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1
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Gao H, Qu L, Li M, Guan X, Zhang S, Deng X, Wang J, Xing F. Unlocking the potential of chimeric antigen receptor T cell engineering immunotherapy: Long road to achieve precise targeted therapy for hepatobiliary pancreatic cancers. Int J Biol Macromol 2025; 297:139829. [PMID: 39814310 DOI: 10.1016/j.ijbiomac.2025.139829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 01/03/2025] [Accepted: 01/11/2025] [Indexed: 01/18/2025]
Abstract
Innovative therapeutic strategies are urgently needed to address the ongoing global health concern of hepatobiliary pancreatic malignancies. This review summarizes the latest and most comprehensive research of chimeric antigen receptor (CAR-T) cell engineering immunotherapy for treating hepatobiliary pancreatic cancers. Commencing with an exploration of the distinct anatomical location and the immunosuppressive, hypoxic tumor microenvironment (TME), this review critically assesses the limitations of current CAR-T therapy in hepatobiliary pancreatic cancers and proposes corresponding solutions. Various studies aim at enhancing CAR-T cell efficacy in these cancers through improving T cell persistence, enhancing antigen specificity and reducing tumor heterogeneity, also modulating the immunosuppressive and hypoxic TME. Additionally, the review examines the application of emerging nanoparticles and biotechnologies utilized in CAR-T therapy for these cancers. The results suggest that constructing optimized CAR-T cells to overcome physical barrier, manipulating the TME to relieve immunosuppression and hypoxia, designing CAR-T combination therapies, and selecting the most suitable delivery strategies, all together could collectively enhance the safety of CAR-T engineering and advance the effectiveness of adaptive cell therapy for hepatobiliary pancreatic cancers.
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Affiliation(s)
- Hongli Gao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Lianyue Qu
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang 110001, China
| | - Mu Li
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xin Guan
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Shuang Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xin Deng
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| | - Jin Wang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Fei Xing
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
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2
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Yagyu S, Nakazawa Y. piggyBac-transposon-mediated CAR-T cells for the treatment of hematological and solid malignancies. Int J Clin Oncol 2023; 28:736-747. [PMID: 36859566 DOI: 10.1007/s10147-023-02319-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 02/17/2023] [Indexed: 03/03/2023]
Abstract
Since the introduction of the use of chimeric antigen receptor T-cell therapy (CAR-T therapy) dramatically changed the therapeutic strategy for B cell tumors, various CAR-T cell products have been developed and applied to myeloid and solid tumors. Although viral vectors have been widely used to produce genetically engineered T cells, advances in genetic engineering have led to the development of methods for producing non-viral, gene-modified CAR-T cells. Recent progress has revealed that non-viral CAR-T cells have a significant impact not only on the simplicity of the production process and the accessibility of non-viral vectors but also on the function of the cells themselves. In this review, we focus on piggyBac-transposon-based CAR-T cells among non-viral, gene-modified CAR-T cells and discuss their characteristics, preclinical development, and recent clinical applications.
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Affiliation(s)
- Shigeki Yagyu
- Innovative Research and Liaison Organization, Shinshu University, 3-1-1, Asahi, Matsumoto, Nagano, Japan. .,Center for Advanced Research of Gene and Cell Therapy, Shinshu University, 3-1-1, Asahi, Matsumoto, Nagano, Japan. .,Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan.
