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CAR-T Cell in Human Cancers: Combinations, Gene-Editing, Payload Delivery, Autonomous...
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CAR-T Cell in Human Cancers: Combinations, Gene-Editing, Payload Delivery, Autonomous Control and Synthetic Biology

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 48357

Special Issue Editors

Dr. Avery D. Posey

E-Mail Website
Guest Editor
Department of Systems Pharmacology and Translational Therapeutics and Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Interests: cancer immunotherapy; tumor microenvironment; immune exhaustion; tumor glycosylation; neoantigens
Dr. Kole T. Roybal

E-Mail Website
Guest Editor
Department of Microbiology and Immunology, Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
Interests: Engineered cell therapies; cancer immunology; tumor microenvironment; synthetic biology; collective cell behavior; immune cell signaling, function, exhaustion, and metabolism

Special Issue Information

Dear Colleagues,

Chimeric antigen receptor T (CAR-T) cell therapies are having an unprecedented impact on the treatment of multiple malignancies. However, the limits of CARs as single-agent effectors, especially in the context of solid tumor treatment, are also crystalizing. The future of engineered cell therapeutics for cancer and beyond includes reprogramming cells with precise therapeutic circuits via synthetic biology, combinational treatment with immune checkpoint blockade and other immune modulators, and strategies to overcome T cell dysfunction/exhaustion and tumor exclusion. This Special Issue will highlight the platforms and approaches that are improving and advancing CAR-T cell development and ushering in the next generation of cell-based immunotherapies.

Dr. Avery D. Posey
Dr. Kole T. Roybal
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 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 cell
  • cancer immunotherapy
  • gene-editing
  • synthetic biology
  • T cell exhaustion

Published Papers (7 papers)

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Research

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16 pages, 2292 KiB  
Article
CRISPR-Mediated Non-Viral Site-Specific Gene Integration and Expression in T Cells: Protocol and Application for T-Cell Therapy
by Zelda Odé, Jose Condori, Nicolas Peterson, Sheng Zhou and Giedre Krenciute
Cancers 2020, 12(6), 1704; https://doi.org/10.3390/cancers12061704 - 26 Jun 2020
Cited by 20 | Viewed by 8120
Abstract
T cells engineered with chimeric antigen receptors (CARs) show great promise in the treatment of some cancers. Modifying T cells to express CARs generally relies on T-cell transduction using viral vectors carrying a transgene, resulting in semi-random DNA integration within the T-cell genome. [...] Read more.
T cells engineered with chimeric antigen receptors (CARs) show great promise in the treatment of some cancers. Modifying T cells to express CARs generally relies on T-cell transduction using viral vectors carrying a transgene, resulting in semi-random DNA integration within the T-cell genome. While this approach has proven successful and is used in generating the Food and Drug Administration (FDA, USA) approved B-lymphocyte antigen CD19-specific CAR T cells, it is possible the transgene could integrate into a locus that would lead to malignant transformation of the engineered T cells. In addition, manufacturing viral vectors is time-consuming and expensive. One way to overcome these challenges is site-specific gene integration, which can be achieved through clustered regularly interspaced short palindromic repeat (CRISPR) mediated editing and non-viral DNA, which serves as a template for homology-directed repair (HDR). This non-viral gene editing approach provides a rapid, highly specific, and inexpensive way to engineer T cells. Here, we describe an optimized protocol for the site-specific knock-in of a large transgene in primary human T cells using non-viral double stranded DNA as a repair template. As proof-of-principle, we targeted the T-cell receptor alpha constant (TRAC) locus for insertion of a large transgene containing green fluorescence protein (GFP) and interleukin-15 (IL-15). To optimize the knock-in conditions we tested template DNA concentration, homology arm length, cell number, and knock-in efficiency over time. We then applied these established guidelines to target the TRAC or interleukin-13 (IL-13) locus for the knock-in of synthetic molecules, such as a CAR, bispecific T-cell engager (BiTE), and other transgenes. While integration efficiency depends on the targeted gene locus and selected transgene, this optimized protocol reliably generates the desired insertion at rates upwards of 20%. Thus, it should serve as a good starting point for investigators who are interested in knocking in transgenes into specific loci. Full article
(This article belongs to the Special Issue CAR-T Cell in Human Cancers: Combinations, Gene-Editing, Payload Delivery, Autonomous Control and Synthetic Biology)
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Review

