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Cancers
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CAR T Therapy of Solid Cancers: Problems and Progress
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CAR T Therapy of Solid Cancers: Problems and Progress

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

Deadline for manuscript submissions: 30 June 2025 | Viewed by 10820

Special Issue Editors

Prof. Dr. John F. Marshall

E-Mail Website
Guest Editor
Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Interests: integrins; cancer microenvironment; tumour invasion; tumour biology; protein structure; biomarker; therapeutic targeting
Dr. Lauren Cutmore

E-Mail Website
Guest Editor
Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Interests: CAR T therapy; integrins

Special Issue Information

Dear Colleagues,

CAR T cell therapy has revolutionized the treatment of hematological malignancies; however, this clinical success has yet to be seen in the treatment of solid cancers. The major issues presented by solid tumors include trafficking to and penetration into the tumor, and CAR T cell cytotoxic function within the tumor microenvironment.  

The reasons for this lack of efficacy appear to be a combination of a powerful immunosuppressive environment driven my multiple elements of the innate and adaptive immune system, in addition to the physical characteristics of the tumor microenvironment, such as desmoplasia and the net positive pressure.

To overcome these challenges, we must investigate the biology of CAR T-cells within immuno-competent models. In this Special Issue of Cancers, entitled “CAR T therapy of solid cancers: Problems and Progress”, we invite experts in the field, many of whom employ syngeneic solid tumor models in mice, to submit articles in the hope that together we can begin to resolve the current lack of clinical success regarding the application of CAR T -cell therapy in solid cancers.

Prof. Dr. John F. Marshall
Dr. Lauren Cutmore
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

  • CAR T therapy
  • tumor microenvironment
  • solid tumor
  • treatment
  • immuno-competent models

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Published Papers (4 papers)

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Research

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17 pages, 4250 KiB  
Article
Targeting HER2-Positive Solid Tumors with CAR NK Cells: CD44 Expression Is a Critical Modulator of HER2-Specific CAR NK Cell Efficacy
by Bence Gergely, Márk A. Vereb, István Rebenku, György Vereb and Árpád Szöőr
Cancers 2025, 17(5), 731; https://doi.org/10.3390/cancers17050731 - 21 Feb 2025
Cited by 1 | Viewed by 933
Abstract
Background/Objectives: Monoclonal antibody therapies for HER2-positive tumors frequently encounter resistance, requiring alternative treatment strategies. This study investigates the use of natural killer (NK) cells expressing HER2-specific chimeric antigen receptor (CAR) to address this issue. CAR NK cells have several benefits over CAR T [...] Read more.
Background/Objectives: Monoclonal antibody therapies for HER2-positive tumors frequently encounter resistance, requiring alternative treatment strategies. This study investigates the use of natural killer (NK) cells expressing HER2-specific chimeric antigen receptor (CAR) to address this issue. CAR NK cells have several benefits over CAR T cells: they are less likely to cause severe side effects such as cytokine release syndrome and neurotoxicity, can be sourced from various origins, and do not trigger Graft versus Host Disease, making them ideal for “off-the-shelf” applications. Methods: We have generated NK-92 cell lines expressing first, second and third-generation HER2-specific CARs with CD28 and/or 41BB costimulatory domains using a retroviral transduction system, followed by FACS sorting and expansion to obtain pure HER2-CAR NK-92 cell products for functional benchmarking. Results: In vitro tests showed that these CAR NK cells were effective against both trastuzumab-sensitive (CD44−) and -resistant (CD44+) tumors in monolayer cultures. However, in three-dimensional spheroid models and in vivo xenografts, they were less effective against CD44+ trastuzumab-resistant tumors. Conclusions: This reduced efficacy highlights the significant role of the tumor microenvironment, particularly the extracellular matrix, in hindering the therapeutic potential of CAR NK cells. Despite the promising in vitro performance of CAR NK cells, this study emphasizes the need for improved strategies to enhance their penetration and effectiveness in resistant tumors: optimizing CAR constructs and devising methods to overcome extracellular matrix barriers are crucial for advancing CAR NK cell therapies in oncology. Full article
(This article belongs to the Special Issue CAR T Therapy of Solid Cancers: Problems and Progress)
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11 pages, 1435 KiB  
Article
Ectopic PU.1 Expression Provides Chimeric Antigen Receptor (CAR) T Cells with Innate Cell Capacities Including IFN-β Release
by Dennis Christoph Harrer, Matthias Eder, Markus Barden, Hong Pan, Wolfgang Herr and Hinrich Abken
Cancers 2024, 16(15), 2737; https://doi.org/10.3390/cancers16152737 - 1 Aug 2024
Viewed by 1444
Abstract
Chimeric antigen receptor (CAR) T cell therapy has achieved extraordinary success in eliminating B cell malignancies; however, so far, it has shown limited efficacy in the treatment of solid tumors, which is thought to be due to insufficient CAR T cell activation. We [...] Read more.
Chimeric antigen receptor (CAR) T cell therapy has achieved extraordinary success in eliminating B cell malignancies; however, so far, it has shown limited efficacy in the treatment of solid tumors, which is thought to be due to insufficient CAR T cell activation. We hypothesized that the transcription factor PU.1, a master regulator of innate cell functionality, may augment pro-inflammatory CAR T cell activation. T cells were engineered with a CEA-specific CAR together with the constitutive expression of PU.1. CAR-redirected T cell activation was recorded for canonical functionality in vitro under conditions of prolonged repetitive antigen exposure. Ectopic PU.1 expression in CAR T cells upregulated the costimulatory receptors CD40, CD80, CD86, and CD70, which, unexpectedly, did not augment effector functions but hampered the upregulation of 4-1BB, decreased IL-2 production, reduced CAR T cell proliferation, and impaired their cytotoxic capacities. Under “stress” conditions of repetitive engagement of cognate tumor cells, CAR T cells with ectopic PU.1 showed reduced persistence, and finally failed to control the growth of cancer cells. Mechanistically, PU.1 caused CAR T cells to secrete IFN-β, a cytokine known to promote CAR T cell attrition and apoptosis. Collectively, PU.1 can polarize the functional capacities of CAR T cells towards innate cells. Full article
(This article belongs to the Special Issue CAR T Therapy of Solid Cancers: Problems and Progress)
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Review

