CAR-T细胞治疗引起细胞因子释放综合征的发生机制研究

doi:10.19803/j.1672-8629.20250258

中国药物警戒 ›› 2025, Vol. 22 ›› Issue (7): 735-741.
DOI: 10.19803/j.1672-8629.20250258

• 细胞和基因治疗产品评价研究专栏 • 上一篇下一篇

CAR-T细胞治疗引起细胞因子释放综合征的发生机制研究

任禹珂¹, 姜华, 李路路¹, 李双星¹, 霍桂桃¹, 杨艳伟¹, 张頔¹, 黄瑛¹, 耿兴超², 林志^1,*, 屈哲^1#

¹中国食品药品检定研究院安全评价研究所,药品监管科学全国重点实验室,北京市重点实验室,细胞及基因治疗药物质量和非临床研究与评价北京市重点实验室,北京 100176;
²中国食品药品检定研究院生物制品检定所,北京 102629

收稿日期:2025-04-27 出版日期:2025-07-15 发布日期:2025-07-17
通讯作者: ^*林志,女,博士,研究员,药物临床前安全性评价。E-mail: linzhi@nifdc.org.cn ^#为共同通信作者。
作者简介:任禹珂,女,在读博士,药物临床前安全性评价。^△为并列第一作者。
基金资助:
国家重点研发计划（2024YFA1107302）

Research Advances in the Pathogenesis of Cytokine Release Syndrome Induced by CAR-T Cell Therapy

REN Yuke¹, JIANG Hua, LI Lulu¹, LI Shuangxing¹, HUO Guitao¹, YANG Yanwei¹, ZHANG Di¹, HUANG Ying¹, GENG Xingchao², LIN Zhi^1,*, QU Zhe^1#

¹National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, State Key Laboratory of Drug Regulatory Science, Beijing Key Laboratory, Beijing Key Laboratory of Quality Control and Non-clinical Research and Evaluation for Cellular and Gene Therapy Medicinal Products, Beijing 100176, China;
²National Institutes for Food and Drug Control, Institute for Biological Product Control, Beijing 102629, China

Received:2025-04-27 Online:2025-07-15 Published:2025-07-17

摘要/Abstract

摘要： 目的探讨嵌合抗原受体T细胞（Chimeric Antigen Receptor T-Cell,CAR-T）治疗中细胞因子释放综合征（Cytokine Release Syndrome,CRS）的发生机制、分级及管理策略,以促进更安全、有效的CAR-T疗法发展。方法通过对现有研究进行综述,分析CRS的发病机制,包括关键细胞因子及信号通路的参与,并总结CRS的分级标准及临床管理方法。结果 CRS是CAR-T治疗的常见不良反应,其发生涉及多种细胞因子（如IL-6、IL-1、IFN-γ等）及信号通路（如JAK/STAT、NF-κB等）的激活。目前已有分级系统指导临床干预,但针对CRS的靶向治疗仍需进一步优化。结论深入理解CRS的机制有助于研发新型靶向药物,从而提升CAR-T治疗的安全性及疗效,为未来研究提供参考。

关键词: 嵌合抗原受体T细胞, 细胞因子释放综合征, IL-6, 发生机制, 信号通路, CRS分级

Abstract: Objective To investigate the mechanisms, grading, and management strategies of cytokine release syndrome (CRS) in chimeric antigen receptor T-cell (CAR-T) therapy in order to enhance the safety and efficacy of CAR-T cell therapy. Methods By reviewing studies currently available, the pathogenesis of CRS was analyzed, involving the key cytokines and signaling pathways before the grading criteria for and clinical approaches to CRS were summarized. Results CRS, a common adverse reaction in CAR-T therapy, involved the activation of cytokines (e.g., IL-6, IL-1, IFN-γ) and signaling pathways (e.g., JAK-STAT, NF-κB). Grading systems that guided clinical interventions were available, but targeted therapies required more optimization. Conclusion A better understanding of CRS mechanisms will facilitate the development of novel targeted drugs while improving the safety/efficacy of CAR-T therapy.

