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Targeting CAR T-cell Therapy: Molecular Research and Its Future Implication
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Targeting CAR T-cell Therapy: Molecular Research and Its Future Implication

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 30 September 2024 | Viewed by 13506

Special Issue Editor

Dr. Stella D. Bouziana

E-Mail Website
Guest Editor
Department of Haematology, King’s College Hospital, London SE5 9RS, UK
Interests: CAR T-cell; acute leukemias; hematopoietic stem cell transplantation; plasma cell dyscrasias
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Technological advances in genetic engineering have resulted in the advent of the very promising chimeric antigen receptor (CAR) T-cell therapies. CAR T-cell therapies have revolutionized the fields of hematology and oncology over the last few years, offering long-term remission to patients with highly aggressive and refractory malignancies. However, CAR T-cell therapies can cause major toxicities, even life-threating ones, confining their application only to eligible patients. Moreover, despite the great success and the high remission rates, the majority of the patients will eventually relapse either due to CAR T-cell exhaustion or antigen escape. In light of this, extensive basic, translational and clinical research is under way to better refine CAR T-cell therapies and render them a safer and more effective treatment modality with a curative potential.

This Special Issue, entitled "Targeting CAR T-cell Therapy: Molecular Research and Its Future Implication", aims to provide a research platform for the collection of the latest original and review articles covering molecular biological studies which investigate the strategies of mitigating CAR T-related toxicities, the mechanisms of relapse post-CAR T-cell therapy and the pathways of augmenting CAR T-cell efficacy and potency in malignant diseases.

Dr. Stella D. Bouziana
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • CAR T-cell therapy
  • malignant diseases
  • molecular pathways
  • CAR T-related toxicities
  • resistance mechanisms

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Published Papers (5 papers)

