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c-Met 特异性 CAR-T 细胞作为一种针对非小细胞肺癌细胞 A549 的靶向治疗方法。

c-Met specific CAR-T cells as a targeted therapy for non-small cell lung cancer cell A549.

机构信息

Department of Basic Medical, Bengbu Medical College, Bengbu, AH, China.

Department of Life Sciences, Bengbu Medical College, Bengbu, AH, China.

出版信息

Bioengineered. 2022 Apr;13(4):9216-9232. doi: 10.1080/21655979.2022.2058149.


DOI:10.1080/21655979.2022.2058149
PMID:35378051
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9161852/
Abstract

Non-small cell lung cancer (NSCLC) is considered to be one of the most prevalent and fatal malignancies, with a poor survival rate. Chimeric antigen receptor T cell (CAR-T) cell therapy is one of the most exciting directions in the field of Cellular immunotherapy. Therefore, CAR-T cells that target c-Met have been developed for use in NSCLC therapy and might be a potential therapeutic strategy. The anti c-Met scFv structure was fused with the transmembrane and intracellular domains. Using a lentiviral vector to load the c-Met CAR gene, then transfected the c-Met CAR lentiviral into human T cells to obtain the second generation c-Met CAR-T expressing CARs stably. In vitro co-culture, experiments revealed that CAR-T cells have high proliferative activity and the potential to secrete cytokines (IL-2, TNF-α, and IFN-γ). c-Met CAR-T cells showed special cellular cytotoxicity in LDH release assay. A subcutaneous tumor model in nude mice was used to test the anticancer effectiveness of c-met CAR-T cells in vivo. For c-Met positive NSCLC tissue, according to tumor volume, weight, fluorescence intensity, and immunohistochemical detection, c-Met CAR-T cells had stronger tumor growth suppression compared to untransduced T cells. HE staining revealed that c-Met CAR-T cells did not produced side effects in nude mice. Taken together, we provided useful method to generate c-Met CAR- T cells, which exhibit enhanced cytotoxicity against NSCLC cells in vitro and in vivo. Thus, providing a new therapeutic avenue for treating NSCLC clinically. (1) c-Met CAR-T capable of stably expressing c-Met CARs were constructed.(2) c-Met CAR-T have strong anti-tumor ability and proliferation ability in vitro.(3) c-Met CAR-T can effectively inhibit the growth of A549 cells subcutaneous xenografts.

摘要

非小细胞肺癌(NSCLC)被认为是最常见和最致命的恶性肿瘤之一,其生存率较低。嵌合抗原受体 T 细胞(CAR-T)细胞疗法是细胞免疫疗法领域最令人兴奋的方向之一。因此,已经开发出针对 c-Met 的 CAR-T 细胞用于 NSCLC 治疗,可能是一种潜在的治疗策略。抗 c-Met scFv 结构与跨膜和细胞内结构域融合。使用慢病毒载体装载 c-Met CAR 基因,然后将 c-Met CAR 慢病毒转染到人 T 细胞中,获得稳定表达 CAR 的第二代 c-Met CAR-T。体外共培养实验表明,CAR-T 细胞具有高增殖活性和分泌细胞因子(IL-2、TNF-α 和 IFN-γ)的潜力。c-Met CAR-T 细胞在 LDH 释放实验中表现出特殊的细胞毒性。在裸鼠皮下肿瘤模型中测试 c-met CAR-T 细胞在体内的抗癌效果。对于 c-Met 阳性 NSCLC 组织,根据肿瘤体积、重量、荧光强度和免疫组织化学检测,c-Met CAR-T 细胞比未转导的 T 细胞具有更强的肿瘤生长抑制作用。HE 染色显示 c-Met CAR-T 细胞在裸鼠中没有产生副作用。总之,我们提供了一种有用的方法来产生 c-Met CAR-T 细胞,这些细胞在体外和体内对 NSCLC 细胞表现出增强的细胞毒性。因此,为临床治疗 NSCLC 提供了新的治疗途径。(1) 构建了能够稳定表达 c-Met CAR 的 c-Met CAR-T。(2) c-Met CAR-T 在体外具有强大的抗肿瘤能力和增殖能力。(3) c-Met CAR-T 能有效抑制 A549 细胞皮下移植瘤的生长。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/33692771d306/KBIE_A_2058149_F0009b_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/1765ee24bd68/KBIE_A_2058149_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/d055b03871fa/KBIE_A_2058149_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/37f8120e4190/KBIE_A_2058149_F0003a_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/a2c7f87743ef/KBIE_A_2058149_F0003b_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/fa2a70293230/KBIE_A_2058149_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/34f84295f813/KBIE_A_2058149_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/6e816acccca4/KBIE_A_2058149_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/811fcca0e8aa/KBIE_A_2058149_F0007_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/4688426c2304/KBIE_A_2058149_F0008_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/0cf8a47439e3/KBIE_A_2058149_F0009a_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/33692771d306/KBIE_A_2058149_F0009b_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/1765ee24bd68/KBIE_A_2058149_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/d055b03871fa/KBIE_A_2058149_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/37f8120e4190/KBIE_A_2058149_F0003a_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/a2c7f87743ef/KBIE_A_2058149_F0003b_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/fa2a70293230/KBIE_A_2058149_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/34f84295f813/KBIE_A_2058149_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/6e816acccca4/KBIE_A_2058149_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/811fcca0e8aa/KBIE_A_2058149_F0007_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/4688426c2304/KBIE_A_2058149_F0008_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/0cf8a47439e3/KBIE_A_2058149_F0009a_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f89e/9161852/33692771d306/KBIE_A_2058149_F0009b_OC.jpg

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[2]
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[3]
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[4]
[Enhanced tumoricidal activity of PD-1 antibody-secreting c-Met CAR-T cells against pancreatic cancer cells].

Nan Fang Yi Ke Da Xue Xue Bao. 2024-10-20

[5]
Targeting the MET gene: unveiling therapeutic opportunities in immunotherapy within the tumor immune microenvironment of non-small cell lung cancer.

Ther Adv Med Oncol. 2024-10-17

[6]
Exploring the potential of the convergence between extracellular vesicles and CAR technology as a novel immunotherapy approach.

J Extracell Biol. 2024-9-26

[7]
Unveiling the Role of HGF/c-Met Signaling in Non-Small Cell Lung Cancer Tumor Microenvironment.

Int J Mol Sci. 2024-8-22

[8]
The DC-T cell axis is an effective target for the treatment of non-small cell lung cancer.

Immun Inflamm Dis. 2023-11

[9]
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[10]
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本文引用的文献

[1]
TRAIL-R1-Targeted CAR-T Cells Exhibit Dual Antitumor Efficacy.

Front Mol Biosci. 2021-12-20

[2]
Targeting Triple-Negative Breast Cancer with Combination Therapy of EGFR CAR T Cells and CDK7 Inhibition.

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Clin Transl Immunology. 2021-1-31

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MET Amplification (MET/CEP7 Ratio ≥ 1.8) Is an Independent Poor Prognostic Marker in Patients With Treatment-naive Non-Small-cell Lung Cancer.

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Zhonghua Xue Ye Xue Za Zhi. 2020-10-14

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Co-expressing LRP6 With Anti-CD19 CAR-T Cells for Improved Therapeutic Effect Against B-ALL.

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Front Oncol. 2020-7-14

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