In-Vivo Induced CAR-T Cell for the Potential Breakthrough to Overcome the Barriers of Current CAR-T Cell Therapy
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Chimeric antigen receptor T cell (CAR-T cell) therapy has shown impressive success in the treatment of hematological malignancies, but the systemic toxicity and complex manufacturing process of current autologous CAR-T cell therapy hinder its broader applications. Universal CAR-T cells have been developed to simplify the production process through isolation and editing of allogeneic T cells from healthy persons, but the allogeneic CAR-T cells have recently encountered safety concerns, and clinical trials have been halted by the FDA. Thus, there is an urgent need to seek new ways to overcome the barriers of current CAR-T cell therapy. In-vivo CAR-T cells induced by nanocarriers loaded with CAR-genes and gene-editing tools have shown efficiency for regressing leukemia and reducing systemic toxicity in a mouse model. The in-situ programming of autologous T-cells avoids the safety concerns of allogeneic T cells, and the manufacture of nanocarriers can be easily standardized. Therefore, the in-vivo induced CAR-T cells can potentially overcome the abovementioned limitations of current CAR-T cell therapy. Here, we provide a review on CAR structures, gene-editing tools, and gene delivery techniques applied in immunotherapy to help design and develop new in-vivo induced CAR-T cells.Keywords:
Cell therapy
Nanocarriers
Abstract Chimeric antigen receptor (CAR) therapy is a method directing T lymphocytes against antigens on the surface of tumors, increasing target cell elimination. Genetic engineering enhances the capability of immune cells to detect new antigens expressed on cell surfaces. CAR T cell therapy is a significant breakthrough for treating human malignancies; however, different side effects (e.g., cytokine release syndrome) restrict its application. Improving design and using various combined receptors enhance the performance of these cells. This review discusses limitations and risk factors associated with CAR T cell therapy. We also review some alternative approaches for developing the next generation of CAR T cells.
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Cytokine Release Syndrome
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Chimeric antigen receptor (CAR) T-cell therapy is a novel therapeutic T-cell engineering option, where T-cells obtained from a patient’s blood are engineered ex vivo to express specific tumour antigen receptors. The highly selective nature of CAR T-cell therapy has led to a revolution in cancer treatment. The use of CAR T-cell therapy has been successful in treating haematological malignancies and there is also a growing interest in using CAR T-cell therapy to target solid tumours. However, there are notable challenges with CAR T-cell therapy, including non-sustained responses, antigen escape, and life-threatening adverse effects. Studies are underway to improve the safety of CAR T-cell therapy by limiting their expression, producing switchable CAR T-cells, and producing genetically engineered T-cells that are equipped with genes to reduce adverse effects.
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CAR T-cell therapy
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The development of chimeric antigen receptor T (CAR-T) cell therapy, a specific type of immunotherapy, in recent decades was a fantastic breakthrough for the treatment of hematological malignancies. However, difficulties in collecting normal T cells from patients and the time cost of manufacturing CAR-T cells have limited the application of CAR-T-cell therapy. In addition, the termination of related clinical trials on universal CAR-T cell therapy has made further research more difficult. Natural killer (NK) cells have drawn great attention in recent years. Chimeric antigen receptor-NK (CAR-NK) cell therapy is a promising strategy in the treatment of malignant tumors because of its lack of potential for causing graft-versus-host disease (GVHD). In this review, we will address the advances in and achievements of CAR-NK cell therapy.
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CAR T-cell therapy
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Chimeric antigen receptor T (CAR-T) cell immunotherapy shows potential and guarantee for clinical application in solid tumor treatment, although a section of difficulties must be overcome. Compared with conventional antitumor therapies, the advantages of CAR-T cell treatment include high specificity, great killing power, and long-term effectiveness. But various difficulties in treating solid tumors by CAR-T immunotherapy include intracellular signaling of CARs, immune escape due to antigenic heterogeneity of malignant tumors, physical or cytokine barriers that prevent CAR-T cell entry or limit their persistence, tumor microenvironment of other immunosuppressive molecules, and side effects. This paper describes CAR-T immunotherapy's mechanisms, development, and applications and discusses the status, difficulties, solutions, and future directions of treating solid tumors by CAR-T immunotherapy.
