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      Patient selection for CAR T or BiTE therapy in multiple myeloma: Which treatment for each patient?

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          Abstract

          Multiple myeloma (MM) is a plasma cell malignancy that affects an increasing number of patients worldwide. Despite all the efforts to understand its pathogenesis and develop new treatment modalities, MM remains an incurable disease. Novel immunotherapies, such as CAR T cell therapy (CAR) and bispecific T cell engagers (BiTE), are intensively targeting different surface antigens, such as BMCA, SLAMF7 (CS1), GPRC5D, FCRH5 or CD38. However, stem cell transplantation is still indispensable in transplant-eligible patients. Studies suggest that the early use of immunotherapy may improve outcomes significantly. In this review, we summarize the currently available clinical literature on CAR and BiTE in MM. Furthermore, we will compare these two T cell-based immunotherapies and discuss potential therapeutic approaches to promote development of new clinical trials, using T cell-based immunotherapies, even as bridging therapies to a transplant.

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          Most cited references130

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          Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma

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            Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection

            Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumour rejection. The most successful CARs used to date are those targeting CD19 (ref. 2), which offer the prospect of complete remission in patients with chemorefractory or relapsed B-cell malignancies. CARs are typically transduced into the T cells of a patient using γ-retroviral vectors or other randomly integrating vectors, which may result in clonal expansion, oncogenic transformation, variegated transgene expression and transcriptional silencing. Recent advances in genome editing enable efficient sequence-specific interventions in human cells, including targeted gene delivery to the CCR5 and AAVS1 loci. Here we show that directing a CD19-specific CAR to the T-cell receptor α constant (TRAC) locus not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T-cell potency, with edited cells vastly outperforming conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukaemia. We further demonstrate that targeting the CAR to the TRAC locus averts tonic CAR signalling and establishes effective internalization and re-expression of the CAR following single or repeated exposure to antigen, delaying effector T-cell differentiation and exhaustion. These findings uncover facets of CAR immunobiology and underscore the potential of CRISPR/Cas9 genome editing to advance immunotherapies.
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              CAR-T cell therapy: current limitations and potential strategies

              Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies. Barriers to effective CAR-T cell therapy include severe life-threatening toxicities, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration. In addition, the host and tumor microenvironment interactions with CAR-T cells critically alter CAR-T cell function. Furthermore, a complex workforce is required to develop and implement these treatments. In order to overcome these significant challenges, innovative strategies and approaches to engineer more powerful CAR-T cells with improved anti-tumor activity and decreased toxicity are necessary. In this review, we discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CAR-T cell therapy in both hematological malignancy and solid tumors.
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                Author and article information

                Contributors
                ciprian.tomuleasa@umfcluj.ro
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                7 June 2022
                7 June 2022
                2022
                : 15
                : 78
                Affiliations
                [1 ]GRID grid.411040.0, ISNI 0000 0004 0571 5814, Medfuture Research Center for Advanced Medicine, , Iuliu Hatieganu University of Medicine and Pharmacy, ; Cluj-Napoca, Romania
                [2 ]GRID grid.411040.0, ISNI 0000 0004 0571 5814, Department of Hematology, , Iuliu Hatieganu University of Medicine and Pharmacy, ; Cluj-Napoca, Romania
                [3 ]Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania
                [4 ]GRID grid.4861.b, ISNI 0000 0001 0805 7253, Laboratory of Hematology, , University of Liège, ; Liège, Belgium
                [5 ]GRID grid.411374.4, ISNI 0000 0000 8607 6858, Department of Hematology, , CHU de Liège, ; Liège, Belgium
                [6 ]GRID grid.415180.9, ISNI 0000 0004 0540 9980, Department of Stem Cell Transplantation, , Fundeni Clinical Institute, ; Bucharest, Romania
                [7 ]GRID grid.8379.5, ISNI 0000 0001 1958 8658, Department of Internal Medicine II, , University of Würzburg, ; Würzburg, Germany
                [8 ]GRID grid.266093.8, ISNI 0000 0001 0668 7243, Hematopoietic Stem Cell Transplantation and Cellular Therapy Program, Division of Hematology/Oncology, Chao Family Comprehensive Cancer Center, , University of California, ; Irvine, USA
                Article
                1296
                10.1186/s13045-022-01296-2
                9171942
                35672793
                67203f91-87bc-4c7d-9769-759141c3c9f5
                © The Author(s) 2022

                Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 7 April 2022
                : 22 May 2022
                Categories
                Review
                Custom metadata
                © The Author(s) 2022

                Oncology & Radiotherapy
                multiple myeloma,immunotherapy,adoptive cell therapy,chimeric antigen receptor,car t,bispecific t cell engager,bite,bispecific antibody,stem cell transplantation,bispecific antibody armed t cell,bat

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