恶性血液病患者CAR-T细胞治疗相关感染的现状与管理

舒畅; 杜艾桦

doi:10.13201/j.issn.1004-2806.2022.07.016

恶性血液病患者CAR-T细胞治疗相关感染的现状与管理

舒畅¹,
杜艾桦^1, ,

- 华中科技大学同济医学院附属同济医院药物临床试验机构办公室(武汉，430030)
基金项目:
湖北省卫健委卫生健康科研项目(No：WJ2021M121)

详细信息

通讯作者: 杜艾桦，E-mail：ahdu@tjh.tjmu.edu.cn

中图分类号: R733

收稿日期: 2022-05-07

刊出日期: 2022-07-01

Status and management of CAR-T cell therapy related infections in patients with hematological malignancies

SHU Chang¹,
DU Aihua^1, ,

- Office of Drug Clinical Trial Institution, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

More Information

Corresponding author: DU Aihua, E-mail: ahdu@tjh.tjmu.edu.cn

Received Date: 07 May 2022

Publish Date: 01 July 2022

摘要

摘要: 嵌合抗原受体T(CAR-T)细胞免疫治疗血液系统肿瘤在最近几年取得了长足进展，成为复发难治患者的新选择。随着CAR-T细胞疗法的不断普及，患者生存期明显延长，此时感染成为了影响患者长期生存的重要因素。造成CAR-T患者感染的主要病原体包括细菌、病毒和真菌，早期感染以细菌为主，晚期感染病毒多见。CAR-T患者易发生感染主要是由于免疫功能受抑制，由宿主因素和CAR-T细胞治疗相关因素导致。尽管早期的感染与细胞因子释放综合征难以鉴别，但对于已出现的发热等症状需要进行积极治疗，并尽可能寻找病原学依据。另外，CAR-T细胞治疗后患者需要加强感染的预防，通过预防性的药物使用和患者教育来减少感染发生的概率，从而提高患者的生存时间和生活质量。
- 恶性血液病 /
- 嵌合抗原受体T细胞治疗 /
- 感染
Abstract: In recent years, chimeric antigen receptor T(CAR-T) cell immunotherapy has made great progress in hematological tumors, and has become a new option for relapsed and refractory patients. With the application of CAR-T therapy, the overall survival of patients has been significantly prolonged, and infectious complication has become one of the most important factors that affect the long-term survival of patients. The pathogens of infection in CAR-T patients mainly include bacteria, viruses and fungi. CAR-T patients are susceptible to infection because of suppressed immune function, which is caused by host factors and CAR-T therapy-related factors. Although it is difficult to distinguish early infection from cytokine release syndrome, anti-infective treatment is immediately needed whenever fever or other infectious symptoms occurred, together with the tests seeking for etiological evidence. In addition, prophylaxis of infection is recommended for CAR-T patients, with both prophylactic drug use and patient education, to reduce the probability of infection, and in order to improve the survival and quality of life.
- hematological malignancies /
- chimeric antigen receptor T cell therapy /
- infection

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参考文献(47)

