Nature子刊:海军军医大学胡适/雷长海团队构建能同时识别超过十万个潜在靶点的合成免疫学治疗方法

2022-06-09 小柯生命 “生物世界”公众号

即使在这部分患者中,针对特定靶点的治疗方式往往不足以应对疾病的进化性特征,反而可能驱动病灶产生人工进化压力,最终导致耐药和复发。

针对特定的已知靶点是目前肿瘤免疫治疗技术的主要手段,但鉴定出可靠的治疗性靶点需要极大的经济和时间成本,而且鉴定出的靶点往往仅对一部分患者有效。即使在这部分患者中,针对特定靶点的治疗方式往往不足以应对疾病的进化性特征,反而可能驱动病灶产生人工进化压力,最终导致耐药和复发。

这成为现代肿瘤免疫治疗应用的现实困境之一。

2022年6月6日,海军军医大学胡适、雷长海课题组在 Nature 子刊 Nature Biomedical Engineering 上发表了题为:Synthetic libraries of immune cells displaying a diverse repertoire of chimaeric antigen receptors as a potent cancer immunotherapy 的研究论文,

研究团队自主创建了一种载有大容量嵌合抗原受体信息的合成免疫细胞组库技术。该技术借鉴适应性免疫系统并不需要预设靶点,而是依赖于多样性的抗体组库来应对病原体和清除体内病变细胞这一经典的免疫学机理,通过合成生物学细胞编程技术,实现对多克隆的工程化免疫细胞的命运控制,最终建立了一套具有“合成免疫”能力的工程化细胞群。

在该项研究中,作者使用 T 细胞和 NK 细胞作为两种不同的细胞底盘,构建了可以识别多样性超过106种潜在抗原的工程化细胞组库。在基因线路控制下,当免疫细胞识别肿瘤组织抗原时,相应的效应免疫细胞克隆即开始扩增富集。当效应免疫细胞达到一定数量规模后,便可以清除表达这些抗原的肿瘤细胞。由于合成免疫细胞组库识别抗原的能力是持续存在的,当肿瘤组织由于免疫细胞的杀伤作用产生生物进化时,合成免疫细胞组库可以对应性的产生全新的效应克隆。因此,该技术获得的免疫细胞群体一方面可以识别病灶的全部抗原信息,另一方面还可以跟随病灶的抗原变化产生相应的进化。

由于合成免疫细胞组库能识别106种多样性的抗原,作者考虑到大容量的组库可能识别健康组织进而产生严重的毒副作用,因此对合成免疫细胞组库所能识别的抗原信息范围在制备组库的过程中进行了限制和预设,预先对受试对象本身的“健康”抗原或自身抗原进行了背景扣除。研究团队随后对合成免疫细胞组库进行了工程化和参数性的表征分析,明确了合成免疫细胞组库在识别抗原后的扩增能力、杀伤活性等,并在同种异型的小鼠模型中进行安全评价,受试动物产生较好的耐受性,并未有明显的毒副作用。

随后,作者在大量的小动物肿瘤模型中进行了治疗性研究,合成免疫细胞组库对包括结肠癌、肺癌、乳腺癌和卵巢癌等肿瘤模型均可以有效的发挥免疫治疗作用。另外,作者还对接受合成免疫细胞组库治疗的动物是否具有持久的“合成免疫力”进行了测试,如荷有肺癌的小鼠接受合成免疫细胞组库治疗至肿瘤全部消失后,再次接种的肿瘤细胞也能全部消退;肺癌治疗消退的动物重新接种乳腺癌细胞时,动物体内的合成免疫细胞组库依然对新接种的肿瘤具有治疗作用。

由于合成免疫细胞组库具有大量的不同细胞克隆,这些细胞克隆在动物体内的行为、整个组库识别能力的变化均是未知的。因此,在动物实验的过程中,作者采用高通量抗体库测序技术,实时探测在治疗过程中免疫组库的变化并描画工程化细胞克隆随时空变化的图谱,对免疫细胞组库的生物进化过程进行实时观察和监控。这些信息可以提供免疫细胞群体在识别肿瘤抗原时的命运变化规律,对理解合成性的免疫细胞群体产生的全新肿瘤免疫力具有巨大的理论价值。

研究团队表示,合成免疫细胞组库实际上是一种建立合成免疫的新途径,可以在患者自身免疫能力不足以应对疾病挑战时,通过人工方法建立合成性的免疫系统。建立的“合成免疫力”不仅仅可以治疗恶性肿瘤,还可以用于其他疾病的治疗性研究,如炎症性疾病、感染类疾病等。

Nature Biomedical Engineering 期刊主编 Pep Pàmie 教授表示,海军军医大学团队开发的全新治疗方法在实施的过程中还可以获得针对未知抗原的合成性受体、抗体,并且可以进一步的鉴定这些靶点信息,因此还是一种非常好的靶点-药物筛选方法,可以广泛应用于临床前研究中,具有广阔的应用范围。

原始出处:

Fu, W., Lei, C., Wang, C. et al. Synthetic libraries of immune cells displaying a diverse repertoire of chimaeric antigen receptors as a potent cancer immunotherapy. Nat. Biomed. Eng (2022). https://doi.org/10.1038/s41551-022-00895-1.

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