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15 pages, 1765 KiB  
Review
CAR-T Therapy, the End of a Chapter or the Beginning of a New One?
by Yasser Mostafa Kamel
Cancers 2021, 13(4), 853; https://doi.org/10.3390/cancers13040853 - 18 Feb 2021
Cited by 7 | Viewed by 3107
Abstract
Chimeric antigen receptor-T (CAR-T) therapy targeting CD19 has revolutionised the treatment of advanced acute lymphoblastic leukaemia (ALL) and diffuse large B-cell lymphoma (DLBCL). The ability to specifically target the cancer cells has shown high positive results as reported in the registration studies. The [...] Read more.
Chimeric antigen receptor-T (CAR-T) therapy targeting CD19 has revolutionised the treatment of advanced acute lymphoblastic leukaemia (ALL) and diffuse large B-cell lymphoma (DLBCL). The ability to specifically target the cancer cells has shown high positive results as reported in the registration studies. The success of CAR-T therapy in the first two indications led to the initiation of a large number of studies testing CAR-T therapy in different haematologic tumours such as acute myelogenous leukaemia (AML), Hodgkin’s disease (HD), chronic lymphocytic leukaemia (CLL), multiple myeloma (MM), as well as different solid tumours. Unfortunately, relapses occurred in patients treated with CAR-T therapy, calling for the development of effective subsequent therapies. Likewise, this novel mechanism of action was also accompanied by a different toxicity profile, such as cytokine release syndrome (CRS). Patients’ access to the treatment is still limited by its cost. Notwithstanding, this did not prohibit further development of this new therapy to treat other malignancies. This research activity of CAR-T therapy moves it from being used as an end-stage treatment for ALL and DLBCL to a new therapeutic option for a wide range of patients with different haematologic and solid tumours. Full article
(This article belongs to the Special Issue CAR-T Cell in Human Cancers: Combinations, Gene-Editing, Payload Delivery, Autonomous Control and Synthetic Biology)
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15 pages, 616 KiB  
Review
Bispecific Chimeric Antigen Receptor T Cell Therapy for B Cell Malignancies and Multiple Myeloma
by Robert J. Cronk, Joanna Zurko and Nirav N. Shah
Cancers 2020, 12(9), 2523; https://doi.org/10.3390/cancers12092523 - 05 Sep 2020
Cited by 27 | Viewed by 5744
Abstract
Chimeric antigen receptor (CAR) modified T cell therapy offers a targeted immunotherapeutic approach to patients with refractory hematological malignancies. This technology is most advanced in B cell malignancies and multiple myeloma and is rapidly evolving as more data become available regarding clinical efficacy [...] Read more.
Chimeric antigen receptor (CAR) modified T cell therapy offers a targeted immunotherapeutic approach to patients with refractory hematological malignancies. This technology is most advanced in B cell malignancies and multiple myeloma and is rapidly evolving as more data become available regarding clinical efficacy and response durability. Despite excellent initial response rates with single antigen targeting CARs, failure to respond to therapy and relapse due to target antigen downregulation remain clinical challenges. To mitigate immunophenotypic selective pressures, simultaneous dual antigen targeting with bispecific CAR T cells or multiple administration of different populations of CAR T cells may prevent relapse by addressing one resistance mechanism attributed to antigenic loss. This article will review recently published data on the use of dual targeting with CAR T cells from early phase clinical trials aimed at treating B cell malignancies and multiple myeloma. Full article
(This article belongs to the Special Issue CAR-T Cell in Human Cancers: Combinations, Gene-Editing, Payload Delivery, Autonomous Control and Synthetic Biology)
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24 pages, 2257 KiB  
Review
Engineering Solutions for Mitigation of Chimeric Antigen Receptor T-Cell Dysfunction
by Artemis Gavriil, Marta Barisa, Emma Halliwell and John Anderson
Cancers 2020, 12(8), 2326; https://doi.org/10.3390/cancers12082326 - 18 Aug 2020
Cited by 6 | Viewed by 4316
Abstract
The clinical successes of chimeric antigen receptor (CAR)-T-cell therapy targeting cell surface antigens in B cell leukaemias and lymphomas has demonstrated the proof of concept that appropriately engineered T-cells have the capacity to destroy advanced cancer with long term remissions ensuing. Nevertheless, it [...] Read more.
The clinical successes of chimeric antigen receptor (CAR)-T-cell therapy targeting cell surface antigens in B cell leukaemias and lymphomas has demonstrated the proof of concept that appropriately engineered T-cells have the capacity to destroy advanced cancer with long term remissions ensuing. Nevertheless, it has been significantly more problematic to effect long term clinical benefit in a solid tumour context. A major contributing factor to the clinical failure of CAR-T-cells in solid tumours has been named, almost interchangeably, as T-cell “dysfunction” or “exhaustion”. While unhelpful ambiguity surrounds the term “dysfunction”, “exhaustion” is canonically regarded as a pejorative term for T-cells. Recent understanding of T-cell developmental biology now identifies exhausted cells as vital for effective immune responses in the context of ongoing antigenic challenge. The purpose of this review is to explore the critical stages in the CAR-T-cell life-cycle and their various contributions to T-cell exhaustion. Through an appreciation of the predominant mechanisms of CAR-T-cell exhaustion and resultant dysfunction, we describe a range of engineering approaches to improve CAR-T-cell function. Full article
