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Antibodies
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CAR-T Cell Metabolism
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CAR-T Cell Metabolism

A special issue of Antibodies (ISSN 2073-4468).

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 32442

Special Issue Editor

Dr. Roddy O'Connor

E-Mail Website
Guest Editor
Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Interests: CAR-T cell metabolism; metabolic reprogramming; metabolism and differentiation; mitochondrial function; mitochondrial fitness

Special Issue Information

Dear Colleagues,

This Special Issue of Antibodies focuses on metabolic approaches to enhance the effectiveness of CAR-T cells in blood-based malignancies and solid tumors. CARs are genetically engineered receptors containing distinct modules, including single chain variable fragments that collectively confer antigen specificity, signal transduction, metabolic reprogramming, and effector function. Previously, we showed how the metabolic properties of T cells can be dynamically regulated by emphasizing signaling and metabolic pathways downstream of the CAR. While CAR-T cells redirected against CD19 provide durable responses in several B cell malignancies, the success of CAR-T cells in solid tumors has been limited. The metabolic nature of solid tumor environment has been implicated as an important factor impeding CAR-T cell effector function. Competition for nutrients in solid tumors provides a barrier to CAR-T cell therapies as antigen-stimulated CARTs can’t overcome the energy cost to proliferate and differentiate into functionally-competed effector cells with cytolytic activity. This Special Issue aims to highlight advanced approaches to confer distinct metabolic attributes to CAR-T cells providing resistance to metabolic checkpoints in the solid tumor environment.

Dr. Roddy O'Connor
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibodies is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • CAR-T cells
  • metabolism
  • metabolic reprogramming
  • blood-based malignancies
  • solid tumors

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Published Papers (5 papers)

