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9.9
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Cells
Special Issues
State of the Art in CAR-T Cell Therapy
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State of the Art in CAR-T Cell Therapy

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (15 March 2022) | Viewed by 41217

Special Issue Editor

Dr. Sébastien Wälchli

E-Mail Website
Guest Editor
Translational Research Unit, Section for Cellular Therapy, Oslo University Hospital, Oslo, Norway
Interests: CAR T cells; immunotherapy of cancer; TCR

Special Issue Information

Dear Colleagues,

Although the first prototype Chimeric Antigen Receptor (CAR) molecule was released more than 30 years ago, the strategies developed to control immune cells are still evolving. At that time, the understanding of the mechanisms that lead an immune cell to recognize and destroy a target was still vague; there were receptors (molecularly isolated the same year) and speculation about the mechanisms that lead to specificity. Yet scientists were already studying tactics to control these cells and make them recognize a defined target, most probably because they could anticipate the power of what we call today “living drugs.”

CAR molecules are not the only immune cells controllers, but they are interesting in their essence first because they are completely artificial and second because they were shown to be therapeutically efficient. Indeed, CAR is a patchwork of molecule domains which have to be adapted to their target, to the environment of this target, and to the type of cells expressing them. This has led to the publication of many forms, designs and compositions of CAR molecules.

This curiosity to further push the limits of controlling the fate of a specialized cell by innovative means is fascinating. We aim at dedicating this issue to the description of the many ways CAR molecules were imagined, thus highlighting the rich panel of modifications that was exploited to control an immune cell to do a precise work in a safe manner.

Dr. Sébastien Wälchli
Guest Editor

Manuscript Submission Information

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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. Cells is an international peer-reviewed open access semimonthly 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 2700 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
  • Chimeric Antigen Receptor
  • Immunotherapy
  • T cell
  • NK cell
  • Macrophage
  • TCR
  • cytotoxicity
  • tumor microenvironment
  • cancer

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Published Papers (8 papers)

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Research

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16 pages, 2005 KiB  
Article
CAR T-Cells Depend on the Coupling of NADH Oxidation with ATP Production
by Juan C. Garcia-Canaveras, David Heo, Sophie Trefely, John Leferovich, Chong Xu, Benjamin I. Philipson, Saba Ghassemi, Michael C. Milone, Edmund K. Moon, Nathaniel W. Snyder, Carl H. June, Joshua D. Rabinowitz and Roddy S. O’Connor
Cells 2021, 10(9), 2334; https://doi.org/10.3390/cells10092334 - 6 Sep 2021
Cited by 6 | Viewed by 5613
Abstract
The metabolic milieu of solid tumors provides a barrier to chimeric antigen receptor (CAR) T-cell therapies. Excessive lactate or hypoxia suppresses T-cell growth, through mechanisms including NADH buildup and the depletion of oxidized metabolites. NADH is converted into NAD+ by the enzyme [...] Read more.
The metabolic milieu of solid tumors provides a barrier to chimeric antigen receptor (CAR) T-cell therapies. Excessive lactate or hypoxia suppresses T-cell growth, through mechanisms including NADH buildup and the depletion of oxidized metabolites. NADH is converted into NAD+ by the enzyme Lactobacillus brevis NADH Oxidase (LbNOX), which mimics the oxidative function of the electron transport chain without generating ATP. Here we determine if LbNOX promotes human CAR T-cell metabolic activity and antitumor efficacy. CAR T-cells expressing LbNOX have enhanced oxygen as well as lactate consumption and increased pyruvate production. LbNOX renders CAR T-cells resilient to lactate dehydrogenase inhibition. But in vivo in a model of mesothelioma, CAR T-cell’s expressing LbNOX showed no increased antitumor efficacy over control CAR T-cells. We hypothesize that T cells in hostile environments face dual metabolic stressors of excessive NADH and insufficient ATP production. Accordingly, futile T-cell NADH oxidation by LbNOX is insufficient to promote tumor clearance. Full article
(This article belongs to the Special Issue State of the Art in CAR-T Cell Therapy)
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Review

