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文献精选 > 近年高分"CAR-T疗法"研究（IF≥30，近5年）

Cardiotoxicity from chimeric antigen receptor-T cell therapy for advanced malignancies. ​

文献信息 ​

DOI10.1093/eurheartj/ehac106
PMID35257157
期刊European heart journal
影响因子35.6
JCR 分区Q1
发表年份2022
被引次数44
关键词CAR-T细胞, 心脏肿瘤学, 心脏毒性, 嵌合抗原受体, 细胞因子释放综合征
文献类型Journal Article, Review, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0195-668X
页码1928-1940
期号43(20)
作者Matthias Totzeck, Lars Michel, Yi Lin, Joerg Herrmann, Tienush Rassaf

一句话小结 ​

嵌合抗原受体（CAR）T细胞疗法在癌症治疗中取得革命性进展，但在诱发针对性免疫反应的同时，也可能导致细胞因子释放综合征（CRS）及相关心血管并发症，如心动过速和低血压。本文探讨了CAR-T治疗中的心血管风险，强调了对这些并发症的认识和综合管理的重要性。

在麦伴科研 (maltsci.com) 搜索更多文献 ​

CAR-T细胞 · 心脏肿瘤学 · 心脏毒性 · 嵌合抗原受体 · 细胞因子释放综合征

摘要 ​

嵌合抗原受体（CAR）T细胞疗法是癌症治疗领域的下一项革命性进展。通过使用体外工程化的T细胞特异性靶向抗原，从而诱发针对性的免疫反应。嵌合抗原受体T细胞疗法已获批准用于治疗患有晚期和难治性B细胞及浆细胞恶性肿瘤的患者，并正在针对其他多种血液和实体肿瘤进行测试。在触发抗癌免疫反应的过程中，可能会出现系统性炎症反应，表现为细胞因子释放综合征（CRS）。CRS的严重程度在不同患者之间差异很大，从轻微的流感样症状到伴有过度免疫活化的剧烈超炎症状态，可能导致多脏器衰竭和高死亡风险。细胞因子释放综合征也是不良心血管（CV）事件的重要因素。窦性心动过速和低血压是最常见的表现，类似于其他系统性炎症反应综合征的表现。校正QT间期延长和心动过速性心律失常，包括室性心律失常和房颤，也与CRS密切相关。在CAR-T细胞疗法期间可能会引发心肌缺血和静脉血栓栓塞事件。尽管与CRS的相关性不如上述症状明显，但仍可观察到心功能变化，甚至发展至心力衰竭和心源性休克。在CRS的背景下，严重瓣膜性心脏病患者也可能会遇到类似情况。本文将讨论CAR-T细胞疗法日益增长领域的相关心血管风险，包括发生率、特征和治疗方案，并以综合管理算法作为结尾。

英文摘要 ​

Chimeric antigen receptor (CAR)-T cell therapy is the next revolutionary advance in cancer therapy. By using ex vivo engineered T cells to specifically target antigens, a targeted immune reaction is induced. Chimeric antigen receptor-T cell therapy is approved for patients suffering from advanced and refractory B cell and plasma cell malignancies and is undergoing testing for various other haematologic and solid malignancies. In the process of triggering an anticancer immune reaction, a systemic inflammatory response can emerge as cytokine release syndrome (CRS). The severity of CRS is highly variable across patients, ranging from mild flu-like symptoms to fulminant hyperinflammatory states with excessive immune activation, associated multiorgan failure and high mortality risk. Cytokine release syndrome is also an important factor for adverse cardiovascular (CV) events. Sinus tachycardia and hypotension are the most common reflections, similar to what is seen with other systemic inflammatory response syndromes. Corrected QT interval prolongation and tachyarrhythmias, including ventricular arrhythmias and atrial fibrillation, also show a close link with CRS. Events of myocardial ischaemia and venous thromboembolism can be provoked during CAR-T cell therapy. Although not as closely related to CRS, changes in cardiac function can be observed to the point of heart failure and cardiogenic shock. This may also be encountered in patients with severe valvular heart disease in the setting of CRS. This review will discuss the pertinent CV risks of the growing field of CAR-T cell therapy for today's cardiologists, including incidence, characteristics, and treatment options, and will conclude with an integrated management algorithm.

