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      Universal CAR 2.0 to overcome current limitations in CAR therapy

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          Abstract

          Chimeric antigen receptor (CAR) T cell therapy has effectively complemented the treatment of advanced relapsed and refractory hematological cancers. The remarkable achievements of CD19- and BCMA-CAR T therapies have raised high expectations within the fields of hematology and oncology. These groundbreaking successes are propelling a collective aspiration to extend the reach of CAR therapies beyond B-lineage malignancies. Advanced CAR technologies have created a momentum to surmount the limitations of conventional CAR concepts. Most importantly, innovations that enable combinatorial targeting to address target antigen heterogeneity, using versatile adapter CAR concepts in conjunction with recent transformative next-generation CAR design, offer the promise to overcome both the bottleneck associated with CAR manufacturing and patient-individualized treatment regimens. In this comprehensive review, we delineate the fundamental prerequisites, navigate through pivotal challenges, and elucidate strategic approaches, all aimed at paving the way for the future establishment of multitargeted immunotherapies using universal CAR technologies.

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          Most cited references251

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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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            Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

            In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
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              A guide to cancer immunotherapy: from T cell basic science to clinical practice

              The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.
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                Author and article information

                Contributors
                Role: Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/2654670Role: Role:
                URI : https://loop.frontiersin.org/people/431581Role: Role: Role:
                URI : https://loop.frontiersin.org/people/70379Role: Role: Role: Role: Role: Role: Role: Role: Role: Role:
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                19 June 2024
                2024
                : 15
                : 1383894
                Affiliations
                [1] 1 School of Medical Sciences, Faculty of Medicine and Health, University of Sydney , Sydney, NSW, Australia
                [2] 2 Department of Pediatric Surgery, University Medical Centre Mannheim, University of Heidelberg , Heidelberg, Germany
                [3] 3 Department of Pediatric Hematology and Oncology, Westmead Children’s Hospital , Sydney, NSW, Australia
                Author notes

                Edited by: Claudia Arndt, Helmholtz Center Dresden-Rossendorf, Germany

                Reviewed by: Yaya Chu, New York Medical College, United States

                Francisco Martin, University of Granada, Spain

                Roman H. Khadka, University of Pennsylvania, United States

                *Correspondence: Patrick Schlegel, patrick.schlegel@ 123456gmail.com

                †ORCID: Lara Sophie Schlegel, orcid.org/0009-0001-6726-8357; Coralie Werbrouck, orcid.org/0009-0000-4797-0619; Michael Boettcher, orcid.org/0000-0003-4972-9866; Patrick Schlegel, orcid.org/0000-0002-5425-2049

                Article
                10.3389/fimmu.2024.1383894
                11219820
                38962014
                09e6e15f-6f7e-476e-a67f-e07e341159e4
                Copyright © 2024 Schlegel, Werbrouck, Boettcher and Schlegel

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 08 February 2024
                : 03 June 2024
                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 251, Pages: 20, Words: 11263
                Funding
                The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
                Categories
                Immunology
                Review
                Custom metadata
                Cancer Immunity and Immunotherapy

                Immunology
                car (chimeric antigen receptor) t-cell therapy,antibody therapies,ipsc (induced pluripotent stem cell),cancer immune cell therapy,individualized cancer therapy

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