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21 pages, 936 KiB  
Review
Syngeneic Mouse Models for Pre-Clinical Evaluation of CAR T Cells
by Eman N. Ahmed, Lauren C. Cutmore and John F. Marshall
Cancers 2024, 16(18), 3186; https://doi.org/10.3390/cancers16183186 - 18 Sep 2024
Cited by 3 | Viewed by 3148
Abstract
Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematological malignancies. Unfortunately, this improvement has yet to be translated into the solid tumor field. Current immunodeficient models used in pre-clinical testing often overestimate the efficacy of CAR T cell therapy as [...] Read more.
Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematological malignancies. Unfortunately, this improvement has yet to be translated into the solid tumor field. Current immunodeficient models used in pre-clinical testing often overestimate the efficacy of CAR T cell therapy as they fail to recapitulate the immunosuppressive tumor microenvironment characteristic of solid tumors. As CAR T cell monotherapy is unlikely to be curative for many solid tumors, combination therapies must be investigated, for example, stromal remodeling agents and immunomodulators. The evaluation of these combination therapies requires a fully immunocompetent mouse model in order to recapitulate the interaction between the host’s immune system and the CAR T cells. This review will discuss the need for improved immunocompetent murine models for the pre-clinical evaluation of CAR T cells, the current use of such models and future directions. Full article
(This article belongs to the Special Issue CAR T Therapy of Solid Cancers: Problems and Progress)
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22 pages, 1700 KiB  
Review
Strategies for Improving CAR T Cell Persistence in Solid Tumors
by Megen C. Wittling, Anna C. Cole, Brianna Brammer, Kailey G. Diatikar, Nicole C. Schmitt and Chrystal M. Paulos
Cancers 2024, 16(16), 2858; https://doi.org/10.3390/cancers16162858 - 16 Aug 2024
Cited by 4 | Viewed by 4562
Abstract
CAR T cells require optimization to be effective in patients with solid tumors. There are many barriers affecting their ability to succeed. One barrier is persistence, as to achieve an optimal antitumor response, infused CAR T cells must engraft and persist. This singular [...] Read more.
CAR T cells require optimization to be effective in patients with solid tumors. There are many barriers affecting their ability to succeed. One barrier is persistence, as to achieve an optimal antitumor response, infused CAR T cells must engraft and persist. This singular variable is impacted by a multitude of factors—the CAR T cell design, lymphodepletion regimen used, expansion method to generate the T cell product, and more. Additionally, external agents can be utilized to augment CAR T cells, such as the addition of novel cytokines, pharmaceutical drugs that bolster memory formation, or other agents during either the ex vivo expansion process or after CAR T cell infusion to support them in the oppressive tumor microenvironment. This review highlights many strategies being used to optimize T cell persistence as well as future directions for improving the persistence of infused cells. Full article
(This article belongs to the Special Issue CAR T Therapy of Solid Cancers: Problems and Progress)
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