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Cancers
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Current Advances in Chimeric Antigen Receptor Technology
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Current Advances in Chimeric Antigen Receptor Technology

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 50162

Special Issue Editors

Dr. Seung-Hwan Lee

E-Mail Website
Guest Editor
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada
Interests: immunotherapy; gene and cell therapy; cytokine signaling
Special Issues, Collections and Topics in MDPI journals
Dr. Scott McComb

E-Mail Website
Guest Editor
Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, Canada
Interests: CAR-T; synthetic immunology; immunotherapy; T-cell biology; Leukemia; genome editing; cell engineering

Special Issue Information

Dear colleagues,

In recent years, there has been a significant advancement in the area of cellular immunotherapy, best exemplified by the remarkable success of the FDA-approved autologous chimeric antigen receptor (CAR) T cell therapy cells in patients with hematological malignancies. The application of CAR has been rapidly applied to other cells, such as natural killer (NK) cells, relieving drawbacks associated with the high cost and toxicity of CAR-T therapy. Currently, accelerated by synthetic biology, the design of CAR constructs is fast developing for specific recognition of cancerous cells and optimal antitumor response. These efforts will provide insight into the generation of safe and robust cytotoxic cells applicable to both blood and solid tumors as deliverable drugs.

In this Special Issue, we welcome authors to submit original research articles and reviews, more precisely:

  1. Original research articles that provide preclinical and clinical evidence for potent CAR-mediated immunotherapies;
  2. Reviews on the advances of CAR technology on each generation, and obstacles to address in future.

Prof. Seung-Hwan Lee
Dr. Scott McComb
Guest Editors

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

  • chimeric antigen receptors (CARs)
  • CAR-T cell therapy
  • CAR-NK cell therapy
  • natural killer (NK) cells
  • adoptive cell therapy
  • cancer immunotherapy
  • cancers
  • cytotoxicity
  • cytokine production

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (7 papers)

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Editorial

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4 pages, 167 KiB  
Editorial
Current Advances and Hurdles in Chimeric Antigen Receptor Technology
by Scott McComb and Seung-Hwan Lee
Cancers 2020, 12(11), 3329; https://doi.org/10.3390/cancers12113329 - 11 Nov 2020
Cited by 1 | Viewed by 1899
Abstract
Since tumor-specific T cells were first utilized to treat melanoma patients in 1986 [...] Full article
(This article belongs to the Special Issue Current Advances in Chimeric Antigen Receptor Technology)

