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Cancers
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CAR T Cell Therapy for Cancers
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CAR T Cell Therapy for Cancers

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

Deadline for manuscript submissions: closed (1 March 2024) | Viewed by 17530

Special Issue Editor

Dr. Simone Krebs

E-Mail Website
Guest Editor
Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA
Interests: molecular imaging; theranostics; CAR T cells

Special Issue Information

Dear Colleagues,

Chimeric antigen receptors (CARs) endow T cells with antigen-specific recognition, activation, and proliferation independent of major histocompatibility complex. Successful treatment of hematologic malignancies with CD19-CAR T cells was a milestone for this approach. However, an enduring antitumor response is still absent in most patients, as they succumb to either CD19+ or CD19− tumor relapse in the long term. Furthermore, treatment success has been hampered in patients with solid tumors. These therapies are currently limited in part by a lack of persistence and expansion of the transplanted T cells. In addition, response is highly variable among individuals. CAR T cells have not only demonstrated profound potency but also severe toxicity from “on-target/off-tumor” effects. In this Special Issue, we invite authors to submit high-quality original research and review articles that advance our understanding of CAR T-cell therapies with a focus on one or several of the following topics: cellular engineering, hematologic malignancies, solid tumors, efficacy, toxicity, safety, combinatorial approaches, antigen escape, trafficking, microenvironment, mechanisms, exhaustion, targets, allogeneic/off-the-shelf approaches, manufacturing, regulation, and biomarkers.

Dr. Simone Krebs
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. 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 cells
  • cellular engineering
  • hematologic malignancies
  • solid tumors
  • toxicity
  • combinatorial approaches
  • antigen escape
  • microenvironment
  • allogeneic/off-the-shelf
  • biomarkers

Published Papers (6 papers)

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Research

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18 pages, 4635 KiB  
Article
Precision Immunotherapy Utilizing Adapter CAR-T Cells (AdCAR-T) in Metastatic Breast Cancer Leads to Target Specific Lysis
by Cansu E. Önder, Moustafa Moustafa-Oglou, Sarah M. Schröder, Andreas D. Hartkopf, André Koch and Christian M. Seitz
Cancers 2024, 16(1), 168; https://doi.org/10.3390/cancers16010168 - 29 Dec 2023
Viewed by 1361
Abstract
A frequent symptom of metastasized breast cancer (BC) includes the development of malignant pleural effusion (MPE), which contains malignant cells derived from the primary tumor site. The poor prognosis of MPE in metastasized BC indicates the necessity for dependable precision oncology and the [...] Read more.
A frequent symptom of metastasized breast cancer (BC) includes the development of malignant pleural effusion (MPE), which contains malignant cells derived from the primary tumor site. The poor prognosis of MPE in metastasized BC indicates the necessity for dependable precision oncology and the importance of models representing the heterogenous nature of metastatic BC. In this study, we cultured MPE-derived metastatic tumor cells from four advanced BC patients using organoid technology. We assessed the expression of tumor-associated antigens on MPE-derived organoid lines by flow cytometry (FC). Based on an individual antigen expression pattern, patient-derived organoids were treated with adapter CAR-T cells (AdCAR-T) and biotinylated monoclonal antibodies targeting CD276, HER2, EGFR, TROP2, or EpCAM. Co-culture assays revealed specific organoid lysis by AdCAR-T depending on individual antigen expression patterns. Our results demonstrate that MPE-derived organoids can serve as a reliable tool for assessing the efficacy of AdCAR-T on metastatic BC in a patient-individualized manner. This approach could potentially be applied in a preclinical setting to instruct therapy decisions. Further, our study demonstrates the feasibility of precision immunotherapy utilizing AdCAR-T to target patient-individualized antigen patterns. Full article
(This article belongs to the Special Issue CAR T Cell Therapy for Cancers)
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15 pages, 1433 KiB  
Article
Population-Based External Validation of the EASIX Scores to Predict CAR T-Cell-Related Toxicities
by Janneke W. de Boer, Kylie Keijzer, Elise R. A. Pennings, Jaap A. van Doesum, Anne M. Spanjaart, Margot Jak, Pim G. N. J. Mutsaers, Suzanne van Dorp, Joost S. P. Vermaat, Marjolein W. M. van der Poel, Lisanne V. van Dijk, Marie José Kersten, Anne G. H. Niezink and Tom van Meerten
Cancers 2023, 15(22), 5443; https://doi.org/10.3390/cancers15225443 - 16 Nov 2023
Viewed by 1168
Abstract
Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index [...] Read more.
Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included (n = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade ≥ 2 (both p = 0.04), and the EASIX approached statistical significance at infusion (p = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61–0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade ≥ 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade ≥ 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade ≥ 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment. Full article
(This article belongs to the Special Issue CAR T Cell Therapy for Cancers)
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17 pages, 6336 KiB  
Article
Evaluation of the Elements of Short Hairpin RNAs in Developing shRNA-Containing CAR T Cells
by Ryan Urak, Brenna Gittins, Citradewi Soemardy, Nicole Grepo, Lior Goldberg, Madeleine Maker, Galina Shevchenko, Alicia Davis, Shirley Li, Tristan Scott, Kevin V. Morris, Stephen J. Forman and Xiuli Wang
Cancers 2023, 15(10), 2848; https://doi.org/10.3390/cancers15102848 - 20 May 2023
Viewed by 1755
Abstract
Short hairpin RNAs (shRNAs) have emerged as a powerful tool for gene knockdown in various cellular systems, including chimeric antigen receptor (CAR) T cells. However, the elements of shRNAs that are crucial for their efficacy in developing shRNA-containing CAR T cells remain unclear. [...] Read more.
Short hairpin RNAs (shRNAs) have emerged as a powerful tool for gene knockdown in various cellular systems, including chimeric antigen receptor (CAR) T cells. However, the elements of shRNAs that are crucial for their efficacy in developing shRNA-containing CAR T cells remain unclear. In this study, we evaluated the impact of different shRNA elements, including promoter strength, orientation, multiple shRNAs, self-targeting, and sense and antisense sequence composition on the knockdown efficiency of the target gene in CAR T cells. Our findings highlight the importance of considering multiple shRNAs and their orientation to achieve effective knockdown. Moreover, we demonstrate that using a strong promoter and avoiding self-targeting can enhance CAR T cell functionality. These results provide a framework for the rational design of CAR T cells with shRNA-mediated knockdown capabilities, which could improve the therapeutic efficacy of CAR T cell-based immunotherapy. Full article
(This article belongs to the Special Issue CAR T Cell Therapy for Cancers)
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Review