| | - Yozo Nakazawa
- Center for Advanced Research of Gene and Cell Therapy, Shinshu University, 3-1-1, Asahi, Matsumoto, Nagano, Japan.,Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, Japan.,Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 3-1-1, Asahi, Matsumoto, Nagano, Japan
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3
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Lin Z, Liu X, Liu T, Gao H, Wang S, Zhu X, Rong L, Cheng J, Cai Z, Xu F, Tan X, Lv L, Li Z, Sun Y, Qian Q. Evaluation of Nonviral piggyBac and lentiviral Vector in Functions of CD19chimeric Antigen Receptor T Cells and Their Antitumor Activity for CD19 + Tumor Cells. Front Immunol 2022; 12:802705. [PMID: 35082789 PMCID: PMC8784881 DOI: 10.3389/fimmu.2021.802705] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/14/2021] [Indexed: 11/13/2022] Open
Abstract
Nonviral transposon piggyBac (PB) and lentiviral (LV) vectors have been used to deliver chimeric antigen receptor (CAR) to T cells. To understand the differences in the effects of PB and LV on CAR T-cell functions, a CAR targeting CD19 was cloned into PB and LV vectors, and the resulting pbCAR and lvCAR were delivered to T cells to generate CD19pbCAR and CD19lvCAR T cells. Both CD19CAR T-cell types were strongly cytotoxic and secreted high IFN-γ levels when incubated with Raji cells. TNF-α increased in CD19pbCAR T cells, whereas IL-10 increased in CD19lvCAR T cells. CD19pbCAR and CD19lvCAR T cells showed similar strong anti-tumor activity in Raji cell-induced mouse models, slightly reducing mouse weight while enhancing mouse survival. High, but not low or moderate, concentrations of CD19pbCAR T cells significantly inhibited Raji cell-induced tumor growth in vivo. These CD19pbCAR T cells were distributed mostly in mesenteric lymph nodes, bone marrow of the femur, spleen, kidneys, and lungs, specifically accumulating at CD19-rich sites and CD19-positive tumors, with CAR copy number being increased on day 7. These results indicate that pbCAR has its specific activities and functions in pbCAR T cells, making it a valuable tool for CAR T-cell immunotherapy.
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MESH Headings
- Animals
- Antigens, CD19/genetics
- Antigens, CD19/immunology
- Antigens, CD19/metabolism
- Cell Line, Tumor
- Cells, Cultured
- Cytotoxicity, Immunologic/immunology
- DNA Transposable Elements/genetics
- DNA Transposable Elements/immunology
- Female
- Genetic Vectors/genetics
- Genetic Vectors/immunology
- Humans
- Immunotherapy, Adoptive/methods
- Lentivirus/genetics
- Lentivirus/immunology
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Neoplasms/immunology
- Neoplasms/pathology
- Neoplasms/therapy
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/metabolism
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Tumor Burden/immunology
- Xenograft Model Antitumor Assays/methods
- Mice
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Affiliation(s)
- Zhicai Lin
- Medical, Cell Product and R&D Department, Center for Cell Pharmaceuticals, Shanghai Cell Therapy Group, Shanghai, China
| | - Xiangzhen Liu
- Medical, Cell Product and R&D Department, Center for Cell Pharmaceuticals, Shanghai Cell Therapy Group, Shanghai, China
| | - Tao Liu
- R&D Department, Nucleotide Center, Shanghai Cell Therapy Group, Shanghai, China
| | - Haixia Gao
- R&D Department, Nucleotide Center, Shanghai Cell Therapy Group, Shanghai, China
| | - Sitong Wang
- Medical, Cell Product and R&D Department, Center for Cell Pharmaceuticals, Shanghai Cell Therapy Group, Shanghai, China
| | - Xingli Zhu
- Medical, Cell Product and R&D Department, Center for Cell Pharmaceuticals, Shanghai Cell Therapy Group, Shanghai, China
| | - Lijie Rong
- Medical, Cell Product and R&D Department, Center for Cell Pharmaceuticals, Shanghai Cell Therapy Group, Shanghai, China
| | - Jingbo Cheng
- Medical, Cell Product and R&D Department, Center for Cell Pharmaceuticals, Shanghai Cell Therapy Group, Shanghai, China
| | - Zhigang Cai
- Medical, Cell Product and R&D Department, Center for Cell Pharmaceuticals, Shanghai Cell Therapy Group, Shanghai, China
| | - Fu Xu
- Medical, Cell Product and R&D Department, Center for Cell Pharmaceuticals, Shanghai Cell Therapy Group, Shanghai, China
| | - Xue Tan
- Medical, Cell Product and R&D Department, Center for Cell Pharmaceuticals, Shanghai Cell Therapy Group, Shanghai, China
| | - Linjie Lv
- Medical, Cell Product and R&D Department, Center for Cell Pharmaceuticals, Shanghai Cell Therapy Group, Shanghai, China
| | - Zhong Li
- Medical, Cell Product and R&D Department, Center for Cell Pharmaceuticals, Shanghai Cell Therapy Group, Shanghai, China