Review

Jump to: Editorial, Other

24 pages, 1132 KiB  
Review
Knowns and Unknowns about CAR-T Cell Dysfunction
by Aleksei Titov, Yaroslav Kaminskiy, Irina Ganeeva, Ekaterina Zmievskaya, Aygul Valiullina, Aygul Rakhmatullina, Alexey Petukhov, Regina Miftakhova, Albert Rizvanov and Emil Bulatov
Cancers 2022, 14(4), 1078; https://doi.org/10.3390/cancers14041078 - 21 Feb 2022
Cited by 39 | Viewed by 7743
Abstract
Immunotherapy using chimeric antigen receptor (CAR) T cells is a promising option for cancer treatment. However, T cells and CAR-T cells frequently become dysfunctional in cancer, where numerous evasion mechanisms impair antitumor immunity. Cancer frequently exploits intrinsic T cell dysfunction mechanisms that evolved [...] Read more.
Immunotherapy using chimeric antigen receptor (CAR) T cells is a promising option for cancer treatment. However, T cells and CAR-T cells frequently become dysfunctional in cancer, where numerous evasion mechanisms impair antitumor immunity. Cancer frequently exploits intrinsic T cell dysfunction mechanisms that evolved for the purpose of defending against autoimmunity. T cell exhaustion is the most studied type of T cell dysfunction. It is characterized by impaired proliferation and cytokine secretion and is often misdefined solely by the expression of the inhibitory receptors. Another type of dysfunction is T cell senescence, which occurs when T cells permanently arrest their cell cycle and proliferation while retaining cytotoxic capability. The first section of this review provides a broad overview of T cell dysfunctional states, including exhaustion and senescence; the second section is focused on the impact of T cell dysfunction on the CAR-T therapeutic potential. Finally, we discuss the recent efforts to mitigate CAR-T cell exhaustion, with an emphasis on epigenetic and transcriptional modulation. Full article
(This article belongs to the Special Issue Current Advances in Chimeric Antigen Receptor Technology)
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14 pages, 635 KiB  
Review
Strategies for Improving the Efficacy of CAR T Cells in Solid Cancers
by Jon Amund Kyte
Cancers 2022, 14(3), 571; https://doi.org/10.3390/cancers14030571 - 23 Jan 2022
Cited by 16 | Viewed by 6118
Abstract
Therapy with T cells equipped with chimeric antigen receptors (CARs) shows strong efficacy against leukaemia and lymphoma, but not yet against solid cancers. This has been attributed to insufficient T cell persistence, tumour heterogeneity and an immunosuppressive tumour microenvironment. The present article provides [...] Read more.
Therapy with T cells equipped with chimeric antigen receptors (CARs) shows strong efficacy against leukaemia and lymphoma, but not yet against solid cancers. This has been attributed to insufficient T cell persistence, tumour heterogeneity and an immunosuppressive tumour microenvironment. The present article provides an overview of key strategies that are currently investigated to overcome these hurdles. Basic aspects of CAR design are revisited, relevant for tuning the stimulatory signal to the requirements of solid tumours. Novel approaches for enhancing T cell persistence are highlighted, based on epigenetic or post-translational modifications. Further, the article describes CAR T strategies that are being developed for overcoming tumour heterogeneity and the escape of cancer stem cells, as well as for countering prevalent mechanisms of immune suppression in solid cancers. In general, personalised medicine is faced with a lack of drugs matching the patient’s profile. The advances and flexibility of modern gene engineering may allow for the filling of some of these gaps with tailored CAR T approaches addressing mechanisms identified as important in the individual patient. At this point, however, CAR T cell therapy remains unproved in solid cancers. The further progress of the field will depend on bringing novel strategies into clinical evaluation, while maintaining safety. Full article
(This article belongs to the Special Issue Current Advances in Chimeric Antigen Receptor Technology)
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19 pages, 13334 KiB  
Review
The Race of CAR Therapies: CAR-NK Cells for Fighting B-Cell Hematological Cancers
by Lara Herrera, Silvia Santos, Miguel Angel Vesga, Tomas Carrascosa, Juan Carlos Garcia-Ruiz, Antonio Pérez-Martínez, Manel Juan and Cristina Eguizabal
Cancers 2021, 13(21), 5418; https://doi.org/10.3390/cancers13215418 - 28 Oct 2021
Cited by 14 | Viewed by 4827
Abstract
Acute lymphoblastic leukemia (ALL) and Chronic lymphocytic leukemia (CLL) are the most common leukemias in children and elderly people, respectively. Standard therapies, such as chemotherapy, are only effective in 40% of ALL adult patients with a five-year survival rate and therefore new alternatives [...] Read more.
Acute lymphoblastic leukemia (ALL) and Chronic lymphocytic leukemia (CLL) are the most common leukemias in children and elderly people, respectively. Standard therapies, such as chemotherapy, are only effective in 40% of ALL adult patients with a five-year survival rate and therefore new alternatives need to be used, such as immunotherapy targeting specific receptors of malignant cells. Among all the options, CAR (Chimeric antigen receptor)-based therapy has arisen as a new opportunity for refractory or relapsed hematological cancer patients. CARs were designed to be used along with T lymphocytes, creating CAR-T cells, but they are presenting such encouraging results that they are already in use as drugs. Nonetheless, their side-effects and the fact that it is not possible to infuse an allogenic CAR-T product without causing graft-versus-host-disease, have meant using a different cell source to solve these problems, such as Natural Killer (NK) cells. Although CAR-based treatment is a high-speed race led by CAR-T cells, CAR-NK cells are slowly (but surely) consolidating their position; their demonstrated efficacy and the lack of undesirable side-effects is opening a new door for CAR-based treatments. CAR-NKs are now in the field to stay. Full article
(This article belongs to the Special Issue Current Advances in Chimeric Antigen Receptor Technology)
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18 pages, 1685 KiB  
Review
Current Perspectives on the Use of off the Shelf CAR-T/NK Cells for the Treatment of Cancer
by Lauren C. Cutmore and John F. Marshall
Cancers 2021, 13(8), 1926; https://doi.org/10.3390/cancers13081926 - 16 Apr 2021
Cited by 26 | Viewed by 5725
Abstract
CAR T cells have revolutionised the treatment of haematological malignancies. Despite this, several obstacles still prohibit their widespread use and efficacy. One of these barriers is the use of autologous T cells as the carrier of the CAR. The individual production of CAR [...] Read more.
CAR T cells have revolutionised the treatment of haematological malignancies. Despite this, several obstacles still prohibit their widespread use and efficacy. One of these barriers is the use of autologous T cells as the carrier of the CAR. The individual production of CAR T cells results in large variation in the product, greater wait times for treatment and higher costs. To overcome this several novel approaches have emerged that utilise allogeneic cells, so called “off the shelf” CAR T cells. In this Review, we describe the different approaches that have been used to produce allogeneic CAR T to date, as well as their current pre-clinical and clinical progress. Full article
(This article belongs to the Special Issue Current Advances in Chimeric Antigen Receptor Technology)
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23 pages, 2780 KiB  
Review
Adoptive Immunotherapy beyond CAR T-Cells
by Aleksei Titov, Ekaterina Zmievskaya, Irina Ganeeva, Aygul Valiullina, Alexey Petukhov, Aygul Rakhmatullina, Regina Miftakhova, Michael Fainshtein, Albert Rizvanov and Emil Bulatov
Cancers 2021, 13(4), 743; https://doi.org/10.3390/cancers13040743 - 11 Feb 2021
Cited by 79 | Viewed by 10156
Abstract
Adoptive cell immunotherapy (ACT) is a vibrant field of cancer treatment that began progressive development in the 1980s. One of the most prominent and promising examples is chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of B-cell hematologic malignancies. Despite success in [...] Read more.
Adoptive cell immunotherapy (ACT) is a vibrant field of cancer treatment that began progressive development in the 1980s. One of the most prominent and promising examples is chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of B-cell hematologic malignancies. Despite success in the treatment of B-cell lymphomas and leukemia, CAR T-cell therapy remains mostly ineffective for solid tumors. This is due to several reasons, such as the heterogeneity of the cellular composition in solid tumors, the need for directed migration and penetration of CAR T-cells against the pressure gradient in the tumor stroma, and the immunosuppressive microenvironment. To substantially improve the clinical efficacy of ACT against solid tumors, researchers might need to look closer into recent developments in the other branches of adoptive immunotherapy, both traditional and innovative. In this review, we describe the variety of adoptive cell therapies beyond CAR T-cell technology, i.e., exploitation of alternative cell sources with a high therapeutic potential against solid tumors (e.g., CAR M-cells) or aiming to be universal allogeneic (e.g., CAR NK-cells, γδ T-cells), tumor-infiltrating lymphocytes (TILs), and transgenic T-cell receptor (TCR) T-cell immunotherapies. In addition, we discuss the strategies for selection and validation of neoantigens to achieve efficiency and safety. We provide an overview of non-conventional TCRs and CARs, and address the problem of mispairing between the cognate and transgenic TCRs. Finally, we summarize existing and emerging approaches for manufacturing of the therapeutic cell products in traditional, semi-automated and fully automated Point-of-Care (PoC) systems. Full article
(This article belongs to the Special Issue Current Advances in Chimeric Antigen Receptor Technology)
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Other