[1]	Hirayama AV, Gauthier J, Hay KA, et al. High rate of durable complete remission in follicular lymphoma after CD19 CAR-T cell immunotherapy[J]. Blood, 2019, 134(7): 636-640. doi: 10.1182/blood.2019000905
[2]	Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma(ZUMA-1): a single-arm, multicentre, phase 1-2 trial[J]. Lancet Oncol, 2019, 20(1): 31-42. doi: 10.1016/S1470-2045(18)30864-7
[3]	Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma[J]. N Engl J Med, 2019, 380(18): 1726-1737. doi: 10.1056/NEJMoa1817226
[4]	Ramos CA, Grover NS, Beaven AW, et al. Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma[J]. J Clin Oncol, 2020, 38(32): 3794-3804. doi: 10.1200/JCO.20.01342
[5]	Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma[J]. N Engl J Med, 2020, 382(14): 1331-1342. doi: 10.1056/NEJMoa1914347
[6]	Wang N, Hu X, Cao W, et al. Efficacy and safety of CAR19/22 T-cell cocktail therapy in patients with refractory/relapsed B-cell malignancies[J]. Blood, 2020, 135(1): 17-27. doi: 10.1182/blood.2019000017
[7]	Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma(CARTITUDE-1): a phase 1b/2 open-label study[J]. Lancet, 2021, 398(10297): 314-324. doi: 10.1016/S0140-6736(21)00933-8
[8]	Pan J, Tan Y, Wang G, et al. Donor-Derived CD7 Chimeric Antigen Receptor T Cells for T-Cell Acute Lymphoblastic Leukemia: First-in-Human, Phase I Trial[J]. J Clin Oncol, 2021, 39(30): 3340-3351. doi: 10.1200/JCO.21.00389
[9]	Wang D, Wang J, Hu G, et al. A phase 1 study of a novel fully human BCMA-targeting CAR(CT103A)in patients with relapsed/refractory multiple myeloma[J]. Blood, 2021, 137(21): 2890-2901. doi: 10.1182/blood.2020008936
[10]	梅恒, 李成功, 胡豫. 嵌合抗原受体T细胞疗法在难治/复发多发性骨髓瘤中的研究进展[J]. 临床血液学杂志, 2020, 33(7): 441-445. https://t.cnki.net/kcms/detail?v=znUxuWmAUteQ67FvanLCNbVs8VhT7QhsH41E4NyzUiqRx18ARIWKwebcipQnzEDUyXn5SbJmo6hzNP3TZ1mJl2msDXaBNPgoUjBnwy45VCP5p1nWxyOJLxLx-d5n5a8a&uniplatform=NZKPT
[11]	Cappell KM, Sherry RM, Yang JC, et al. Long-Term Follow-Up of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy[J]. J Clin Oncol, 2020, 38(32): 3805-3815. doi: 10.1200/JCO.20.01467
[12]	Chakraborty R, Hill BT, Majeed A, et al. Late Effects after Chimeric Antigen Receptor T cell Therapy for Lymphoid Malignancies[J]. Transplant Cell Ther, 2021, 27(3): 222-229. doi: 10.1016/j.jtct.2020.10.002
[13]	Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium[J]. J Clin Oncol, 2020, 38(27): 3119-3128. doi: 10.1200/JCO.19.02104
[14]	Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma[J]. N Engl J Med, 2019, 380(1): 45-56. doi: 10.1056/NEJMoa1804980
[15]	Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas(TRANSCEND NHL 001): a multicentre seamless design study[J]. Lancet, 2020, 396(10254): 839-852. doi: 10.1016/S0140-6736(20)31366-0
[16]	Hill JA, Li D, Hay KA, et al. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy[J]. Blood, 2018, 131(1): 121-130. doi: 10.1182/blood-2017-07-793760
[17]	Wudhikarn K, Palomba ML, Pennisi M, et al. Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma[J]. Blood Cancer J, 2020, 10(8): 79. doi: 10.1038/s41408-020-00346-7
[18]	Logue JM, Zucchetti E, Bachmeier CA, et al. Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma[J]. Haematologica, 2021, 106(4): 978-986.
[19]	Vora SB, Waghmare A, Englund JA, et al. Infectious Complications Following CD19 Chimeric Antigen Receptor T-cell Therapy for Children, Adolescents, and Young Adults[J]. Open Forum Infect Dis, 2020, 7(5): ofaa121. doi: 10.1093/ofid/ofaa121
[20]	Strati P, Varma A, Adkins S, et al. Hematopoietic recovery and immune reconstitution after axicabtagene ciloleucel in patients with large B-cell lymphoma[J]. Haematologica, 2021, 106(10): 2667-2672.
[21]	Cordeiro A, Bezerra ED, Hirayama AV, et al. Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells[J]. Biol Blood Marrow Transplant, 2020, 26(1): 26-33. doi: 10.1016/j.bbmt.2019.08.003
[22]	Park JH, Romero FA, Taur Y, et al. Cytokine Release Syndrome Grade as a Predictive Marker for Infections in Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia Treated With Chimeric Antigen Receptor T Cells[J]. Clin Infect Dis, 2018, 67(4): 533-540. doi: 10.1093/cid/ciy152
[23]	Wang D, Mao X, Que Y, et al. Viral infection/reactivation during long-term follow-up in multiple myeloma patients with anti-BCMA CAR therapy[J]. Blood Cancer J, 2021, 11(10): 168. doi: 10.1038/s41408-021-00563-8
