美国宾夕法尼亚大学佩雷尔曼医学院Daniel J. Powell Jr.研究组发现诱导因子的表达重新编程CAR-T细胞以增强功能和安全性。2022年12月12日出版的《癌细胞》发表了这项成果。

他们开发了一个遗传平台，该平台结合了单一慢病毒载体Uni-Vect中抗原诱导的辅助分子的自主生产和CAR的组成性表达。Uni-Vect的广泛治疗应用在体内通过提高激活依赖性表达(1)改善疗效的免疫刺激细胞因子，(2)改善细胞因子释放综合征的抗体，以及(3)调节T细胞生物学的转录因子。Uni-Vect也作为一个平台来表征免疫受体。总的来说，他们证明Uni-Vect为更临床可行的下一代细胞免疫疗法提供了基础。

据了解，尽管CAR-T细胞癌症免疫治疗取得了成功，但在疗效和安全性方面仍然存在挑战。研究人员已经开始通过辅助分子的表达来增强CAR-T细胞，以应对这些挑战。目前的系统依赖于组成型转基因表达或多种病毒载体，导致不受调节的反应和产物异质性。

附：英文原文

Title: Expression of inducible factors reprograms CAR-T cells for enhanced function and safety

Author: Ane Smole, Alexander Benton, Mathilde A. Poussin, Monika A. Eiva, Claudia Mezzanotte, Barbara Camisa, Beatrice Greco, Prannda Sharma, Nicholas G. Minutolo, Falon Gray, Adham S. Bear, Miren L. Baroja, Casey Cummins, Chong Xu, Francesca Sanvito, Andrea Lang Goldgewicht, Tatiana Blanchard, Alba Rodriguez-Garcia, Michael Klichinsky, Chiara Bonini, Carl H. June, Avery D. Posey, Gerald P. Linette, Beatriz M. Carreno, Monica Casucci, Daniel J. Powell

Issue&Volume: 2022/12/12

Abstract: Despite the success of CAR-T cell cancer immunotherapy, challenges in efficacy andsafety remain. Investigators have begun to enhance CAR-T cells with the expressionof accessory molecules to address these challenges. Current systems rely on constitutivetransgene expression or multiple viral vectors, resulting in unregulated responseand product heterogeneity. Here, we develop a genetic platform that combines autonomousantigen-induced production of an accessory molecule with constitutive CAR expressionin a single lentiviral vector called Uni-Vect. The broad therapeutic application ofUni-Vect is demonstrated in vivo by activation-dependent expression of (1) an immunostimulatory cytokine that improvesefficacy, (2) an antibody that ameliorates cytokine-release syndrome, and (3) transcriptionfactors that modulate T cell biology. Uni-Vect is also implemented as a platform tocharacterize immune receptors. Overall, we demonstrate that Uni-Vect provides a foundationfor a more clinically actionable next-generation cellular immunotherapy.

DOI: 10.1016/j.ccell.2022.11.006

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00553-0