- Department of Immunotherapy, Shanghai Cell Therapy Research Institute, Shanghai, China
| | - Yan Sun
- Medical, Cell Product and R&D Department, Center for Cell Pharmaceuticals, Shanghai Cell Therapy Group, Shanghai, China
| | - Qijun Qian
- Medical, Cell Product and R&D Department, Center for Cell Pharmaceuticals, Shanghai Cell Therapy Group, Shanghai, China
- Department of Immunotherapy, Shanghai Cell Therapy Research Institute, Shanghai, China
- Shanghai Menchao Cancer Hospital, Shanghai University, Shanghai, China
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Songjang W, Nensat C, Pongcharoen S, Jiraviriyakul A. The role of immunogenic cell death in gastrointestinal cancer immunotherapy (Review). Biomed Rep 2021; 15:86. [PMID: 34512974 PMCID: PMC8411483 DOI: 10.3892/br.2021.1462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 07/30/2021] [Indexed: 12/24/2022] Open
Abstract
Modern cancer immunotherapy techniques are aimed at enhancing the responses of the patients' immune systems to fight against the cancer. The main promising strategies include active vaccination of tumor antigens, passive vaccination with antibodies specific to cancer antigens, adoptive transfer of cancer-specific T cells and manipulation of the patient's immune response by inhibiting immune checkpoints. The application of immunogenic cell death (ICD) inducers has been proven to enhance the immunity of patients undergoing various types of immunotherapy. The dying, stressed or injured cells release or present molecules on the cell surface, which function as either adjuvants or danger signals for detection by the innate immune system. These molecules are now termed 'damage-associated molecular patterns'. The term 'ICD' indicates a type of cell death that triggers an immune response against dead-cell antigens, particularly those derived from cancer cells, and it was initially proposed with regards to the effects of anticancer chemotherapy with conventional cytotoxic drugs. The aim of the present study was to review and discuss the role and mechanisms of ICD as a promising combined immunotherapy for gastrointestinal tumors.
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Affiliation(s)
- Worawat Songjang
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Chatchai Nensat
- Biomedical Sciences, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Sutatip Pongcharoen
- Division of Immunology, Department of Medicine, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand
| | - Arunya Jiraviriyakul
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
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5
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Szöőr Á, Szöllősi J, Vereb G. From antibodies to living drugs: Quo vadis cancer immunotherapy? Biol Futur 2021; 72:85-99. [PMID: 34554498 DOI: 10.1007/s42977-021-00072-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 01/12/2021] [Indexed: 01/16/2023]
Abstract
In the last few decades, monoclonal antibodies targeting various receptors and ligands have shown significant advance in cancer therapy. However, still a great percentage of patients experiences tumor relapse despite persistent antigen expression. Immune cell therapy with adoptively transferred modified T cells that express chimeric antigen receptors (CAR) is an engaging option to improve disease outcome. Designer T cells have been applied with remarkable success in the treatment for acute B cell leukemias, yielding unprecedented antitumor activity and significantly improved overall survival. Relying on the success of CAR T cells in leukemias, solid tumors are now emerging potential targets; however, their complexity represents a significant challenge. In preclinical models, CAR T cells recognized and efficiently killed the wide spectrum of tumor xenografts; however, in human clinical trials, limited antitumor efficacy and serious side effects, including cytokine release syndrome, have emerged as potential limitations. The next decade will be an exciting time to further optimize this novel cellular therapeutics to improve effector functions and, at the same time, keep adverse events in check. Moreover, we need to establish whether gene-modified T cells which are yet exclusively used for cancer patients could also be successful in the treatment for other diseases. Here, we provide a concise overview about the transition from monoclonal antibodies to the generation of chimeric antigen receptor T cells. We summarize lessons learned from preclinical models, including our own HER2-positive tumor models, as well as from clinical trials worldwide. We also discuss the challenges we are facing today and outline future prospects.
