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Cancers
Special Issues
CAR-T Cells: Past, Present, and Future
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CAR-T Cells: Past, Present, and Future

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 13015

Special Issue Editor

Prof. Dr. Dimitrios Mougiakakos

E-Mail Website
Guest Editor
Department of Hematology and Oncology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39104 Magdeburg, Germany
Interests: immunotherapy; tumor microenvironment; immunometabolism

Special Issue Information

Dear Colleagues,

Immunotherapy has ushered in a new era of cancer treatment. Chimeric antigen receptor (CAR-)T cells are at the forefront of this development. Like the eponymous hybrid creature chimera from Greek mythology, they are composed of various components that are not found in this constellation in nature. This opens up completely new possibilities in the recognition of target structures but also in the quantitative control of immune responses. This concept, which was launched 30 years ago, has now found its way into clinical practice. We see how the number of indications is increasing and patients are being treated earlier. Nevertheless, many questions remain unanswered. These include how we can improve the safety profile, accelerate the production time, and also prevent disease recurrences. It will be important for the future to better target solid tumors, to test alternative cell types such as CAR-NK cells, and to explore indications in other areas, such as autoimmunity. In this Special Issue, we will highlight developments in the past and the prospects for the future of this promising cell therapy together.

Prof. Dr. Dimitrios Mougiakakos
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 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. Cancers 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 2900 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
  • TRUCK
  • immunotherapy
  • cell therapy
  • immunoescape
  • immunometabolism
  • cell products
  • T cells
  • NK cells
  • macrophages
  • cancer
  • autoimmunity

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Published Papers (3 papers)

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Research

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16 pages, 3475 KiB  
Article
CD45-Directed CAR-T Cells with CD45 Knockout Efficiently Kill Myeloid Leukemia and Lymphoma Cells In Vitro Even after Extended Culture
by Maraike Harfmann, Tanja Schröder, Dawid Głów, Maximilian Jung, Almut Uhde, Nicolaus Kröger, Stefan Horn, Kristoffer Riecken, Boris Fehse and Francis A. Ayuk
Cancers 2024, 16(2), 334; https://doi.org/10.3390/cancers16020334 - 12 Jan 2024
Cited by 3 | Viewed by 2187
Abstract
Background: CAR-T cell therapy has shown impressive results and is now part of standard-of-care treatment of B-lineage malignancies, whereas the treatment of myeloid diseases has been limited by the lack of suitable targets. CD45 is expressed on almost all types of blood cells [...] Read more.
Background: CAR-T cell therapy has shown impressive results and is now part of standard-of-care treatment of B-lineage malignancies, whereas the treatment of myeloid diseases has been limited by the lack of suitable targets. CD45 is expressed on almost all types of blood cells including myeloid leukemia cells, but not on non-hematopoietic tissue, making it a potential target for CAR-directed therapy. Because of its high expression on T and NK cells, fratricide is expected to hinder CD45CAR-mediated therapy. Due to its important roles in effector cell activation, signal transduction and cytotoxicity, CD45 knockout aimed at preventing fratricide in T and NK cells has been expected to lead to considerable functional impairment. Methods: CD45 knockout was established on T and NK cell lines using CRISPR/Cas9-RNPs and electroporation, and the successful protocol was transferred to primary T cells. A combined protocol was developed enabling CD45 knockout and retroviral transduction with a third-generation CAR targeting CD45 or CD19. The functionality of CD45ko effector cells, CD45ko/CD45CAR-T and CD45ko/CD19CAR-T cells was studied using proliferation as well as short- and long-term cytotoxicity assays. Results: As expected, the introduction of a CD45-CAR into T cells resulted in potent fratricide that can be avoided by CD45 knockout. Unexpectedly, the latter had no negative impact on T- and NK-cell proliferation in vitro. Moreover, CD45ko/CD45CAR-T cells showed potent cytotoxicity against CD45-expressing AML and lymphoma cell lines in short-term and long-term co-culture assays. A pronounced cytotoxicity of CD45ko/CD45CAR-T cells was maintained even after four weeks of culture. In a further setup, we confirmed the conserved functionality of CD45ko cells using a CD19-CAR. Again, the proliferation and cytotoxicity of CD45ko/CD19CAR-T cells showed no differences from those of their CD45-positive counterparts in vitro. Conclusions: We report the efficient production of highly and durably active CD45ko/CAR-T cells. CD45 knockout did not impair the functionality of CAR-T cells in vitro, irrespective of the target antigen. If their activity can be confirmed in vivo, CD45ko/CD45CAR-T cells might, for example, be useful as part of conditioning regimens prior to stem cell transplantation. Full article
(This article belongs to the Special Issue CAR-T Cells: Past, Present, and Future)
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Review