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12 pages, 1954 KiB  
Systematic Review
Systematic Review of Available CAR-T Cell Trials around the World
by Luciana Rodrigues Carvalho Barros, Samuel Campanelli Freitas Couto, Daniela da Silva Santurio, Emanuelle Arantes Paixão, Fernanda Cardoso, Viviane Jennifer da Silva, Paulo Klinger, Paula do Amaral Costa Ribeiro, Felipe Augusto Rós, Théo Gremen Mimary Oliveira, Eduardo Magalhães Rego, Rodrigo Nalio Ramos and Vanderson Rocha
Cancers 2022, 14(11), 2667; https://doi.org/10.3390/cancers14112667 - 27 May 2022
Cited by 56 | Viewed by 12227
Abstract
In this systematic review, we foresee what could be the approved scenario in the next few years for CAR-T cell therapies directed against hematological and solid tumor malignancies. China and the USA are the leading regions in numbers of clinical studies involving CAR-T. [...] Read more.
In this systematic review, we foresee what could be the approved scenario in the next few years for CAR-T cell therapies directed against hematological and solid tumor malignancies. China and the USA are the leading regions in numbers of clinical studies involving CAR-T. Hematological antigens CD19 and BCMA are the most targeted, followed by mesothelin, GPC3, CEA, MUC1, HER2, and EGFR for solid tumors. Most CAR constructs are second-generation, although third and fourth generations are being largely explored. Moreover, the benefit of combining CAR-T treatment with immune checkpoint inhibitors and other drugs is also being assessed. Data regarding product formulation and administration, such as cell phenotype, transfection technique, and cell dosage, are scarce and could not be retrieved. Better tracking of trials’ status and results on the ClinicalTrials.gov database should aid in a more concise and general view of the ongoing clinical trials involving CAR-T cell therapy. Full article
(This article belongs to the Special Issue Current Advances in Chimeric Antigen Receptor Technology)
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