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19 pages, 2444 KiB  
Review
Immune Checkpoint Proteins, Metabolism and Adhesion Molecules: Overlooked Determinants of CAR T-Cell Migration?
by Luca Simula, Emma Ollivier, Philippe Icard and Emmanuel Donnadieu
Cells 2022, 11(11), 1854; https://doi.org/10.3390/cells11111854 - 6 Jun 2022
Cited by 8 | Viewed by 4062
Abstract
Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CAR) has demonstrated striking efficacy for the treatment of several hematological malignancies, including B-cell lymphoma, leukemia, and multiple myeloma. However, many patients still do not respond to this therapy or eventually [...] Read more.
Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CAR) has demonstrated striking efficacy for the treatment of several hematological malignancies, including B-cell lymphoma, leukemia, and multiple myeloma. However, many patients still do not respond to this therapy or eventually relapse after an initial remission. In most solid tumors for which CAR T-cell therapy has been tested, efficacy has been very limited. In this context, it is of paramount importance to understand the mechanisms of tumor resistance to CAR T cells. Possible factors contributing to such resistance have been identified, including inherent CAR T-cell dysfunction, the presence of an immunosuppressive tumor microenvironment, and tumor-intrinsic factors. To control tumor growth, CAR T cells have to migrate actively enabling a productive conjugate with their targets. To date, many cells and factors contained within the tumor microenvironment have been reported to negatively control the migration of T cells and their ability to reach cancer cells. Recent evidence suggests that additional determinants, such as immune checkpoint proteins, cellular metabolism, and adhesion molecules, may modulate the motility of CAR T cells in tumors. Here, we review the potential impact of these determinants on CAR T-cell motility, and we discuss possible strategies to restore intratumoral T-cell migration with a special emphasis on approaches targeting these determinants. Full article
(This article belongs to the Special Issue State of the Art in CAR-T Cell Therapy)
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28 pages, 1105 KiB  
Review
CAR-T Cells Shoot for New Targets: Novel Approaches to Boost Adoptive Cell Therapy for B Cell-Derived Malignancies
by Katsiaryna Marhelava, Marta Krawczyk, Malgorzata Firczuk and Klaudyna Fidyt
Cells 2022, 11(11), 1804; https://doi.org/10.3390/cells11111804 - 31 May 2022
Cited by 5 | Viewed by 5732
Abstract
Chimeric antigen receptor (CAR)-T cell therapy is undeniably a promising tool in combating various types of hematological malignancies. However, it is not yet optimal and a significant number of patients experience a lack of response or relapse after the treatment. Therapy improvement requires [...] Read more.
Chimeric antigen receptor (CAR)-T cell therapy is undeniably a promising tool in combating various types of hematological malignancies. However, it is not yet optimal and a significant number of patients experience a lack of response or relapse after the treatment. Therapy improvement requires careful analysis of the occurring problems and a deeper understanding of the reasons that stand behind them. In this review, we summarize the recent knowledge about CAR-T products’ clinical performance and discuss diversified approaches taken to improve the major shortcomings of this therapy. Especially, we prioritize the challenges faced by CD19 CAR-T cell-based treatment of B cell-derived malignancies and revise the latest insights about mechanisms mediating therapy resistance. Since the loss of CD19 is one of the major obstacles to the success of CAR-T cell therapy, we present antigens that could be alternatively used for the treatment of various types of B cell-derived cancers. Full article
(This article belongs to the Special Issue State of the Art in CAR-T Cell Therapy)
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16 pages, 2077 KiB  
Review
How CAR T Cells Breathe
by Christopher Forcados, Sandy Joaquina, Nicholas Paul Casey, Benjamin Caulier and Sébastien Wälchli
Cells 2022, 11(9), 1454; https://doi.org/10.3390/cells11091454 - 25 Apr 2022
Cited by 6 | Viewed by 4008
Abstract
The manufacture of efficacious CAR T cells represents a major challenge in cellular therapy. An important aspect of their quality concerns energy production and consumption, known as metabolism. T cells tend to adopt diverse metabolic profiles depending on their differentiation state and their [...] Read more.
