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A Metabolism Toolbox for CAR T Therapy. ​

文献信息 ​

DOI10.3389/fonc.2019.00322
PMID31114756
期刊Frontiers in oncology
影响因子3.3
JCR 分区Q2
发表年份2019
被引次数47
关键词抗肿瘤免疫反应, 嵌合抗原受体（CAR）, 免疫疗法, 代谢, 肿瘤微环境（TME）
文献类型Journal Article, Review
ISSN2234-943X
页码322
期号9()
作者Xuequn Xu, J N Rashida Gnanaprakasam, John Sherman, Ruoning Wang

一句话小结 ​

本综述探讨了通过基因工程转移表达嵌合抗原受体（CARs）的T细胞在癌症治疗中的潜力，强调肿瘤微环境中营养竞争对CAR T细胞功能的影响。研究提出了一种代谢工具箱，以增强CAR T细胞的代谢适应性，从而提高其在治疗实体瘤中的疗效，具有重要的临床意义。

在麦伴科研 (maltsci.com) 搜索更多文献 ​

抗肿瘤免疫反应 · 嵌合抗原受体（CAR） · 免疫疗法 · 代谢 · 肿瘤微环境（TME）

摘要 ​

通过基因工程转移表达嵌合抗原受体（CARs）的T细胞是治疗癌症患者的最有前景的新疗法之一。强有力的CAR T细胞介导的抗肿瘤反应需要营养和能量供应与CAR T细胞扩增及功能之间的协调。然而，肿瘤细胞的高代谢需求通过在肿瘤微环境（TME）中竞争营养物质来削弱CAR T细胞的功能。为了在治疗实体瘤时显著改善CAR T免疫治疗的临床结果，必须在代谢上准备CAR T细胞，以克服TME所施加的代谢障碍。在本综述中，我们讨论了一种潜在的代谢工具箱，以改善CAR T细胞的代谢适应性，最大化CAR T治疗的疗效。

英文摘要 ​

The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) through genetic engineering is one of the most promising new therapies for treating cancer patients. A robust CAR T cell-mediated anti-tumor response requires the coordination of nutrient and energy supplies with CAR T cell expansion and function. However, the high metabolic demands of tumor cells compromise the function of CAR T cells by competing for nutrients within the tumor microenvironment (TME). To substantially improve clinical outcomes of CAR T immunotherapy while treating solid tumors, it is essential to metabolically prepare CAR T cells to overcome the metabolic barriers imposed by the TME. In this review, we discuss a potential metabolism toolbox to improve the metabolic fitness of CAR T cells and maximize the efficacy of CAR T therapy.

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主要研究问题 ​

  1. 如何评估不同代谢工具对CAR T细胞功能的具体影响？
  2. 在肿瘤微环境中，哪些营养物质对CAR T细胞的代谢适应性最为关键？
  3. 目前有哪些新兴技术可以用于优化CAR T细胞的代谢状态？
  4. CAR T细胞在不同类型肿瘤中的代谢需求是否存在显著差异？
  5. 如何将代谢调节策略与其他免疫疗法结合，以提高癌症治疗的整体效果？

核心洞察 ​

研究背景和目的 ​

CAR T细胞疗法是通过基因工程技术转移表达嵌合抗原受体（CAR）的T细胞，以治疗癌症患者的有前景的新疗法。然而，肿瘤微环境（TME）中肿瘤细胞的高代谢需求会与CAR T细胞争夺营养，从而影响其功能。因此，本研究旨在探讨一种代谢工具箱，以改善CAR T细胞的代谢适应性，从而提高其在实体瘤治疗中的疗效。

主要方法/材料/实验设计 ​

本研究通过以下几个步骤构建代谢工具箱，以优化CAR T细胞的代谢状态：

Mermaid diagram
  1. 患者外周血单核细胞(PBMC)采集：通过白细胞分离技术获取患者的PBMC。
  2. T细胞富集和激活：利用抗体和细胞因子激活T细胞。
  3. 基因修饰：通过病毒或非病毒方法将CAR基因转入T细胞。
  4. 细胞扩增：在适当的培养条件下扩增CAR T细胞。
  5. 细胞注入患者：将扩增后的CAR T细胞注入患者体内。
  6. 评估T细胞在TME中的代谢适应性：监测T细胞在肿瘤微环境中的表现。
  7. 优化T细胞的代谢状态：根据代谢状态进行进一步的营养和环境调整。

