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时空 PET 成像揭示了三阴性乳腺癌模型中 CAR-T 肿瘤滞留的差异。

Spatiotemporal PET Imaging Reveals Differences in CAR-T Tumor Retention in Triple-Negative Breast Cancer Models.

机构信息

Imaging Therapies and Cancer Group, Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK.

Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK.

出版信息

Mol Ther. 2020 Oct 7;28(10):2271-2285. doi: 10.1016/j.ymthe.2020.06.028. Epub 2020 Jun 27.


DOI:10.1016/j.ymthe.2020.06.028
PMID:32645298
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7544977/
Abstract

Chimeric antigen receptor T cell therapy (CAR-T) has been rolled out as a new treatment for hematological malignancies. For solid tumor treatment, CAR-T has been disappointing so far. Challenges include the quantification of CAR-T trafficking, expansion and retention in tumors, activity at target sites, toxicities, and long-term CAR-T survival. Non-invasive serial in vivo imaging of CAR-T using reporter genes can address several of these challenges. For clinical use, a non-immunogenic reporter that is detectable with exquisite sensitivity by positron emission tomography (PET) using a clinically available non-toxic radiotracer would be beneficial. Here, we employed the human sodium iodide symporter to non-invasively quantify tumor retention of pan-ErbB family targeted CAR-T by PET. We generated and characterized traceable CAR T cells and examined potential negative effects of radionuclide reporter use. We applied our platform to two different triple-negative breast cancer (TNBC) models and unexpectedly observed pronounced differences in CAR-T tumor retention by PET/CT (computed tomography) and confirmed data ex vivo. CAR-T tumor retention inversely correlated with immune checkpoint expression in the TNBC models. Our platform enables highly sensitive non-invasive PET tracking of CAR-T thereby addressing a fundamental unmet need in CAR-T development and offering to provide missing information needed for future clinical CAR-T imaging.

摘要

嵌合抗原受体 T 细胞疗法(CAR-T)已被推出用于治疗血液系统恶性肿瘤。对于实体瘤治疗,CAR-T 迄今为止令人失望。挑战包括 CAR-T 在肿瘤中的迁移、扩增和保留的定量、靶部位的活性、毒性和 CAR-T 的长期存活。使用报告基因对 CAR-T 进行非侵入性连续体内成像可以解决其中的一些挑战。对于临床应用,使用临床可用的无毒放射性示踪剂通过正电子发射断层扫描(PET)以极高的灵敏度检测到的非免疫原性报告基因将是有益的。在这里,我们使用人甲状腺钠碘转运体通过 PET 非侵入性地定量分析泛 ErbB 家族靶向 CAR-T 在肿瘤中的保留情况。我们生成并表征了可追踪的 CAR T 细胞,并检查了放射性核素报告基因使用的潜在负面影响。我们将我们的平台应用于两种不同的三阴性乳腺癌(TNBC)模型,出人意料地观察到通过 PET/CT(计算机断层扫描)对 CAR-T 肿瘤保留的显著差异,并在体外证实了数据。CAR-T 肿瘤保留与 TNBC 模型中的免疫检查点表达呈负相关。我们的平台能够进行高度敏感的非侵入性 PET 追踪 CAR-T,从而解决了 CAR-T 开发中的一个基本未满足的需求,并为未来的临床 CAR-T 成像提供所需的缺失信息。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/5a95f5064b0d/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/8ae8f38b8ffc/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/753d6cbc0f04/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/e5800fd8cdfb/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/458b0ecfcebe/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/5c28c050f671/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/0ce91c4604a6/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/1975204e9046/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/c236fb99a475/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/5a95f5064b0d/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/8ae8f38b8ffc/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/753d6cbc0f04/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/e5800fd8cdfb/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/458b0ecfcebe/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/5c28c050f671/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/0ce91c4604a6/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/1975204e9046/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/c236fb99a475/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/563c/7544977/5a95f5064b0d/gr8.jpg

相似文献

[1]
Spatiotemporal PET Imaging Reveals Differences in CAR-T Tumor Retention in Triple-Negative Breast Cancer Models.

Mol Ther. 2020-10-7

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

[1]
CAR-T cell therapy in brain malignancies: obstacles in the face of cellular trafficking and persistence.

Front Immunol. 2025-6-19

[2]
An Analysis of Monitoring Solutions for CAR T Cell Production.

Healthc Technol Lett. 2025-5-13

[3]
From Multi-Omics to Visualization and Beyond: Bridging Micro and Macro Insights in CAR-T Cell Therapy.

Adv Sci (Weinh). 2025-5

[4]
Reprogramming the breast tumor immune microenvironment: cold-to-hot transition for enhanced immunotherapy.

J Exp Clin Cancer Res. 2025-4-25

[5]
Gene editing enables non-invasive PET imaging of human induced pluripotent stem cell-derived liver bud organoids.

Mol Ther Methods Clin Dev. 2025-1-7

[6]
Development of an antigen-based approach to noninvasively image CAR T cells in real time and as a predictive tool.

Sci Adv. 2024-9-20

[7]
Nuclear-Based Labeling of Cellular Immunotherapies: A Simple Protocol for Preclinical Use.

Mol Imaging Biol. 2024-8

[8]
Mathematical modeling of endogenous and exogenously administered T cell recirculation in mouse and its application to pharmacokinetic studies of cell therapies.

Front Immunol. 2024

[9]
Imaging CAR-NK cells targeted to HER2 ovarian cancer with human sodium-iodide symporter-based positron emission tomography.

Eur J Nucl Med Mol Imaging. 2024-9

[10]
Finding Your CAR: The Road Ahead for Engineered T Cells.

Am J Pathol. 2024-8

本文引用的文献

[1]
How Non-invasive Cell Tracking Supports the Development and Translation of Cancer Immunotherapies.

Front Physiol. 2020-4-3

[2]
Non-invasive Reporter Gene Imaging of Cell Therapies, including T Cells and Stem Cells.

Mol Ther. 2020-6-3

[3]
Reporter gene-engineering of human induced pluripotent stem cells during differentiation renders in vivo traceable hepatocyte-like cells accessible.

Stem Cell Res. 2019-12

[4]
Imaging of T-cells and their responses during anti-cancer immunotherapy.

Theranostics. 2019-10-16

[5]
Inhibitory receptors and ligands beyond PD-1, PD-L1 and CTLA-4: breakthroughs or backups.

Nat Immunol. 2019-10-14

[6]
Imaging CAR T cell therapy with PSMA-targeted positron emission tomography.

Sci Adv. 2019-7-3

[7]
CAR T Cells Targeting the Tumor MUC1 Glycoprotein Reduce Triple-Negative Breast Cancer Growth.

Front Immunol. 2019-5-24

[8]
CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment.

Front Immunol. 2019-2-5

[9]
Enhanced noninvasive imaging of oncology models using the NIS reporter gene and bioluminescence imaging.

Cancer Gene Ther. 2020-4

[10]
PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8 T-cell Function.

Cancer Immunol Res. 2019-1-18

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