别和摧毁癌细胞,并且它们仍然停留在体内。

在这项于2017年4月17日在线发表在Nature Nanotechnology期刊上的研究中,这些研究人员证实在一种白血病模式小鼠体内,这些纳米颗粒编程的T细胞能够快速地清除这种疾病,或者延缓它的进展。

论文通信作者、弗雷德-哈金森癌症研究中心研究员Matthias Stephan博士说,“据我们所知,我们的技术是首次快速地让T细胞具有肿瘤识别能力,而不需要在实验室中将它们提取出来。这些重编程T细胞在24小时到48小时内开 始发挥功能,并且在几周的时间内持续产生这些识别肿瘤细胞的受体。这提示着我们的技术有潜力允许免疫系统在这种疾病变得致命性之前,快速地发起足够强的免疫反应来摧毁癌变的细胞。”

细胞免疫疗法在临床试验中显示出广阔的应用前景,但是所面临的挑战一直是让它们更加广泛地可获得,和能够快速地部署它们。当前,它通常需要几周的时间来制备CAR-T细胞:必须将T细胞从病人体内提取出,让它们接 受基因改造,在特殊的细胞处理设备中生长,随后将它们灌注到病人体内。这些新的纳米颗粒可能消除了对这些费用高昂的耗时的步骤的需求。

尽管这种T细胞编程方法仍然离实际应用有几步之遥,但是Stephan展望,在未来,纳米颗粒会将细胞免疫疗法(不论是用于治疗癌症,还是用于治疗传染病)转换为一种容易服用的在任何地方都能够获得的现存疗法。

Stephan说,“迄今为止,我没有患上癌症,但是如果经诊断我确实患上癌症,那么我想要立即开始接受治疗。我想要在癌症确诊之日,让细胞免疫疗法成为一种治疗选择,并且在病人”生活的地方附近的门诊中开展这种治疗。

身体是一个基因工程实验室

Stephan构建出他的T细胞归巢纳米颗粒(T-cell homing nanoparticle),旨在让更多的病人受益于癌症细胞免疫疗法。

在他的方法中,这些费时费力的T细胞编程步骤都在体内发生,从而在几天内产生大量的潜在的“连环杀手(serial killer)”。

正如在这项新的研究中所报道的那样,Stephan和他的团队开发出生物可降解的纳米颗粒,可将T细胞转换为CAR-T细胞。CAR-T细胞疗法是一种特定类型的细胞免疫疗法,已在针对白血病的临床试验中获得有前景的结果。

这些研究人员设计出的这些纳米颗粒携带着编码靶向和清除癌症的嵌合抗原受体(chimeric antigen receptor, CAR)的基因。他们也给这些纳米颗粒标记上让它们附着到T细胞上的分子,从而使得T细胞吞噬这些纳米颗粒。这些T 细胞的内部运送系统随后指导这些纳米颗粒进入细胞核,并且在那里,这些纳米颗粒会溶解掉。

这些概念验证研究证实这些纳米颗粒能够让免疫系统靶向癌细胞。Stephan和他的团队设计出这些新的CAR基因,并将它们整合到细胞核内容纳的染色体上,从而使得T细胞开始翻译这些新的CAR基因,仅需一到两天就产生 CAR受体。

在Stephan团队确定他们的携带CAR基因的纳米颗粒让相当数量的T细胞发生基因重编程之后,他们测试了它们的效果。利用一种临床前白血病模式小鼠,Stephan和他的同事们将他们的纳米颗粒编程策略与先化疗再灌注在实验 室中经过编程表达CAR的T细胞(模拟当前的CAR-T细胞疗法)进行比较。

与这些灌注的CAR-T细胞相比,这些纳米颗粒编程的CAR-T细胞毫不逊色。利用纳米颗粒或灌注的CAR-T细胞进行治疗可让这些小鼠的存活期从平均两周增加到平均58天。

下一步和其他的应用

在能够开展人体临床试验之前,Stephan开发的这些纳米颗粒仍然存在几种障碍。他正在与有能力制造临床级纳米颗粒的公司合作开发新的策略让这种基因运送-表达系统在人体中是安全的。此外,Stephan也将他的目光转向实 体瘤,并且为实现这种目的,正在与来自弗雷德-哈金森癌症研究中心的几个研究团队开展合作。

他说,免疫疗法可能仅仅是个开始。在理论上,纳米颗粒可能能够经修饰后满足免疫系统性能需要加以改善但不能够等待几个月的时间接种一种常见疫苗的病人的需求。

Stephan说,“我们希望这能够用于治疗肝炎或HIV等传染病。”他解释道,这种方法可能“给病人提供他们自身没有的受体。他们仅需微量的纳米颗粒编程的T细胞来抵抗病毒。”

原始出处:

Tyrel T. Smith, Sirkka B. Stephan, Howell F. Moffett et al. In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers. Nature Nanotechnology, Published online:17 April 2017, doi:10.1038/nnano.2017.57

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    2018-03-24 仁者大医
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    2017-05-16 shock_melon
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    2017-09-20 liye789132251
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    2017-06-22 jyzxjiangqin

    纳米颗粒的应用。

    0

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    2017-06-14 jyzxjiangqin

    利用纳米颗粒在体内制造CAR一T细胞。

    0

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    2017-04-21 xxxx1054

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