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Targeting B7-H3 via chimeric antigen receptor T cells and bispecific killer cell engagers augments antitumor response of cytotoxic lymphocytes
Liu,Jie1,2; Yang,Shuo1,2; Cao,Bihui3; Zhou,Guangyu1,2; Zhang,Fengjuan1,2; Wang,Yuan1,2; Wang,Rixin1,2; Zhu,Lipeng1,2; Meng,Ya4; Hu,Cong4; Liang,Hui4; Lin,Xu4; Zhu,Kangshun3; Chen,Guokai1,2; Luo,Kathy Qian1,2; Di,Lijun1,2; Zhao,Qi1,2
2021-12-01
Source PublicationJournal of Hematology and Oncology
ISSN1756-8722
Volume14Issue:1
Abstract

Background: B7-H3, an immune-checkpoint molecule and a transmembrane protein, is overexpressed in non-small cell lung cancer (NSCLC), making it an attractive therapeutic target. Here, we aimed to systematically evaluate the value of B7-H3 as a target in NSCLC via T cells expressing B7-H3-specific chimeric antigen receptors (CARs) and bispecific killer cell engager (BiKE)-redirected natural killer (NK) cells. Methods: We generated B7-H3 CAR and B7-H3/CD16 BiKE derived from an anti-B7-H3 antibody omburtamab that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. Antitumor efficacy and induced-immune response of CAR and BiKE were evaluated in vitro and in vivo. The effects of B7-H3 on aerobic glycolysis in NSCLC cells were further investigated. Results: B7-H3 CAR-T cells effectively inhibited NSCLC tumorigenesis in vitro and in vivo. B7-H3 redirection promoted highly specific T-cell infiltration into tumors. Additionally, NK cell activity could be specially triggered by B7-H3/CD16 BiKE through direct CD16 signaling, resulting in significant increase in NK cell activation and target cell death. BiKE improved antitumor efficacy mediated by NK cells in vitro and in vivo, regardless of the cell surface target antigen density on tumor tissues. Furthermore, we found that anti-B7-H3 blockade might alter tumor glucose metabolism via the reactive oxygen species-mediated pathway. Conclusions: Together, our results suggest that B7-H3 may serve as a target for NSCLC therapy and support the further development of two therapeutic agents in the preclinical and clinical studies.

KeywordB7-h3 Bike Bispecific Antibody Car t Chimeric Antigen Receptor Non-small Cell Lung Cancer Pd-l1
DOI10.1186/s13045-020-01024-8
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaOncology ; Hematology
WOS SubjectOncology ; Hematology
WOS IDWOS:000613425700001
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Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorZhao,Qi
Affiliation1.Cancer Centre,Faculty of Health Sciences,University of Macau,Taipa,China
2.Institute of Translational Medicine,Faculty of Health Sciences,University of Macau,Taipa,China
3.Department of Minimally Invasive Interventional Radiology and Department of Radiology,The Second Affiliated Hospital of Guangzhou Medical University,Guangzhou,China
4.Zhuhai People’s Hospital Affiliated with Jinan University,Zhuhai,China
First Author AffilicationCancer Centre;  Faculty of Health Sciences
Corresponding Author AffilicationCancer Centre;  Faculty of Health Sciences
Recommended Citation
GB/T 7714
Liu,Jie,Yang,Shuo,Cao,Bihui,et al. Targeting B7-H3 via chimeric antigen receptor T cells and bispecific killer cell engagers augments antitumor response of cytotoxic lymphocytes[J]. Journal of Hematology and Oncology,2021,14(1).
APA Liu,Jie.,Yang,Shuo.,Cao,Bihui.,Zhou,Guangyu.,Zhang,Fengjuan.,...&Zhao,Qi.(2021).Targeting B7-H3 via chimeric antigen receptor T cells and bispecific killer cell engagers augments antitumor response of cytotoxic lymphocytes.Journal of Hematology and Oncology,14(1).
MLA Liu,Jie,et al."Targeting B7-H3 via chimeric antigen receptor T cells and bispecific killer cell engagers augments antitumor response of cytotoxic lymphocytes".Journal of Hematology and Oncology 14.1(2021).
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