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嵌合抗原受体 T 细胞疗法治疗癌症:最新进展和挑战,重点关注 B 淋巴细胞恶性肿瘤和部分实体瘤。

CAR T-Cell Therapy for Cancer: Latest Updates and Challenges, with a Focus on B-Lymphoid Malignancies and Selected Solid Tumours.

机构信息

Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.

University of Cambridge, Trinity Hall, Cambridge CB3 9DP, UK.

出版信息

Cells. 2023 Jun 8;12(12):1586. doi: 10.3390/cells12121586.


DOI:10.3390/cells12121586
PMID:37371056
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10296619/
Abstract

Although exponential progress in treating advanced malignancy has been made in the modern era with immune checkpoint blockade, survival outcomes remain suboptimal. Cellular immunotherapy, such as chimeric antigen receptor T cells, has the potential to improve this. CAR T cells combine the antigen specificity of a monoclonal antibody with the cytotoxic 'power' of T-lymphocytes through expression of a transgene encoding the scFv domain, CD3 activation molecule, and co-stimulatory domains. Although, very rarely, fatal cytokine-release syndrome may occur, CAR T-cell therapy gives patients with refractory CD19-positive B-lymphoid malignancies an important further therapeutic option. However, low-level expression of epithelial tumour-associated-antigens on non-malignant cells makes the application of CAR T-cell technology to common solid cancers challenging, as does the potentially limited ability of CAR T cells to traffic outside the blood/lymphoid microenvironment into metastatic lesions. Despite this, in advanced neuroblastoma refractory to standard therapy, 60% long-term overall survival and an objective response in 63% was achieved with anti GD2-specific CAR T cells.

摘要

尽管在现代时代通过免疫检查点阻断取得了治疗晚期恶性肿瘤的指数级进展,但生存结果仍不理想。细胞免疫疗法,如嵌合抗原受体 T 细胞,有可能改善这一点。CAR T 细胞通过表达编码 scFv 结构域、CD3 激活分子和共刺激结构域的转基因,将单克隆抗体的抗原特异性与 T 淋巴细胞的细胞毒性“威力”结合在一起。虽然非常罕见,但可能会发生致命的细胞因子释放综合征,CAR T 细胞疗法为难治性 CD19 阳性 B 淋巴细胞恶性肿瘤患者提供了一个重要的额外治疗选择。然而,非恶性细胞上低水平表达上皮肿瘤相关抗原,使得 CAR T 细胞技术在常见实体癌症中的应用具有挑战性,CAR T 细胞在血液/淋巴样微环境外进入转移病灶的潜在能力也有限。尽管如此,在对标准治疗耐药的晚期神经母细胞瘤中,抗 GD2 特异性 CAR T 细胞使 60%的患者获得长期总生存,63%的患者获得客观缓解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a75b/10296619/75acfa787321/cells-12-01586-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a75b/10296619/75acfa787321/cells-12-01586-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a75b/10296619/75acfa787321/cells-12-01586-g001.jpg

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本文引用的文献

[1]
GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma.

N Engl J Med. 2023-4-6

[2]
Dasatinib for treatment of CAR T-cell therapy-related complications.

J Immunother Cancer. 2022-12

[3]
Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial.

J Clin Oncol. 2023-3-20

[4]
Local immunotherapy with the RNA-based immune stimulator CV8102 induces substantial anti-tumor responses and enhances checkpoint inhibitor activity.

Cancer Immunol Immunother. 2023-5

[5]
Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: a phase 2 trial.

Nat Med. 2022-11

[6]
Non-viral, specifically targeted CAR-T cells achieve high safety and efficacy in B-NHL.

Nature. 2022-9

[7]
Current Status and Perspectives of Dual-Targeting Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Hematological Malignancies.

Cancers (Basel). 2022-6-30

[8]
Ciltacabtagene Autoleucel, an Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up.

J Clin Oncol. 2023-2-20

[9]
Novel treatments in B cell non-Hodgkin's lymphomas.

BMJ. 2022-4-20

[10]
A guide to antigen processing and presentation.

Nat Rev Immunol. 2022-12

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