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Review

14 pages, 1190 KiB  
Review
Immune Cell Metabolic Fitness for Life
by Kevin S. Bittman
Antibodies 2022, 11(2), 32; https://doi.org/10.3390/antib11020032 - 30 Apr 2022
Cited by 1 | Viewed by 4366
Abstract
Adoptive cell therapy holds great promise for treating a myriad of diseases, especially cancer. Within the last decade, immunotherapy has provided a significant leap in the successful treatment of leukemia. The research conducted throughout this period to understand the interrelationships between cancer cells [...] Read more.
Adoptive cell therapy holds great promise for treating a myriad of diseases, especially cancer. Within the last decade, immunotherapy has provided a significant leap in the successful treatment of leukemia. The research conducted throughout this period to understand the interrelationships between cancer cells and infiltrating immune cells winds up having one very common feature, bioenergetics. Cancer cells and immune cells both need ATP to perform their individual functions and cancer cells have adopted means to limit immune cell activity via changes in immune cell bioenergetics that redirect immune cell behavior to encourage tumor growth. Current leading strategies for cancer treatment super-charge an individual’s own immune cells against cancer. Successful Chimeric Antigen Receptor T Cells (CAR T) target pathways that ultimately influence bioenergetics. In the last decade, scientists identified that mitochondria play a crucial role in T cell physiology. When modifying T cells to create chimeras, a unique mitochondrial fitness emerges that establishes stemness and persistence. This review highlights many of the key findings leading to this generation’s CAR T treatments and the work currently being done to advance immunotherapy, to empower not just T cells but other immune cells as well against a variety of cancers. Full article
(This article belongs to the Special Issue CAR-T Cell Metabolism)
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10 pages, 536 KiB  
Review
Advances in Chimeric Antigen Receptor (CAR) T-Cell Therapies for the Treatment of Primary Brain Tumors
by Christopher W. Mount and Luis Nicolas Gonzalez Castro
Antibodies 2022, 11(2), 31; https://doi.org/10.3390/antib11020031 - 27 Apr 2022
Cited by 5 | Viewed by 4374
Abstract
Immunotherapy has revolutionized the care of cancer patients. A diverse set of strategies to overcome cancer immunosuppression and enhance the tumor-directed immune response are in clinical use, but have not achieved transformative benefits for brain tumor patients. Adoptive cell therapies, which employ a [...] Read more.
Immunotherapy has revolutionized the care of cancer patients. A diverse set of strategies to overcome cancer immunosuppression and enhance the tumor-directed immune response are in clinical use, but have not achieved transformative benefits for brain tumor patients. Adoptive cell therapies, which employ a patient’s own immune cells to generate directed anti-tumor activity, are emerging technologies that hold promise to improve the treatment of primary brain tumors in children and adults. Here, we review recent advances in chimeric antigen receptor (CAR) T-cell therapies for the treatment of aggressive primary brain tumors, including glioblastoma and diffuse midline glioma, H3 K27M-mutant. We highlight current approaches, discuss encouraging investigational data, and describe key challenges in the development and implementation of these types of therapies in the neuro-oncology setting. Full article
(This article belongs to the Special Issue CAR-T Cell Metabolism)
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13 pages, 1244 KiB  
Review
Precision-Cut Tumor Slices (PCTS) as an Ex Vivo Model in Immunotherapy Research
by Paraskevi Dimou, Sumita Trivedi, Maria Liousia, Reena R. D'Souza and Astero Klampatsa
Antibodies 2022, 11(2), 26; https://doi.org/10.3390/antib11020026 - 6 Apr 2022
Cited by 11 | Viewed by 7214
Abstract
Precision-cut tumor slices (PCTS) have recently emerged as important ex vivo human tumor models, offering the opportunity to study individual patient responses to targeted immunotherapies, including CAR-T cell therapies. In this review, an outline of different human tumor models available in laboratory settings [...] Read more.
Precision-cut tumor slices (PCTS) have recently emerged as important ex vivo human tumor models, offering the opportunity to study individual patient responses to targeted immunotherapies, including CAR-T cell therapies. In this review, an outline of different human tumor models available in laboratory settings is provided, with a focus on the unique characteristics of PCTS. Standard PCTS generation and maintenance procedures are outlined, followed by an in-depth overview of PCTS utilization in preclinical research aiming to better understand the unique functional characteristics of cytotoxic T cells within human tumors. Furthermore, recent studies using PCTS as an ex vivo model for predicting patient responses to immunotherapies and other targeted therapies against solid tumors are thoroughly presented. Finally, the advantages and limitations of the PCTS models are discussed. PCTS are expected to gain momentum and be fully utilized as a significant tool towards better patient stratification and personalized medicine. Full article
(This article belongs to the Special Issue CAR-T Cell Metabolism)
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12 pages, 613 KiB  
Review
Beyond the Lactate Paradox: How Lactate and Acidity Impact T Cell Therapies against Cancer
by Violet Y. Tu, Asma Ayari and Roddy S. O’Connor
Antibodies 2021, 10(3), 25; https://doi.org/10.3390/antib10030025 - 28 Jun 2021
Cited by 35 | Viewed by 7357
Abstract
T cell therapies, including CAR T cells, have proven more effective in hematologic malignancies than solid tumors, where the local metabolic environment is distinctly immunosuppressive. In particular, the acidic and hypoxic features of the tumor microenvironment (TME) present a unique challenge for T [...] Read more.
T cell therapies, including CAR T cells, have proven more effective in hematologic malignancies than solid tumors, where the local metabolic environment is distinctly immunosuppressive. In particular, the acidic and hypoxic features of the tumor microenvironment (TME) present a unique challenge for T cells. Local metabolism is an important consideration for activated T cells as they undergo bursts of migration, proliferation and differentiation in hostile soil. Tumor cells and activated T cells both produce lactic acid at high rates. The role of lactic acid in T cell biology is complex, as lactate is an often-neglected carbon source that can fuel TCA anaplerosis. Circulating lactate is also an important means to regulate redox balance. In hypoxic tumors, lactate is immune-suppressive. Here, we discuss how intrinsic- (T cells) as well as extrinsic (tumor cells and micro-environmental)-derived metabolic factors, including lactate, suppress the ability of antigen-specific T cells to eradicate tumors. Finally, we introduce recent discoveries that target the TME in order to potentiate T cell-based therapies against cancer. Full article
(This article belongs to the Special Issue CAR-T Cell Metabolism)
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12 pages, 1132 KiB  
Review
Tinkering under the Hood: Metabolic Optimisation of CAR-T Cell Therapy
by Yasmin Jenkins, Joanna Zabkiewicz, Oliver Ottmann and Nicholas Jones
Antibodies 2021, 10(2), 17; https://doi.org/10.3390/antib10020017 - 26 Apr 2021
Cited by 16 | Viewed by 7572
Abstract
Chimeric antigen receptor (CAR)-T cells are one of the most exciting areas of immunotherapy to date. Clinically available CAR-T cells are used to treat advanced haematological B-cell malignancies with complete remission achieved at around 30–40%. Unfortunately, CAR-T cell success rates are even less [...] Read more.
Chimeric antigen receptor (CAR)-T cells are one of the most exciting areas of immunotherapy to date. Clinically available CAR-T cells are used to treat advanced haematological B-cell malignancies with complete remission achieved at around 30–40%. Unfortunately, CAR-T cell success rates are even less impressive when considering a solid tumour. Reasons for this include the paucity of tumour specific targets and greater degree of co-expression on normal tissues. However, there is accumulating evidence that considerable competition for nutrients such as carbohydrates and amino acids within the tumour microenvironment (TME) coupled with immunosuppression result in mitochondrial dysfunction, exhaustion, and subsequent CAR-T cell depletion. In this review, we will examine research avenues being pursued to dissect the various mechanisms contributing to the immunosuppressive TME and outline in vitro strategies currently under investigation that focus on boosting the metabolic program of CAR-T cells as a mechanism to overcome the immunosuppressive TME. Various in vitro and in vivo techniques boost oxidative phosphorylation and mitochondrial fitness in CAR-T cells, resulting in an enhanced central memory T cell compartment and increased anti-tumoural immunity. These include intracellular metabolic enhancers and extracellular in vitro culture optimisation pre-infusion. It is likely that the next generation of CAR-T products will incorporate these elements of metabolic manipulation in CAR-T cell design and manufacture. Given the importance of immunometabolism and T cell function, it is critical that we identify ways to metabolically armour CAR-T cells to overcome the hostile TME and increase clinical efficacy. Full article
(This article belongs to the Special Issue CAR-T Cell Metabolism)
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