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Curated Papers > Recent high-impact studies on "CAR-T therapy" (IF ≥ 30, last 5 years)

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

Literature Information ​

DOI10.1186/s13045-021-01101-6
PMID34108020
JournalJournal of hematology & oncology
Impact Factor40.4
JCR QuartileQ1
Publication Year2021
Times Cited13
KeywordsCAR-T therapy, Cytokine release syndrome, LPCAT1, Multiple myeloma, Platelet-activating factor
Literature TypeLetter, Research Support, Non-U.S. Gov't
ISSN1756-8722
Pages90
Issue14(1)
AuthorsMengying Ke, Liqing Kang, Ling Wang, Shu Yang, Yajun Wang, Haiyan Liu, Chunyan Gu, Hongming Huang, Ye Yang

TL;DR ​

This study investigates the metabolic changes in plasma of relapsed or refractory multiple myeloma (MM) patients undergoing CAR T cell therapy, identifying glycerophosphocholine (GPC) and lysophosphatidylcholines (lysoPCs) as potential biomarkers for cytokine release syndrome (CRS) and clinical efficacy. The findings suggest that alterations in the platelet-activating factor (PAF) remodeling pathway could provide insights into improving CAR-T therapy outcomes for MM patients.

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CAR-T therapy · Cytokine release syndrome · LPCAT1 · Multiple myeloma · Platelet-activating factor

Abstract ​

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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Primary Questions Addressed ​

  1. What are the specific mechanisms by which CAR-T therapy influences the remodeling of platelet-activating factor in multiple myeloma?
  2. How do changes in glycerophosphocholine and lysophosphatidylcholines correlate with the severity of cytokine release syndrome in CAR-T therapy patients?
  3. In what ways can targeting the PAF remodeling pathway enhance the efficacy of CAR-T therapy in multiple myeloma?
  4. What role does LPCAT1 expression play in the prognosis of multiple myeloma patients undergoing CAR-T therapy?
  5. Are there other metabolites or lipidomic profiles that could serve as potential biomarkers for evaluating clinical outcomes in CAR-T therapy for multiple myeloma?

Key Findings ​

Research Background and Objective ​

Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a promising treatment for relapsed or refractory multiple myeloma (MM), yet its clinical application is hindered by complications such as cytokine release syndrome (CRS) and variable efficacy. This study aims to identify potential plasma biomarkers for evaluating CRS and clinical efficacy in MM patients undergoing CAR-T therapy, focusing on lipidomic and metabolomic changes.

Main Methods/Materials/Experimental Design ​

The study involved plasma samples from 17 relapsed or refractory MM patients who received CAR-T therapy. The key methods used include:

  1. Metabolomic and Lipidomic Profiling:

    • Plasma samples were analyzed using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) in positive electrospray ionization (ESI+) mode.
    • Principal Component Analysis (PCA) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) were utilized to differentiate between groups based on CRS and clinical efficacy.

  2. Key Measurements:

    • Levels of glycerophosphocholine (GPC) and lysophosphatidylcholines (lysoPCs) were quantified to assess their roles in the platelet-activating factor (PAF) remodeling pathway.

  3. Gene Expression Profiling:

    • LPCAT1 gene expression was evaluated in bone marrow plasma cells to correlate its levels with clinical outcomes.
Mermaid diagram

Key Results and Findings ​

  • Metabolite Changes:

    • GPC levels significantly decreased in patients experiencing CRS, while levels of lysoPCs increased, indicating altered lipid metabolism.
    • LPC(16:0) showed a high area under the receiver operating characteristic (ROC) curve (0.9833), suggesting its potential as a prognostic biomarker.

  • LPCAT1 Expression:

    • Increased expression of LPCAT1 was observed in MM patients compared to normal individuals and correlated with poor overall survival in multiple datasets.

Main Conclusions/Significance/Innovation ​

The study concludes that CAR-T therapy modifies PAF synthesis in MM patients, with significant implications for understanding CRS and treatment efficacy. The identification of GPC and lysoPCs as biomarkers provides new avenues for monitoring patient responses to CAR-T therapy. Furthermore, targeting LPCAT1 may enhance the effectiveness of CAR-T treatments, positioning it as a potential therapeutic target in MM management.

Research Limitations and Future Directions ​

  • Limitations:

    • The study is limited by its small sample size and the need for validation in larger cohorts.
    • The mechanistic understanding of how PAF remodeling affects CAR-T efficacy requires further exploration.

  • Future Directions:

    • Future research should focus on larger, multi-center studies to validate the identified biomarkers.
    • Investigating the therapeutic targeting of LPCAT1 in clinical settings could provide insights into improving CAR-T therapy outcomes in MM patients.

References ​

  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)

Literatures Citing This Work ​

  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 more literatures)

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