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      B7-H3 as a Novel CAR-T Therapeutic Target for Glioblastoma

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          Abstract

          Glioblastoma (GBM) remains one of the most malignant primary tumors in adults, with a 5-year survival rate less than 10% because of lacking effective treatment. Here, we aimed to explore whether B7-H3 could serve as a novel therapeutic target for GBM in chimeric antigen receptor (CAR) T cell therapy. In this study, a CAR targeting B7-H3 was constructed and transduced into T cells by lentivirus. Antitumor effects of B7-H3-specific CAR-T cells were assessed with primary and GBM cell lines both in vitro and in vivo. Our results indicated that B7-H3 was positively stained in most of the clinical glioma samples, and its expression levels were correlated to the malignancy grade and poor survival in both low-grade glioma (LGG) and GBM patients. Specific antitumor functions of CAR-T cells were confirmed by cytotoxic and ELISA assay both in primary glioblastoma cells and GBM cell lines. In the orthotropic GBM models, the median survival of the CAR-T-cell-treated group was significantly longer than that of the control group. In conclusion, B7-H3 is frequently overexpressed in GBM patients and may serve as a therapeutic target in CAR-T therapy.

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          Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy.

          Christine E. Brown, Darya Alizadeh, Renate Starr … (2016)
          A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes - infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13Rα2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362 .).
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            CAR T Cell Therapy for Solid Tumors

            Kheng Newick, Shaun O'Brien, Edmund Moon … (2017)
            The field of cancer immunotherapy has been re-energized by the application of chimeric antigen receptor (CAR) T cell therapy in cancers. These CAR T cells are engineered to express synthetic receptors that redirect polyclonal T cells to surface antigens for subsequent tumor elimination. Many CARs are designed with elements that augment T cell persistence and activity. To date, CAR T cells have demonstrated tremendous success in eradicating hematologic malignancies (e.g., CD19 CARs in leukemias). However, this success has yet to be extrapolated to solid tumors, and the reasons for this are being actively investigated. We characterize some of the challenges that CAR T cells have to surmount in the solid tumor microenvironment and new approaches that are being considered to overcome these hurdles.
            Article 0 comments Cited 334 times – based on 0 reviews     Review now
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              Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape.

              Meenakshi Hegde, Malini Mukherjee, Zakaria Grada … (2016)
              In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.
              Article 0 comments Cited 301 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Aiping Tong
                Liangxue Zhou
                Journal
                Journal ID (nlm-ta): Mol Ther Oncolytics
                Journal ID (iso-abbrev): Mol Ther Oncolytics
                Title: Molecular Therapy Oncolytics
                Publisher: American Society of Gene & Cell Therapy
                ISSN (Electronic): 2372-7705
                Publication date PMC-release: 23 July 2019
                Publication date Collection: 27 September 2019
                Publication date (Electronic): 23 July 2019
                Volume: 14
                Pages: 279-287
                Affiliations
                [1 ]Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China
                [2 ]State Key Laboratory of Biotherapy, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China
                Author notes
                [∗ ]Corresponding author: Aiping Tong, PhD, State Key Laboratory of Biotherapy, West China Medical School, Sichuan University, No. 37 Guo Xue Xiang Chengdu, Sichuan 610041, China. aipingtong@ 123456scu.edu.cn
                [∗∗ ]Corresponding author: Liangxue Zhou, PhD, State Key Laboratory of Biotherapy, West China Medical School, Sichuan University, No. 37 Guo Xue Xiang Chengdu, Sichuan 610041, China. liangxue_zhou@ 123456126.com
                [3]

                These authors contributed equally to this work.

                Article
                Publisher ID: S2372-7705(19)30068-3
                DOI: 10.1016/j.omto.2019.07.002
                PMC ID: 6713854
                PubMed ID: 31485480
                SO-VID: 4c381664-70a8-4f67-92b8-76a1d16d9522
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 2 April 2019
                Date accepted : 12 July 2019
                Categories
                Subject: Article

                Keywords: b7-h3,chimeric antigen receptor,glioblastoma,low grade glioma,immunotherapy
                Data availability:
                Keywords: b7-h3, chimeric antigen receptor, glioblastoma, low grade glioma, immunotherapy

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