(This article belongs to the Special Issue CAR-T Cell in Human Cancers: Combinations, Gene-Editing, Payload Delivery, Autonomous Control and Synthetic Biology)
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20 pages, 1529 KiB  
Review
Adaptor CAR Platforms—Next Generation of T Cell-Based Cancer Immunotherapy
by Claudia Arndt, Frederick Fasslrinner, Liliana R. Loureiro, Stefanie Koristka, Anja Feldmann and Michael Bachmann
Cancers 2020, 12(5), 1302; https://doi.org/10.3390/cancers12051302 - 21 May 2020
Cited by 44 | Viewed by 5419
Abstract
The success of conventional chimeric antigen receptor (CAR) therapy in the treatment of refractory hematologic malignancies has triggered the development of novel exciting experimental CAR technologies. Among them, adaptor CAR platforms have received much attention. They combine the flexibility and controllability of recombinant [...] Read more.
The success of conventional chimeric antigen receptor (CAR) therapy in the treatment of refractory hematologic malignancies has triggered the development of novel exciting experimental CAR technologies. Among them, adaptor CAR platforms have received much attention. They combine the flexibility and controllability of recombinant antibodies with the power of CARs. Due to their modular design, adaptor CAR systems propose answers to the central problems of conventional CAR therapy, such as safety and antigen escape. This review provides an overview on the different adaptor CAR platforms available, discusses the possibilities and challenges of adaptor CAR therapy, and summarizes the first clinical experiences. Full article
(This article belongs to the Special Issue CAR-T Cell in Human Cancers: Combinations, Gene-Editing, Payload Delivery, Autonomous Control and Synthetic Biology)
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17 pages, 6272 KiB  
Review
Chimeric Antigen Receptor Cell Therapy: Overcoming Obstacles to Battle Cancer
by Amy J. Petty, Benjamin Heyman and Yiping Yang
Cancers 2020, 12(4), 842; https://doi.org/10.3390/cancers12040842 - 31 Mar 2020
Cited by 20 | Viewed by 5007
Abstract
Chimeric antigen receptors (CAR) are fusion proteins engineered from antigen recognition, signaling, and costimulatory domains that can be used to reprogram T cells to specifically target tumor cells expressing specific antigens. Current CAR-T cell technology utilizes the patient’s own T cells to stably [...] Read more.
Chimeric antigen receptors (CAR) are fusion proteins engineered from antigen recognition, signaling, and costimulatory domains that can be used to reprogram T cells to specifically target tumor cells expressing specific antigens. Current CAR-T cell technology utilizes the patient’s own T cells to stably express CARs and has achieved exciting clinical success in the past few years. However, current CAR-T cell therapy still faces several challenges, including suboptimal persistence and potency, impaired trafficking to solid tumors, local immunosuppression within the tumor microenvironment and intrinsic toxicity associated with CAR-T cells. This review focuses on recent strategies to improve the clinical efficacy of CAR-T cell therapy and other exciting CAR approaches currently under investigation, including CAR natural killer (NK) and NKT cell therapies. Full article
(This article belongs to the Special Issue CAR-T Cell in Human Cancers: Combinations, Gene-Editing, Payload Delivery, Autonomous Control and Synthetic Biology)
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22 pages, 1452 KiB  
Review
Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment
by Aleksei Titov, Aygul Valiullina, Ekaterina Zmievskaya, Ekaterina Zaikova, Alexey Petukhov, Regina Miftakhova, Emil Bulatov and Albert Rizvanov
Cancers 2020, 12(1), 125; https://doi.org/10.3390/cancers12010125 - 03 Jan 2020
Cited by 53 | Viewed by 15840
Abstract
Chimeric antigen receptor (CAR) immunotherapy is one of the most promising modern approaches for the treatment of cancer. To date only two CAR T-cell products, Kymriah® and Yescarta®, have been approved by the Food and Drug Administration (FDA) for the [...] Read more.
Chimeric antigen receptor (CAR) immunotherapy is one of the most promising modern approaches for the treatment of cancer. To date only two CAR T-cell products, Kymriah® and Yescarta®, have been approved by the Food and Drug Administration (FDA) for the treatment of lymphoblastic leukemia and B-cell lymphoma. Administration of CAR T-cells to control solid tumors has long been envisaged as one of the most difficult therapeutic tasks. The first two clinical trials conducted in sarcoma and neuroblastoma patients showed clinical benefits of CAR T-cells, yet multiple obstacles still hold us back from having accessible and efficient therapy. Why did such an effective treatment for relapsed and refractory hematological malignancies demonstrate only relatively modest efficiency in the context of solid tumors? Is it due to the lucky selection of the “magic” CD19 antigen, which might be one of a kind? Or do lymphomas lack the immunosuppressive features of solid tumors? Here we review the existing knowledge in the field of CAR T-cell therapy and address the heterogeneity of solid tumors and their diverse strategies of immunoevasion. We also provide an insight into prospective developments of CAR T-cell technologies against solid tumors. Full article
(This article belongs to the Special Issue CAR-T Cell in Human Cancers: Combinations, Gene-Editing, Payload Delivery, Autonomous Control and Synthetic Biology)
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