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Affiliation(s)
- Árpád Szöőr
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1., 4032, Debrecen, Hungary
| | - János Szöllősi
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1., 4032, Debrecen, Hungary
- MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Egyetem tér 1., 4032, Debrecen, Hungary
| | - György Vereb
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1., 4032, Debrecen, Hungary.
- MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Egyetem tér 1., 4032, Debrecen, Hungary.
- Faculty of Pharmacy, University of Debrecen, Egyetem tér 1., 4032, Debrecen, Hungary.
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6
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Park CH. Making Potent CAR T Cells Using Genetic Engineering and Synergistic Agents. Cancers (Basel) 2021; 13:cancers13133236. [PMID: 34209505 PMCID: PMC8269169 DOI: 10.3390/cancers13133236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/16/2021] [Accepted: 06/23/2021] [Indexed: 12/16/2022] Open
Abstract
Immunotherapies are emerging as powerful weapons for the treatment of malignancies. Chimeric antigen receptor (CAR)-engineered T cells have shown dramatic clinical results in patients with hematological malignancies. However, it is still challenging for CAR T cell therapy to be successful in several types of blood cancer and most solid tumors. Many attempts have been made to enhance the efficacy of CAR T cell therapy by modifying the CAR construct using combination agents, such as compounds, antibodies, or radiation. At present, technology to improve CAR T cell therapy is rapidly developing. In this review, we particularly emphasize the most recent studies utilizing genetic engineering and synergistic agents to improve CAR T cell therapy.
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Affiliation(s)
- Chi Hoon Park
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Daejeon 34114, Korea; ; Tel.: +82-42-860-7416; Fax: +82-42-861-4246
- Medicinal & Pharmaceutical Chemistry, Korea University of Science and Technology, Daejeon 34113, Korea
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7
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Robbins GM, Wang M, Pomeroy EJ, Moriarity BS. Nonviral genome engineering of natural killer cells. Stem Cell Res Ther 2021; 12:350. [PMID: 34134774 PMCID: PMC8207670 DOI: 10.1186/s13287-021-02406-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 05/21/2021] [Indexed: 12/02/2022] Open
Abstract
Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system capable of immune surveillance. Given their ability to rapidly and effectively recognize and kill aberrant cells, especially transformed cells, NK cells represent a unique cell type to genetically engineer to improve its potential as a cell-based therapy. NK cells do not express a T cell receptor and thus do not contribute to graft-versus-host disease, nor do they induce T cell-driven cytokine storms, making them highly suited as an off-the-shelf cellular therapy. The clinical efficacy of NK cell-based therapies has been hindered by limited in vivo persistence and the immunosuppressive tumor microenvironment characteristic of many cancers. Enhancing NK cell resistance to tumor inhibitory signaling through genome engineering has the potential to improve NK cell persistence in the tumor microenvironment and restore cytotoxic functions. Alongside silencing NK cell inhibitory receptors, NK cell killing can be redirected by the integration of chimeric antigen receptors (CARs). However, NK cells are associated with technical and biological challenges not observed in T cells, typically resulting in low genome editing efficiencies. Viral vectors have achieved the greatest gene transfer efficiencies but carry concerns of random, insertional mutagenesis given the high viral titers necessary. As such, this review focuses on nonviral methods of gene transfer within the context of improving cancer immunotherapy using engineered NK cells.
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Affiliation(s)
- Gabrielle M Robbins
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, 55455, USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.,Center for Genome Engineering, University of Minnesota, Minneapolis, MN, 55455, USA.,College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, 55455, USA
| | - Minjing Wang
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, 55455, USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.,Center for Genome Engineering, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Emily J Pomeroy
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, 55455, USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.,Center for Genome Engineering, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Branden S Moriarity
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, 55455, USA. .,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA. .,Center for Genome Engineering, University of Minnesota, Minneapolis, MN, 55455, USA.
