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文献精选 > 近年高分"CAR-T疗法"研究（IF≥30，近5年）

CAR-T therapy alters synthesis of platelet-activating factor in multiple myeloma patients. ​

文献信息 ​

DOI10.1186/s13045-021-01101-6
PMID34108020
期刊Journal of hematology & oncology
影响因子40.4
JCR 分区Q1
发表年份2021
被引次数13
关键词CAR-T疗法, 细胞因子释放综合征, LPCAT1, 多发性骨髓瘤, 血小板激活因子
文献类型Letter, Research Support, Non-U.S. Gov't
ISSN1756-8722
页码90
期号14(1)
作者Mengying Ke, Liqing Kang, Ling Wang, Shu Yang, Yajun Wang, Haiyan Liu, Chunyan Gu, Hongming Huang, Ye Yang

一句话小结 ​

本研究通过对17名复发或难治性多发性骨髓瘤患者的血浆样本进行代谢组学和脂质组学分析，发现甘油磷酰胆碱（GPC）在细胞因子释放综合症（CRS）中显著减少，而溶血磷脂酰胆碱（lysoPCs）明显升高，这些代谢特征与CAR-T治疗的预后相关。研究表明，靶向PAF重塑可能成为增强MM CAR-T治疗效果的有效策略。

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CAR-T疗法 · 细胞因子释放综合征 · LPCAT1 · 多发性骨髓瘤 · 血小板激活因子

摘要 ​

嵌合抗原受体（CAR）T细胞治疗是一种新型的潜在靶向治疗，近年来在复发或难治性多发性骨髓瘤（MM）患者中取得了令人满意的疗效。然而，细胞因子释放综合症（CRS）和临床疗效已成为限制CAR-T在临床应用中的主要障碍。为了探索评估CRS和临床疗效的潜在生物标志物，我们对17名接受CAR-T治疗的复发或难治性MM患者的血浆样本进行了代谢组学和脂质组学分析。我们的研究表明，甘油磷酰胆碱（GPC），作为血小板激活因子（PAF）类似分子的中间体，在参与者经历CRS时显著减少，而溶血磷脂酰胆碱（lysoPCs）的显著升高，受溶血磷脂酰胆碱酰基转移酶（LPCAT）催化，是复发或难治性MM患者在CAR-T治疗后具有预后价值的独特代谢特征。GPC和lysoPC都参与了血小板激活因子（PAF）的重塑途径。此外，这些发现通过LPCAT1的表达得到了验证，LPCAT1是PAF途径中的关键因素，与三组MM基因表达谱数据集中较差的预后相关。总之，CAR-T治疗改变了MM患者的PAF合成，靶向PAF重塑可能是增强MM CAR-T治疗的一个有前景的策略。

英文摘要 ​

The chimera antigen receptor (CAR) T cell therapy is a novel and potential targeted therapy and has achieved satisfactory efficacy in patients with relapsed or refractory multiple myeloma (MM) in recent years. However, cytokine release syndrome (CRS) and clinical efficacy have become the major obstacles which limit the application of CAR-T in clinics. To explore the potential biomarkers in plasma for evaluating CRS and clinical efficacy, we performed metabolomic and lipidomic profiling of plasma samples from 17 relapsed or refractory MM patients received CAR-T therapy. Our study showed that glycerophosphocholine (GPC), an intermediate of platelet-activating factor (PAF)-like molecule, was significantly decreased when the participants underwent CRS, and the remarkable elevation of lysophosphatidylcholines (lysoPCs), which were catalyzed by lysoPC acyltransferase (LPCAT) was a distinct metabolism signature of relapsed or refractory MM patients with prognostic value post-CAR-T therapy. Both GPC and lysoPC are involved in platelet-activating factor (PAF) remodeling pathway. Besides, these findings were validated by LPCAT1 expression, a key factor in the PAF pathway, associated with poor outcome in three MM GEP datasets of MM. In conclusion, CAR-T therapy alters PAF synthesis in MM patients, and targeting PAF remodeling may be a promising strategy to enhance MM CAR-T therapy.

