CAR-T之父最新Nature论文:无需放化疗,合成IL-9受体增强T细胞疗法,治愈实体肿瘤

2022-06-28 nagashi “生物世界”公众号

人工合成的白细胞介素-9(IL-9)受体可以让过继 T 细胞疗法(CAR-T、TCR-T、TIL)在不需要预先化疗或放疗的情况下发挥癌症治疗作用。

免疫疗法是当前肿瘤治疗领域的大热门,并在肿瘤治疗中展现出极佳的治疗效果,在这之中,过继T细胞疗法无疑是最令人期待的。遗憾的是,虽然该疗法对血液癌患者有显着的抗肿瘤活性,但对实体瘤患者的疗效十分有限。

造成这一结果的主要限制因素在于过继转移的 T 细胞在体内的增殖能力和持久性较差,这就要求患者在接受过继 T 细胞疗法(CAR-T、TCR-T、TIL)之前,通常要先通过大剂量化疗或放疗进行清髓,以清除体内免疫抑制细胞,但大剂量化疗或放疗带来的副作用也非常明显,包括恶心、极度疲劳和脱发等等。这也导致一些患者无法进行此类治疗。

2022年6月8日,斯坦福大学 Christopher Garcia、宾夕法尼亚大学 Carl H. June、加州大学洛杉矶分校 Antoni Ribas、Anusha Kalbasi 等人在 Nature 发表了题为:Potentiating adoptive cell therapy using synthetic IL-9 receptors 的研究论文。

该研究表明,人工合成的白细胞介素-9(IL-9)受体可以让过继 T 细胞疗法(CAR-T、TCR-T、TIL)在不需要预先化疗或放疗的情况下发挥癌症治疗作用。更重要的是,研究团队在实体肿瘤小鼠模型中证明了这种新疗法的强大抗肿瘤能力,最高治愈率超过50%。

CAR-T 细胞,是将来自癌症患者血液的天然抗感染和抗癌的免疫细胞T细胞在体外进行基因重编程,使其表达能够识别患者体内癌细胞上特定抗原的受体蛋白,也就是所谓的嵌合抗原受体(CAR)。然后利用细胞培养技术扩增这些基因工程改造而来的CAR-T细胞,并将其重新注入患者体内以攻击癌细胞。

自2017年以来,美国FDA先后批准了5种 CAR-T 细胞疗法,用于治疗白血病、淋巴瘤和骨髓瘤。Carl June 估计现在全世界已经有数万人接受了 CAR-T 细胞治疗。

Carl June 教授

这篇最新论文的第一作者 Anusha Kalbasi 博士表示,有些癌症患者在有副作用的化疗中挣扎,只为清除身体的免疫系统,以便回输的 T 细胞与癌细胞战斗。但有了这项最新技术,就可以直接进行 T 细胞治疗,而不必再实现清除自身免疫系统。

早在2018年,该研究的通讯作者 Christopher Garcia 在 Science 发表论文,聚焦于正交细胞因子及其受体的概念。正交细胞因子受体是正常受体的一种突变形式,可选择性地结合突变的细胞因子,而不与正常的细胞因子结合。

这篇 Science 论文验证了这一概念是切实可行的,人工合成的正交 IL-2 受体(o2R)可以选择性地结合正交 IL-2(oIL-2),而不结合野生型 IL-2,同时,oIL-2 也不与野生型 IL-2 受体结合。也就是说,正交 IL-2 细胞因子及其受体可以在小鼠体内选择性调节过继 T 细胞的活性,而无需经过化疗或放疗的预先处理。

在这篇最新的 Nature 论文中,研究团队做出了新的尝试,他们设计了一种新的嵌合受体,它具有一个正交 IL-2 受体胞外结构域(ECD)与一个融合的受体胞内结构域(ICD),从而使正交 IL-2 细胞因子引发相应的 γc 细胞因子信号,如 IL-4、IL-7、IL-9 和 IL-21。

野生型IL-2Rβ,正交IL-2Rβ或γc家族嵌合正交受体复合物示意图

在这些 γc 细胞因子中,IL-9 更值得研究——与其他 γc 细胞因子不同,IL-9 信号在自然发生的 T 细胞中并不活跃。因此,人工合成的嵌合正交 IL-9 受体(o9R)将使过继性 T 细胞在对抗肿瘤时更加强大。

o9R T细胞激活STAT1、STAT3和STAT5

进一步研究发现,通过 o9R 发出信号的 T 细胞以伴随激活 STAT1、STAT3 和 STAT5 而区分,并呈现出一种独特的干细胞和杀伤细胞的混合特性。与之前的 o2R T 细胞相比,o9R T 细胞在两种难治性的黑色素瘤和胰腺癌小鼠实体瘤模型中具有更好的抗肿瘤效果,最高治愈率超过50%!

o9R T细胞呈现出一种独特的干细胞和杀伤细胞的混合特性

论文第一作者 Anusha Kalbasi 表示,无论是将细胞因子对小鼠进行全身性递送还是直接注射到肿瘤中,这种疗法都是有效的。在各种情况下,用人工合成的正交 IL-9 受体改造的 T 细胞都表现得更优秀,能够治愈了一些难治性实体肿瘤。

o9R改造的T细胞具有强大的抗肿瘤功效

总的来说,这项研究表明,通过人工合成的正交 IL-9 及其受体 IL-9R,可以无需化疗或放疗清除免疫系统的情况下激活过继 T 细胞,使之获得了新的功能,增强对难治性实体肿瘤的抗肿瘤活性。这些发现将为人类攻克癌症打开了一扇新的大门,在未来,过继 T 细胞疗法或许就会变得像输血一样简单、迅速。

 

原始出处:

Kalbasi, A., Siurala, M., Su, L.L. et al. Potentiating adoptive cell therapy using synthetic IL-9 receptors. Nature (2022). https://doi.org/10.1038/s41586-022-04801-2.

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    2023-05-28 贵阳
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    2023-01-17 liye789132251
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    2022-10-14 仁者大医
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    2022-06-19 yzh399
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