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Curated Papers > High-Impact Authoritative Literature on CAR-T Therapy

A Metabolism Toolbox for CAR T Therapy. ​

Literature Information ​

DOI10.3389/fonc.2019.00322
PMID31114756
JournalFrontiers in oncology
Impact Factor3.3
JCR QuartileQ2
Publication Year2019
Times Cited47
Keywordsanti-tumor immune response, chimeric antigen receptor (CAR), immunotherapy, metabolism, tumor microenvironment (TME)
Literature TypeJournal Article, Review
ISSN2234-943X
Pages322
Issue9()
AuthorsXuequn Xu, J N Rashida Gnanaprakasam, John Sherman, Ruoning Wang

TL;DR ​

This review highlights the challenges posed by the tumor microenvironment (TME) on the efficacy of CAR T cell therapy due to the high metabolic demands of tumor cells that compete for essential nutrients. It proposes a "metabolism toolbox" to enhance the metabolic fitness of CAR T cells, aiming to improve their expansion and function, thereby potentially increasing the therapeutic success against solid tumors.

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anti-tumor immune response · chimeric antigen receptor (CAR) · immunotherapy · metabolism · tumor microenvironment (TME)

Abstract ​

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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Primary Questions Addressed ​

  1. What specific metabolic strategies can be employed to enhance the efficacy of CAR T cells in solid tumors?
  2. How do the metabolic demands of tumor cells specifically interfere with CAR T cell function in the tumor microenvironment?
  3. What role does nutrient availability play in the expansion and function of CAR T cells during therapy?
  4. Are there particular metabolic pathways that can be targeted to improve CAR T cell survival and persistence in patients?
  5. How can understanding the metabolic profiles of different tumor types inform the design of CAR T cell therapies?

Key Findings ​

Research Background and Purpose ​

Chimeric Antigen Receptor (CAR) T cell therapy represents a promising new approach for cancer treatment, particularly in hematological malignancies. However, the efficacy of CAR T cells is often compromised in solid tumors due to the high metabolic demands of tumor cells, which compete for nutrients and create a hostile tumor microenvironment (TME). This review discusses the need for a "metabolism toolbox" to enhance the metabolic fitness of CAR T cells, aiming to improve their efficacy in solid tumors.

Main Methods/Materials/Experimental Design ​

The authors propose a structured approach to optimize CAR T cell therapy by addressing metabolic challenges. The following flowchart summarizes the key steps involved in the proposed methodology:

Mermaid diagram
  1. Patient PBMC Collection: Peripheral blood mononuclear cells (PBMCs) are obtained through leukapheresis.
  2. T Cell Activation: T cells are activated using specific antibodies.
  3. Genetic Modification: T cells are genetically modified to express CARs targeting tumor antigens.
  4. T Cell Expansion: Expanded to the required number for therapeutic use.
  5. Nutritional Optimization: Tailored nutritional formulations are developed to enhance metabolic fitness during expansion.
  6. Functional Assessment: The efficacy and functionality of CAR T cells are assessed.
  7. Infusion into Patient: Modified T cells are infused back into the patient.
  8. Post-Infusion Monitoring: Continuous monitoring of patient response and T cell activity.

Key Results and Findings ​

  • Metabolic Competition: Tumor cells deplete essential nutrients (glucose, glutamine) and produce metabolites (lactate, adenosine) that suppress T cell function.
  • Metabolic Pathways: Different T cell subsets exhibit unique metabolic requirements; effector T cells rely on glycolysis, while memory T cells depend on oxidative phosphorylation (OXPHOS).
  • Enhanced Efficacy: Strategies such as nutrient supplementation (e.g., arginine) and metabolic reprogramming can enhance CAR T cell persistence and function in the TME.
  • Engineering CAR T Cells: The incorporation of hypoxia-responsive elements in CAR constructs has shown potential in improving T cell activity under low oxygen conditions typical of solid tumors.

Main Conclusions/Significance/Innovation ​

The review emphasizes the critical role of metabolic optimization in CAR T cell therapy, particularly for solid tumors. By enhancing the metabolic fitness of CAR T cells through tailored nutritional strategies and innovative engineering approaches, the efficacy of this therapy can be significantly improved. This metabolic focus represents a novel direction in the development of CAR T cell therapies and highlights the importance of understanding the TME in cancer treatment.

Research Limitations and Future Directions ​

  • Limitations: The review primarily discusses theoretical frameworks and preclinical findings, which require further validation in clinical settings. The complex interplay of metabolic pathways in the TME and the need for individualized approaches present additional challenges.
  • Future Directions: Further research is needed to explore:
    • The long-term effects of metabolic interventions on CAR T cell functionality.
    • The integration of metabolic modulation strategies with other immunotherapies, such as checkpoint inhibitors.
    • The development of real-time monitoring techniques to assess metabolic states in vivo during therapy.

By addressing these areas, future studies could lead to more effective CAR T cell therapies and improved outcomes for patients with solid tumors.

References ​

  1. The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture. - J M Brown - Cancer research (1999)
  2. Severe combined immunodeficiency and adenosine deaminase deficiency. - R Parkman;E W Gelfand;F S Rosen;A Sanderson;R Hirschhorn - The New England journal of medicine (1975)
  3. [Mechanism and treatment of cancer cachexia in tumor-bearing mice]. - T Li;C Li - Zhonghua zhong liu za zhi [Chinese journal of oncology] (1997)
  4. Comparison of Unisol with Euro-Collins solution as a vehicle solution for cryoprotectants. - M J Taylor;L H Campbell;R N Rutledge;K G Brockbank - Transplantation proceedings (2001)
  5. Defining the specific physiological requirements for c-Myc in T cell development. - N C Douglas;H Jacobs;A L Bothwell;A C Hayday - Nature immunology (2001)
  6. Expression of nitric oxide synthase, cyclooxygenase, and p53 in different stages of human gastric cancer. - A Rajnakova;S Moochhala;P M Goh;S Ngoi - Cancer letters (2001)
  7. IL-7 enhances the survival and maintains the size of naive T cells. - J C Rathmell;E A Farkash;W Gao;C B Thompson - Journal of immunology (Baltimore, Md. : 1950) (2001)
  8. Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogen-activated protein kinase activation and fas ligand expression. - Satish Devadas;Luba Zaritskaya;Sue Goo Rhee;Larry Oberley;Mark S Williams - The Journal of experimental medicine (2002)
  9. Antigen-presenting dendritic cells provide the reducing extracellular microenvironment required for T lymphocyte activation. - Giovanna Angelini;Stefania Gardella;Massimo Ardy;Maria Rosa Ciriolo;Giuseppe Filomeni;Giovanna Di Trapani;Frank Clarke;Roberto Sitia;Anna Rubartelli - Proceedings of the National Academy of Sciences of the United States of America (2002)
  10. Adenosine deaminase activity of normal lymphocytes and leukemic cells. - I Ben-Bassat;F Simoni;F Holtzman;B Ramot - Israel journal of medical sciences (1979)

Literatures Citing This Work ​

  1. Research progress and design optimization of CAR-T therapy for pancreatic ductal adenocarcinoma. - Tianjiao Li;Hao Li;Shuo Li;Shuaishuai Xu;Wuhu Zhang;Heli Gao;Huaxiang Xu;Chuntao Wu;Wenquan Wang;Xianjun Yu;Liang Liu - Cancer medicine (2019)
  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)

... (37 more literatures)

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