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环孢素 A 耐药的 CAR-T 细胞在同种异体细胞存在的情况下介导抗肿瘤免疫。

Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells.

机构信息

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.

Research Units of Infectious disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, 310003, China.

出版信息

Nat Commun. 2023 Dec 20;14(1):8491. doi: 10.1038/s41467-023-44176-0.

DOI:10.1038/s41467-023-44176-0
PMID:38123592
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10733396/
Abstract

Chimeric antigen receptor (CAR)-T therapy requires autologous T lymphocytes from cancer patients, a process that is both costly and complex. Universal CAR-T cell treatment from allogeneic sources can overcome this limitation but is impeded by graft-versus-host disease (GvHD) and host versus-graft rejection (HvGR). Here, we introduce a mutated calcineurin subunit A (CNA) and a CD19-specific CAR into the T cell receptor α constant (TRAC) locus to generate cells that are resistant to the widely used immunosuppressant, cyclosporine A (CsA). These immunosuppressant-resistant universal (IRU) CAR-T cells display improved effector function in vitro and anti-tumour efficacy in a leukemia xenograft mouse model in the presence of CsA, compared with CAR-T cells carrying wild-type CNA. Moreover, IRU CAR-T cells retain effector function in vitro and in vivo in the presence of both allogeneic T cells and CsA. Lastly, CsA withdrawal restores HvGR, acting as a safety switch that can eliminate IRU CAR-T cells. These findings demonstrate the efficacy of CsA-resistant CAR-T cells as a universal, 'off-the-shelf' treatment option.

摘要

嵌合抗原受体 (CAR)-T 疗法需要从癌症患者身上提取自体 T 淋巴细胞，这个过程既昂贵又复杂。来自异体来源的通用 CAR-T 细胞治疗可以克服这一限制，但受到移植物抗宿主病 (GvHD) 和宿主抗移植物排斥反应 (HvGR) 的阻碍。在这里，我们将突变型钙调神经磷酸酶亚基 A (CNA) 和 CD19 特异性 CAR 引入 T 细胞受体 α 恒定 (TRAC) 基因座，以生成对广泛使用的免疫抑制剂环孢素 A (CsA) 具有抗性的细胞。与携带野生型 CNA 的 CAR-T 细胞相比，这些免疫抑制剂抗性的通用 (IRU) CAR-T 细胞在 CsA 存在的情况下显示出体外增强的效应功能和抗白血病异种移植小鼠模型中的抗肿瘤功效。此外，IRU CAR-T 细胞在体外和体内均保留效应功能，同时存在同种异体 T 细胞和 CsA。最后，CsA 的停用恢复了 HvGR，作为一种安全开关，可以消除 IRU CAR-T 细胞。这些发现证明了 CsA 抗性 CAR-T 细胞作为一种通用的、“现成”治疗选择的有效性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8017/10733396/3bb2984ec986/41467_2023_44176_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8017/10733396/7a72f1c1fb92/41467_2023_44176_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8017/10733396/1075bfc801e6/41467_2023_44176_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8017/10733396/f3792024e6fc/41467_2023_44176_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8017/10733396/9b17868cd44f/41467_2023_44176_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8017/10733396/5991d437d465/41467_2023_44176_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8017/10733396/3bb2984ec986/41467_2023_44176_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8017/10733396/7a72f1c1fb92/41467_2023_44176_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8017/10733396/1075bfc801e6/41467_2023_44176_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8017/10733396/f3792024e6fc/41467_2023_44176_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8017/10733396/9b17868cd44f/41467_2023_44176_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8017/10733396/5991d437d465/41467_2023_44176_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8017/10733396/3bb2984ec986/41467_2023_44176_Fig6_HTML.jpg

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[1]
Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells.

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[4]
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[6]
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[7]
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[8]
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[9]
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[4]
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[5]
Turning "trashed" genomic loci into treasurable sites for integrating chimeric antigen receptors in T and NK cells.

Mol Ther. 2025-4-2

[6]
Dasatinib-resistant universal CAR-T cells proliferate in the presence of host immune cells and exhibit antitumor activity.

Mol Ther. 2025-4-2

[7]
LLT1 overexpression renders allogeneic-NK resistance and facilitates the generation of enhanced universal CAR-T cells.

J Exp Clin Cancer Res. 2025-1-25

[8]
Managing allorejection in off-the-shelf CAR-engineered cell therapies.

Mol Ther. 2024-11-26

[9]
Allogeneic CAR-T cells for cancer immunotherapy.

Immunotherapy. 2024

[10]
Engineering a solution for allogeneic CAR-T rejection.

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本文引用的文献

[1]
Identification of direct transcriptional targets of NFATC2 that promote β cell proliferation.

J Clin Invest. 2021-11-1

[2]
Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors.

Cell Mol Immunol. 2021-9

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Development of CAR T Cells Expressing a Suicide Gene Plus a Chimeric Antigen Receptor Targeting Signaling Lymphocytic-Activation Molecule F7.

Mol Ther. 2021-2-3

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Nat Rev Immunol. 2021-5

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Abrogation of HLA surface expression using CRISPR/Cas9 genome editing: a step toward universal T cell therapy.

Sci Rep. 2020-10-20

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Improving CAR T cell therapy by optimizing critical quality attributes.

Semin Hematol. 2020-4

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Engineered off-the-shelf therapeutic T cells resist host immune rejection.

Nat Biotechnol. 2021-1

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Genetic Ablation of HLA Class I, Class II, and the T-cell Receptor Enables Allogeneic T Cells to Be Used for Adoptive T-cell Therapy.

Cancer Immunol Res. 2020-7

[9]
Cdk4 and Cdk6 Couple the Cell-Cycle Machinery to Cell Growth via mTORC1.

Cell Rep. 2020-4-14

[10]
Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model.

Oncoimmunology. 2019-5-27

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