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科学家开发出用于个性化细胞治疗的非病毒性精确T细胞受体替代
作者:小柯机器人 发布时间:2022/11/13 14:34:42

美国PACT医药公司Stefanie J. Mandl等研究人员合作开发出用于个性化细胞治疗的非病毒性精确T细胞受体替代。2022年11月10日,《自然》杂志在线发表了这项成果。

研究人员开发了一种基于CRISPR/Cas9非病毒精确基因组编辑的临床级方法,用于同时敲除两个内源性T细胞受体(TCR)基因,TCRα(TRAC)和TCRβ(TRBC),并在TRAC基因座上插入新抗原特异性TCR(neoTCR)的两条链,然后使用可溶性预测新抗原-HLA捕获试剂的个性化库从患者自己的循环T细胞中分离出来。

16名难治性实体癌患者在细胞剂量递增、首次人体一期临床试验(NCT03970382)中接受了多达三种不同的新TCR-转基因细胞产品,每一种都表达了患者特异的新TCR。一名患者出现了1级细胞因子释放综合征,一名患者出现了3级脑炎。所有患者都有预期的淋巴消融化疗的副作用。5名患者病情稳定,其他11名患者的疾病进展为治疗的最佳反应。灌注后的肿瘤活检中检测到NeoTCR-转基因T细胞,其频率高于灌注前的自身TCR。

这项研究证明了1)分离和克隆识别突变新抗原的多个TCR的可行性,2)利用单步非病毒精确基因组编辑同时敲除内源性TCR和敲入新TCR,3)以临床等级制造新TCR工程T细胞,输注多达三个基因编辑的新TCR T细胞产品的安全性,以及4)转基因T细胞在患者肿瘤中运输的能力。

据悉,TCR提供了T细胞识别癌细胞变异的精细特异性。

附:英文原文

Title: Non-viral precision T cell receptor replacement for personalized cell therapy

Author: Foy, Susan P., Jacoby, Kyle, Bota, Daniela A., Hunter, Theresa, Pan, Zheng, Stawiski, Eric, Ma, Yan, Lu, William, Peng, Songming, Wang, Clifford L., Yuen, Benjamin, Dalmas, Olivier, Heeringa, Katharine, Sennino, Barbara, Conroy, Andy, Bethune, Michael T., Mende, Ines, White, William, Kukreja, Monica, Gunturu, Swetha, Humphrey, Emily, Hussaini, Adeel, An, Duo, Litterman, Adam J., Quach, Boi Bryant, Ng, Alphonsus H. C., Lu, Yue, Smith, Chad, Campbell, Katie M., Anaya, Daniel, Skrdlant, Lindsey, Huang, Eva Yi-Hsuan, Mendoza, Ventura, Mathur, Jyoti, Dengler, Luke, Purandare, Bhamini, Moot, Robert, Yi, Michael C., Funke, Roel, Sibley, Alison, Stallings-Schmitt, Todd, Oh, David Y., Chmielowski, Bartosz, Abedi, Mehrdad, Yuan, Yuan, Sosman, Jeffrey A., Lee, Sylvia M., Schoenfeld, Adam J., Baltimore, David, Heath, James R., Franzusoff, Alex, Ribas, Antoni, Rao, Arati V., Mandl, Stefanie J.

Issue&Volume: 2022-11-10

Abstract: The T cell receptor (TCR) provides the fine specificity of T cells to recognize mutations in cancer cells 1-3. We developed a clinical-grade approach based on CRISPR/Cas9 non-viral precision genome editing to simultaneously knock-out the two endogenous TCR genes, TCRα (TRAC) and TCRβ (TRBC), and insert in the TRAC locus the two chains of a neoantigen-specific TCR (neoTCR), isolated from the patient’s own circulating T cells using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with refractory solid cancers received up to three distinct neoTCR-transgenic cell products, each expressing a patient-specific neoTCR, in a cell dose-escalation, first-in-human phase 1 clinical trial (NCT03970382). One patient had grade 1 cytokine release syndrome, and one grade 3 encephalitis. All had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease, and the other 11 had disease progression as best response on therapy. NeoTCR-transgenic T cells were detected in tumour biopsies post-infusion at frequencies higher than the native TCRs pre-infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs recognizing mutational neoantigens, the simultaneous knock-out of the endogenous TCR and knock-in of the neoTCRs using single-step, non-viral precision genome editing, the manufacturing of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene edited neoTCR T cell products, and the ability of the transgenic T cells to traffic to the patients’ tumours.

DOI: 10.1038/s41586-022-05531-1

Source: https://www.nature.com/articles/s41586-022-05531-1

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html