Current status and problems of chimeric antigen receptor T cell immunotherapy in treatment of hematological malignancies
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Abstract:
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 therapyKeywords:
Cancer Immunotherapy
CAR T-cell therapy
Hematologic Neoplasms
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Research progress on clinical application of chimeric antigen receptor t cells in blood malignancies
With the development of tumor immunological theory and technology, the treatment of blood malignancies is in a new era. Adoptive cellular immunotherapy (ACI) has become the hotspot of researches. Chimeric antigen receptor (CAR) modified T cell shows prominent therapeutic effect in various trails treating blood malignancies. In this paper, we describe the construction of CAR-T cell, choice of targets, clinical experiments related to CAR-T cell therapy in recent years, and the problems remain to be solved.
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Receptors, antigen; Hematologic neoplasms; Cellular immunotherapy, adoptive
Cell therapy
Adoptive immunotherapy
Adoptive Cell Transfer
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The survival of patients with hematological malignancies has been significantly improved due to the development of new therapeutic agents. However, relapse remains a major matter for concern. Recently, T cells engineered with chimeric antigen receptor (CAR) were reported to show unprecedented responses in a range of hematological malignancies. The persistence of the CAR-T cell can last for years and tends toward long-term antitumor memory by which relapses can be effectively prevented. The primary side effects that appear in most clinical trials are cytokine release syndrome and neurotoxicity. However, these symptoms can be treated and reversed. In this review, we describe CAR structure and function and summarize recent advances in CAR-T cell therapy in hematological malignancies.
Cytokine Release Syndrome
Neurotoxicity
CAR T-cell therapy
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Chimeric antigen receptor T cell (CAR-T cell) therapy is a novel adoptive immunotherapy where T lymphocytes are engineered with synthetic receptors known as chimeric antigen receptors (CAR). The CAR-T cell is an effector T cell that recognizes and eliminates specific cancer cells, independent of major histocompatibility complex molecules. The whole procedure of CAR-T cell production is not well understood. The CAR-T cell has been used predominantly in the treatment of hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, and multiple myeloma. Solid tumors including melanoma, breast cancer and sarcoma offer great promise in CAR-T cell research and development. CD19 CAR-T cell is most commonly used, and other targets, including CD20, CD30, CD38 and CD138 are being studied. Although this novel therapy is promising, there are several disadvantages. In this review we discuss the applications of CAR-T cells in different hematological malignancies, and pave a way for future improvement on the effectiveness and persistence of these adoptive cell therapies.
Cell therapy
Adoptive Cell Transfer
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Multiple myeloma (MM) is a clonal B cell malignant disease that is characterized by the proliferation of plasma cells in the bone marrow, leading to bone destruction, hematopoietic failure and producing M protein. In recent years, the remission rate and survival of MM patients have been significantly improved with the application of new drugs. But most patients still experience relapse, progression or drug resistance. It′s urgent to seek new treatment strategies of MM. Chimeric antigen receptor-modified T cell (CAR-T) immunotherapy is one of the important biotherapy techniques in the field of tumor immunotherapy in recent years. CAR-T can kill MM cells by specifically identifying target antigens and provide new therapy for patients with MM. This article intends to expound the relevant targets, existing problems and the measures to improve the effectiveness of CAR-T in treatment of MM.
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Multiple myeloma; Immunotherapy, adoptive; Molecular targeted therapy; Clinical protocols; Chimeric antigen receptor T cell immunotherapy
Cell therapy
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Tumor treatment is still complicated in the field of medicine. Tumor immunotherapy has been the most interesting research field in cancer therapy. Application of chimeric antigen receptor T (CAR-T) cell therapy has recently achieved excellent clinical outcome in patients, especially those with CD19-positive hematologic malignancies. This phenomenon has induced intense interest to develop CAR-T cell therapy for cancer, especially for solid tumors. However, the performance of CAR-T cell treatment in solid tumor is not as satisfactory as that in hematologic disease. Clinical studies on some neoplasms, such as glioblastoma, ovarian cancer, and cholangiocarcinoma, have achieved desirable outcome. This review describes the history and evolution of CAR-T, generalizes the structure and preparation of CAR-T, and summarizes the latest advances on CAR-T cell therapy in different tumor types. The last section presents the current challenges and prospects of CAR-T application to provide guidance for subsequent research.