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8
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Klampatsa A, Dimou V, Albelda SM. Mesothelin-targeted CAR-T cell therapy for solid tumors. Expert Opin Biol Ther 2020; 21:473-486. [PMID: 33176519 DOI: 10.1080/14712598.2021.1843628] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Mesothelin (MSLN) is a tumor differentiation antigen normally restricted to the body's mesothelial surfaces, but significantly overexpressed in a broad range of solid tumors. For this reason, MSLN has emerged as an important target for the development of novel immunotherapies. This review focuses on anti-MSLN chimeric antigen receptor (CAR) T cell immunotherapy approaches.Areas covered: A brief overview of MSLN as a therapeutic target and existing anti-MSLN antibody-based drugs and vaccines is provided. A detailed account of anti-MSLN CAR-T cell approaches utilized in preclinical models is presented. Finally, a comprehensive summary of currently ongoing and completed anti-MSLN CAR-T cell clinical trials is discussed.Expert opinion: Initial trials using anti-MSLN CAR-T cells have been safe, but efficacy has been limited. Employing regional routes of delivery, introducing novel modifications leading to enhanced tumor infiltration and persistence, and improved safety profiles and combining anti-MSLN CAR-T cells with standard therapies, could render them more efficacious in the treatment of solid malignancies.
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Affiliation(s)
- Astero Klampatsa
- Thoracic Oncology Immunotherapy Group, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK
| | - Vivian Dimou
- Thoracic Oncology Immunotherapy Group, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK
| | - Steven M Albelda
- Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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9
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Kumar D, Anand T, Talluri TR, Kues WA. Potential of transposon-mediated cellular reprogramming towards cell-based therapies. World J Stem Cells 2020; 12:527-544. [PMID: 32843912 PMCID: PMC7415244 DOI: 10.4252/wjsc.v12.i7.527] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/09/2020] [Accepted: 05/28/2020] [Indexed: 02/07/2023] Open
Abstract
Induced pluripotent stem (iPS) cells present a seminal discovery in cell biology and promise to support innovative treatments of so far incurable diseases. To translate iPS technology into clinical trials, the safety and stability of these reprogrammed cells needs to be shown. In recent years, different non-viral transposon systems have been developed for the induction of cellular pluripotency, and for the directed differentiation into desired cell types. In this review, we summarize the current state of the art of different transposon systems in iPS-based cell therapies.
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Affiliation(s)
- Dharmendra Kumar
- Animal Physiology and Reproduction Division, ICAR-Central Institute for Research on Buffaloes, Hisar 125001, India.
| | - Taruna Anand
- NCVTC, ICAR-National Research Centre on Equines, Hisar 125001, India
| | - Thirumala R Talluri
- Equine Production Campus, ICAR-National Research Centre on Equines, Bikaner 334001, India
| | - Wilfried A Kues
- Friedrich-Loeffler-Institut, Institute of Farm Animal Genetics, Department of Biotechnology, Mariensee 31535, Germany
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Wang L, Tan Su Yin E, Zhao H, Ni F, Hu Y, Huang H. CAR-T cells: the Chinese experience. Expert Opin Biol Ther 2020; 20:1293-1308. [PMID: 32605454 DOI: 10.1080/14712598.2020.1790521] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Chimeric antigen receptor T (CAR-T) cells are harnessed to identify and lyse malignant cells specifically, efficiently, and independently of the major histocompatibility complex (MHC). As a result, prognoses of relapsed or refractory (R/R) B cell hematological malignancies as well as limited types of solid tumors, have been ameliorated to a great extent. In China, a rising number of clinical trials that contribute to the development of novel CAR-T therapeutic strategies have been conducted on an extensive scale. AREAS COVERED We summarize registered clinical trials related to CAR-T therapy conducted in China by evaluating various parameters such as distribution, study phase, CAR structure, target antigen, and disease. The efficacy, toxicity, and, more importantly, the new strategies for optimization of CAR-T therapy of Chinese studies and clinical trials are elaborated in detail. EXPERT OPINION In terms of the number of CAR-T clinical trials, China is second to the USA, registering approximately 33% of trials worldwide. China's extensive explorations and breakthroughs in the search of novel target antigens, optimization of CAR structure, cocktail CAR-T therapy, combination therapy, and extension of CAR-T cell applications, imply that we are currently on the verge of a revolution in CAR-T therapy.
