Regulation of CD19 CAR-T cell activation based on an engineered downstream transcription factor.

IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI:10.1016/j.omto.2023.04.005
Duško Lainšček, Anja Golob-Urbanc, Veronika Mikolič, Jelica Pantović-Žalig, Špela Malenšek, Roman Jerala
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引用次数: 1

Abstract

CAR-T cells present a highly effective therapeutic option for several malignant diseases, based on their ability to recognize the selected tumor surface marker in an MHC-independent manner. This triggers cell activation and cytokine production, resulting in the killing of the cancerous cell presenting markers recognized by the chimeric antigen receptor. CAR-T cells are highly potent serial killers that may cause serious side effects, so their activity needs to be carefully controlled. Here we designed a system to control the proliferation and activation state of CARs based on downstream NFAT transcription factors, whose activity can be regulated via chemically induced heterodimerization systems. Chemical regulators were used to either transiently trigger engineered T cell proliferation or suppress CAR-mediated activation when desired or to enhance activation of CAR-T cells upon engagement of cancer cells, shown also in vivo. Additionally, an efficient sensor to monitor activated CD19 CAR-T cells in vivo was introduced. This implementation in CAR-T cell regulation offers an efficient way for on-demand external control of CAR-T cell activity to improve their safety.

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基于工程下游转录因子的CD19 CAR-T细胞活化调控。
基于CAR-T细胞以不依赖mhc的方式识别选定的肿瘤表面标记物的能力,CAR-T细胞为几种恶性疾病提供了一种非常有效的治疗选择。这触发了细胞活化和细胞因子的产生,导致癌细胞被嵌合抗原受体识别的标记物杀死。CAR-T细胞是非常强大的连环杀手,可能会导致严重的副作用,因此需要仔细控制它们的活动。我们设计了一个基于下游NFAT转录因子的系统来控制CARs的增殖和激活状态,其活性可以通过化学诱导的异源二聚化系统来调节。化学调节剂用于瞬间触发工程T细胞增殖或在需要时抑制car介导的激活,或在癌细胞参与时增强CAR-T细胞的激活,也显示在体内。此外,还介绍了一种有效的传感器来监测体内活化的CD19 CAR-T细胞。这种在CAR-T细胞调控中的实现为CAR-T细胞活性的按需外部控制提供了一种有效的方法,从而提高了它们的安全性。
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来源期刊
Molecular Therapy Oncolytics
Molecular Therapy Oncolytics Medicine-Oncology
CiteScore
10.90
自引率
3.50%
发文量
152
审稿时长
6 weeks
期刊介绍: Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.
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