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Research

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17 pages, 1303 KiB  
Article
A Comprehensive ddPCR Strategy for Sensitive and Reliable Monitoring of CAR-T Cell Kinetics in Clinical Applications
by Gertrud Wiedemann, Ulrike Bacher, Raphael Joncourt, Françoise Solly, Corinne C. Widmer, Sacha Zeerleder, Urban Novak, Thomas Pabst and Naomi A. Porret
Int. J. Mol. Sci. 2024, 25(16), 8556; https://doi.org/10.3390/ijms25168556 - 6 Aug 2024
Viewed by 844
Abstract
In this study, we present the design, implementation, and successful use of digital droplet PCR (ddPCR) for the monitoring of chimeric antigen receptor T-cell (CAR-T) expansion in patients with B-cell malignancies treated with different CAR-T products at our clinical center. Initially, we designed [...] Read more.
In this study, we present the design, implementation, and successful use of digital droplet PCR (ddPCR) for the monitoring of chimeric antigen receptor T-cell (CAR-T) expansion in patients with B-cell malignancies treated with different CAR-T products at our clinical center. Initially, we designed a specific and highly sensitive ddPCR assay targeting the junction between the 4-1BB and CD3ζ domains of tisa-cel, normalized with RPP30, and validated it using blood samples from the first tisa-cel-treated patient in Switzerland. We further compared this assay with a published qPCR (quantitative real-time PCR) design. Both assays showed reliable quantification of CAR-T copies down to 20 copies/µg DNA. The reproducibility and precision were confirmed through extensive testing and inter-laboratory comparisons. With the introduction of other CAR-T products, we also developed a corresponding ddPCR assay targeting axi-cel and brexu-cel, demonstrating high specificity and sensitivity with a limit of detection of 20 copies/µg DNA. These assays are suitable for CAR-T copy number quantification across multiple sample types, including peripheral blood, bone marrow, and lymph node biopsy material, showing robust performance and indicating the presence of CAR-T cells not only in the blood but also in target tissues. Longitudinal monitoring of CAR-T cell kinetics in 141 patients treated with tisa-cel, axi-cel, or brexu-cel revealed significant expansion and long-term persistence. Peak expansion correlated with clinical outcomes and adverse effects, as is now well known. Additionally, we quantified the CAR-T mRNA expression, showing a high correlation with DNA copy numbers and confirming active transgene expression. Our results highlight the quality of ddPCR for CAR-T monitoring, providing a sensitive, precise, and reproducible method suitable for clinical applications. This approach can be adapted for future CAR-T products and will support the monitoring and the management of CAR-T cell therapies. Full article
(This article belongs to the Special Issue Targeting CAR T-cell Therapy: Molecular Research and Its Future Implication)
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21 pages, 4110 KiB  
Article
Endogenous Signaling Molecule Activating (ESMA) CARs: A Novel CAR Design Showing a Favorable Risk to Potency Ratio for the Treatment of Triple Negative Breast Cancer
by Mira Ebbinghaus, Katharina Wittich, Benjamin Bancher, Valeriia Lebedeva, Anijutta Appelshoffer, Julia Femel, Martin S. Helm, Jutta Kollet, Olaf Hardt and Rita Pfeifer
Int. J. Mol. Sci. 2024, 25(1), 615; https://doi.org/10.3390/ijms25010615 - 3 Jan 2024
Cited by 1 | Viewed by 2135
Abstract
As chimeric antigen receptor (CAR) T cell therapy continues to gain attention as a valuable treatment option against different cancers, strategies to improve its potency and decrease the side effects associated with this therapy have become increasingly relevant. Herein, we report an alternative [...] Read more.
As chimeric antigen receptor (CAR) T cell therapy continues to gain attention as a valuable treatment option against different cancers, strategies to improve its potency and decrease the side effects associated with this therapy have become increasingly relevant. Herein, we report an alternative CAR design that incorporates transmembrane domains with the ability to recruit endogenous signaling molecules, eliminating the need for stimulatory signals within the CAR structure. These endogenous signaling molecule activating (ESMA) CARs triggered robust cytotoxic activity and proliferation of the T cells when directed against the triple-negative breast cancer (TNBC) cell line MDA-MB-231 while exhibiting reduced cytokine secretion and exhaustion marker expression compared to their cognate standard second generation CARs. In a NOD SCID Gamma (NSG) MDA-MB-231 xenograft mouse model, the lead candidate maintained longitudinal therapeutic efficacy and an enhanced T cell memory phenotype. Profound tumor infiltration by activated T cells repressed tumor growth, further manifesting the proliferative capacity of the ESMA CAR T cell therapy. Consequently, ESMA CAR T cells entail promising features for improved clinical outcome as a solid tumor treatment option. Full article
(This article belongs to the Special Issue Targeting CAR T-cell Therapy: Molecular Research and Its Future Implication)
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23 pages, 5291 KiB  
Article
Targeting Stage-Specific Embryonic Antigen 4 (SSEA-4) in Triple Negative Breast Cancer by CAR T Cells Results in Unexpected on Target/off Tumor Toxicities in Mice
by Rita Pfeifer, Wa’el Al Rawashdeh, Janina Brauner, Manuel Martinez-Osuna, Dominik Lock, Christoph Herbel, Dominik Eckardt, Mario Assenmacher, Andreas Bosio, Olaf T. Hardt and Ian C. D. Johnston
Int. J. Mol. Sci. 2023, 24(11), 9184; https://doi.org/10.3390/ijms24119184 - 24 May 2023
Cited by 2 | Viewed by 4140
Abstract
Due to the paucity of targetable antigens, triple-negative breast cancer (TNBC) remains a challenging subtype of breast cancer to treat. In this study, we developed and evaluated a chimeric antigen receptor (CAR) T cell-based treatment modality for TNBC by targeting stage-specific embryonic antigen [...] Read more.
Due to the paucity of targetable antigens, triple-negative breast cancer (TNBC) remains a challenging subtype of breast cancer to treat. In this study, we developed and evaluated a chimeric antigen receptor (CAR) T cell-based treatment modality for TNBC by targeting stage-specific embryonic antigen 4 (SSEA-4), a glycolipid whose overexpression in TNBC has been correlated with metastasis and chemoresistance. To delineate the optimal CAR configuration, a panel of SSEA-4-specific CARs containing alternative extracellular spacer domains was constructed. The different CAR constructs mediated antigen-specific T cell activation characterized by degranulation of T cells, secretion of inflammatory cytokines, and killing of SSEA-4-expressing target cells, but the extent of this activation differed depending on the length of the spacer region. Adoptive transfer of the CAR-engineered T cells into mice with subcutaneous TNBC xenografts mediated a limited antitumor effect but induced severe toxicity symptoms in the cohort receiving the most bioactive CAR variant. We found that progenitor cells in the lung and bone marrow express SSEA-4 and are likely co-targeted by the CAR T cells. Thus, this study has revealed serious adverse effects that raise safety concerns for SSEA-4-directed CAR therapies because of the risk of eliminating vital cells with stem cell properties. Full article
(This article belongs to the Special Issue Targeting CAR T-cell Therapy: Molecular Research and Its Future Implication)
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Review

