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肿瘤浸润淋巴细胞来源的嵌合抗原受体T细胞在治疗CD19人源化小鼠结直肠癌中可改善免疫细胞浸润和生存期。

TIL-Derived CAR T Cells Improve Immune Cell Infiltration and Survival in the Treatment of CD19-Humanized Mouse Colorectal Cancer.

作者信息

Zhu Can, Zhao Yuanyuan, He Jiaheng, Zhao Huan, Ni Li, Cheng Xinyi, Chen Yida, Mu Liqian, Zhou Xiaojun, Shi Qin, Sun Jie

机构信息

Department of Orthopedics, The First Affiliated Hospital of Soochow University, Orthopedic Institute of Soochow University, Suzhou Medical College, Soochow University, 899 Pinghai Road, Suzhou 215031, China.

National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou 215031, China.

出版信息

Cancers (Basel). 2023 Nov 24;15(23):5567. doi: 10.3390/cancers15235567.


DOI:10.3390/cancers15235567
PMID:38067271
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10705672/
Abstract

Chimeric antigen receptor-engineered T cells (CAR Ts) targeting CD19 have shown unprecedented prognosis in treating hematological cancers. However, the lack of a tumor-specific antigen as the target and an inhospitable tumor environment limit the clinical application of CAR T in solid tumors. Tumor-infiltrating T lymphocytes (TIL) exhibit diverse T cell receptor clonality and superior tumor-homing abilities. Therefore, in our study, human CD19-target TIL CAR-Ts armed with CD3ζ and 4-1BB signaling domains were constructed. Mouse colorectal cancer CT26 cells expressing human CD19 (hCD19-CT26) were developed to assess the anti-tumor activity of TIL CAR-T cells, both in vitro and in vivo. Compared with splenic CAR T adoptive transfer, TIL CAR-T administration showed superior tumor suppression ability in hCD19-CT26 tumor-bearing mice. Furthermore, more T cells were found at the tumor site and had lower exhaustion-related inhibitory receptor (T cell immunoglobulin and mucin domain-containing protein 3, Tim3) expression and higher immune memory molecule (CD62L) expression. Overall, we provided an artificial tumor-specific antigen in solid tumors and demonstrated that combined CAR-expressing TIL-Ts (TIL CAR-Ts) exhibited strong anti-tumor activity, with improved T cell infiltration and immune memory. Our humanized tumor antigen presented platform of mice suggests that TIL CAR-T-based adoptive therapy could be a promising strategy for solid cancer treatment.

摘要

靶向CD19的嵌合抗原受体工程化T细胞(CAR Ts)在治疗血液系统癌症方面显示出前所未有的预后效果。然而,缺乏肿瘤特异性抗原作为靶点以及恶劣的肿瘤环境限制了CAR T在实体瘤中的临床应用。肿瘤浸润性T淋巴细胞(TIL)表现出多样的T细胞受体克隆性和卓越的肿瘤归巢能力。因此,在我们的研究中,构建了携带CD3ζ和4-1BB信号域的人CD19靶向TIL CAR-Ts。开发了表达人CD19(hCD19-CT26)的小鼠结直肠癌CT26细胞,以评估TIL CAR-T细胞在体外和体内的抗肿瘤活性。与脾CAR T过继转移相比,TIL CAR-T给药在hCD19-CT26荷瘤小鼠中显示出更强的肿瘤抑制能力。此外,在肿瘤部位发现了更多的T细胞,其与耗竭相关的抑制性受体(含T细胞免疫球蛋白和粘蛋白结构域蛋白3,Tim3)表达较低,免疫记忆分子(CD62L)表达较高。总体而言,我们在实体瘤中提供了一种人工肿瘤特异性抗原,并证明联合表达CAR的TIL-Ts(TIL CAR-Ts)表现出强大的抗肿瘤活性,同时改善了T细胞浸润和免疫记忆。我们的人源化小鼠肿瘤抗原呈递平台表明,基于TIL CAR-T的过继性治疗可能是实体癌治疗的一种有前景的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a142/10705672/858c102b49fd/cancers-15-05567-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a142/10705672/9e96d950126d/cancers-15-05567-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a142/10705672/b5da7a23417b/cancers-15-05567-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a142/10705672/789aeb8f6108/cancers-15-05567-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a142/10705672/1a690165157c/cancers-15-05567-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a142/10705672/ad33e3eaa4e3/cancers-15-05567-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a142/10705672/858c102b49fd/cancers-15-05567-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a142/10705672/9e96d950126d/cancers-15-05567-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a142/10705672/b5da7a23417b/cancers-15-05567-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a142/10705672/789aeb8f6108/cancers-15-05567-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a142/10705672/1a690165157c/cancers-15-05567-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a142/10705672/ad33e3eaa4e3/cancers-15-05567-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a142/10705672/858c102b49fd/cancers-15-05567-g006.jpg

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本文引用的文献

[1]
Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs.

Cancers (Basel). 2023-1-20

[2]
Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours.

Nat Rev Clin Oncol. 2023-1

[3]
Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results.

Nat Med. 2022-6

[4]
Next-Generation CAR T-cell Therapies.

Cancer Discov. 2022-7-6

[5]
Tumor-infiltrating lymphocytes for adoptive cell therapy: recent advances, challenges, and future directions.

Expert Opin Biol Ther. 2022-5

[6]
Assessing the Future of Solid Tumor Immunotherapy.

Biomedicines. 2022-3-11

[7]
CAR-T cell therapy for triple-negative breast cancer and other solid tumors: preclinical and clinical progress.

Expert Opin Investig Drugs. 2022-6

[8]
CAR-T cell therapy for lung cancer: Potential and perspective.

Thorac Cancer. 2022-4

[9]
Utility of a Recombinant HSV-1 Vaccine Vector for Personalized Cancer Vaccines.

Front Mol Biosci. 2022-1-26

[10]
Hallmarks of response, resistance, and toxicity to immune checkpoint blockade.

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