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      Immunotherapy in hematologic malignancies: achievements, challenges and future prospects

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          Abstract

          The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape, which has accelerated the progress of immunotherapy. Several categories of immunotherapies have been developed and are being further evaluated in clinical trials for the treatment of blood cancers, including stem cell transplantation, immune checkpoint inhibitors, antigen-targeted antibodies, antibody-drug conjugates, tumor vaccines, and adoptive cell therapies. These immunotherapies have shown the potential to induce long-term remission in refractory or relapsed patients and have led to a paradigm shift in cancer treatment with great clinical success. Different immunotherapeutic approaches have their advantages but also shortcomings that need to be addressed. To provide clinicians with timely information on these revolutionary therapeutic approaches, the comprehensive review provides historical perspectives on the applications and clinical considerations of the immunotherapy. Here, we first outline the recent advances that have been made in the understanding of the various categories of immunotherapies in the treatment of hematologic malignancies. We further discuss the specific mechanisms of action, summarize the clinical trials and outcomes of immunotherapies in hematologic malignancies, as well as the adverse effects and toxicity management and then provide novel insights into challenges and future directions.

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Oncology meets immunology: the cancer-immunity cycle.

            The genetic and cellular alterations that define cancer provide the immune system with the means to generate T cell responses that recognize and eradicate cancer cells. However, elimination of cancer by T cells is only one step in the Cancer-Immunity Cycle, which manages the delicate balance between the recognition of nonself and the prevention of autoimmunity. Identification of cancer cell T cell inhibitory signals, including PD-L1, has prompted the development of a new class of cancer immunotherapy that specifically hinders immune effector inhibition, reinvigorating and potentially expanding preexisting anticancer immune responses. The presence of suppressive factors in the tumor microenvironment may explain the limited activity observed with previous immune-based therapies and why these therapies may be more effective in combination with agents that target other steps of the cycle. Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma

              In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.
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                Author and article information

                Contributors
                hmei@hust.edu.cn
                dr_huyu@126.com
                Journal
                Signal Transduct Target Ther
                Signal Transduct Target Ther
                Signal Transduction and Targeted Therapy
                Nature Publishing Group UK (London )
                2095-9907
                2059-3635
                18 August 2023
                18 August 2023
                2023
                : 8
                : 306
                Affiliations
                [1 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Institute of Hematology, Union Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; 430022 Wuhan, China
                [2 ]Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, 430022 Wuhan, China
                [3 ]GRID grid.419897.a, ISNI 0000 0004 0369 313X, Key Laboratory of Biological Targeted Therapy, the Ministry of Education, ; 430022 Wuhan, China
                [4 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; 430022 Wuhan, China
                Author information
                http://orcid.org/0000-0002-2815-4568
                Article
                1521
                10.1038/s41392-023-01521-5
                10435569
                37591844
                823fee95-9902-4b4e-99e1-176e4c6018d9
                © West China Hospital, Sichuan University 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 29 December 2022
                : 31 May 2023
                : 4 June 2023
                Funding
                Funded by: the National Natural Science Foundation of China 81873434
                Funded by: National Natural Science Foundation of China 82100190; China Postdoctoral Innovative Talent Support Foundation BX2021106
                Funded by: the National Key R&D Program of China 2022YFC2502700
                Categories
                Review Article
                Custom metadata
                © West China Hospital, Sichuan University 2023

                cancer therapy,immunotherapy
                cancer therapy, immunotherapy

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