Key words: CAR-T Cell, Cytokine Release Syndrome, IL-6, Pathogenesis, Signaling Pathway, CRS Grading

中图分类号:

R979.1

任禹珂, 姜华, 李路路, 李双星, 霍桂桃, 杨艳伟, 张頔, 黄瑛, 耿兴超, 林志, 屈哲. CAR-T细胞治疗引起细胞因子释放综合征的发生机制研究[J]. 中国药物警戒, 2025, 22(7): 735-741.

REN Yuke, JIANG Hua, LI Lulu, LI Shuangxing, HUO Guitao, YANG Yanwei, ZHANG Di, HUANG Ying, GENG Xingchao, LIN Zhi, QU Zhe. Research Advances in the Pathogenesis of Cytokine Release Syndrome Induced by CAR-T Cell Therapy[J]. Chinese Journal of Pharmacovigilance, 2025, 22(7): 735-741.

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https://zgywjj.magtechjournal.com/CN/Y2025/V22/I7/735

参考文献

[1] JOY R, PHAIR K, O'HARA R, et al. Recent Advances and Current Challenges in CAR-T Cell Therapy[J]. Biotechnol Lett, 2024, 46(1): 115-126.
[2] YANG C, NGUYEN J, YEN Y.Complete Spectrum of Adverse Events Associated with Chimeric Antigen Receptor (CAR)-T Cell Therapies[J]. J Biomed Sci, 2023, 30(1): 89.
[3] MOLINOS-QUINTANA Á, ALONSO-SALADRIGUES A, HERRERO B, et al.Impact of Disease Burden and Late Loss of B Cell Aplasia on the Risk of Relapse after CD19 Chimeric Antigen Receptor T Cell (Tisagenlecleucel) Infusion in Pediatric and Young Adult Patients with Relapse/Refractory Acute Lymphoblastic Leukemia: Role of B-Cell Monitoring[J]. Front Immunol, 2024, 14: 1280580.
[4] PAN J, TANG K, LUO Y, et al.Sequential CD19 and CD22 Chimeric Antigen Receptor T-Cell Therapy for Childhood Refractory or Relapsed B-Cell Acute Lymphocytic Leukaemia: a Single-Arm, Phase 2 Study[J]. Lancet Oncol, 2023, 24(11): 1229-1241.
[5] RENNINGER J, KURZ L, STEIN H.Mitigation and Management of Common Toxicities Associated with the Administration of CAR-T Therapies in Oncology Patients[J]. Drug Saf, 2025, 48(7): 719-737.
[6] CHOHAN KL, SIEGLER EL, KENDERIAN SS.CAR-T Cell Therapy: the Efficacy and Toxicity Balance[J]. Curr Hematol Malig Rep, 2023, 18(2): 9-18.
[7] TEACHEY DT, BISHOP MR, MALONEY DG, et al.Toxicity Management after Chimeric Antigen Receptor T Cell Therapy: One Size Does Not Fit 'ALL'[J]. Nat Rev Clin Oncol, 2018, 15(4): 218.
[8] CHATENOUD L, FERRAN C, LEGENDRE C, et al.In vivo Cell Activation Following OKT3 Administration. Systemic Cytokine Release and Modulation by Corticosteroids[J]. Transplantation, 1990, 49(4): 697-702.
[9] WING MG, MOREAU T, GREENWOOD J, et al.Mechanism of First-Dose Cytokine-Release Syndrome by CAMPATH 1-H: Involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK Cells[J]. Clin Invest, 1996, 98: 2819-2826.
[10] WINKLER U, JENSEN M, MANZKE O, et al.Cytokinerelease Syndrome in Patients with B-Cell Chronic Lymphocytic Leukemia and High Lymphocyte Counts after Treatment with an Anti-CD20 Monoclonal Antibody (Rituximab, IDEC-C2B8)[J]. Blood, 1999, 94(7): 2217.
[11] PIHUSCH R, HOLLER E, MÜHLBAYER D, et al. The Impact of Antithymocyte Globulin on Short-Term Toxicity after Allogeneic Stem Cell Transplantation[J]. Bone Marrow Transplant, 2002, 30: 347-354.
[12] MACLEOD E, RAJAGOPAL D, VESSILLIER S.Using Reference Reagents to Confirm Robustness of Cytokine Release Assays for the Prediction of Monoclonal Antibody Safety[J]. J Vis Exp, 2023(199): 65087.