关键结果和发现 ​

  1. 代谢适应性：CAR T细胞在肿瘤微环境中面临营养竞争和酸性环境的挑战，代谢适应性对其抗肿瘤效应至关重要。
  2. 营养补充：通过补充特定氨基酸（如L-精氨酸）和优化培养基成分，能够显著增强CAR T细胞的增殖和功能。
  3. 工程化CAR T细胞：设计了响应肿瘤微环境的CAR T细胞，如HIF1-CAR T细胞，能够在低氧环境中增强细胞毒性。

主要结论/意义/创新性 ​

本研究提出了一种代谢工具箱，通过改善CAR T细胞的代谢适应性，增强其在肿瘤微环境中的生存能力和抗肿瘤活性。这一策略为CAR T细胞疗法在实体瘤中的应用提供了新的思路，可能推动未来的临床研究和治疗策略的发展。

研究局限性和未来方向 ​

  1. 局限性：目前的研究主要集中在细胞培养和小动物模型中，临床应用效果仍需验证。
  2. 未来方向：进一步探索不同肿瘤类型的TME特征，开发个性化的代谢优化策略；同时，研究其他免疫细胞在TME中的代谢动态，以增强整体免疫疗法的效果。

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  2. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. - Sarwish Rafiq;Christopher S Hackett;Renier J Brentjens - Nature reviews. Clinical oncology (2020)
  3. A Proposed Treatment Approach to Treat Lethal Mutating Cancers. - Kevin Roe - Pharmaceutical research (2020)
  4. Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction. - Tingting Wang;J N Rashida Gnanaprakasam;Xuyong Chen;Siwen Kang;Xuequn Xu;Hua Sun;Lingling Liu;Hayley Rodgers;Ethan Miller;Teresa A Cassel;Qiushi Sun;Sara Vicente-Muñoz;Marc O Warmoes;Penghui Lin;Zayda Lizbeth Piedra-Quintero;Mireia Guerau-de-Arellano;Kevin A Cassady;Song Guo Zheng;Jun Yang;Andrew N Lane;Xiaotong Song;Teresa W-M Fan;Ruoning Wang - Nature metabolism (2020)
  5. Innovative CAR-T Cell Therapy for Solid Tumor; Current Duel between CAR-T Spear and Tumor Shield. - Yuna Jo;Laraib Amir Ali;Ju A Shim;Byung Ha Lee;Changwan Hong - Cancers (2020)
  6. Innovative strategies to advance CAR T cell therapy for solid tumors. - Meijuan Huang;Jinniu Deng;Lili Gao;Jianfeng Zhou - American journal of cancer research (2020)
  7. The Role of Immunological Synapse in Predicting the Efficacy of Chimeric Antigen Receptor (CAR) Immunotherapy. - Dongfang Liu;Saiaditya Badeti;Gianpietro Dotti;Jie-Gen Jiang;He Wang;James Dermody;Patricia Soteropoulos;Deanna Streck;Raymond B Birge;Chen Liu - Cell communication and signaling : CCS (2020)
  8. Revisiting Glycogen in Cancer: A Conspicuous and Targetable Enabler of Malignant Transformation. - Tashbib Khan;Mitchell A Sullivan;Jennifer H Gunter;Thomas Kryza;Nicholas Lyons;Yaowu He;John D Hooper - Frontiers in oncology (2020)
  9. Linking Immunoevasion and Metabolic Reprogramming in B-Cell-Derived Lymphomas. - Martin Böttcher;Rebecca Baur;Andrej Stoll;Andreas Mackensen;Dimitrios Mougiakakos - Frontiers in oncology (2020)
  10. Fueling chimeric antigen receptor T cells with cytokines. - Jin Jin;Jiali Cheng;Meijuan Huang;Hui Luo;Jianfeng Zhou - American journal of cancer research (2020)

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