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主要研究问题 ​

  1. CAR-T治疗如何具体影响多发性骨髓瘤患者的PAF合成路径？
  2. 在CAR-T治疗过程中，GPC和lysoPC的变化对患者预后的影响是什么？
  3. 目前有哪些方法可以有效监测CAR-T治疗中CRS的发生与PAF合成的关系？
  4. 针对PAF重塑的靶向治疗在多发性骨髓瘤患者中的潜在应用有哪些？
  5. 除了PAF合成，CAR-T治疗对多发性骨髓瘤患者的其他代谢通路有何影响？

核心洞察 ​

研究背景和目的 ​

多发性骨髓瘤（MM）是一种难治性的血液恶性肿瘤，患者大多数会出现复发或耐药。CAR-T细胞疗法作为一种新型的靶向治疗方法，近年来在复发或耐药的MM患者中取得了良好的疗效。然而，细胞因子释放综合症（CRS）和临床疗效的评估成为其临床应用的主要障碍。本研究旨在通过代谢组学和脂质组学分析，探讨评估CRS和临床疗效的潜在生物标志物。

主要方法/材料/实验设计 ​

本研究共纳入17名接受CAR-T治疗的复发或耐药MM患者的血浆样本。研究采用代谢组学和脂质组学分析技术，具体流程如下：

Mermaid diagram
  1. 样本采集：收集患者的血浆样本。
  2. 代谢组学分析：利用UPLC-MS技术进行正电喷雾离子化模式下的代谢物检测。
  3. 脂质组学分析：进行脂质组学分析，识别与CRS和临床疗效相关的差异脂质。
  4. 数据统计分析：使用主成分分析（PCA）和正交偏最小二乘判别分析（OPLS-DA）进行数据处理。
  5. 结果验证：通过基因表达谱分析（GEP）验证LPCAT1的表达与患者预后的相关性。

关键结果和发现 ​

  • 在经历CRS的患者中，甘油磷酸胆碱（GPC）显著降低，而溶血磷脂酰胆碱（lysoPCs）显著升高，表明这些代谢物在CRS中的重要性。
  • 研究发现，LPCAT1的表达与不良预后相关，且在多项GEP数据集中均表现出升高。
  • LPC(16:0)的ROC曲线下面积为0.9833，表明其作为预后生物标志物的潜力。

主要结论/意义/创新性 ​

本研究表明，CAR-T疗法可以通过抑制PAF合成重塑途径，改变MM患者的代谢特征，特别是影响GPC和lysoPC的水平。LPCAT1可能作为一种肿瘤基因在MM中发挥作用，因此针对PAF重塑的策略可能成为增强MM CAR-T疗法的有效方法。

研究局限性和未来方向 ​

  • 本研究的样本量较小，未来应扩大样本量以验证结果的普适性。
  • 需要进一步的临床研究以确认LPCAT1作为生物标志物的有效性及其机制。
  • 探索PAF重塑相关靶点的治疗策略，为MM的个性化治疗提供新的思路。

参考文献 ​

  1. Modulation of inflammatory platelet-activating factor (PAF) receptor by the acyl analogue of PAF. - Vyala Hanumanthareddy Chaithra;Shancy Petsel Jacob;Chikkamenahalli Lakshminarayana Lakshmikanth;Mosale Seetharam Sumanth;Kandahalli Venkataranganayaka Abhilasha;Chu-Huang Chen;Anita Thyagarajan;Ravi P Sahu;Jeffery Bryant Travers;Thomas M McIntyre;Kempaiah Kemparaju;Gopal Kedihithlu Marathe - Journal of lipid research (2018)
  2. HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA. - Fengjie Jiang;Xiaozhu Tang;Chao Tang;Zhen Hua;Mengying Ke;Chen Wang;Jiamin Zhao;Shengyao Gao;Artur Jurczyszyn;Siegfried Janz;Meral Beksac;Fenghuang Zhan;Chunyan Gu;Ye Yang - Journal of hematology & oncology (2021)
  3. Emerging agents and regimens for multiple myeloma. - Yang Yang;Yi Li;Huiyao Gu;Mengmeng Dong;Zhen Cai - Journal of hematology & oncology (2020)
  4. Glutamine inhibits platelet-activating factor-mediated pulmonary tumour metastasis. - Han-A Kim;Kyoung-Jin Kim;So Young Yoon;Hern-Ku Lee;Suhn-Young Im - European journal of cancer (Oxford, England : 1990) (2012)
  5. Forty Years Since the Structural Elucidation of Platelet-Activating Factor (PAF): Historical, Current, and Future Research Perspectives. - Ronan Lordan;Alexandros Tsoupras;Ioannis Zabetakis;Constantinos A Demopoulos - Molecules (Basel, Switzerland) (2019)
  6. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. - S Vincent Rajkumar - American journal of hematology (2020)
  7. Topical photodynamic therapy induces systemic immunosuppression via generation of platelet-activating factor receptor ligands. - Matheus Ferracini;Ravi P Sahu;Kathleen A Harrison;Robert A Waeiss;Robert C Murphy;Sonia Jancar;Raymond L Konger;Jeffrey B Travers - The Journal of investigative dermatology (2015)
  8. Platelet-activating factor (PAF) receptor as a promising target for cancer cell repopulation after radiotherapy. - I A da Silva;R Chammas;A P Lepique;S Jancar - Oncogenesis (2017)
  9. European Myeloma Network perspective on CAR T-Cell therapies for multiple myeloma. - Benedetto Bruno;Ralph Wäsch;Monika Engelhardt;Francesca Gay;Luisa Giaccone;Mattia D'Agostino;Luis-Gerardo Rodríguez-Lobato;Sophia Danhof;Nico Gagelmann;Nicolaus Kröger;Rakesh Popat;Niels W C J Van de Donk;Evangelos Terpos;Meletios A Dimopoulos;Pieter Sonneveld;Hermann Einsele;Mario Boccadoro - Haematologica (2021)
  10. Involvement of platelets in tumor cell metastasis. - Belay Tesfamariam - Pharmacology & therapeutics (2016)

