嵌合抗原受体T细胞免疫细胞疗法的应用进展与前景

辛军 汪百川 肖润

解剖学报 ›› 2025, Vol. 56 ›› Issue (3) : 371-380.

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解剖学报 ›› 2025, Vol. 56 ›› Issue (3) : 371-380. DOI: 10.16098/j.issn.0529-1356.2025.03.017
综述

嵌合抗原受体T细胞免疫细胞疗法的应用进展与前景

  • 辛军1,2,3 汪百川2,3,4 肖润1,2,3* 
作者信息 +

Progress and prospects of chimeric antigen receptor T cells immunocellular therapy

  • XIN  Jun1,2,3  WANG  Bai-chuan2,3,4  XIAO  Run1,2,3* 
Author information +
文章历史 +

摘要

肿瘤是当前人类面对的主要致死类重大疾病。传统的治疗手段,如化疗、手术和放疗等在很长时间内依然将作为肿瘤治疗的主要方式,但效果仍有各自的局限性。近年,以免疫检查点抑制剂、嵌合抗原受体T 细胞(CAR-T)过继疗法、抗肿瘤疫苗等策略的兴起,使肿瘤的免疫治疗备受瞩目。其中,CAR-T免疫疗法作为一种突破性的肿瘤免疫治疗方法,通过改造患者自身的T细胞,使其表达针对特定肿瘤抗原的重组抗原受体,突破了天然T细胞自身的主要组织相容性复合体(MHC)的限制性,在细胞和分子水平上精准地靶向肿瘤,从而能够高效特异地识别和杀伤癌细胞,为治疗肿瘤提供了新途径。自2017年美国食品药品监督管理局(FDA)批准首个CAR-T疗法以来,除在多种血液恶性肿瘤领域依然保持显著优势,也在部分实体瘤和自身免疫性疾病等的治疗和临床试验中取得了突出的进展。我们将对当前CAR-T技术的原理、应用及所要面临的挑战和发展方向进行简要综述。

Abstract

 Tumor is the main lethal type of major diseases that human beings are facing nowadays. Traditional therapies, such as chemotherapy, surgery, radiotherapy, etc, have been the mainstay of tumor treatment for a long time, and still have their own limitations in terms of effectiveness. In recent years, immunotherapy for tumors has attracted much attention with the rise of strategies such as immune checkpoint inhibitors, chimeric antigen receptor T-cell (CAR-T) relay therapy, and anti-tumor vaccines. Among them, CAR-T cell therapy, as a breakthrough tumor immunotherapy method, can precisely target tumors at the cellular and molecular levels by modifying the patient’s own T cells to express recombinant antigen receptors targeting specific tumor antigens, breaking the restriction of the major histocompatibility complex (MHC) of the natural T cells themselves. It can precisely target tumors at the cellular and molecular levels, and thus can efficiently and specifically identify and kill cancer cells, providing a new perspective for treatment. Since the approval of the first CAR-T therapy by the US Food and Drug Administration (FDA) in 2017, in addition to still maintaining significant advantages in the field of classical multiple hematologic malignancies, it has also made outstanding progress in the treatment and clinical trials of some solid tumors and autoimmune diseases, among others. This paper  will briefly review the current principles, applications, challenges and directions of development of CAR-T technology. 

关键词

 肿瘤免疫治疗
/ 嵌合抗原受体 / T细胞 / 精准医学 / 免疫细胞疗法

Key words

 Tumor Immunotherapy / Chimeric antigen receptor / T cell / Precision medicine / Immunocellular therapy

引用本文

导出引用
辛军 汪百川 肖润. 嵌合抗原受体T细胞免疫细胞疗法的应用进展与前景[J]. 解剖学报. 2025, 56(3): 371-380 https://doi.org/10.16098/j.issn.0529-1356.2025.03.017
XIN Jun WANG Bai-chuan XIAO Run. Progress and prospects of chimeric antigen receptor T cells immunocellular therapy[J]. Acta Anatomica Sinica. 2025, 56(3): 371-380 https://doi.org/10.16098/j.issn.0529-1356.2025.03.017
中图分类号:      R392.9    

