Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell. 2022 May 12;185(10):1745-1763.e22. doi: 10.1016/j.cell.2022.03.041. Epub 2022 Apr 27.
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.
可调节的 CAR 平台可以规避与 CAR-T 疗法相关的毒性，但现有的系统存在缺陷，包括渗漏和活性减弱。在这里，我们提出了 SNIP CARs，这是一种基于蛋白酶的平台，可使用 FDA 批准的小分子来调节 CAR 活性。经过多次设计迭代，产生了 CAR-T 细胞，这些细胞在有药物存在的情况下具有完全的功能能力，而在没有药物的情况下没有渗漏活性。在许多模型中，SNIP CAR-T 细胞比组成型 CAR-T 细胞更有效，表现出减少的 T 细胞耗竭和更大的干性。在基于 ROR1 的 CAR 致死性模型中，毒性发作后停止用药可逆转毒性，从而证实该平台可作为安全开关。在相同的模型中，减少药物剂量开辟了一个治疗窗口，导致在没有毒性的情况下消除肿瘤。SNIP CARs 能够远程调节 CAR 活性，为解决安全性和疗效方面的障碍提供了方案，这些障碍目前限制了使用 CAR-T 细胞治疗实体瘤的进展。