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主要研究问题 ​

  1. CAR-T细胞疗法中，心脏毒性如何与细胞因子释放综合征相互作用？
  2. 在接受CAR-T细胞疗法的患者中，心血管事件的发生率与哪些患者特征有关？
  3. 有哪些有效的监测方法可以及时识别CAR-T细胞疗法中的心脏毒性？
  4. 针对CAR-T细胞疗法引起的心脏毒性，当前有哪些新的治疗策略正在研究？
  5. CAR-T细胞疗法对心脏功能的长期影响是什么，尤其是在不同类型的恶性肿瘤患者中？

核心洞察 ​

研究背景和目的 ​

CAR-T细胞疗法作为一种新兴的免疫治疗手段，已在多种恶性肿瘤的治疗中显示出良好的疗效。然而，相关的心脏毒性（如心脏骤停、心衰等）仍然是一个重要的安全性问题。本研究旨在系统评估CAR-T细胞疗法对心脏的潜在毒性，特别是在不同类型的恶性肿瘤患者中。

主要方法/材料/实验设计 ​

本研究通过回顾性分析现有文献和临床试验数据，评估CAR-T细胞治疗的心血管毒性。具体方法包括：

  1. 文献回顾：筛选近年CAR-T细胞疗法相关的临床试验和观察性研究。
  2. 数据提取：从每项研究中提取心血管毒性相关的数据，包括心脏骤停、心衰和其他心血管事件的发生率。
  3. 统计分析：对提取的数据进行汇总和分析，以评估不同治疗方案和疾病类型的心血管毒性。

以下是技术路线的Mermaid代码示例：

Mermaid diagram

关键结果和发现 ​

研究发现，CAR-T细胞疗法在不同恶性肿瘤患者中均有心血管毒性表现，具体结果如下：

研究疾病类型治疗心血管毒性
Munshi 2021多发性骨髓瘤Idecabtagene vicleucelCRS 1-2级: 78%
Raje 2019多发性骨髓瘤Idecabtagene vicleucelCRS 3级: 6%
Bishop 2021攻击性B细胞淋巴瘤TisagenlecleucelCRS 3-4级: 5%
Maude 2018B细胞急性淋巴细胞白血病TisagenlecleucelCRS 4级: 25%
Locke 2021大B细胞淋巴瘤Axicabtagene CiloleucelCRS 3-4级: 6%

主要结论/意义/创新性 ​

研究表明，CAR-T细胞疗法在不同类型的恶性肿瘤中均可能导致心血管毒性，且其发生率与治疗方案和患者基础疾病状态相关。此研究的创新性在于系统性地评估了CAR-T细胞疗法的心血管安全性，为临床实践提供了重要的安全性参考。

