让CAR-T疗法迈向实体瘤,科学家发现关键机制 | PNAS
2018/02/22
如何让CAR-T疗法更安全?适用于更广泛的癌症类型? 这是很多科学家正在积极解决的问题。近日,发表在PNAS杂志上的一项研究解释了CAR-T疗法能够快速靶向和杀死癌细胞的关键机制,以及为什么这种疗法会产生严重的副作用。


图片来源:PNAS(DOI:https://doi.org/10.1073/pnas.1716266115)

CAR-T疗法是一种“使用改造后的患者T细胞来唤醒免疫系统抗癌作用”的创新免疫疗法。2017年,美国FDA已批准2款这类疗法上市,用于治疗儿童白血病和某些淋巴瘤。然而,在实体瘤治疗方面,CAR-T疗法的“成绩却不是很理想”,常常导致严重的副作用,如细胞因子风暴——1种潜在的致命炎症反应,可能会导致某些患者的器官衰竭。


A new study led by Dr Misty Jenkins and colleagues at Peter Mac could lead to safer immunotherapies for solid cancers.

在这篇题为“Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity”的论文中,Walter and Eliza Hall 医学研究所的Misty Jenkins博士带领的团队首次揭示了CAR-T细胞是如何与癌细胞互相作用的。

科学家们发现,嵌合抗原受体(chimeric antigen receptor,CAR)免疫突触结构与T细胞受体(T cell receptor,TCR)突触不同。与TCR相比,CAR免疫突触形成了一种无组织的Lck模式(a disorganized pattern of Lck),能够更迅速地招募裂解颗粒(lytic granules)。而这种不同的CAR免疫突触与CAR-T细胞更快地杀伤肿瘤靶细胞,以及与死亡肿瘤细胞的分离有关。

作者们认为,这些发现提供了一种机制,利用这种机制,CAR-T细胞能够有效地减轻患者巨大的肿瘤负担。同时,该研究也为优化受体的设计,改善CAR-T疗法用于实体瘤的治疗奠定了基础。


图片来源:网络

据悉,Jenkins博士的研究小组主要聚焦于如何用CAR-T疗法治疗脑癌。她说:“脑肿瘤通常对传统疗法(如化疗)具有耐药性,而通过外科手术切除肿瘤会带来许多附带损伤。虽然对于CAR-T细胞来说,大脑是一个非常微妙和具有挑战性的环境,但如果能够用这类免疫疗法治疗脑肿瘤,就可以实现通过有限的侵入来杀死肿瘤细胞,且带来很少的炎症和副作用,这将显著改善脑癌的治疗。”

参考资料:

Cancer killing clue could lead to safer and more powerful immunotherapies

Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity

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  • Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity

    Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters. Both proximal and distal receptor signaling pathways were induced more rapidly and subsequently decreased more rapidly in carCTL than in tcrCTL. The functional consequence of this rapid signaling in carCTL cells included faster lytic granule recruitment to the immune synapse, correlating with faster detachment of the CTL from the target cell. This study provides a mechanism for how CAR-T cells can debulk large tumor burden quickly and may contribute to further refinement of CAR design for enhancing the quality of signaling and programming of the T cell.

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