用于个性化细胞治疗的非病毒精确T细胞受体替代
Susan P Foy1, Kyle Jacoby2, Daniela A Bota3
1PACT Pharma, South San Francisco, CA, USA. sfoy@pactpharma.com.
Nature
|November 10, 2022
概括
这项研究开发了一种临床级的CRISPR- Cas9基因编辑方法,用于设计具有新抗原特异性T细胞受体 (neoTCRs) 的T细胞用于癌症治疗. 这种方法成功地消除了内源性TCR,并插入了新TCR,证明了可行性和T细胞贩运到瘤.
科学领域:
- 免疫学
- 遗传学
- 癌症学
背景情况:
- 对于T细胞来说,T细胞受体 (TCR) 对于识别癌症特异性突变至关重要.
- 目前的T细胞疗法在针对固体瘤的特异性和有效性方面经常面临挑战.
研究的目的:
- 开发和评估一种临床级别的非病毒CRISPR-Cas9基因组编辑方法,用于设计具有新抗原特异性TCR (新TCR) 的T细胞.
- 在耐火固体癌症患者中评估新TCR工程T细胞产品的安全性,可行性和体内T细胞贩运.
主要方法:
- 使用CRISPR-Cas9非病毒基因组编辑同时淘汰内源性TRAC和TRBC基因.
- 将新抗原特异性TCR (新TCR) 插入TRAC位点,使用个性化新抗原-HLA捕获试剂分离新TCR.
- 一期临床试验,对耐火性固体癌症患者进行多达三种不同的新TCR转基因T细胞产品的剂量升级.
主要成果:
- 通过单步,非病毒精确基因组编辑方法,成功同时淘汰内源性TCR基因和新TCR基因.
- 在输液后的瘤活检中检测到新TCR转基因T细胞的频率高于输液前的内源性TCRs,这表明瘤贩运成功.
- 观察到可控的副作用,包括细胞因子释放综合征和脑炎,以及预期的化疗相关副作用.
结论:
- 证明了针对突变新抗原的多个TCR的隔离和克隆的可行性.
- 确立了多个基因编辑新TCRT细胞产品的临床级别制造和安全性.
- 证实了工程T细胞向患者的瘤部位传输的能力, 支持这种方法在癌症免疫治疗中的潜力.
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