Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectin
Background The suppression of chimeric antigen receptor (CAR) T cells by the tumor microenvironment (TME) is a crucial obstacle in the T-cell-based treatment of solid tumors. Extra domain B (EDB)-fibronectin is an oncofetal antigen expressed on the endothelium layer of the neovasculature and cancer...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/8/e007199.full |
| _version_ | 1797740933041618944 |
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| author | Chang Liu Zhen Hua Mengting Wu Wen Qiu Hang Wang Zhe Yang Zhijie Zhang Muhan Wang Rongcheng Sun Yushuang Wu Hongping Yin Meijia Yang |
| author_facet | Chang Liu Zhen Hua Mengting Wu Wen Qiu Hang Wang Zhe Yang Zhijie Zhang Muhan Wang Rongcheng Sun Yushuang Wu Hongping Yin Meijia Yang |
| author_sort | Chang Liu |
| collection | DOAJ |
| description | Background The suppression of chimeric antigen receptor (CAR) T cells by the tumor microenvironment (TME) is a crucial obstacle in the T-cell-based treatment of solid tumors. Extra domain B (EDB)-fibronectin is an oncofetal antigen expressed on the endothelium layer of the neovasculature and cancer cells. Though recognized as a T cell therapy target, engineered CAR T cells thus far have failed to demonstrate satisfactory in vivo efficacy. In this study, we report that targeting EDB-fibronectin by redirected TCR-CAR T cells (rTCR-CAR) bypasses the suppressive TME for solid tumor treatment and sufficiently suppressed tumor growth.We generated EDB-targeting CAR by fusing single-chain variable fragment to CD3ε, resulting in rTCR-CAR. Human primary T cells and Jurkat cells were used to study the EDB-targeting T cells. Differences to the traditional second-generation CAR T cell in signaling, immune synapse formation, and T cell exhaustion were characterized. Cytotoxicity of the rTCR-CAR T cells was tested in vitro, and therapeutic efficacies were demonstrated using xenograft models.Methods Results In the xenograft models, the rTCR-CAR T cells demonstrated in vivo efficacies superior to that based on traditional CAR design. A significant reduction in tumor vessel density was observed alongside tumor growth inhibition, extending even to tumor models established with EDB-negative cancer cells. The rTCR-CAR bound to immobilized EDB, and the binding led to immune synapse structures superior to that formed by second-generation CARs. By a mechanism similar to that for the conventional TCR complex, EDB-fibronectin activated the rTCR-CAR, resulting in rTCR-CAR T cells with low basal activation levels and increased in vivo expansion.Conclusion Our study has demonstrated the potential of rTCR-CAR T cells targeting the EDB-fibronectin as an anticancer therapeutic. Engineered to possess antiangiogenic and cytotoxic activities, the rTCR-CAR T cells showed therapeutic efficacies not impacted by the suppressive TMEs. These combined characteristics of a single therapeutic agent point to its potential to achieve sustained control of solid tumors. |
| first_indexed | 2024-03-12T14:19:34Z |
| format | Article |
| id | doaj.art-7b03442e869948fca12b28b380de9b2a |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T14:19:34Z |
| publishDate | 2023-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-7b03442e869948fca12b28b380de9b2a2023-08-19T15:00:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-08-0111810.1136/jitc-2023-007199Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectinChang Liu0Zhen Hua1Mengting Wu2Wen Qiu3Hang Wang4Zhe Yang5Zhijie Zhang6Muhan Wang7Rongcheng Sun8Yushuang Wu9Hongping Yin10Meijia Yang11School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, ChinaSchool of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, ChinaJiangsu Cell Tech Medical Research Institute, Nanjing, Jiangsu, ChinaDepartment of Immunology, Nanjing Medical University, Nanjing, Jiangsu, ChinaSchool of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, ChinaSchool of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, ChinaSchool of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, ChinaSchool of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, ChinaSchool of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, ChinaJiangsu Cell Tech Medical Research Institute, Nanjing, Jiangsu, ChinaSchool of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, ChinaJiangsu Cell Tech Medical Research Institute, Nanjing, Jiangsu, ChinaBackground The suppression of chimeric antigen receptor (CAR) T cells by the tumor microenvironment (TME) is a crucial obstacle in the T-cell-based treatment of solid tumors. Extra domain B (EDB)-fibronectin is an oncofetal antigen expressed on the endothelium layer of the neovasculature and cancer cells. Though recognized as a T cell therapy target, engineered CAR T cells thus far have failed to demonstrate satisfactory in vivo efficacy. In this study, we report that targeting EDB-fibronectin by redirected TCR-CAR T cells (rTCR-CAR) bypasses the suppressive TME for solid tumor treatment and sufficiently suppressed tumor growth.We generated EDB-targeting CAR by fusing single-chain variable fragment to CD3ε, resulting in rTCR-CAR. Human primary T cells and Jurkat cells were used to study the EDB-targeting T cells. Differences to the traditional second-generation CAR T cell in signaling, immune synapse formation, and T cell exhaustion were characterized. Cytotoxicity of the rTCR-CAR T cells was tested in vitro, and therapeutic efficacies were demonstrated using xenograft models.Methods Results In the xenograft models, the rTCR-CAR T cells demonstrated in vivo efficacies superior to that based on traditional CAR design. A significant reduction in tumor vessel density was observed alongside tumor growth inhibition, extending even to tumor models established with EDB-negative cancer cells. The rTCR-CAR bound to immobilized EDB, and the binding led to immune synapse structures superior to that formed by second-generation CARs. By a mechanism similar to that for the conventional TCR complex, EDB-fibronectin activated the rTCR-CAR, resulting in rTCR-CAR T cells with low basal activation levels and increased in vivo expansion.Conclusion Our study has demonstrated the potential of rTCR-CAR T cells targeting the EDB-fibronectin as an anticancer therapeutic. Engineered to possess antiangiogenic and cytotoxic activities, the rTCR-CAR T cells showed therapeutic efficacies not impacted by the suppressive TMEs. These combined characteristics of a single therapeutic agent point to its potential to achieve sustained control of solid tumors.https://jitc.bmj.com/content/11/8/e007199.full |
| spellingShingle | Chang Liu Zhen Hua Mengting Wu Wen Qiu Hang Wang Zhe Yang Zhijie Zhang Muhan Wang Rongcheng Sun Yushuang Wu Hongping Yin Meijia Yang Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectin Journal for ImmunoTherapy of Cancer |
| title | Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectin |
| title_full | Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectin |
| title_fullStr | Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectin |
| title_full_unstemmed | Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectin |
| title_short | Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectin |
| title_sort | treating solid tumors with tcr based chimeric antigen receptor targeting extra domain b containing fibronectin |
| url | https://jitc.bmj.com/content/11/8/e007199.full |
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