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下一代抗实体瘤的CEA-CAR-NK-92细胞:克服结直肠癌中的肿瘤微环境挑战

Next-Generation CEA-CAR-NK-92 Cells against Solid Tumors: Overcoming Tumor Microenvironment Challenges in Colorectal Cancer.

作者信息

Franzén Alexander Sebastian, Boulifa Abdelhadi, Radecke Clarissa, Stintzing Sebastian, Raftery Martin J, Pecher Gabriele

机构信息

Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.

Competence Center of Immuno-Oncology and Translational Cell Therapy (KITZ), Department of Hematology, Oncology and Tumor Immunology, CCM, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany.

出版信息

Cancers (Basel). 2024 Jan 16;16(2):388. doi: 10.3390/cancers16020388.


DOI:10.3390/cancers16020388
PMID:38254876
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10814835/
Abstract

Colorectal carcinoma (CRC) presents a formidable medical challenge, demanding innovative therapeutic strategies. Chimeric antigen receptor (CAR) natural killer (NK) cell therapy has emerged as a promising alternative to CAR T-cell therapy for cancer. A suitable tumor antigen target on CRC is carcinoembryonic antigen (CEA), given its widespread expression and role in tumorigenesis and metastasis. CEA is known to be prolifically shed from tumor cells in a soluble form, thus hindering CAR recognition of tumors and migration through the TME. We have developed a next-generation CAR construct exclusively targeting cell-associated CEA, incorporating a PD1-checkpoint inhibitor and a CCR4 chemokine receptor to enhance homing and infiltration of the CAR-NK-92 cell line through the TME, and which does not induce fratricidal killing of CAR-NK-92-cells. To evaluate this therapeutic approach, we harnessed intricate 3D multicellular tumor spheroid models (MCTS), which emulate key elements of the TME. Our results demonstrate the effective cytotoxicity of CEA-CAR-NK-92 cells against CRC in colorectal cell lines and MCTS models. Importantly, minimal off-target activity against non-cancerous cell lines underscores the precision of this therapy. Furthermore, the integration of the CCR4 migration receptor augments homing by recognizing target ligands, CCL17 and CCL22. Notably, our CAR design results in no significant trogocytosis-induced fratricide. In summary, the proposed CEA-targeting CAR-NK cell therapy could offer a promising solution for CRC treatment, combining precision and efficacy in a tailored approach.

摘要

结直肠癌(CRC)是一项严峻的医学挑战,需要创新的治疗策略。嵌合抗原受体(CAR)自然杀伤(NK)细胞疗法已成为一种有前景的替代CAR T细胞疗法的癌症治疗方法。鉴于癌胚抗原(CEA)在结直肠癌中广泛表达且在肿瘤发生和转移中起作用,它是结直肠癌合适的肿瘤抗原靶点。已知CEA以可溶性形式从肿瘤细胞中大量脱落,从而阻碍CAR对肿瘤的识别以及通过肿瘤微环境(TME)的迁移。我们开发了一种专门靶向细胞相关CEA的下一代CAR构建体,它整合了PD1检查点抑制剂和CCR4趋化因子受体,以增强CAR-NK-92细胞系通过TME的归巢和浸润,并且不会诱导CAR-NK-92细胞的自相残杀。为了评估这种治疗方法,我们利用了复杂的3D多细胞肿瘤球体模型(MCTS),该模型模拟了TME的关键要素。我们的结果表明,CEA-CAR-NK-92细胞在结直肠癌细胞系和MCTS模型中对CRC具有有效的细胞毒性。重要的是,对非癌细胞系的脱靶活性极小,突出了这种疗法的精确性。此外,CCR4迁移受体的整合通过识别靶配体CCL17和CCL22增强了归巢。值得注意的是,我们的CAR设计不会导致明显的由胞啃作用诱导的自相残杀。总之,所提出的靶向CEA的CAR-NK细胞疗法可能为CRC治疗提供一种有前景的解决方案,以量身定制的方法将精确性和有效性结合起来。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/3bc1cfaa0bc8/cancers-16-00388-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/6656a5a3b2c4/cancers-16-00388-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/605b9d5186c1/cancers-16-00388-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/622dacadb2bf/cancers-16-00388-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/a3d00c2612b3/cancers-16-00388-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/adf365131ac7/cancers-16-00388-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/72205931c1bf/cancers-16-00388-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/42ec99bdf586/cancers-16-00388-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/3bc1cfaa0bc8/cancers-16-00388-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/6656a5a3b2c4/cancers-16-00388-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/605b9d5186c1/cancers-16-00388-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/622dacadb2bf/cancers-16-00388-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/a3d00c2612b3/cancers-16-00388-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/adf365131ac7/cancers-16-00388-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/72205931c1bf/cancers-16-00388-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/42ec99bdf586/cancers-16-00388-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef20/10814835/3bc1cfaa0bc8/cancers-16-00388-g008.jpg

相似文献

[1]
Next-Generation CEA-CAR-NK-92 Cells against Solid Tumors: Overcoming Tumor Microenvironment Challenges in Colorectal Cancer.