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Affiliation(s)
- Linqin Wang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy , Hangzhou, China.,Institute of Hematology, Zhejiang University , Hangzhou, China
| | - Elaine Tan Su Yin
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy , Hangzhou, China.,Institute of Hematology, Zhejiang University , Hangzhou, China
| | - Houli Zhao
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy , Hangzhou, China.,Institute of Hematology, Zhejiang University , Hangzhou, China
| | - Fang Ni
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy , Hangzhou, China.,Institute of Hematology, Zhejiang University , Hangzhou, China
| | - Yongxian Hu
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy , Hangzhou, China.,Institute of Hematology, Zhejiang University , Hangzhou, China
| | - He Huang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy , Hangzhou, China.,Institute of Hematology, Zhejiang University , Hangzhou, China
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11
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Sur D, Havasi A, Cainap C, Samasca G, Burz C, Balacescu O, Lupan I, Deleanu D, Irimie A. Chimeric Antigen Receptor T-Cell Therapy for Colorectal Cancer. J Clin Med 2020; 9:182. [PMID: 31936611 PMCID: PMC7019711 DOI: 10.3390/jcm9010182] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 01/03/2020] [Accepted: 01/07/2020] [Indexed: 02/06/2023] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy represents a new genetically engineered method of immunotherapy for cancer. The patient's T-cells are modified to express a specific receptor that sticks to the tumor antigen. This modified cell is then reintroduced into the patient's body to fight the resilient cancer cells. After exhibiting positive results in hematological malignancies, this therapy is being proposed for solid tumors like colorectal cancer. The clinical data of CAR T-cell therapy in colorectal cancer is rather scarce. In this review, we summarize the current state of knowledge, challenges, and future perspectives of CAR T-cell therapy in colorectal cancer. A total of 22 articles were included in this review. Eligible studies were selected and reviewed by two researchers from 49 articles found on Pubmed, Web of Science, and clinicaltrials.gov. This therapy, at the moment, provides modest benefits in solid tumors. Not taking into consideration the high manufacturing and retail prices, there are still limitations like increased toxicities, relapses, and unfavorable tumor microenvironment for CAR T-cell therapy in colorectal cancer.
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Affiliation(s)
- Daniel Sur
- 11th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania; (D.S.); (C.C.); (O.B.)
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania; (A.H.); (C.B.)
| | - Andrei Havasi
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania; (A.H.); (C.B.)
| | - Calin Cainap
- 11th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania; (D.S.); (C.C.); (O.B.)
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania; (A.H.); (C.B.)
| | - Gabriel Samasca
- Department of Immunology and Allergology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400162 Cluj-Napoca, Romania;
| | - Claudia Burz
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania; (A.H.); (C.B.)
- Department of Immunology and Allergology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400162 Cluj-Napoca, Romania;
| | - Ovidiu Balacescu
- 11th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania; (D.S.); (C.C.); (O.B.)
- Department of Functional Genomics, Proteomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania
| | - Iulia Lupan
- Department of Molecular Biology and Biotehnology, Babeș-Bolyai University, 400084 Cluj-Napoca, Romania
| | - Diana Deleanu
- Department of Immunology and Allergology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400162 Cluj-Napoca, Romania;
| | - Alexandru Irimie
- 11th Department of Oncological Surgery and Gynecological Oncology, “IuliuHatieganu” University of Medicine and Pharmacy, 400015 Cluj-Napoca, Romania;
- Department of Surgery, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania
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Abstract
CAR-T cell therapy targeting CD19 has achieved remarkable success in the treatment of B cell malignancies, while various solid malignancies are still refractory for lack of suitable target. In recent years, a large number of studies have sought to find suitable targets with low “on target, off tumor” concern for the treatment of solid tumors. Mesothelin (MSLN), a tumor-associated antigen broadly overexpressed on various malignant tumor cells, while its expression is generally limited to normal mesothelial cells, is an attractive candidate for targeted therapy. Strategies targeting MSLN, including antibody-based drugs, vaccines and CAR-T therapies, have been assessed in a large number of preclinical investigations and clinical trials. In particular, the development of CAR-T therapy has shown great promise as a treatment for various types of cancers. The safety, efficacy, doses, and pharmacokinetics of relevant strategies have been evaluated in many clinical trials. This review is intended to provide a brief overview of the characteristics of mesothelin and the development of strategies targeting MSLN for solid tumors. Further, we discussed the challenges and proposed potential strategies to improve the efficacy of MSLN targeted immunotherapy.