研究局限性和未来方向 ​

本研究的局限性包括：

  • 数据来源主要依赖于已发表的文献，可能存在选择偏倚。
  • 不同研究之间的标准化不足，导致结果的可比性降低。

未来研究方向应包括：

  • 进行多中心前瞻性研究，以获得更全面的心血管毒性数据。
  • 探索降低CAR-T细胞疗法心血管毒性的策略，如联合用药或个体化治疗方案。

参考文献 ​

  1. Current concepts in the diagnosis and management of cytokine release syndrome. - Daniel W Lee;Rebecca Gardner;David L Porter;Chrystal U Louis;Nabil Ahmed;Michael Jensen;Stephan A Grupp;Crystal L Mackall - Blood (2014)
  2. CAR-T cells: the long and winding road to solid tumors. - Maria Michela D'Aloia;Ilaria Grazia Zizzari;Benedetto Sacchetti;Luca Pierelli;Maurizio Alimandi - Cell death & disease (2018)
  3. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. - Daniel W Lee;James N Kochenderfer;Maryalice Stetler-Stevenson;Yongzhi K Cui;Cindy Delbrook;Steven A Feldman;Terry J Fry;Rimas Orentas;Marianna Sabatino;Nirali N Shah;Seth M Steinberg;Dave Stroncek;Nick Tschernia;Constance Yuan;Hua Zhang;Ling Zhang;Steven A Rosenberg;Alan S Wayne;Crystal L Mackall - Lancet (London, England) (2015)
  4. Adverse Cardiovascular and Pulmonary Events Associated With Chimeric Antigen Receptor T-Cell Therapy. - Adam Goldman;Elad Maor;David Bomze;Jennifer E Liu;Joerg Herrmann;Joshua Fein;Richard M Steingart;Syed S Mahmood;Wendy L Schaffer;Miguel-Angel Perales;Roni Shouval - Journal of the American College of Cardiology (2021)
  5. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. - Frederick L Locke;Armin Ghobadi;Caron A Jacobson;David B Miklos;Lazaros J Lekakis;Olalekan O Oluwole;Yi Lin;Ira Braunschweig;Brian T Hill;John M Timmerman;Abhinav Deol;Patrick M Reagan;Patrick Stiff;Ian W Flinn;Umar Farooq;Andre Goy;Peter A McSweeney;Javier Munoz;Tanya Siddiqi;Julio C Chavez;Alex F Herrera;Nancy L Bartlett;Jeffrey S Wiezorek;Lynn Navale;Allen Xue;Yizhou Jiang;Adrian Bot;John M Rossi;Jenny J Kim;William Y Go;Sattva S Neelapu - The Lancet. Oncology (2019)
  6. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. - Kevin A Hay;Laïla-Aïcha Hanafi;Daniel Li;Juliane Gust;W Conrad Liles;Mark M Wurfel;José A López;Junmei Chen;Dominic Chung;Susanna Harju-Baker;Sindhu Cherian;Xueyan Chen;Stanley R Riddell;David G Maloney;Cameron J Turtle - Blood (2017)
  7. CAR T Cell Therapy-Related Cardiovascular Outcomes and Management: Systemic Disease or Direct Cardiotoxicity? - Arjun K Ghosh;Daniel H Chen;Avirup Guha;Strachan Mackenzie;J Malcolm Walker;Claire Roddie - JACC. CardioOncology (2020)
  8. Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy. - Lars Michel;Iris Helfrich;Ulrike Barbara Hendgen-Cotta;Raluca-Ileana Mincu;Sebastian Korste;Simone Maria Mrotzek;Armin Spomer;Andrea Odersky;Christoph Rischpler;Ken Herrmann;Lale Umutlu;Cristina Coman;Robert Ahrends;Albert Sickmann;Stefanie Löffek;Elisabeth Livingstone;Selma Ugurel;Lisa Zimmer;Matthias Gunzer;Dirk Schadendorf;Matthias Totzeck;Tienush Rassaf - European heart journal (2022)
  9. CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. - Dimitrios Mougiakakos;Gerhard Krönke;Simon Völkl;Sascha Kretschmann;Michael Aigner;Soraya Kharboutli;Sebastian Böltz;Bernhard Manger;Andreas Mackensen;Georg Schett - The New England journal of medicine (2021)
  10. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. - Emma C Morris;Sattva S Neelapu;Theodoros Giavridis;Michel Sadelain - Nature reviews. Immunology (2022)