Cell therapy
Cancer Immunotherapy
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In recent years, genetically modified autologous T cell therapy has made remarkble achievements in clinical trials of oncotherapy, among which chimeric antigen receptor T-cell (CAR-T) immunotherapy has generated dramatic clinical successes in patients with acute lymphoblastic leukemia (ALL). Chimeric antigen receptor (CAR) is a hybrid molecule composed of antigen-binding domains fused to T-cell activation and costimulatory domains. CAR-T can bind tumor cells specifically. Unlike traditional medicines, CAR-T has potential to eradicate widespread cancer and provides long-term protection in the form of immunologic memory. Therefore, CAR-T immunotherapy is attracting more and more attention, and has become a promising therapy in hematologic malignancies, especially B-cell malignancies. This review will discuss the currently clinical trials of CAR-T immunotherapy in hematologic malignancies.
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Lymphoma, B-cell; Leukemia; Multiple myeloma; Chimeric antigen receptor T cell immunotherapy
Cancer Immunotherapy
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Introduction: Chimeric antigen receptor (CAR) T cell therapy has provided patients with relapsed/refractory B cell malignancies a new therapeutic option, but this class of therapeutics has not demonstrated consistent therapeutic benefit in solid tumors.Areas Covered: Here we review the literature to identify numerous factors that contribute to this discrepancy, using pediatric cancers as a platform to understand these limitations. We discuss an inability to target highly and homogenously expressed lineage-associated antigens due to risks of on-target off-tumor toxicity, T cell dysfunction related to T cell exhaustion and the suppressive tumor microenvironment (TME), and inefficient CAR T cell trafficking into solid tumors. As our understanding of the biology of CAR T cells improves and innovations in engineering CAR platforms emerge, next generation CAR T cell therapeutics designed to overcome these challenges will enter the clinic for testing.Expert Opinion: New approaches to address the challenges that have limited the efficacy of CAR T cell therapeutics in solid tumors are emerging. These approaches include next-generation CAR T cell engineering to overcome antigen heterogeneity, to mitigate T cell exhaustion and to prevent suppression by the TME, as well as novel approaches for regional delivery to facilitate tumor T cell trafficking.
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Recent reports on the impressive efficacy of chimeric antigen receptor (CAR)-modified T cells against hematologic malignancies have inspired oncologists to extend these efforts for the treatment of solid tumors. Clinical trials of CAR-T-based cancer immunotherapy for solid tumors showed that the efficacies are not as remarkable as in the case of hematologic malignancies. There are several challenges that researchers must face when treating solid cancers with CAR-T cells, these include choosing an ideal target, promoting efficient trafficking and infiltration, overcoming the immunosuppressive microenvironment, and avoiding associated toxicity. In this review, we discuss the obstacles imposed by solid tumors on CAR-T cell-based immunotherapy and strategies adopted to improve the therapeutic potential of this approach. Continued investigations are necessary to improve therapeutic outcomes and decrease the adverse effects of CAR-T cell therapy in patients with solid malignancies in the future.
Solid tumor
Cancer Immunotherapy
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Chimeric antigen receptor (CAR) is a molecular modifier, and T cells modified by CAR have the antibody sequence to recognize tumor antigens, and have a specific recognition and killing ability against tumors. Since 1990s, the research and development of chimeric antigen receptor T cell (CAR-T) immunotherapy have gone through nearly 30 years, including the first concept, design, basic research, animal experiments, clinical trials, etc.. From the first generation of CAR-T to the third and the fourth generation of CAR-T, the types of CAR-T are increasing and showing more and more advantages in the treatment of a variety of hematological malignant diseases. CAR-T immunotherapy has remarkable curative effect in the treatment of B cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). It is considered as one of the most advanced gene therapies. This article intends to review the brief history of the development, optimization and improvement of CAR-T immunotherapy.
Key words:
Immunotherapy, adoptive; Leukemia, B-cell; Lymphoma, non-Hodgkin; Multiple myeloma; Relapse; Chimeric antigen receptor T cell immunotherapy
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