小柯机器人

浙江大学黄河等研究人员合作发现，非病毒性、特异性靶向CAR-T细胞在B-NHL中实现高安全性和高疗效。相关论文于2022年8月31日在线发表在《自然》杂志上。

研究人员成功地开发了一种二合一的方法，通过CRISPR-Cas9产生非病毒、基因特异性的靶向嵌合抗原受体（CAR）-T细胞细胞。通过使用优化的方案，研究人员在临床前研究中证明了将抗CD19的CAR盒插入到AAVS1安全港位点的可行性。此外，研究人员还开发了一种具有PD1整合的创新类型的抗CD19 CAR-T细胞，并在异种移植模型中显示出消灭肿瘤细胞的卓越能力。在复发/难治性侵袭性B细胞非霍奇金淋巴瘤的过继治疗中（ClinicalTrials.gov，NCT04213469），研究人员观察到8名患者的完全缓解率很高（87.5%），并有持久的反应，没有严重的不良事件。

值得注意的是，这些增强的CAR-T细胞即使在低输注剂量和低比例的CAR⁺细胞情况下也是有效的。单细胞分析显示，电穿孔方法导致注入产品中记忆T细胞的比例很高，而PD1干扰增强了抗肿瘤免疫功能，进一步验证了非病毒、PD1整合的CAR-T细胞优势。总之，这些结果证明了非病毒、基因特异性整合CAR-T细胞的高安全性和有效性，从而为CAR-T细胞治疗提供了一种创新技术。

据悉，最近，CAR-T细胞疗法在治疗血液学恶性肿瘤方面显示出巨大的前景。然而，CAR-T细胞疗法目前有几个局限性。

附：英文原文

Title: Non-viral, specifically targeted CAR-T cells achieve high safety and efficacy in B-NHL

Author: Zhang, Jiqin, Hu, Yongxian, Yang, Jiaxuan, Li, Wei, Zhang, Mingming, Wang, Qingcan, Zhang, Linjie, Wei, Guoqing, Tian, Yue, Zhao, Kui, Chen, Ang, Tan, Binghe, Cui, Jiazhen, Li, Deqi, Li, Yi, Qi, Yalei, Wang, Dongrui, Wu, Yuxuan, Li, Dali, Du, Bing, Liu, Mingyao, Huang, He

Issue&Volume: 2022-08-31

Abstract: Recently, chimeric antigen receptor (CAR)-T cell therapy has shown great promise in treating haematological malignancies1,2,3,4,5,6,7. However, CAR-T cell therapy currently has several limitations8,9,10,11,12. Here we successfully developed a two-in-one approach to generate non-viral, gene-specific targeted CAR-T cells through CRISPR–Cas9. Using the optimized protocol, we demonstrated feasibility in a preclinical study by inserting an anti-CD19 CAR cassette into the AAVS1 safe-harbour locus. Furthermore, an innovative type of anti-CD19 CAR-T cell with PD1 integration was developed and showed superior ability to eradicate tumour cells in xenograft models. In adoptive therapy for relapsed/refractory aggressive B cell non-Hodgkin lymphoma (ClinicalTrials.gov, NCT04213469), we observed a high rate (87.5%) of complete remission and durable responses without serious adverse events in eight patients. Notably, these enhanced CAR-T cells were effective even at a low infusion dose and with a low percentage of CAR+ cells. Single-cell analysis showed that the electroporation method resulted in a high percentage of memory T cells in infusion products, and PD1 interference enhanced anti-tumour immune functions, further validating the advantages of non-viral, PD1-integrated CAR-T cells. Collectively, our results demonstrate the high safety and efficacy of non-viral, gene-specific integrated CAR-T cells, thus providing an innovative technology for CAR-T cell therapy.

DOI: 10.1038/s41586-022-05140-y

Source: https://www.nature.com/articles/s41586-022-05140-y

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