[13] FREEMAN CL, MORSCHHAUSER F, SEHN L, et al.Cytokine Release in Patients with CLL Treated with Obinutuzumab and Possible Relationship with Infusion-Related Reactions[J]. Blood, 2015, 126(24): 2646-2649.
[14] ALIG SK, DREYLING M, SEPPI B, et al.Severe Cytokine Release Syndrome after the First Dose of Brentuximab Vedotin in a Patient with Relapsed Systemic Anaplastic Large Cell Lymphoma (sALCL): a Case Report and Review of Literature[J]. Eur J Haematol, 2015, 94: 554-557.
[15] PICARD M, FILION CA, AUCLAIR MH, et al. Cytokine Profiling, Pretreatment with Anakinra,Tolerance Development in Platinum-Induced Mixed Hypersensitivity Reactions[J]. Ann Allergy Asthma Immunol, 2023, 131(4): 501-512. e9.
[16] TISONCIK JR, KORTH MJ, SIMMONS CP, et al.Into the Eye of the Cytokine Storm[J]. Microbiol Mol Biol Rev, 2012, 76: 16-32.
[17] DE JONG MD, SIMMONS CP, THANH TT, et al.Fatal Outcome of Human Influenza a (H5N1) is Associated with High Viral Load and Hypercytokinemia[J]. Nat Med, 2006, 12: 1203-1207.
[18] ATTIQ A, AFZAL S, WAHAB HA, et al.Cytokine Storm-Induced Thyroid Dysfunction in COVID-19: Insights into Pathogenesis and Therapeutic Approaches[J]. Drug Des Devel Ther, 2024, 18: 4215-4240.
[19] MAUDE SL, TEACHEY DT, PORTER DL, et al.CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy for Acute Lymphoblastic Leukemia[J]. Blood, 2015, 25(26): 4017-4023.
[20] ARVANITIS P, TZIOTIS A, PAPADIMATOS S, et al.Pathogenesis, Diagnosis, and Management of Cytokine Release Syndrome in Patients with Cancer: Focus on Infectious Disease Considerations[J]. Curr Oncol, 2025, 32(4): 198.
[21] ZHENG X, ZHANG S, WU H, et al.Plasma Exchange as an Effective Treatment for Cytokine Release Syndrome Following T Cell Receptor Engineered T Cell Immunotherapy: a Case Report[J]. Oncol Lett, 2024, 28(6): 607.
[22] SCHROEDER T, MARTENS T, FRANSECKY L, et al.Management of Chimeric Antigen Receptor T (CAR-T) Cell-Associated Toxicities[J]. Intensive Care Med, 2024, 50(9): 1459-1469.
[23] SINGH N, HOFMANN TJ, GERSHENSON Z, et al.Monocyte Lineage-Derived IL-6 Does not Affect Chimeric Antigen Receptor T-Cell Function[J]. Cytotherapy, 2017, 19(7): 867-880.
[24] MAJUMDER A.Evolving CAR-T-Cell Therapy for Cancer Treatment: from Scientific Discovery to Cures[J]. Cancers (Basel), 2023, 16(1): 39.
[25] SARHAN NM, WARDA AEA, IBRAHIM HSG, et al.Evaluation of Infliximab/Tocilizumab Versus Tocilizumab among COVID-19 Patients with Cytokine Storm Syndrome[J]. Sci Rep, 2023, 13(1): 6456.
[26] HAO Z, LI R, MENG L, et al.Macrophage, the Potential Key Mediator in CAR-T Related CRS[J]. Exp Hematol Oncol, 2020, 9: 15.
[27] HEIDARVAND M, HOSSEINI R, KAZEMI M, et al.Differentially Expressed Inflammatory Cell Death-Related Genes and the Serum Levels of IL-6 are Determinants for Severity of Coronaviruses Diseases-2019 (COVID-19)[J]. Adv Biomed Res, 2023, 12: 102.
[28] BARRETT D.IL-6 Blockade in Cytokine Storm Syndromes[J]. Adv Exp Med Biol, 2024, 1448: 565-572.
[29] TANAKA T, NARAZAKI M, KISHIMOTO T.Immunotherapeutic Implications of IL-6 Blockade for Cytokine Storm[J]. Immunotherapy, 2016, 8(8): 959-970.