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27 pages, 4451 KiB  
Review
Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming
by Maria Alvanou, Memnon Lysandrou, Panayota Christophi, Nikoleta Psatha, Alexandros Spyridonidis, Anastasia Papadopoulou and Evangelia Yannaki
Cancers 2023, 15(7), 1935; https://doi.org/10.3390/cancers15071935 - 23 Mar 2023
Cited by 5 | Viewed by 3695
Abstract
T-cell-based, personalized immunotherapy can nowadays be considered the mainstream treatment for certain blood cancers, with a high potential for expanding indications. Chimeric antigen receptor T cells (CAR-Ts), an ex vivo genetically modified T-cell therapy product redirected to target an antigen of interest, have [...] Read more.
T-cell-based, personalized immunotherapy can nowadays be considered the mainstream treatment for certain blood cancers, with a high potential for expanding indications. Chimeric antigen receptor T cells (CAR-Ts), an ex vivo genetically modified T-cell therapy product redirected to target an antigen of interest, have achieved unforeseen successes in patients with B-cell hematologic malignancies. Frequently, however, CAR-T cell therapies fail to provide durable responses while they have met with only limited success in treating solid cancers because unique, unaddressed challenges, including poor persistence, impaired trafficking to the tumor, and site penetration through a hostile microenvironment, impede their efficacy. Increasing evidence suggests that CAR-Ts’ in vivo performance is associated with T-cell intrinsic features that may be epigenetically altered or dysregulated. In this review, we focus on the impact of epigenetic regulation on T-cell differentiation, exhaustion, and tumor infiltration and discuss how epigenetic reprogramming may enhance CAR-Ts’ memory phenotype, trafficking, and fitness, contributing to the development of a new generation of potent CAR-T immunotherapies. Full article
(This article belongs to the Special Issue CAR-T Cells: Past, Present, and Future)
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20 pages, 2206 KiB  
Review
Role of CAR T Cell Metabolism for Therapeutic Efficacy
by Judit Rial Saborido, Simon Völkl, Michael Aigner, Andreas Mackensen and Dimitrios Mougiakakos
Cancers 2022, 14(21), 5442; https://doi.org/10.3390/cancers14215442 - 4 Nov 2022
Cited by 15 | Viewed by 6465
Abstract
Chimeric antigen receptor (CAR) T cells hold enormous potential. However, a substantial proportion of patients receiving CAR T cells will not reach long-term full remission. One of the causes lies in their premature exhaustion, which also includes a metabolic anergy of adoptively transferred [...] Read more.
Chimeric antigen receptor (CAR) T cells hold enormous potential. However, a substantial proportion of patients receiving CAR T cells will not reach long-term full remission. One of the causes lies in their premature exhaustion, which also includes a metabolic anergy of adoptively transferred CAR T cells. T cell phenotypes that have been shown to be particularly well suited for CAR T cell therapy display certain metabolic characteristics; whereas T-stem cell memory (TSCM) cells, characterized by self-renewal and persistence, preferentially meet their energetic demands through oxidative phosphorylation (OXPHOS), effector T cells (TEFF) rely on glycolysis to support their cytotoxic function. Various parameters of CAR T cell design and manufacture co-determine the metabolic profile of the final cell product. A co-stimulatory 4-1BB domain promotes OXPHOS and formation of central memory T cells (TCM), while T cells expressing CARs with CD28 domains predominantly utilize aerobic glycolysis and differentiate into effector memory T cells (TEM). Therefore, modification of CAR co-stimulation represents one of the many strategies currently being investigated for improving CAR T cells’ metabolic fitness and survivability within a hostile tumor microenvironment (TME). In this review, we will focus on the role of CAR T cell metabolism in therapeutic efficacy together with potential targets of intervention. Full article
(This article belongs to the Special Issue CAR-T Cells: Past, Present, and Future)
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