参考文献

 [1] Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity[J]. Proc Natl Acad Sci USA, 1989, 86(24):10024-10028.
 [2] Mohamed-Reda B, Clara K, Bruno C, et al. Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells[J]. Int J Mol Sci, 2019, 20(6):1283.
 [3] Ghosh A, Smith M, James SE, et al. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity[J]. Nat Med, 2017, 23(2): 242-249.
 [4] Martin P, Barbara S, Douglas M, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma[J]. Nat Med, 2008, 14(11): 1264-1270.
 [5] Eleanor C, Hannah G, Vania B, et al. CAR T cells: driving the road from the laboratory to the clinic[J]. Immunol Rev, 2014, 257(1):91-106.
 [6] Pan K, Farrukh H, Chittepu VCSR, et al. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy[J]. J Exp Clin Cancer Res, 2022, 41(1):119.
 [7] Daniel G, Camillia A, Kendall K, et al. Pooled screening of CAR T cells identifies diverse immune signaling domains for next-generation immunotherapies[J]. Sci Transl Med, 2022, 14(670):eabm1463.
 [8] Kevin P, Hizra F, Veera C, et al. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy[J]. J Exp Clin Cancer Res, 2022, 41(1):119.
 [9] Sattva N, Frederick L, Nancy B, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large b-cell lymphoma[J]. N Engl J Med, 2017, 377(26):2531-2544.
 [10] Shannon M, Theodore L, Jochen B, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia[J]. N Engl J Med, 2018, 378(5):439-448.
 [11] Eric T, Dan L, Walter U. A Milestone for CAR T cells[J]. N Engl J Med. 2017, 377(26):2593-2596.
 [12] Yi-Ju C, Bams A, Yasser K. CART: what is next [J]? Cancers, 2023, 15(3):663.
 [13] David P, Bruce L, Michael K, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia[J]. N Engl J Med, 2011, 365(8):725-733.
 [14] Pouya K, Pooria K, Fatemeh R. CAR-T cell therapy in T-cell malignancies: is success a low-hanging fruit [J]? Stem Cell Res Ther, 2021, 12(1): 527.
 [15] Bridget K, Christopher L, Marwan F, et al. A phase 1 dose escalation study of a novel coupled CAR T cell therapy, GCC19CART, for patients with metastatic colorectal cancer[J]. J Clin Oncol, 2024, 42 (16): e15572.
 [16] Bamdad C, Mortimer J, Yuan Y, et al. Phase I first-in-human MUC1* targeted autologous CAR T cells for the treatment of metastatic breast cancers[J]. Cancer Res, 2024, 84 (Suppl 7): CT096. 
 [17] Tianhang L, Zhengmao L, Zhongen W, et al. Targeting EpCAM via CAR T-cells is an effective treatment for gastric cancer patients and subsequent toll-like receptor signaling activation in CD36+ monocyte underlies the resulting cytokine release syndrome[J]. Cancer Res, 2024, 84 (Suppl 7): CT069. 
 [18] Sumanta P, Ben T, John H, et al. CTX130 allogeneic CRISPR-Cas9-engineered chimeric antigen receptor (CAR) T cells in patients with advanced clear cell renal cell carcinoma: long-term follow-up and translational data from the phase 1 COBALT-RCC study[J]. Cancer Res, 2024, 84 (Suppl 7): CT002. 
 [19] Luciana Rodrigues Carvalho B, Samuel Campanelli Freitas C, da Silva Santurio D, et al. Systematic review of available CAR-T cell trials around the world[J]. Cancers, 2022, 14(11):2667.
 [20] Qiuqiang C, Lingeng L, Wenxue M. Efficacy, Safety, and challenges of CAR T-cells in the treatment of solid tumors[J]. Cancers, 2022, 14(23):5983.
 [21] Cameron T, Elizabeth B, Krina P, et al. Pharmacodynamic analysis of CAR-T cell persistence in patients with hematologic malignancies treated with NKTR-255, an IL-15 receptor agonist that enhances CD8+ T-cells: preliminary results from a phase 1 study[J]. Blood, 2021, 138 (Suppl 1): 2815. 
 [22] Pietrobon V, Todd LT, Goswami A, et al. Improving CAR T-cell persistence[J]. Int J Mol Sci, 2021, 22(19):10828.
 [23] Hao Z,Zhenlong Y,Zhen-gang Y, et al. New Strategies for the Treatment of Solid Tumors with CART Cells[J]. Int J Biol Sci, 2016, 12(6):718-729.
 [24] Zhang K, Chen H, Li F, et al. Bright future or blind alley? CAR-T cell therapy for solid tumors[J]. Front Immunol, 2023, 14:1045024.