The manufacture of efficacious CAR T cells represents a major challenge in cellular therapy. An important aspect of their quality concerns energy production and consumption, known as metabolism. T cells tend to adopt diverse metabolic profiles depending on their differentiation state and their stimulation level. It is therefore expected that the introduction of a synthetic molecule such as CAR, activating endogenous signaling pathways, will affect metabolism. In addition, upon patient treatment, the tumor microenvironment might influence the CAR T cell metabolism by compromising the energy resources. The access to novel technology with higher throughput and reduced cost has led to an increased interest in studying metabolism. Indeed, methods to quantify glycolysis and mitochondrial respiration have been available for decades but were rarely applied in the context of CAR T cell therapy before the release of the Seahorse XF apparatus. The present review will focus on the use of this instrument in the context of studies describing the impact of CAR on T cell metabolism and the strategies to render of CAR T cells more metabolically fit. Full article
(This article belongs to the Special Issue State of the Art in CAR-T Cell Therapy)
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25 pages, 1611 KiB  
Review
Natural Receptor- and Ligand-Based Chimeric Antigen Receptors: Strategies Using Natural Ligands and Receptors for Targeted Cell Killing
by Gianna M. Branella and Harold Trent Spencer
Cells 2022, 11(1), 21; https://doi.org/10.3390/cells11010021 - 22 Dec 2021
Cited by 19 | Viewed by 7658
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has been widely successful in the treatment of B-cell malignancies, including B-cell lymphoma, mantle cell lymphoma, and multiple myeloma; and three generations of CAR designs have led to effective FDA approved therapeutics. Traditionally, CAR antigen specificity is [...] Read more.
Chimeric antigen receptor (CAR) T-cell therapy has been widely successful in the treatment of B-cell malignancies, including B-cell lymphoma, mantle cell lymphoma, and multiple myeloma; and three generations of CAR designs have led to effective FDA approved therapeutics. Traditionally, CAR antigen specificity is derived from a monoclonal antibody where the variable heavy (VH) and variable light (VL) chains are connected by a peptide linker to form a single-chain variable fragment (scFv). While this provides a level of antigen specificity parallel to that of an antibody and has shown great success in the clinic, this design is not universally successful. For instance, issues of stability, immunogenicity, and antigen escape hinder the translational application of some CARs. As an alternative, natural receptor- or ligand-based designs may prove advantageous in some circumstances compared to scFv-based designs. Herein, the advantages and disadvantages of scFv-based and natural receptor- or ligand-based CAR designs are discussed. In addition, several translational aspects of natural receptor- and ligand-based CAR approaches that are being investigated in preclinical and clinical studies will be examined. Full article
(This article belongs to the Special Issue State of the Art in CAR-T Cell Therapy)
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27 pages, 1101 KiB  
Review
Facing CAR T Cell Challenges on the Deadliest Paediatric Brain Tumours
by Cristina Ferreras, Lucía Fernández, Laura Clares-Villa, Marta Ibáñez-Navarro, Carla Martín-Cortázar, Isabel Esteban-Rodríguez, Javier Saceda and Antonio Pérez-Martínez
Cells 2021, 10(11), 2940; https://doi.org/10.3390/cells10112940 - 29 Oct 2021
Cited by 6 | Viewed by 4664
Abstract
Central nervous system (CNS) tumours comprise 25% of the paediatric cancer diagnoses and are the leading cause of cancer-related death in children. Current treatments for paediatric CNS tumours are far from optimal and fail for those that relapsed or are refractory to treatment. [...] Read more.