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19 pages, 1057 KiB  
Review
The Black Hole: CAR T Cell Therapy in AML
by Erden Atilla and Karim Benabdellah
Cancers 2023, 15(10), 2713; https://doi.org/10.3390/cancers15102713 - 11 May 2023
Cited by 6 | Viewed by 4025
Abstract
Despite exhaustive studies, researchers have made little progress in the field of adoptive cellular therapies for relapsed/refractory acute myeloid leukemia (AML), unlike the notable uptake for B cell malignancies. Various single antigen-targeting chimeric antigen receptor (CAR) T cell Phase I trials have been [...] Read more.
Despite exhaustive studies, researchers have made little progress in the field of adoptive cellular therapies for relapsed/refractory acute myeloid leukemia (AML), unlike the notable uptake for B cell malignancies. Various single antigen-targeting chimeric antigen receptor (CAR) T cell Phase I trials have been established worldwide and have recruited approximately 100 patients. The high heterogeneity at the genetic and molecular levels within and between AML patients resembles a black hole: a great gravitational field that sucks in everything. One must consider the fact that only around 30% of patients show a response; there are, however, consequential off-tumor effects. It is obvious that a new point of view is needed to achieve more promising results. This review first introduces the unique therapeutic challenges of not only CAR T cells but also other adoptive cellular therapies in AML. Next, recent single-cell sequencing data for AML to assess somatically acquired alterations at the DNA, epigenetic, RNA, and protein levels are discussed to give a perspective on cellular heterogeneity, intercellular hierarchies, and the cellular ecosystem. Finally, promising novel strategies are summarized, including more sophisticated next-generation CAR T, TCR-T, and CAR NK therapies; the approaches with which to tailor the microenvironment and target neoantigens; and allogeneic approaches. Full article
(This article belongs to the Special Issue CAR T Cell Therapy for Cancers)
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21 pages, 782 KiB  
Review
The New Frontier of Immunotherapy: Chimeric Antigen Receptor T (CAR-T) Cell and Macrophage (CAR-M) Therapy against Breast Cancer
by Giuseppe Schepisi, Caterina Gianni, Michela Palleschi, Sara Bleve, Chiara Casadei, Cristian Lolli, Laura Ridolfi, Giovanni Martinelli and Ugo De Giorgi
Cancers 2023, 15(5), 1597; https://doi.org/10.3390/cancers15051597 - 04 Mar 2023
Cited by 9 | Viewed by 4213
Abstract
Breast cancer represents one of the most common tumor histologies. To date, based on the specific histotype, different therapeutic strategies, including immunotherapies, capable of prolonging survival are used. More recently, the astonishing results that were obtained from CAR-T cell therapy in haematological neoplasms [...] Read more.
Breast cancer represents one of the most common tumor histologies. To date, based on the specific histotype, different therapeutic strategies, including immunotherapies, capable of prolonging survival are used. More recently, the astonishing results that were obtained from CAR-T cell therapy in haematological neoplasms led to the application of this new therapeutic strategy in solid tumors as well. Our article will deal with chimeric antigen receptor-based immunotherapy (CAR-T cell and CAR-M therapy) in breast cancer. Full article
(This article belongs to the Special Issue CAR T Cell Therapy for Cancers)
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26 pages, 1222 KiB  
Review
Current Status and Perspectives of Dual-Targeting Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Hematological Malignancies
by Bailu Xie, Zhengdong Li, Jianfeng Zhou and Wen Wang
Cancers 2022, 14(13), 3230; https://doi.org/10.3390/cancers14133230 - 30 Jun 2022
Cited by 28 | Viewed by 4140
Abstract
Single-targeted chimeric antigen receptor (CAR) T cells tremendously improve outcomes for patients with relapsed/refractory hematological malignancies and are considered a breakthrough therapy. However, over half of treated patients experience relapse or refractory disease, with antigen escape being one of the main contributing mechanisms. [...] Read more.
Single-targeted chimeric antigen receptor (CAR) T cells tremendously improve outcomes for patients with relapsed/refractory hematological malignancies and are considered a breakthrough therapy. However, over half of treated patients experience relapse or refractory disease, with antigen escape being one of the main contributing mechanisms. Dual-targeting CAR T-cell therapy is being developed to minimize the risk of relapse or refractory disease. Preclinical and clinical data on five categories of dual-targeting CAR T-cell therapies and approximately fifty studies were summarized to offer insights and support the development of dual-targeting CAR T-cell therapy for hematological malignancies. The clinical efficacy (durability and survival) is validated and the safety profiles of dual-targeting CAR T-cell therapy are acceptable, although there is still room for improvement in the bispecific CAR structure. It is one of the best approaches to optimize the bispecific CAR structure by boosting T-cell transduction efficiency and leveraging evidence from preclinical activity and clinical efficacy. Full article
(This article belongs to the Special Issue CAR T Cell Therapy for Cancers)
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