4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2nd Generation Chimeric Antigen Receptor-Modified T Cells
While chimeric antigen receptor-modified T (CAR-T) cells have shown great success for the treatment of B cell leukemia, their efficacy appears to be compromised in B cell derived lymphoma and solid tumors. Optimization of the CAR design to improve persistence and cytotoxicity is a focus of the curre...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2020.539654/full |
| _version_ | 1818886285321830400 |
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| author | Qiang Dai Qiang Dai Ping Han Ping Han Xinyue Qi Xinyue Qi Fanlin Li Fanlin Li Min Li Min Li Lilv Fan Lilv Fan Huihui Zhang Huihui Zhang Xiaoqing Zhang Xiaoqing Zhang Xuanming Yang Xuanming Yang Xuanming Yang |
| author_facet | Qiang Dai Qiang Dai Ping Han Ping Han Xinyue Qi Xinyue Qi Fanlin Li Fanlin Li Min Li Min Li Lilv Fan Lilv Fan Huihui Zhang Huihui Zhang Xiaoqing Zhang Xiaoqing Zhang Xuanming Yang Xuanming Yang Xuanming Yang |
| author_sort | Qiang Dai |
| collection | DOAJ |
| description | While chimeric antigen receptor-modified T (CAR-T) cells have shown great success for the treatment of B cell leukemia, their efficacy appears to be compromised in B cell derived lymphoma and solid tumors. Optimization of the CAR design to improve persistence and cytotoxicity is a focus of the current CAR-T study. Herein, we established a novel CAR structure by adding a full length 4-1BB co-stimulatory receptor to a 28Z-based second generation CAR that targets CD20. Our data indicated that this new 2028Z-4-1BB CAR-T cell showed improved proliferation and cytotoxic ability. To further understand the mechanism of action, we found that constitutive 4-1BB sensing significantly reduced the apoptosis of CAR-T cells, enhanced proliferation, and increased NF-κB pathway activation. Consistent with the enhanced proliferation and cytotoxicity in vitro, this new structure of CAR-T cells exhibited robust persistence and anti-tumor activity in a mouse xenograft lymphoma model. This work provides evidence for a new strategy to optimize the function of CAR-T against lymphoma. |
| first_indexed | 2024-12-19T16:18:54Z |
| format | Article |
| id | doaj.art-db9d350a6df9418a9d77903e60fcba47 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T16:18:54Z |
| publishDate | 2020-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-db9d350a6df9418a9d77903e60fcba472022-12-21T20:14:33ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-11-011110.3389/fimmu.2020.5396545396544-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2nd Generation Chimeric Antigen Receptor-Modified T CellsQiang Dai0Qiang Dai1Ping Han2Ping Han3Xinyue Qi4Xinyue Qi5Fanlin Li6Fanlin Li7Min Li8Min Li9Lilv Fan10Lilv Fan11Huihui Zhang12Huihui Zhang13Xiaoqing Zhang14Xiaoqing Zhang15Xuanming Yang16Xuanming Yang17Xuanming Yang18Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, ChinaJoint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, ChinaSheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, ChinaJoint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, ChinaSheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, ChinaJoint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, ChinaSheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, ChinaJoint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, ChinaSheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, ChinaJoint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, ChinaSheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, ChinaJoint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, ChinaSheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, ChinaJoint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, ChinaSheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, ChinaJoint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, ChinaSheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, ChinaJoint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, ChinaKey Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, ChinaWhile chimeric antigen receptor-modified T (CAR-T) cells have shown great success for the treatment of B cell leukemia, their efficacy appears to be compromised in B cell derived lymphoma and solid tumors. Optimization of the CAR design to improve persistence and cytotoxicity is a focus of the current CAR-T study. Herein, we established a novel CAR structure by adding a full length 4-1BB co-stimulatory receptor to a 28Z-based second generation CAR that targets CD20. Our data indicated that this new 2028Z-4-1BB CAR-T cell showed improved proliferation and cytotoxic ability. To further understand the mechanism of action, we found that constitutive 4-1BB sensing significantly reduced the apoptosis of CAR-T cells, enhanced proliferation, and increased NF-κB pathway activation. Consistent with the enhanced proliferation and cytotoxicity in vitro, this new structure of CAR-T cells exhibited robust persistence and anti-tumor activity in a mouse xenograft lymphoma model. This work provides evidence for a new strategy to optimize the function of CAR-T against lymphoma.https://www.frontiersin.org/articles/10.3389/fimmu.2020.539654/full4-1BBchimeric antigen receptor-modified TlymphomaimmunotherapyCD20 |
| spellingShingle | Qiang Dai Qiang Dai Ping Han Ping Han Xinyue Qi Xinyue Qi Fanlin Li Fanlin Li Min Li Min Li Lilv Fan Lilv Fan Huihui Zhang Huihui Zhang Xiaoqing Zhang Xiaoqing Zhang Xuanming Yang Xuanming Yang Xuanming Yang 4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2nd Generation Chimeric Antigen Receptor-Modified T Cells Frontiers in Immunology 4-1BB chimeric antigen receptor-modified T lymphoma immunotherapy CD20 |
| title | 4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2nd Generation Chimeric Antigen Receptor-Modified T Cells |
| title_full | 4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2nd Generation Chimeric Antigen Receptor-Modified T Cells |
| title_fullStr | 4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2nd Generation Chimeric Antigen Receptor-Modified T Cells |
| title_full_unstemmed | 4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2nd Generation Chimeric Antigen Receptor-Modified T Cells |
| title_short | 4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2nd Generation Chimeric Antigen Receptor-Modified T Cells |
| title_sort | 4 1bb signaling boosts the anti tumor activity of cd28 incorporated 2nd generation chimeric antigen receptor modified t cells |
| topic | 4-1BB chimeric antigen receptor-modified T lymphoma immunotherapy CD20 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2020.539654/full |
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