Cancers (Basel). 2024-1-16

[2]
Next Generation CD44v6-Specific CAR-NK Cells Effective against Triple Negative Breast Cancer.

Int J Mol Sci. 2023-5-20

[3]
Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells.

BMC Immunol. 2018-8-3

[4]
Preclinical efficacy of a HER2 synNotch/CEA-CAR combinatorial immunotherapy against colorectal cancer with HER2 amplification.

Mol Ther. 2024-8-7

[5]
Outsmarting trogocytosis to boost CAR NK/T cell therapy.

Mol Cancer. 2023-11-16

[6]
Radiotherapy enhances the anti-tumor effect of CAR-NK cells for hepatocellular carcinoma.

J Transl Med. 2024-10-13

[7]
In Vitro Evaluation of CD276-CAR NK-92 Functionality, Migration and Invasion Potential in the Presence of Immune Inhibitory Factors of the Tumor Microenvironment.

Cells. 2021-4-26

[8]
KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape.

Nat Med. 2022-10

[9]
Circumventing resistance within the Ewing sarcoma microenvironment by combinatorial innate immunotherapy.

J Immunother Cancer. 2024-9-12

[10]
Empowering pancreatic tumor homing with augmented anti-tumor potency of CXCR2-tethered CAR-NK cells.

Mol Ther Oncol. 2024-2-19

引用本文的文献

[1]
Association of Serum PSA, fPSA, and CEA Levels with Prognosis and Clinicopathological Characteristics in Prostate Cancer.

Cancer Manag Res. 2025-8-6

[2]
Precision sniper for solid tumors: CAR-NK cell therapy.

Cancer Immunol Immunother. 2025-7-24

[3]
Rendering NK Cells Antigen-Specific for the Therapy of Solid Tumours.

Int J Mol Sci. 2025-6-29

[4]
Chimeric Antigen Receptor (CAR)-NK92 cells effective against glioblastoma, breast- and pancreatic cancer in vitro and in a murine xenograft model of ovarian cancer.

Cancer Cell Int. 2025-7-11

[5]
Advancing CAR-based cell therapies for solid tumours: challenges, therapeutic strategies, and perspectives.

Mol Cancer. 2025-7-7

[6]
CAR-NK cells: harnessing the power of natural killers for advanced cancer therapy.

Front Immunol. 2025-5-30

[7]
Trogocytosis in CAR immune cell therapy: a key mechanism of tumor immune escape.

Cell Commun Signal. 2024-10-28

[8]
CAR-NK cells for gastrointestinal cancer immunotherapy: from bench to bedside.

Mol Cancer. 2024-10-23

[9]
Chimeric antigen receptor-natural killer (CAR-NK) cell immunotherapy: A bibliometric analysis from 2004 to 2023.

Hum Vaccin Immunother. 2024-12-31

[10]
Engineered T cells for Colorectal Cancer.

Immunotherapy. 2024

本文引用的文献

[1]
Chimeric antigen receptor engineered natural killer cells for cancer therapy.

Exp Hematol Oncol. 2023-8-10

[2]
Next Generation CD44v6-Specific CAR-NK Cells Effective against Triple Negative Breast Cancer.

Int J Mol Sci. 2023-5-20

[3]
Characterization of the immune cell landscape in CRC: Clinical implications of tumour-infiltrating leukocytes in early- and late-stage CRC.

Front Immunol. 2022

[4]
Efficient Redirection of NK Cells by Genetic Modification with Chemokine Receptors CCR4 and CCR2B.

Int J Mol Sci. 2023-2-4

[5]
The NK-92 cell line-30 years later: its impact on natural killer cell research and treatment of cancer.

Cytotherapy. 2023-5

[6]
Natural killer cells in clinical development as non-engineered, engineered, and combination therapies.

J Hematol Oncol. 2022-11-8

[7]
KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape.

Nat Med. 2022-10

[8]
A comparative study of tumour-on-chip models with patient-derived xenografts for predicting chemotherapy efficacy in colorectal cancer patients.

Front Bioeng Biotechnol. 2022-8-16

[9]
Trogocytosis and fratricide killing impede MSLN-directed CAR T cell functionality.

Oncoimmunology. 2022

[10]
Measuring trogocytosis between ovarian tumor and natural killer cells.

STAR Protoc. 2022-6-17

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