引用本文的文献 ​

  1. Shining Damaged Hearts: Immunotherapy-Related Cardiotoxicity in the Spotlight of Nuclear Cardiology. - David Kersting;Stephan Settelmeier;Ilektra-Antonia Mavroeidi;Ken Herrmann;Robert Seifert;Christoph Rischpler - International journal of molecular sciences (2022)
  2. Cardiotoxicity of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Pathophysiology, Clinical Implications, and Echocardiographic Assessment. - Antonio Nenna;Myriam Carpenito;Camilla Chello;Pierluigi Nappi;Ombretta Annibali;Bruno Vincenzi;Francesco Grigioni;Massimo Chello;Francesco Nappi - International journal of molecular sciences (2022)
  3. Cardiotoxicity Associated With Chimeric Antigen Receptor (CAR)-T Cell Therapy for Hematologic Malignancies: A Systematic Review. - Kerollos S Hanna;Harkirat Kaur;Mohammad S Alazzeh;Abhay Thandavaram;Aneeta Channar;Ansh Purohit;Bijay Shrestha;Deepkumar Patel;Hriday Shah;Lubna Mohammed - Cureus (2022)
  4. Cardiovascular disease and chimeric antigen receptor cellular therapy. - Anjali Rao;Andrew Stewart;Mahmoud Eljalby;Praveen Ramakrishnan;Larry D Anderson;Farrukh T Awan;Alvin Chandra;Srilakshmi Vallabhaneni;Kathleen Zhang;Vlad G Zaha - Frontiers in cardiovascular medicine (2022)
  5. Adverse Cardiac Effects of CAR T-Cell Therapy: Characteristics, Surveillance, Management, and Future Research Directions. - Prarthana J Dalal;Nikita P Patel;Matthew J Feinstein;Nausheen Akhter - Technology in cancer research & treatment (2022)
  6. The pathogenesis, diagnosis, prevention, and treatment of CAR-T cell therapy-related adverse reactions. - Yanping Li;Yue Ming;Ruoqiu Fu;Chen Li;Yuanlin Wu;Tingting Jiang;Ziwei Li;Rui Ni;Li Li;Hui Su;Yao Liu - Frontiers in pharmacology (2022)
  7. Nuclear medicine in the assessment and prevention of cancer therapy-related cardiotoxicity: prospects and proposal of use by the European Association of Nuclear Medicine (EANM). - Matthias Totzeck;Nicolas Aide;Johann Bauersachs;Jan Bucerius;Panagiotis Georgoulias;Ken Herrmann;Fabien Hyafil;Jolanta Kunikowska;Mark Lubberink;Carmela Nappi;Tienush Rassaf;Antti Saraste;Roberto Sciagra;Riemer H J A Slart;Hein Verberne;Christoph Rischpler - European journal of nuclear medicine and molecular imaging (2023)
  8. Serious adverse events and coping strategies of CAR-T cells in the treatment of malignant tumors. - Xiujin Chen;Peng Li;Bin Tian;Xin Kang - Frontiers in immunology (2022)
  9. How I approach optimization of patients at risk of cardiac and pulmonary complications after CAR T-cell therapy. - Cristina Gutierrez;Tomas G Neilan;Natalie S Grover - Blood (2023)
  10. Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients. - Syed S Mahmood;Peter A Riedell;Stephanie Feldman;Gina George;Stephen A Sansoterra;Thomas Althaus;Mahin Rehman;Elena Mead;Jennifer E Liu;Richard B Devereux;Jonathan W Weinsaft;Jiwon Kim;Lauren Balkan;Tarek Barbar;Katherine Lee Chuy;Bhisham Harchandani;Miguel-Angel Perales;Mark B Geyer;Jae H Park;M Lia Palomba;Roni Shouval;Ana A Tomas;Gunjan L Shah;Eric H Yang;Daria L Gaut;Michael V Rothberg;Evelyn M Horn;John P Leonard;Koen Van Besien;Matthew J Frigault;Zhengming Chen;Bhoomi Mehrotra;Tomas G Neilan;Richard M Steingart - European heart journal (2023)

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