Genetically Engineered CLDN18.2 CAR-T Cells Expressing Synthetic PD1/CD28 Fusion Receptors Produced Using a Lentiviral Vector.

IF 3.3 4区 生物学 Q2 MICROBIOLOGY
Journal of Microbiology Pub Date : 2024-07-01 Epub Date: 2024-05-03 DOI:10.1007/s12275-024-00133-0
Heon Ju Lee, Seo Jin Hwang, Eun Hee Jeong, Mi Hee Chang
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引用次数: 0

Abstract

This study aimed to develop synthetic Claudin18.2 (CLDN18.2) chimeric antigen receptor (CAR)-T (CAR-T) cells as a treatment for advanced gastric cancer using lentiviral vector genetic engineering technology that targets the CLDN18.2 antigen and simultaneously overcomes the immunosuppressive environment caused by programmed cell death protein 1 (PD-1). Synthetic CAR T cells are a promising approach in cancer immunotherapy but face many challenges in solid tumors. One of the major problems is immunosuppression caused by PD-1. CLDN18.2, a gastric-specific membrane protein, is considered a potential therapeutic target for gastric and other cancers. In our study, CLDN18.2 CAR was a second-generation CAR with inducible T-cell costimulatory (CD278), and CLDN18.2-PD1/CD28 CAR was a third-generation CAR, wherein the synthetic PD1/CD28 chimeric-switch receptor (CSR) was added to the second-generation CAR. In vitro, we detected the secretion levels of different cytokines and the killing ability of CAR-T cells. We found that the secretion of cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) secreted by three types of CAR-T cells was increased, and the killing ability against CLDN18.2-positive GC cells was enhanced. In vivo, we established a xenograft GC model and observed the antitumor effects and off-target toxicity of CAR-T cells. These results support that synthetic anti-CLDN18.2 CAR-T cells have antitumor effect and anti-CLDN18.2-PD1/CD28 CAR could provide a promising design strategy to improve the efficacy of CAR-T cells in advanced gastric cancer.

Abstract Image

表达使用慢病毒载体生产的合成 PD1/CD28 融合受体的基因工程 CLDN18.2 CAR-T 细胞。
本研究旨在利用慢病毒载体基因工程技术开发合成Claudin18.2(CLDN18.2)嵌合抗原受体(CAR)-T(CAR-T)细胞,作为晚期胃癌的治疗方法,该技术以CLDN18.2抗原为靶点,同时克服了程序性细胞死亡蛋白1(PD-1)导致的免疫抑制环境。合成 CAR T 细胞是一种前景广阔的癌症免疫疗法,但在实体瘤中面临许多挑战。其中一个主要问题就是PD-1造成的免疫抑制。CLDN18.2是一种胃特异性膜蛋白,被认为是胃癌和其他癌症的潜在治疗靶点。在我们的研究中,CLDN18.2 CAR是第二代CAR,具有可诱导的T细胞成本刺激(CD278);CLDN18.2-PD1/CD28 CAR是第三代CAR,在第二代CAR中加入了合成的PD1/CD28嵌合开关受体(CSR)。在体外,我们检测了不同细胞因子的分泌水平和CAR-T细胞的杀伤能力。我们发现,三种 CAR-T 细胞分泌的干扰素-γ(IFN-γ)和肿瘤坏死因子-α(TNF-α)等细胞因子水平均有所提高,对 CLDN18.2 阳性 GC 细胞的杀伤能力也有所增强。在体内,我们建立了GC异种移植模型,观察了CAR-T细胞的抗肿瘤效果和脱靶毒性。这些结果支持合成的抗CLDN18.2 CAR-T细胞具有抗肿瘤作用,而抗CLDN18.2-PD1/CD28 CAR可以为提高CAR-T细胞在晚期胃癌中的疗效提供一种有前景的设计策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Microbiology
Journal of Microbiology 生物-微生物学
CiteScore
5.70
自引率
3.30%
发文量
0
审稿时长
3 months
期刊介绍: Publishes papers that deal with research on microorganisms, including archaea, bacteria, yeasts, fungi, microalgae, protozoa, and simple eukaryotic microorganisms. Topics considered for publication include Microbial Systematics, Evolutionary Microbiology, Microbial Ecology, Environmental Microbiology, Microbial Genetics, Genomics, Molecular Biology, Microbial Physiology, Biochemistry, Microbial Pathogenesis, Host-Microbe Interaction, Systems Microbiology, Synthetic Microbiology, Bioinformatics and Virology. Manuscripts dealing with simple identification of microorganism(s), cloning of a known gene and its expression in a microbial host, and clinical statistics will not be considered for publication by JM.
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