 [25] Alain A, Andrada C, Stphanie B, et al. Engineering next-generation CAR-T cells for better toxicity management[J]. Int J Mol Sci, 2020, 21(22):8620.
 [26] Gina L, Claudia U, Bernardo C, et al. CAR-T Cell performance: how to improve their persistence [J]? Front Immunol, 2022, 13:878209. 
 [27] Kong Y, Tang L, You Y, et al. Analysis of causes for poor persistence of CAR-T cell therapy in vivo[J]. Front Immunol, 2023, 14:1063454. 
 [28] Violena P, Lauren T, Anghsumala G, et al. Improving CAR T-cell persistence[J]. Int J Mol Sci, 2021, 22(19): 10828.
 [29] Carlos R, Rayne R, Catherine R, et al. In vivo fate and activity of second versus third-generation CD19-specific CAR-T cells in B cell non-hodgkin’s lymphomas[J]. Mol Ther, 2018, 26(12):2727-2737.
 [30] Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia[J]. N Engl J Med, 2013,368(16):1509-1518.
 [31] Benjamin C, Jorrit E, Sébastien W. Pharmacologic control of CAR T cells[J]. Int J Mol Sci, 2021, 22(9):4320.
 [32] Nan F, Fu X, Chen X, et al. Strategies to overcome CAR-T cell resistance in clinical work: a single-institute experience[J]. Front Immunol, 2022,
13:929221. 
 [33] Neelapu S. Managing the toxicities of CAR T-cell therapy[J]. Hematol Oncol, 2019, 37(Suppl 1):48-52. 
 [34] Joseph F, Nirjal B. CAR-T cell therapy: mechanism, management, and mitigation of inflammatory toxicities[J]. Front Immunol, 2021, 12:693016. 
 [35] Sun S, Hao H, Yang G, et al. Immunotherapy with CAR-Modified T cells: toxicities and overcoming strategies[J]. J Immunol Res, 2018, 2018:2386187.
 [36] Nandini M, Mariana S, Castano A, et al. Overcoming a Critical obstacle towards effective and safe CAR T-cell therapeutics[J]. Blood, 2018, 132 (Suppl 1): 2056.
 [37] Dimitrios W, Ulrike K, Markus C, et al. Review: sustainable clinical development of CAR-T cellsswitching from viral transduction towards CRISPR-Cas gene editing[J]. Front Immunol, 2022, 13:865424. 
 [38] Crystal M. Abstract PL01-05: Next-generation CAR T cells designed to overcome tumor resistance[J]. Cancer Res, 2019, 79 (Suppl 13): PL01-05. 
 [39] Young R, Engel W, Uslu U, et al. Next-generation CAR T-cell therapies[J]. Cancer Discov, 2022, 12(7):1625-1633.
 [40] Majumder A. Evolving CAR-T-cell therapy for cancer treatment: from scientific discovery to cures[J]. Cancers, 2023, 16(1):39.
 [41] Lifeng W, Fu-Sheng W, Merrill G. Human autoimmune diseases: a comprehensive update[J]. J Intern Med, 2015, 278(4): 369-395. 
 [42] Tur C, Eckstein M, Velden J, et al. CD19-CAR T-cell therapy induces deep tissue depletion of B cells[J]. Ann Rheum Dis, 2025, 84(1): 106-114.
 [43] John B, Carly S, Nikhita P, et al. CD20 CAR T cells safely and reversibly ablate B cell follicles in a non-human primate model of HIV persistence[J]. Mol Ther, 2024, 32(5): 1238-1251.
 [44] Renier B. Abstract IA20: moving CAR T cell therapy forward: CARs and armored CARs[J]. Clin Cancer Res, 2016, 22(Suppl 1):IA20. 
 [45] Titov A, Kaminskiy Y, Ganeeva I, et al. Knowns and unknowns about CAR-T cell dysfunction[J]. Cancers, 2022, 14(4):1078.
 [46] Hartmann J, Schü?ler-Lenz M, Bondanza A, et al. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts[J]. EMBO Mol Med, 2017, 9(9):1183-1197.
 [47] Luciana Rodrigues Carvalho B, Samuel Campanelli Freitas C, Daniela da Silva S, et al. Systematic review of available CAR-T cell trials around the world[J]. Cancers(Based), 2022, 14(11):2667.
 [48] Michael H, Angela K. Current and future concepts for the generation and application of genetically engineered CAR-T and TCR-T cells[J]. Front Immunol, 2023, 14:1121030. 
 [49] Abken H. Driving CARs on the highway to solid cancer: some considerations on the adoptive therapy with CAR T cells[J]. Hum Gene Ther, 2017, 28(11):1047-1060.
 [50] Miao L, Zhang J, Zhang Z, et al. A bibliometric and knowledge-map analysis of CAR-T cells from 2009 to 2021[J]. Front Immunol, 2022, 13:840956.
 [51] Freitag F, Maucher M, Riester Z, et al. New targets and technologies for CAR-T cells[J]. Curr Opin Oncol, 2020, 32(5):510-517.


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