Sci Tran Med:CAR-T新开关——来那度胺:Science子刊全新成果

2021-01-26 医药魔方 医药魔方

在血液癌症的治疗中,CAR-T细胞疗法获得了很多的成就,各家药企和研究机构围绕CAR-T的竞争也十分激烈。全球目前已有3款CAR-T细胞疗法获批上市,而处于临床和临床前阶段的CAR-T细胞疗法更是多达

在血液癌症的治疗中,CAR-T细胞疗法获得了很多的成就,各家药企和研究机构围绕CAR-T的竞争也十分激烈。全球目前已有3款CAR-T细胞疗法获批上市,而处于临床和临床前阶段的CAR-T细胞疗法更是多达500个。在CAR-T高疗效的背后,安全性也一直备受关注,细胞因子释放综合症(CRS)便是其中之一。

如果CAR-T细胞在被输注入患者体内后发生增殖不受控的情况,则可能会引发CRS,导致的毒性反应轻到发烧,重到器官衰竭,危及生命。科学家们也正在研究如何更好地控制CAR-T细胞的体内活性。

1月6日,Science Translational Medicine发表了一篇CAR-T细胞开关的相关研究,Dana-Farber癌症研究所和麻省总医院癌症中心的研究人员发现,利用一种常用的癌症药物来那度胺,可以实现CAR-T细胞的开启或关闭。使用来那度胺可以使具有OFF开关的T细胞失活,而具有ON开关的T细胞则需要同时使用来那度胺和靶抗原才能激活,从而可以控制T细胞激活的时间。

研究人员使用靶向蛋白降解技术来创建CAR-T细胞的开关系统。在细胞中,E3(泛素)连接酶可通过将一种叫做泛素的小蛋白贴在靶蛋白上将其标记为缺陷或受损蛋白。之后,细胞内的蛋白粉碎机(即,蛋白酶体)会降解被标记的靶蛋白。2004年,来自以色列和美国的三位科学家曾因发现“泛素介导的这种蛋白质降解过程”获诺贝尔化学奖。来那度胺就是借助了这一机制来发挥作用。这类药物可重定向E3泛素连接酶CRL4CRBN,从而使转录因子IKZF1和IKZF3多聚泛素化,导致IKZF1和IKZF3被蛋白酶体降解。

在OFF开关中,研究人员设计了降解标签,并且系统筛选确定了对来那度胺诱导的降解敏感性增强的"超级降解"标签,当这种降解标签贴在CAR上时,来那度胺(或另一种沙利度胺类似物)将诱导贴上降解标签的CAR的泛素化和蛋白酶体降解,从而阻止T细胞继续识别癌细胞。由于这些工程化的T细胞会持续制造CAR蛋白,在来那度胺治疗后,新的CAR蛋白会不断积累,T细胞的抗肿瘤功能会得到恢复;在ON开关结构中,研究人员设计了一个来那度胺诱导的二聚体系统,开发了需要来那度胺和靶抗原同时激活的CAR。

在体内实验中,研究人员使用具有与来那度胺相似活性和毒性并且具有相同的降解特异性的泊马度胺评估ON-开关CAR-T细胞在体内的抗肿瘤效力,因为泊马度胺的体内半衰期比来那度胺更长。 NSG小鼠被植入了CD19+萤光素酶和人套细胞淋巴瘤细胞,在泊马度胺治疗期间,研究人员观察到总体肿瘤负担减少,T细胞扩增增强。而在泊马度胺治疗停止后,残留的肿瘤负担扩大,T细胞群缩小。

超级降解标签的添加使来那度胺可以对CAR-T细胞效应器功能进行关闭,每天使用来那度胺或泊马利度胺治疗会暂时停止CAR的表达,CAR的丰度在停药后得到恢复,而且抗肿瘤效力得到了保留。

来那度胺OFF-开关控制可降解的CAR(来源:Science Translational Medicine)

此外,泊马利度胺能限制细胞因子的释放。与未经治疗的小鼠相比,每日1次或每日2次泊马度胺治疗时,IFN-γ的浓度分别降低了4倍和6倍,每日泊马度胺治疗还可使IL-2浓度降低4倍。 来源:Science Translational Medicine 总的来说,这种开关系统的可逆性将来可能用于暂时中止患者体内的CAR-T细胞治疗,减轻短期毒性,而且对癌症的长期治疗作用也能得到保留。 "我们的长远目标是拥有多种控制不同开关的药物,这样科学家们就可以开发越来越复杂的细胞疗法。"论文通讯作者Benjamin Ebert教授总结道。

原始出处:

M. Jan el al. Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide. Science Translational Medicine (2020).

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    2021-04-29 wgx306
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    2021-05-26 仁者大医
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    2021-04-04 446993560

    棒棒哒

    0

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    2021-12-16 bsmagic9140
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    2021-01-27 jichang
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    2021-01-26 病毒猎手

    #CAR-T#新开关——#来那度胺#,事实上,来那度胺这一类可以作为免疫调节剂,辅助用于CAR-T带来的#细胞因子风暴#。还可以与IL-6抗体等联合使用

    0

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Blood:Tafasitamab联合来那度胺治疗复发难治大B细胞淋巴瘤的回顾性研究

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来那度胺联合R-ESHAP治疗复发或难治性弥漫性大B细胞淋巴瘤:GELTAMO的一项2期研究(NCT02340936)

这项2期研究旨在进一步提供来那度胺联合R-ESHAP治疗难治性/复发性DLBCL患者的有效性和安全性信息。

Lancet Oncol:卡非佐米和来那度胺治疗原发性浆细胞白血病(EMN12/HOVON-129研究最终分析)

尽管卡非佐米和来那度胺为基础的诱导、巩固和维持治疗在年轻和老年原发性浆细胞白血病患者中均产生了强效抗肿瘤活性,但无进展生存期和总生存期仍存在不足

IELSG40/CLEO:克拉霉素联合来那度胺治疗复发/难治性结外边缘区淋巴瘤的II期试验

际结外淋巴瘤研究小组设计了IELSG40/CLEO II期试验,以研究克拉霉素联合来那度胺联合治疗R/R MZL患者的疗效和安全性。