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      Target selection for CAR-T therapy

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          Abstract

          Chimeric antigen receptor-modified T (CAR-T) cells have achieved significant success in the treatment of several hematological malignancies. However, the translation of the existing achievements into the treatment of other tumors, especially solid tumors, is not smooth. In addition to the optimization of CAR structures, preparation, and clinical protocols, rational selecting and utilizing the targets was more pivotal. In this review, the criteria for target selection and some new strategies for targets utilization were summarized and discussed. This systematic review will help researchers better understand how the efficacy and safety of CAR-T treatment would be affected by targets and thus more rationally select targets and conduct clinical trials.

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          CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL

          Terry Fry, Nirali Shah, Rimas Orentas … (2017)
          Chimeric antigen receptor (CAR) T-cells targeting CD19 mediate potent effects in relapsed/refractory pre-B cell acute lymphoblastic leukemia (B-ALL) but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed on most B-ALL and usually retained following CD19 loss. We report results from a phase I trial testing a novel CD22-CAR in twenty-one children and adults, including 17 previously treated with CD19-directed immunotherapy. Dose dependent anti-leukemic activity was observed with complete remission in 73% (11/15) of patients receiving ≥ 1 × 106 CD22-CART cells/kg, including 5/5 patients with CD19dim/neg B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted escape from killing by CD22-CART cells. These results are the first to eastablish the clinical activity of a CD22-CAR in pre-B cell ALL, including in leukemia resistant to anti-CD19 immunotherapy, demonstrating comparable potency to CD19-CART at biologically active doses in B-ALL. They also highlight the critical role played by antigen density in regulating CAR function. (Funded by NCI Intramural Research Program)
          Article 0 comments Cited 617 times – based on 0 reviews     Review now
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            Mechanisms of resistance to CAR T cell therapy

            Nirali Shah, Terry Fry (2019)
            The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B cell lymphomas have revolutionized anticancer therapy, providing a potentially curative option for patients who are refractory to standard treatments. These trials resulted in rapid FDA approvals of anti-CD19 CAR T cell products for both ALL and certain types of B cell lymphoma - the first approved gene therapies in the USA. However, growing experience with these agents has revealed that remissions will be brief in a substantial number of patients owing to poor CAR T cell persistence and/or cancer cell resistance resulting from antigen loss or modulation. Furthermore, the initial experience with CAR T cells has highlighted challenges associated with manufacturing a patient-specific therapy. Understanding the limitations of CAR T cell therapy will be critical to realizing the full potential of this novel treatment approach. Herein, we discuss the factors that can preclude durable remissions following CAR T cell therapy, with a primary focus on the resistance mechanisms that underlie disease relapse. We also provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms.
            Article 0 comments Cited 421 times – based on 0 reviews     Review now
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              IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor

              Keishi Adachi, Yukimi Sakoda, Koji Tamada … (2018)
              Infiltration, accumulation, and survival of chimeric antigen receptor T (CAR-T) cells in solid tumors is crucial for tumor clearance. We engineered CAR-T cells to express interleukin (IL)-7 and CCL19 (7 × 19 CAR-T cells), as these factors are essential for the maintenance of T-cell zones in lymphoid organs. In mice, 7 × 19 CAR-T cells achieved complete regression of pre-established solid tumors and prolonged mouse survival, with superior anti-tumor activity compared to conventional CAR-T cells. Histopathological analyses showed increased infiltration of dendritic cells (DC) and T cells into tumor tissues following 7 × 19 CAR-T cell therapy. Depletion of recipient T cells before 7 × 19 CAR-T cell administration dampened the therapeutic effects of 7 × 19 CAR-T cell treatment, suggesting that CAR-T cells and recipient immune cells collaborated to exert anti-tumor activity. Following treatment of mice with 7 × 19 CAR-T cells, both recipient conventional T cells and administered CAR-T cells generated memory responses against tumors.
              Article 0 comments Cited 364 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Weidong Han: +86-10-66937463 , hanwdrsw69@yahoo.com
                Journal
                Journal ID (nlm-ta): J Hematol Oncol
                Journal ID (iso-abbrev): J Hematol Oncol
                Title: Journal of Hematology & Oncology
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1756-8722
                Publication date (Electronic): 20 June 2019
                Publication date PMC-release: 20 June 2019
                Publication date Collection: 2019
                Volume: 12
                Electronic Location Identifier: 62
                Affiliations
                [1 ]ISNI 0000 0004 1761 8894, GRID grid.414252.4, Molecular & Immunological Department, Bio-therapeutic Department, , Chinese PLA General Hospital, ; No. 28 Fuxing Road, Beijing, 100853 China
                [2 ]ISNI 0000 0004 1761 8894, GRID grid.414252.4, Department of Hematology, , Chinese PLA General Hospital, ; Beijing, 100853 China
                Article
                Publisher ID: 758
                DOI: 10.1186/s13045-019-0758-x
                PMC ID: 6587237
                PubMed ID: 31221182
                SO-VID: db515e75-076a-49fa-b9b2-28eace534462
                Copyright © © The Author(s). 2019
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 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.

                History
                Date received : 24 April 2019
                Date accepted : 14 June 2019
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: chimeric antigen receptor-modified t cells,coverage,specificity,off-tumor effect,expression stability,target combination
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: chimeric antigen receptor-modified t cells, coverage, specificity, off-tumor effect, expression stability, target combination

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