肿瘤细胞治疗研究
英文原题：Genetically Engineered CLDN18.2 CAR-T Cells Expressing Synthetic PD1/CD28 Fusion Receptors Produced Using a Lentiviral Vector.
Genetically Engineered CLDN18.2 CAR-T Cells Expressing Synthetic PD1/CD28 Fusion Receptors Produced Using a Lentiviral Vector.
这些结果支持合成的抗 CLDN18.2 CAR-T 细胞具有抗肿瘤作用，且抗 CLDN18.2-PD1/CD28 CAR 可为提高 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 细胞治疗晚期胃癌，并克服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 是癌症免疫治疗的有前景方法，但用于实体瘤仍面临诸多挑战，其中重要问题之一是 PD-1 介导的免疫抑制。CLDN18.2 是胃特异性膜蛋白，被认为是胃癌及其他癌症的潜在治疗靶点。本研究中，CLDN18.2 CAR 为含诱导型 T 细胞共刺激分子（CD278）的第二代 CAR；CLDN18.2-PD1/CD28 CAR 为第三代 CAR，在第二代 CAR 基础上加入了合成 PD1/CD28 嵌合开关受体（CSR）。体外检测不同 CAR-T 的细胞因子分泌和杀伤能力。结果发现，三种 CAR-T 均增加 IFN-γ 和肿瘤坏死因子-α（TNF-α）等细胞因子的分泌，并增强对 CLDN18.2 阳性胃癌（GC）细胞的杀伤。体内建立 GC 异种移植模型，观察 CAR-T 的抗肿瘤作用和脱靶毒性。结果支持合成抗 CLDN18.2 CAR-T 具有抗肿瘤作用，并提示抗 CLDN18.2-PD1/CD28 CAR 可作为提高晚期胃癌 CAR-T 疗效的有前景设计策略。
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- ) and tumor necrosis factor-alpha (TNF- ) 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.
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