[30] LEE DW, KOCHENDERFER JN, STETLER-STEVENSON M, et al.T Cells Expressing CD19 Chimeric Antigen Receptors for Acute Lymphoblastic Leukaemia in Lhildren and Young Adults: a Phase 1 Dose-Escalation Trial[J]. Lancet, 2015, 385(9967): 517-528.
[31] NORELLI M, CAMISA B, BARBIERA G, FALCONE L, et al.Monocyte-Derived IL-1 and IL-6 are Differentially Required for Cytokine Release Syndrome and Neurotoxicity Due to CAR-T Cells[J]. Nat Med, 2018, 24(6): 739-748.
[32] GIAVRIDIS T, VAN DER STEGEN SJC, EYQUEM J, et al. CAR T Cell-Induced Cytokine Release Syndrome is Mediated by Macrophages and Abated by IL-1 Blockade[J]. Nat Med, 2018, 24(6): 731-738.
[33] NOURI Y, WEINKOVE R, PERRET R.An in vitro Model to Assess CRS Potential of CAR T Cells Using a Tumor Cell Line and Autologous Monocytes[J]. Curr Protoc, 2023, 3(8): e864.
[34] JAWALE D, KHANDIBHARAD S, SINGH S.Innate Immune Response and Epigenetic Regulation: a Closely Intertwined Tale in Inflammation[J]. Adv Biol (Weinh), 2025, 9(2): e2400278.
[35] CIRELLA A, OLIVERA I, LURI-REY C, et al.Interleukin-18 in Cancer Immunology and Immunotherapy[J]. Expert Opin Ther Targets, 2023, 27(11): 1035-1042.
[36] KANG K, BACHU M, PARK SH, et al.IFN-γ Selectively Suppresses a Subset of TLR4-Activated Genes and Enhancers to Potentiate Macrophage Activation[J]. Nat Commun, 2019, 10(1): 3320.
[37] SONG M, PING Y, ZHANG K, et al.Low-Dose IFN-γ Induces Tumor Cell Stemness in Tumor Microenvironment of Non-Small Cell Lung Cancer[J]. Cancer Res, 2019, 79(14): 3737-3748.
[38] FERRERI CJ, BHUTANI M.Mechanisms and Management of CAR-T Toxicity[J]. Front Oncol, 2024, 14: 1396490.
[39] BAILEY SR, VATSA S, LARSON RC, et al.Blockade or Deletion of IF-γ Reduces Macrophage Activation without Compromising CAR T-Cell Function in Hematologic Malignancies[J]. Blood Cancer Discov, 2022, 3(2): 136-153.
[40] MANNI S, DEL BUFALO F, MERLI P, et al.Neutralizing IFN-γ Improves Safety without Compromising Efficacy of CAR-T Cell Therapy in B-cell Malignancies[J]. Nat Commun, 2023, 14(1): 3423.
[41] GUO H, QIAN L, CUI J.Focused Evaluation of the Roles of Macrophages in Chimeric Antigen Receptor (CAR) T Cell Therapy Associated Cytokine Release Syndrome[J]. Cancer Biol Med, 2021, 19(3): 333-342.
[42] RECCHIA LUCIANI G, BARILLI A, VISIGALLI R, et al.Cytokines from SARS-CoV-2 Spike-Activated Macrophages Hinder Proliferation and Cause Cell Dysfunction in Endothelial Cells[J]. Biomolecules, 2024 , 14(8): 927.
[43] SHANG S, CHEN Y, YANG X, et al.RNA Silencing of GM-CSF in CAR-T Cells Reduces the Secretion of Multiple Inflammatory Cytokines[J]. Invest New Drugs, 2023, 41(2): 220-225.
[44] STERNER RM, SAKEMURA R, COX MJ, et al.GM-CSF Inhibition Reduces Cytokine Release Syndrome and Neuroinflammation but Enhances CAR-T Cell Function in Xenografts[J]. Blood, 2019, 133: 697-709.
[45] KAGOYA Y.Cytokine Signaling in Chimeric Antigen Receptor T-Cell Therapy[J]. Int Immunol, 2024, 36(2): 49-56.
[46] SINGH S, ANSHITA D, RAVICHANDIRAN V.MCP-1: Function, Regulation, and Involvement in Disease[J]. Int Immunopharmacol, 2021, 101(Pt B): 107598.