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Affiliation(s)
- Jiang Lv
- 1Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,2Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,3University of Chinese Academy of Sciences, Shijingshan District, Beijing, China
| | - Peng Li
- 1Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,2Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
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13
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Chen Y, E CY, Gong ZW, Liu S, Wang ZX, Yang YS, Zhang XW. Chimeric antigen receptor-engineered T-cell therapy for liver cancer. Hepatobiliary Pancreat Dis Int 2018; 17:301-309. [PMID: 29861325 DOI: 10.1016/j.hbpd.2018.05.005] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 05/09/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND Chimeric antigen receptor-engineered T-cell (CAR-T) therapy is a newly developed immunotherapy used in the treatment of cancers. Because CAR-T therapy has shown great success in treating CD19-positive hematological malignancies, its application has been explored in the treatment of solid tumors, such as liver cancer. In this review, we discuss the immune characteristics of liver cancer, the obstacles encountered during the application of CAR-T therapy, and preclinical and clinical progress in the use of CAR-T therapy in patients with liver cancer. DATA SOURCES The data on CAR-T therapy related to liver cancers were collected by searching PubMed and the Web of Science databases prior to December 2017 with the keywords "chimeric antigen receptor", "CAR-T", "liver cancer", "hepatocellular carcinoma", and "solid tumor". Additional articles were identified by manual search of references found in the primary articles. The data for clinical trials were collected by searching ClinicalTrials.gov. RESULTS The liver has a tolerogenic nature in the intrahepatic milieu and its tumor microenvironment significantly affects tumor progression. The obstacles that reduce the efficacy of CAR-T therapy in solid tumors include a lack of specific tumor antigens, limited trafficking and penetration of CAR-T cells to tumor sites, and an immunosuppressive tumor microenvironment. To overcome these obstacles, several strategies have emerged. In addition, several strategies have been developed to manage the side effects of CAR-T, including enhancing the selectivity of CARs and controlling CAR-T activity. To date, no clinical trials of CAR-T therapy against HCC have been completed. However, preclinical studies in vitro and in vivo have shown potent antitumor efficacy. Glypican-3, mucin-1, epithelial cell adhesion molecule, carcinoembryonic antigen, and other targets are currently being studied. CONCLUSIONS The application of CAR-T therapy for liver cancer is just beginning to be explored and more research is needed. However, we are optimistic that CAR-T therapy will offer a new approach for the treatment of liver cancers in the future.
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Affiliation(s)
- Yang Chen
- Department of Hepatobiliary and Pancreas Surgery, the Second Hospital of Jilin University, Changchun 130041, China
| | - Chang-Yong E
- Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130021, China
| | - Zhi-Wen Gong
- Department of Hepatobiliary and Pancreas Surgery, the Second Hospital of Jilin University, Changchun 130041, China
| | - Shui Liu
- Department of Hepatobiliary and Pancreas Surgery, the Second Hospital of Jilin University, Changchun 130041, China
| | - Zhen-Xiao Wang
- Department of Hepatobiliary and Pancreas Surgery, the Second Hospital of Jilin University, Changchun 130041, China
| | - Yong-Sheng Yang
- Department of Hepatobiliary and Pancreas Surgery, the Second Hospital of Jilin University, Changchun 130041, China
| | - Xue-Wen Zhang
- Department of Hepatobiliary and Pancreas Surgery, the Second Hospital of Jilin University, Changchun 130041, China.
