A self-activated and protective module enhances the preclinical performance of allogeneic anti-CD70 CAR-T cells
IntroductionAllogeneic chimeric antigen receptor T (CAR-T) therapy, also known as universal CAR-T (UCAR-T) therapy, offers broad applicability, high production efficiency, and reduced costs, enabling quicker access for patients. However, clinical application remains limited by challenges such as imm...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1531294/full |
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| author | Zhao Zhang Lianfeng Zhao Tinghui Huang Zhengliang Chen Zhengliang Chen Yaoyao Zhao Yaoyao Zhao Junqing Liang Xudong Ao Xiaoqiong Jia Lei Kang Linghui Kong Qi Jing Jianhua Hu Lili Gu Feiyan Pan Zhigang Hu Lingfeng He Muya Zhou Jiannan Chen Zhigang Guo |
| author_facet | Zhao Zhang Lianfeng Zhao Tinghui Huang Zhengliang Chen Zhengliang Chen Yaoyao Zhao Yaoyao Zhao Junqing Liang Xudong Ao Xiaoqiong Jia Lei Kang Linghui Kong Qi Jing Jianhua Hu Lili Gu Feiyan Pan Zhigang Hu Lingfeng He Muya Zhou Jiannan Chen Zhigang Guo |
| author_sort | Zhao Zhang |
| collection | DOAJ |
| description | IntroductionAllogeneic chimeric antigen receptor T (CAR-T) therapy, also known as universal CAR-T (UCAR-T) therapy, offers broad applicability, high production efficiency, and reduced costs, enabling quicker access for patients. However, clinical application remains limited by challenges such as immune rejection, and issues with potency and durability.MethodsWe first screened a safe and effective anti-CD70 scFv to construct anti-CD70 CAR-T cells. Anti-CD70 UCAR-T cells were then generated by knocking out TRAC, B2M, and HLA-DRA. To address the limitations of UCAR-T therapy, we developed an 'all-in-one' self-activated and protective (SAP) module, integrated into the CAR scaffold. The SAP module consists of the CD47 extracellular domain, a mutant interleukin 7 receptor alpha (IL7Rα) transmembrane domain, and the IL7Rα intracellular domain, designed to protect UCAR-T cells from host immune attacks and enhance their survival. ResultsSAP UCAR-T cells demonstrated significantly reduced immune rejection from the innate immune system, as evidenced by enhanced survival and functionality both in vitro and in vivo. The modified UCAR-T cells exhibited improved persistence, with no observed safety concerns. Furthermore, SAP UCAR-T cells maintained process stability during scale-up production, indicating the potential for large-scale manufacturing.DiscussionOur findings highlight the SAP module as a promising strategy for the preclinical development of anti-CD70 UCAR-T, paving the way for an 'off-the-shelf' cell therapy product. |
| format | Article |
| id | doaj-art-f6ab5c4e875844a2ae5ec23cc566d016 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-f6ab5c4e875844a2ae5ec23cc566d0162025-01-21T14:05:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.15312941531294A self-activated and protective module enhances the preclinical performance of allogeneic anti-CD70 CAR-T cellsZhao Zhang0Lianfeng Zhao1Tinghui Huang2Zhengliang Chen3Zhengliang Chen4Yaoyao Zhao5Yaoyao Zhao6Junqing Liang7Xudong Ao8Xiaoqiong Jia9Lei Kang10Linghui Kong11Qi Jing12Jianhua Hu13Lili Gu14Feiyan Pan15Zhigang Hu16Lingfeng He17Muya Zhou18Jiannan Chen19Zhigang Guo20Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaDepartment of Research and Development, Nanjing Calmhome Cell & Gene Engineering Institute Co., Ltd., Nanjing, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaDepartment of Research and Development, Nanjing Calmhome Cell & Gene Engineering Institute Co., Ltd., Nanjing, ChinaPeking University Cancer Hospital (Inner Mongolia Campus), Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, ChinaPeking University Cancer Hospital (Inner Mongolia Campus), Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, ChinaPeking University Cancer Hospital (Inner Mongolia Campus), Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, ChinaPeking University Cancer Hospital (Inner Mongolia Campus), Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, ChinaPeking University Cancer Hospital (Inner Mongolia Campus), Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, ChinaPeking University Cancer Hospital (Inner Mongolia Campus), Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, ChinaCenter of Biotherapy, Jiangsu Province Geriatric Hospital, Nanjing, ChinaDepartment of Research and Development, Nanjing Calmhome Cell & Gene Engineering Institute Co., Ltd., Nanjing, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaIntroductionAllogeneic chimeric antigen receptor T (CAR-T) therapy, also known as universal CAR-T (UCAR-T) therapy, offers broad applicability, high production efficiency, and reduced costs, enabling quicker access for patients. However, clinical application remains limited by challenges such as immune rejection, and issues with potency and durability.MethodsWe first screened a safe and effective anti-CD70 scFv to construct anti-CD70 CAR-T cells. Anti-CD70 UCAR-T cells were then generated by knocking out TRAC, B2M, and HLA-DRA. To address the limitations of UCAR-T therapy, we developed an 'all-in-one' self-activated and protective (SAP) module, integrated into the CAR scaffold. The SAP module consists of the CD47 extracellular domain, a mutant interleukin 7 receptor alpha (IL7Rα) transmembrane domain, and the IL7Rα intracellular domain, designed to protect UCAR-T cells from host immune attacks and enhance their survival. ResultsSAP UCAR-T cells demonstrated significantly reduced immune rejection from the innate immune system, as evidenced by enhanced survival and functionality both in vitro and in vivo. The modified UCAR-T cells exhibited improved persistence, with no observed safety concerns. Furthermore, SAP UCAR-T cells maintained process stability during scale-up production, indicating the potential for large-scale manufacturing.DiscussionOur findings highlight the SAP module as a promising strategy for the preclinical development of anti-CD70 UCAR-T, paving the way for an 'off-the-shelf' cell therapy product.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1531294/fullchimeric antigen receptor T (CAR-T)allogeneic CAR-Tcancer immunotherapysolid tumorCD70-positive cancer |
| spellingShingle | Zhao Zhang Lianfeng Zhao Tinghui Huang Zhengliang Chen Zhengliang Chen Yaoyao Zhao Yaoyao Zhao Junqing Liang Xudong Ao Xiaoqiong Jia Lei Kang Linghui Kong Qi Jing Jianhua Hu Lili Gu Feiyan Pan Zhigang Hu Lingfeng He Muya Zhou Jiannan Chen Zhigang Guo A self-activated and protective module enhances the preclinical performance of allogeneic anti-CD70 CAR-T cells Frontiers in Immunology chimeric antigen receptor T (CAR-T) allogeneic CAR-T cancer immunotherapy solid tumor CD70-positive cancer |
| title | A self-activated and protective module enhances the preclinical performance of allogeneic anti-CD70 CAR-T cells |
| title_full | A self-activated and protective module enhances the preclinical performance of allogeneic anti-CD70 CAR-T cells |
| title_fullStr | A self-activated and protective module enhances the preclinical performance of allogeneic anti-CD70 CAR-T cells |
| title_full_unstemmed | A self-activated and protective module enhances the preclinical performance of allogeneic anti-CD70 CAR-T cells |
| title_short | A self-activated and protective module enhances the preclinical performance of allogeneic anti-CD70 CAR-T cells |
| title_sort | self activated and protective module enhances the preclinical performance of allogeneic anti cd70 car t cells |
| topic | chimeric antigen receptor T (CAR-T) allogeneic CAR-T cancer immunotherapy solid tumor CD70-positive cancer |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1531294/full |
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