[47] HAY KA, HANAFI LA, LI D, et al.Kinetics and Biomarkers of Severe Cytokine Release Syndrome after CD19 Chimeric Antigen Receptor-Modified T-Cell Therapy[J]. Blood, 2017, 130(21): 2295-2306.
[48] LECLERCQ-COHEN G, STEINHOFF N, ALBERTÍ SERVERA L, et al.Dissecting the Mechanisms Underlying the Cytokine Release Syndrome (CRS) Mediated by T-Cell Bispecific Antibodies[J]. Clin Cancer Res, 2023, 29(21): 4449-4463.
[49] WEI Z, CHENG Q, XU N, et al.Investigation of CRS-Associated Cytokines in CAR-T Therapy with Meta-GNN and Pathway Crosstalk[J]. BMC Bioinformatics, 2022, 23(1): 373.
[50] ZHANG D, SUN Y, LEI M, et al.Deciphering the Potential Ability of RG108 in Cisplatin-Induced HEI-OC1 Ototoxicity: a Research Based on RNA-seq and Molecular Biology Experiment[J]. Hereditas, 2023, 160(1): 18.
[51] ASHAYERI AHMADABAD H, MOHAMMADI PANAH S, GHASEMNEJAD-BERENJI H, et al.Metformin and the PI3K/AKT Signaling Pathway: Implications for Cancer, Cardiovascular, and Central Nervous System Diseases[J]. Naunyn Schmiedebergs Arch Pharmacol, 2025, 398(2): 1035-1055.
[52] OLÍMPIO F, ANDREATA-SANTOS R, ROSA PC, et al. Lactobacillus Rhamnosus Restores Antiviral Signaling and Attenuates Cytokines Secretion from Human Bronchial Epithelial Cells Exposed to Cigarette Smoke and Infected with SARS-CoV-2[J]. Probiotics Antimicrob Proteins, 2023, 15(6): 1513-1528.
[53] MALMSTRÖM E, KHAN HN, VEER CV', et al. The Long Non-Coding Antisense RNA JHDM1D-AS1 Regulates Inflammatory Responses in Human Monocytes[J]. Front Cell Infect Microbiol, 2022, 12: 934313.
[54] NG GYQ, LOH ZW, FANN DY, et al.Role of Mitogen-Activated Protein (MAP) Kinase Pathways in Metabolic Diseases[J]. Genome Integr, 2024, 15: e20230003.
[55] SCHUSTER SJ, MAZIARZ RT, RUSCH ES, et al.Grading and Management of Cytokine Release Syndrome in Patients Treated with Tisagenlecleucel in the JULIET Trial[J]. Blood Adv, 2020, 4(7): 1432-1439.
[56] PORTER D, FREY N, WOOD PA, et al.Grading of Cytokine Release Syndrome Associated with the CAR T Cell Therapy Tisagen-lecleucel[J]. J Hematol Oncol, 2018, 11(1): 35.
[57] LEE DW, GARDNER R, PORTER DL, et al.Current Concepts in the Diagnosis and Management of Cytokine Release Syndrome[J]. Blood, 2014, 124(2): 188-195.
[58] LEE DW, SANTOMASSO BD, LOCKE FL, et al.ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells[J]. Biol Blood Marrow Transplant, 2019, 25(4): 625-638.
[59] TU S, LUO X, MEI H, et al.Recommendations for the Timing, Dosage, and Usage of Corticosteroids During Cytokine Release Syndrome (CRS) Caused by Chimeric Antigen Receptor (CAR)-T Cell Therapy for Hematologic Malignancies[J]. Chin Med J (Engl), 2024, 137(22): 2681-2683.
[60] WALTON ZE, FRIGAULT MJ, MAUS MV.Current and Emerging Pharmacotherapies for Cytokine Release Syndrome, Neurotoxicity, and Hemophagocytic Lymphohistiocytosis-Like Syndrome due to CAR T Cell Therapy[J]. Expert Opin Pharmacother, 2024, 25(3): 263-279.

CAR-T细胞治疗引起细胞因子释放综合征的发生机制研究

Research Advances in the Pathogenesis of Cytokine Release Syndrome Induced by CAR-T Cell Therapy

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