肿瘤细胞治疗研究
英文原题：Enhanced safety and efficacy of protease-regulated CAR-T cell receptors.
可调控CAR平台可以规避与CAR-T疗法相关的毒性，但现有系统存在不足，包括渗漏性和活性减弱。
可调控的CAR平台可以规避与CAR-T疗法相关的毒性，但现有系统存在缺陷，包括渗漏性和活性减弱。在此，我们提出SNIP CAR，一种基于蛋白酶的平台，利用FDA批准的小分子来调控CAR活性。经过设计迭代，得到的CAR-T细胞在药物存在时表现出完整的功能能力，而在无药物时没有渗漏活性。在众多模型中，SNIP CAR-T细胞比组成型CAR-T细胞更有效，并显示出减少的T细胞耗竭和更强的干性。在一个基于ROR1的CAR致死性模型中，毒性出现后停止给药可逆转毒性，从而证明该平台可作为安全开关。在同一模型中，减少给药剂量打开了治疗窗口，在无毒性情况下实现了肿瘤根除。SNIP CAR能够远程调节CAR活性，为解决当前限制CAR-T细胞治疗实体瘤进展的安全性和有效性障碍提供了方案。
Regulatable CAR platforms could circumvent toxicities associated with CAR-T therapy, but existing systems have shortcomings including leakiness and attenuated activity. Here, we present SNIP CARs, a protease-based platform for regulating CAR activity using an FDA-approved small molecule. Design iterations yielded CAR-T cells that manifest full functional capacity with drug and no leaky activity in the absence of drug. In numerous models, SNIP CAR-T cells were more potent than constitutive CAR-T cells and showed diminished T cell exhaustion and greater stemness. In a ROR1-based CAR lethality model, drug cessation following toxicity onset reversed toxicity, thereby credentialing the platform as a safety switch. In the same model, reduced drug dosing opened a therapeutic window that resulted in tumor eradication in the absence of toxicity. SNIP CARs enable remote tuning of CAR activity, which provides solutions to safety and efficacy barriers that are currently limiting progress in using CAR-T cells to treat solid tumors.
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