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He J, Zhang Z, Lv S, Liu X, Cui L, Jiang D, Zhang Q, Li L, Qin W, Jin H, Qian Q. Engineered CAR T cells targeting mesothelin by piggyBac transposon system for the treatment of pancreatic cancer. Cell Immunol 2018; 329:31-40. [PMID: 29859625 DOI: 10.1016/j.cellimm.2018.04.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 04/11/2018] [Accepted: 04/15/2018] [Indexed: 12/22/2022]
Abstract
Patients with pancreatic cancer have a poor prognosis largely due to the poor efficacy of the available treatment modalities. In this study, we engineered mesothelin-targeting chimeric antigen receptor T cells (mesoCAR T) using the piggyBac transposon based plasmid electroporation technique for specific targeting of pancreatic cancer cells expressing mesothelin. In vitro, mesoCAR T cells exhibited rapid and robust killing effect against ASPC1 cells with high expression levels of mesothelin with high production of IFN-γ; the cytotoxic effect on PANC1 cells with low expressions of mesothelin was relatively attenuated. In the ASPC1 xenograft mice model, mesoCAR T cells significantly suppressed the tumor growth accompanied with higher-level IFN-γ secretion as compared to control T cells. Besides, more mesoCAR T cells differentiated into memory T cells after tumor remission, whilst causing minimal lesions in major organs. Our study suggests promising efficacy of piggyBac transposon-based mesoCAR T cell therapy for pancreatic cancer, which is a potential candidate for clinical translation.
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Affiliation(s)
- Jiangchuan He
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Zhiwei Zhang
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China; Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai 201805, China
| | - Saiqun Lv
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Xiangzhen Liu
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Lianzhen Cui
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Duqing Jiang
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Qi Zhang
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Linfang Li
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Wenxia Qin
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China
| | - Huajun Jin
- Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China; Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai 201805, China.
| | - Qijun Qian
- Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China; Shanghai Cell Therapy Research Institute, Shanghai Engineering Research Center for Cell Therapy, Shanghai 201805, China; Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University of Chinese PLA, Shanghai 201805, China.
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15
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Preclinical and clinical advances in transposon-based gene therapy. Biosci Rep 2017; 37:BSR20160614. [PMID: 29089466 PMCID: PMC5715130 DOI: 10.1042/bsr20160614] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 10/26/2017] [Accepted: 10/30/2017] [Indexed: 02/08/2023] Open
Abstract
Transposons derived from Sleeping Beauty (SB), piggyBac (PB), or Tol2 typically require cotransfection of transposon DNA with a transposase either as an expression plasmid or mRNA. Consequently, this results in genomic integration of the potentially therapeutic gene into chromosomes of the desired target cells, and thus conferring stable expression. Non-viral transfection methods are typically preferred to deliver the transposon components into the target cells. However, these methods do not match the efficacy typically attained with viral vectors and are sometimes associated with cellular toxicity evoked by the DNA itself. In recent years, the overall transposition efficacy has gradually increased by codon optimization of the transposase, generation of hyperactive transposases, and/or introduction of specific mutations in the transposon terminal repeats. Their versatility enabled the stable genetic engineering in many different primary cell types, including stem/progenitor cells and differentiated cell types. This prompted numerous preclinical proof-of-concept studies in disease models that demonstrated the potential of DNA transposons for ex vivo and in vivo gene therapy. One of the merits of transposon systems relates to their ability to deliver relatively large therapeutic transgenes that cannot readily be accommodated in viral vectors such as full-length dystrophin cDNA. These emerging insights paved the way toward the first transposon-based phase I/II clinical trials to treat hematologic cancer and other diseases. Though encouraging results were obtained, controlled pivotal clinical trials are needed to corroborate the efficacy and safety of transposon-based therapies.
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Tipanee J, VandenDriessche T, Chuah MK. Transposons: Moving Forward from Preclinical Studies to Clinical Trials. Hum Gene Ther 2017; 28:1087-1104. [DOI: 10.1089/hum.2017.128] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Jaitip Tipanee
- Department of Gene Therapy and Regenerative Medicine, Free University of Brussels (VUB), Brussels, Belgium
| | - Thierry VandenDriessche
- Department of Gene Therapy and Regenerative Medicine, Free University of Brussels (VUB), Brussels, Belgium
- Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
| | - Marinee K. Chuah
- Department of Gene Therapy and Regenerative Medicine, Free University of Brussels (VUB), Brussels, Belgium
- Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
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