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Cellular immunotherapy is recognized as the fourth tumor treatment after surgery, radiotherapy and chemotherapy.Chimeric antigen receptor (CAR)-T-cell therapy belongs to adoptive cellular immunotherapy.CAR-T not only has made great breakthroughs in cancer treatment, but also has good application prospects in the treatment of infectious diseases and autoimmune diseases.This article reviews the development history, clinical applications, current problems and the latest research progress of CAR-T cell immunotherapy.
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Chimeric antigen receptor; T cell; Immunotherapy; Tumor
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Abstract BACKGROUND We have entered a new era of cancer therapy, with a number of immune-based therapies already used clinically as a standard of care. Adoptive cellular immunotherapy using T cells genetically modified with chimeric antigen receptors (CAR-T cells) represents a novel therapeutic approach. CAR-T cells have produced clinical responses in B-cell malignancies that are otherwise refractory to conventional therapies. Two CAR-T cell therapies obtained regulatory approval in 2017, with many more of these therapies under clinical development. CONTENT This review focuses on the current state of adoptive cellular immunotherapy, specifically CAR-T cells, in the clinic and how this therapy differs from traditional small molecule and biologic therapies. Areas in which the clinical laboratory is affected by these novel therapies are discussed. Opportunities for the clinical laboratory to help guide these therapies are also highlighted. SUMMARY The clinical laboratory will play an integral role in the care of patients undergoing adoptive cellular therapy with engineered T cells. There are many ways that this new therapeutic approach affects the clinical laboratory, and the clinical laboratory will likely play a critical role in managing patients that are treated with CAR-T cell therapy.
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Adoptive Cell Transfer
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Adoptive cell therapy with chimeric antigen receptor T (CAR-T) cells has achieved remarkable efficacy in the treatment of hematological malignancies, which has inspired researchers to expand the application of CAR-T-cell therapy to other medical conditions. Here, we review the current understanding and development of CAR-T-cell therapy for infectious diseases, autoimmune diseases and allotransplantation. The limitations and challenges of CAR-T-cell therapy in the treatment of these diseases and potential solutions to overcome these shortcomings are also discussed. With the development of novel designs of CARs and preclinical/clinical investigations, CAR-T-cell therapy is expected to be a potential cure option in a wide array of disease settings in the future.
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Some patients with hematologic malignancies as acute lymphoblastic leukemia (ALL), can achieve complete remission (CR) after chimeric antigen receptor T cell (CAR-T) immunotherapy. However, many constraints still limit the wide application of CAR-T immunotherapy in patients with hematological malignancies and other cancers, especially in patients with solid tumors. The main challenges related to CAR-T immunotherapy include: relapse caused by immune escape of tumor antigens, cytokine release syndrome (CRS), poor survival time in vivo, low infiltration capacity and inactivation of CAR-T in solid tumors, etc.. This article summarizes effects and problems of CAR-T immunotherapy in clinical trials for hematological malignancies, and how to use comprehensive treatment and biotechnology strategies to solve the current problems, in order to improve safety and effectiveness of CAR-T immunotherapy, and expand clinical benefits of CAR-T immunotherapy for patients with different tumors.
Key words:
Immunotherapy, adoptive; Receptors, chimeric antigen; Hematologic neoplasms; Chimeric antigen receptor-T cell; Solid tumors; Chimeric antigen receptor T cells immunotherapy; Combined modality therapy
Cancer Immunotherapy
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Autologous CAR-T therapy has shown promising outcomes in the treatment of tumors, particularly hematological malignancies over the past years. However, the application of autologous CAR-T therapy is limited, due to undesirable patient and/or peripheral blood characteristics, the high cost and long time period of manufacturing, and other challenges. Universal CAR-T therapy could overcome major limitations of autologous CAR-T therapy. In this review, we described the research and development status of universal CAR-T therapy for hematological malignancies. In addition, we also summarized the challenges had been encountered and the current solutions.
CAR T-cell therapy
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