[24]	Wittmann Dayagi T, Sherman G, Bielorai B, et al. Characteristics and risk factors of infections following CD28-based CD19 CAR-T cells[J]. Leuk Lymphoma, 2021, 62(7): 1692-1701. doi: 10.1080/10428194.2021.1881506
[25]	Baird JH, Epstein DJ, Tamaresis JS, et al. Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma[J]. Blood Adv, 2021, 5(1): 143-155. doi: 10.1182/bloodadvances.2020002732
[26]	Kusumoto S, Arcaini L, Hong X, et al. Risk of HBV reactivation in patients with B-cell lymphomas receiving obinutuzumab or rituximab immunochemotherapy[J]. Blood, 2019, 133(2): 137-146. doi: 10.1182/blood-2018-04-848044
[27]	Wei J, Zhu X, Mao X, et al. Severe early hepatitis B reactivation in a patient receiving anti-CD19 and anti-CD22 CAR T cells for the treatment of diffuse large B-cell lymphoma[J]. J Immunother Cancer, 2019, 7(1): 315. doi: 10.1186/s40425-019-0790-y
[28]	Bao L, Hao C, Wang J, et al. High-Dose Cyclophosphamide Administration Orchestrates Phenotypic and Functional Alterations of Immature Dendritic Cells and Regulates Th Cell Polarization[J]. Front Pharmacol, 2020, 11: 775. doi: 10.3389/fphar.2020.00775
[29]	Fried S, Avigdor A, Bielorai B, et al. Early and late hematologic toxicity following CD19 CAR-T cells[J]. Bone Marrow Transplant, 2019, 54(10): 1643-1650. doi: 10.1038/s41409-019-0487-3
[30]	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. doi: 10.1016/j.bbmt.2018.12.758
[31]	Cain DW, Cidlowski JA. Immune regulation by glucocorticoids[J]. Nat Rev Immunol, 2017, 17(4): 233-247. doi: 10.1038/nri.2017.1
[32]	Bhoj VG, Arhontoulis D, Wertheim G, et al. Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy[J]. Blood, 2016, 128(3): 360-370. doi: 10.1182/blood-2016-01-694356
[33]	Hill JA, Giralt S, Torgerson TR, et al. CAR-T - and a side order of IgG, to go?-Immunoglobulin replacement in patients receiving CAR-T cell therapy[J]. Blood Rev, 2019, 38: 100596. doi: 10.1016/j.blre.2019.100596
[34]	Schuster SJ, Svoboda J, Chong EA, et al. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas[J]. N Engl J Med, 2017, 377(26): 2545-2554. doi: 10.1056/NEJMoa1708566
[35]	Donnelly JP, Chen SC, Kauffman CA, et al. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium[J]. Clin Infect Dis, 2020, 71(6): 1367-1376. doi: 10.1093/cid/ciz1008
[36]	宏基因组分析和诊断技术在急危重症感染应用专家共识组. 宏基因组分析和诊断技术在急危重症感染应用的专家共识[J]. 中华急诊医学杂志, 2019, 28(2): 151-155.
[37]	Luo H, Wang N, Huang L, et al. Inflammatory signatures for quick diagnosis of life-threatening infection during the CAR T-cell therapy[J]. J Immunother Cancer, 2019, 7(1): 271. doi: 10.1186/s40425-019-0767-x
[38]	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. doi: 10.1182/blood-2017-06-793141
[39]	Bartolini L, Theodore WH, Jacobson S, et al. Infection with HHV-6 and its role in epilepsy[J]. Epilepsy Res, 2019, 153: 34-39. doi: 10.1016/j.eplepsyres.2019.03.016
[40]	Hill JA, Seo SK. How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies[J]. Blood, 2020, 136(8): 925-935. doi: 10.1182/blood.2019004000
[41]	DoiY. Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections[J]. Clin Infect Dis, 2019, 69(Suppl 7): S565-S575.
[42]	Los-Arcos I, Iacoboni G, Aguilar-Guisado M, et al. Recommendations for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T-cell therapy: a position paper[J]. Infection, 2021, 49(2): 215-231. doi: 10.1007/s15010-020-01521-5
[43]	Jakharia N, Howard D, Riedel DJ. CMV Infection in Hematopoietic Stem Cell Transplantation: Prevention and Treatment Strategies[J]. Curr Treat Options Infect Dis, 2021, 13(3): 123-140. doi: 10.1007/s40506-021-00253-w
[44]	European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2018[J]. J Hepatol, 2018, 69(2): 461-511. doi: 10.1016/j.jhep.2018.03.026
[45]	Haidar G, Dorritie K, Farah R, et al. Invasive Mold Infections After Chimeric Antigen Receptor-Modified T-Cell Therapy: A Case Series, Review of the Literature, and Implications for Prophylaxis[J]. Clin Infect Dis, 2020, 71(3): 672-676. doi: 10.1093/cid/ciz1127
[46]	Cao W, Wei J, Wang N, et al. Entecavir prophylaxis for hepatitis B virus reactivation in patients with CAR T-cell therapy[J]. Blood, 2020, 136(4): 516-519. doi: 10.1182/blood.2020004907
[47]	Lewis RE, Kontoyiannis DP. Chimeric Antigen Receptor T-cell Immunotherapy and Need for Prophylaxis for Invasive Mold Infections[J]. Clin Infect Dis, 2020, 71(7): 1802-1803. doi: 10.1093/cid/ciaa031