CAR-T技术,一种免疫治疗技术,一种或许能治愈癌症的技术,你或许听说过,或许没听说过,但它确实给我们带来了惊喜,给癌症病人带来了希望和期待。你肯定很想了解,什么是CAR-T技术?它的疗效如何?副反应又如何?它的出现是否真的预示着癌症将被彻底攻克?本文为你掰一掰。
一、什么是CAR-T免疫疗法?
我们的免疫系统在很多时候,都可以通过相应的细胞表面分子识别体内产生的异常细胞,并把它清除,但随着基因突变的产生,有些异常细胞的表面分子发生了变化,免疫系统不再把它当做敌人,无法把它清除,这时候,癌症就产生了。CAR-T(Chimeric Antigen Receptor T-Cell Immunotherapy),即嵌合抗原受体T细胞免疫疗法。CAR-T的治疗策略就是帮助免疫系统,主要是T淋巴细胞识别癌细胞,从而促使T细胞把癌细胞清除。科学家在研究中发现了癌细胞与正常细胞表达差异的一些分子,根据这些分子,设计一种名为CAR(嵌合抗原受体)的基因,这种CAR(嵌合抗原受体)可以和癌细胞表达的特异性分子结合。通过一种类似血液透析的方法,分选出病人体内的一些T细胞,然后在实验室将编码这种CAR(嵌合抗原受体)的基因导入,这样这些T细胞就能够表达这种新的受体。这些经过基因修饰的T细胞在实验室进行增殖,随后将它们输注回病人体内。这些T细胞利用它们表达的CAR(嵌合抗原受体)能够结合癌细胞表面上的分子,强效地激活这些T细胞,从而快速地摧毁癌细胞。
听着一头雾水吧?是不是很高大上?其实,说白了,它并不是一种药物,而是一种技术,确切地说是一种免疫疗法,而且是一种细胞疗法。一听细胞疗法,很多人马上会说,细胞疗法不是前几年那个魏则西事件被大家批判的东西吗?非也,此细胞疗法非彼细胞疗法,CAR-T免疫治疗本质上也是利用病人自身的免疫细胞来清除肿瘤细胞,但它是一种改良的新型细胞疗法。通俗一点说,就是把病人体内的T细胞(一种免疫细胞)拿出来,在体外进行一些改造(基因修饰,这个过程和原理普通老百姓弄不清楚也没关系),这可是关键操作,经过改造,就成了我们需要的CAR-T细胞,也就是嵌合抗原受体T细胞,它带有“导航系统”能够精准地找到并杀灭肿瘤细胞,这个威力就大增了,当然,一个或几个这样的细胞可不行,还得在体外进行扩增,说白了,就是多生一点子孙,然后将这些改造扩增后的“武器”回输到病人体内,癌细胞,你就等着颤抖吧,看我怎么收拾你!
CAR-T疗法的基本流程
二、CAR-T免疫疗法取得哪些“战绩”?
2014年CAR-T细胞技术获得美国FDA“突破性疗法”认证,被誉为“癌症治疗的第四次革命”。2017年7月12日,美国FDA肿瘤药物咨询委员会(Oncologic Drugs Advisory Committee,ODAC)以10:0的投票结果一致推荐批准诺华公司的CAR-T疗法CTL019的生物制剂许可申请(BLA),用于治疗患有晚期白血病的儿童和年轻成人患者。8月31日,FDA正式批准诺华突破性CAR-T疗法 Kymriah上市。从1989年,美国科学院院刊(PNAS)报道了第一代CAR-T疗法,现在CAR-T已经发展到了第四代。CAR-T在治疗白血病中取得了长足的进展。
很多研究表明,对于难治复发性白血病,缓解率在70%-80%左右,个别小样本甚至达到了100%。其中急性淋巴细胞白血病的治疗效果尤为突出。同时,也有大量的小样本试验表明,CAR-T在淋巴瘤、多发性骨髓瘤等血液系统肿瘤,均取得了可喜的结果。最近国际多个杂志分别发表了关于CAR-T的最新研究,NEJM报道了一例关于脑胶质瘤转移到脊髓,使用CAR-T治疗获得了有效缓解,肿瘤大部分消失的病例。Science子刊报道了晚期淋巴瘤病人经CAR-T细胞免疫疗法治疗后病情完全缓解的研究,OncoImmunology报道了体外对肺癌细胞系进行杀伤实验获得成功等等一系列的关于实体肿瘤的研究进展。还有更多的研究正在进行,很多研究都显示出了CAR-T令人欣喜的结果。目前有很多关于CAR-T技术治疗癌症(除了白血病,还有淋巴瘤,还有实体肿瘤)的临床试验在进行中,期待带给我们新的惊喜。
三、CAR-T免疫疗法是否“完美无缺”?
尽管CAR-T疗法取得诸如“战绩”,而且“战果”(适应症)似乎仍在扩大之中,但必须承认,CAR-T疗法也面临着很多挑战。随着研究的深入,临床样本的增加,越来越多的研究发现了CAR-T存在的副作用。主要包括以下几个方面:细胞因子风暴、神经毒性和B细胞发育不全。对于副反应的防治,虽然已经取得一些进展,但还需要进一步探索。
除了副反应,使用CAR-T治疗后的远期疗效,也存在很大的考验。在CAR-T治疗效果最为明显的白血病领域,复发率也非常高。多个研究表明对于急性淋巴细胞白血病,虽然临床缓解率可达80%以上,但是1年内的复发率也可达到40%以上。这可能与改造的T细胞无法长期存在于体内,以及存在由于癌细胞表达的多种免疫逃逸因子,引起T细胞衰老效应有关,具体还有待进一步探索。虽然在部分的实体瘤相关临床研究中看到了星星之火,但是,众多的研究表明,基于实体瘤血管紊乱,部分瘤体中心血运差,T细胞无法进入,以及细胞表面靶向分子标记有限等等困难,CAR-T在实体瘤中的应用还需进一步探索。
四、CAR-T免疫疗法是否预示着癌症将被彻底攻克?
结论来了!综上以上分析,在长时间和癌症抗争的过程中,CAR-T免疫治疗如一缕清风,让我们在攻克癌症的道理上看到了新的希望,也让我们有理由不断去期待。但也不得不承认,现在就下结论说CAR-T免疫疗法预示着癌症将被彻底攻克,为时尚早。革命尚未成功,同志还须努力。
部分主要参考文献:
1. Bridget M. Kuehn. The Promise and Challenges of CAR-T Gene Therapy. JAMA. Published online November 22, 2017. 2017.15605
2. Pettitt D, Arshad Z, Smith J, et al. CAR-T: A Systematic Review and Mixed-Methods Analysis of the Clinical Trial Landscape[J]. Molecular Therapy, 2017.
3. Brown C E, Alizadeh D, Starr R, et al. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy[J]. New England Journal of Medicine, 2016, 375(26):2561.
4. Wei X, Lai Y, Li J, et al. PSCA and MUC1 in non-small-cell lung cancer as targets of chimeric antigen receptor T cells.[J]. Oncoimmunology, 2017, 6(3):-.
5. Turtle C J, Hanafi L, Berger C, et al. Immunotherapy of non-Hodgkin lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells[J]. Science Translational Medicine, 2016, 8(355):355ra116
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