引用本文的文献 ​

  1. Acupuncture Synergized With Bortezomib Improves Survival of Multiple Myeloma Mice via Decreasing Metabolic Ornithine. - Mengying Ke;Jinjun Qian;Feng Hao;Xinying Li;Hongjie Wu;Xian Luo;Bin Xu;Chunyan Gu;Ye Yang - Frontiers in oncology (2021)
  2. G6PD promotes cell proliferation and dexamethasone resistance in multiple myeloma via increasing anti-oxidant production and activating Wnt/β-catenin pathway. - Rui Li;Mengying Ke;Mingming Qi;Zhenru Han;Yuhao Cao;Zhendong Deng;Jinjun Qian;Ye Yang;Chunyan Gu - Experimental hematology & oncology (2022)
  3. CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation. - Zigen Lin;Xiaozhu Tang;Yuhao Cao;Lijin Yang;Mingmei Jiang;Xinying Li;Jie Min;Bing Chen;Ye Yang;Chunyan Gu - Aging (2022)
  4. Small molecule metabolites: discovery of biomarkers and therapeutic targets. - Shi Qiu;Ying Cai;Hong Yao;Chunsheng Lin;Yiqiang Xie;Songqi Tang;Aihua Zhang - Signal transduction and targeted therapy (2023)
  5. The role of platelets in the regulation of tumor growth and metastasis: the mechanisms and targeted therapy. - Kaili Liao;Xue Zhang;Jie Liu;Feifei Teng;Yingcheng He;Jinting Cheng;Qijun Yang;Wenyige Zhang;Yuxuan Xie;Daixin Guo;Gaoquan Cao;Yanmei Xu;Bo Huang;Xiaozhong Wang - MedComm (2023)
  6. Exploring the diversity, bioactivity of endophytes, and metabolome in Synsepalum dulcificum. - Sisi Liu;Yage Hou;Kaixuan Zheng;Qian Ma;Meng Wen;Shicheng Shao;Shaohua Wu - Frontiers in microbiology (2024)
  7. Advances and challenges in gene therapy strategies for pediatric cancer: a comprehensive update. - Amir Kian Moaveni;Maryam Amiri;Behrouz Shademan;Arezoo Farhadi;Javad Behroozi;Alireza Nourazarian - Frontiers in molecular biosciences (2024)
  8. Activated platelet-derived exosomal LRG1 promotes multiple myeloma cell growth. - Meng Gao;Hang Dong;Siyi Jiang;Fangping Chen;Yunfeng Fu;Yanwei Luo - Oncogenesis (2024)
  9. Identification of lipid metabolism-related gene signature in the bone marrow microenvironment of multiple myelomas through deep analysis of transcriptomic data. - Dan Feng;Zhen Wang;Shengji Cao;Hui Xu;Shijun Li - Clinical and experimental medicine (2024)
  10. Comprehensive pancancer analysis reveals that LPCAT1 is a novel predictive biomarker for prognosis and immunotherapy response. - Hongyu Gao;Jinfeng Zhu;Tong Wu;Qian Long;Xinyu Guan;Qitong Chen;Wenjun Yi - Apoptosis : an international journal on programmed cell death (2024)

... (3 更多 篇文献)

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