Central nervous system (CNS) tumours comprise 25% of the paediatric cancer diagnoses and are the leading cause of cancer-related death in children. Current treatments for paediatric CNS tumours are far from optimal and fail for those that relapsed or are refractory to treatment. Besides, long-term sequelae in the developing brain make it mandatory to find new innovative approaches. Chimeric antigen receptor T cell (CAR T) therapy has increased survival in patients with B-cell malignancies, but the intrinsic biological characteristics of CNS tumours hamper their success. The location, heterogeneous antigen expression, limited infiltration of T cells into the tumour, the selective trafficking provided by the blood–brain barrier, and the immunosuppressive tumour microenvironment have emerged as the main hurdles that need to be overcome for the success of CAR T cell therapy. In this review, we will focus mainly on the characteristics of the deadliest high-grade CNS paediatric tumours (medulloblastoma, ependymoma, and high-grade gliomas) and the potential of CAR T cell therapy to increase survival and patients’ quality of life. Full article
(This article belongs to the Special Issue State of the Art in CAR-T Cell Therapy)
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14 pages, 685 KiB  
Review
From Hematopoietic Stem Cell Transplantation to Chimeric Antigen Receptor Therapy: Advances, Limitations and Future Perspectives
by Elisaveta Voynova and Damian Kovalovsky
Cells 2021, 10(11), 2845; https://doi.org/10.3390/cells10112845 - 22 Oct 2021
Cited by 9 | Viewed by 3482
Abstract
Chimeric antigen receptor (CAR) T-cell therapy was envisioned as a mechanism to re-direct effector T-cells to eliminate tumor cells. CARs are composed of the variable region of an antibody that binds a native cancer antigen coupled to the signaling domain of a TCR [...] Read more.
Chimeric antigen receptor (CAR) T-cell therapy was envisioned as a mechanism to re-direct effector T-cells to eliminate tumor cells. CARs are composed of the variable region of an antibody that binds a native cancer antigen coupled to the signaling domain of a TCR and co-stimulatory molecules. Its success and approval by the U.S. Food and Drug Administration for the treatment of B-cell malignancies revolutionized the immunotherapy field, leading to extensive research on its possible application for other cancer types. In this review, we will focus on the evolution of CAR-T cell therapy outlining current technologies as well as major obstacles for its wide application. We will highlight achievements, the efforts to increase efficacy and to evolve into an off-the-shelf treatment, and as a possible future treatment for non-cancer related diseases. Full article
(This article belongs to the Special Issue State of the Art in CAR-T Cell Therapy)
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23 pages, 2043 KiB  
Review
The “Magic Bullet” Is Here? Cell-Based Immunotherapies for Hematological Malignancies in the Twilight of the Chemotherapy Era
by Nina Miazek-Zapala, Aleksander Slusarczyk, Aleksandra Kusowska, Piotr Zapala, Matylda Kubacz, Magdalena Winiarska and Malgorzata Bobrowicz
Cells 2021, 10(6), 1511; https://doi.org/10.3390/cells10061511 - 15 Jun 2021
Cited by 4 | Viewed by 3560
Abstract
Despite the introduction of a plethora of different anti-neoplastic approaches including standard chemotherapy, molecularly targeted small-molecule inhibitors, monoclonal antibodies, and finally hematopoietic stem cell transplantation (HSCT), there is still a need for novel therapeutic options with the potential to cure hematological malignancies. Although [...] Read more.
Despite the introduction of a plethora of different anti-neoplastic approaches including standard chemotherapy, molecularly targeted small-molecule inhibitors, monoclonal antibodies, and finally hematopoietic stem cell transplantation (HSCT), there is still a need for novel therapeutic options with the potential to cure hematological malignancies. Although nowadays HSCT already offers a curative effect, its implementation is largely limited by the age and frailty of the patient. Moreover, its efficacy in combating the malignancy with graft-versus-tumor effect frequently coexists with undesirable graft-versus-host disease (GvHD). Therefore, it seems that cell-based adoptive immunotherapies may constitute optimal strategies to be successfully incorporated into the standard therapeutic protocols. Thus, modern cell-based immunotherapy may finally represent the long-awaited “magic bullet” against cancer. However, enhancing the safety and efficacy of this treatment regimen still presents many challenges. In this review, we summarize the up-to-date state of the art concerning the use of CAR-T cells and NK-cell-based immunotherapies in hemato-oncology, identify possible obstacles, and delineate further perspectives. Full article
(This article belongs to the Special Issue State of the Art in CAR-T Cell Therapy)
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