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15 pages, 1920 KiB  
Review
β2-Adrenergic Receptor Mediated Inhibition of T Cell Function and Its Implications for CAR-T Cell Therapy
by Muhammad Asad Farooq, Iqra Ajmal, Xinhui Hui, Yiran Chen, Yaojun Ren and Wenzheng Jiang
Int. J. Mol. Sci. 2023, 24(16), 12837; https://doi.org/10.3390/ijms241612837 - 16 Aug 2023
Cited by 6 | Viewed by 2824
Abstract
The microenvironment of most tumors is complex, comprising numerous aspects of immunosuppression. Several studies have indicated that the adrenergic system is vital for controlling immunological responses. In the context of the tumor microenvironment, nor-adrenaline (NA) is poured in by innervating nerves and tumor [...] Read more.
The microenvironment of most tumors is complex, comprising numerous aspects of immunosuppression. Several studies have indicated that the adrenergic system is vital for controlling immunological responses. In the context of the tumor microenvironment, nor-adrenaline (NA) is poured in by innervating nerves and tumor tissues itself. The receptors for nor-adrenaline are present on the surfaces of cancer and immune cells and are often involved in the activation of pro-tumoral signaling pathways. Beta2-adrenergic receptors (β2-ARs) are an emerging class of receptors that are capable of modulating the functioning of immune cells. β2-AR is reported to activate regulatory immune cells and inhibit effector immune cells. Blocking β2-AR increases activation, proliferation, and cytokine release of T lymphocytes. Moreover, β2-AR deficiency during metabolic reprogramming of T cells increases mitochondrial membrane potential and biogenesis. In the view of the available research data, the immunosuppressive role of β2-AR in T cells presents it as a targetable checkpoint in CAR-T cell therapies. In this review, we have abridged the contemporary knowledge about adrenergic-stress-mediated β2-AR activation on T lymphocytes inside tumor milieu. Full article
(This article belongs to the Special Issue Targeting CAR T-cell Therapy: Molecular Research and Its Future Implication)
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23 pages, 2830 KiB  
Review
Strategies for Reducing Toxicity and Enhancing Efficacy of Chimeric Antigen Receptor T Cell Therapy in Hematological Malignancies
by Haobing Wang, Ling Tang, Yingjie Kong, Wen Liu, Xiaojian Zhu and Yong You
Int. J. Mol. Sci. 2023, 24(11), 9115; https://doi.org/10.3390/ijms24119115 - 23 May 2023
Cited by 7 | Viewed by 2358
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies has made great progress, but there are still some problems. First, T cells from tumor patients show an exhaustion phenotype; thus, the persistence and function of the CAR-Ts are poor, and achieving a [...] Read more.
Chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies has made great progress, but there are still some problems. First, T cells from tumor patients show an exhaustion phenotype; thus, the persistence and function of the CAR-Ts are poor, and achieving a satisfactory curative effect is difficult. Second, some patients initially respond well but quickly develop antigen-negative tumor recurrence. Thirdly, CAR-T treatment is not effective in some patients and is accompanied by severe side effects, such as cytokine release syndrome (CRS) and neurotoxicity. The solution to these problems is to reduce the toxicity and enhance the efficacy of CAR-T therapy. In this paper, we describe various strategies for reducing the toxicity and enhancing the efficacy of CAR-T therapy in hematological malignancies. In the first section, strategies for modifying CAR-Ts using gene-editing technologies or combining them with other anti-tumor drugs to enhance the efficacy of CAR-T therapy are introduced. The second section describes some methods in which the design and construction of CAR-Ts differ from the conventional process. The aim of these methods is to enhance the anti-tumor activity of CAR-Ts and prevent tumor recurrence. The third section describes modifying the CAR structure or installing safety switches to radically reduce CAR-T toxicity or regulating inflammatory cytokines to control the symptoms of CAR-T-associated toxicity. Together, the knowledge summarized herein will aid in designing better-suited and safer CAR-T treatment strategies. Full article
(This article belongs to the Special Issue Targeting CAR T-cell Therapy: Molecular Research and Its Future Implication)
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