Xiaomeng Zhang, Rachel Xu, Dmitry Zorin, Evan G Pappas, Jiawei Tang, Yuchen Bai, Vicky M Qin, Bianca von Scheidt, Ruihong Huang, Weronika Kulakowska, Charbel Darido, Phillip K Darcy, Michael H Kershaw, Clare Y Slaney
{"title":"优化模块化抗flag CAR - T细胞用于实体瘤治疗","authors":"Xiaomeng Zhang, Rachel Xu, Dmitry Zorin, Evan G Pappas, Jiawei Tang, Yuchen Bai, Vicky M Qin, Bianca von Scheidt, Ruihong Huang, Weronika Kulakowska, Charbel Darido, Phillip K Darcy, Michael H Kershaw, Clare Y Slaney","doi":"10.1002/cti2.70046","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Objectives</h3>\n \n <p>Chimeric antigen receptor (CAR) T cell therapies have transformed the treatment of B cell malignancies and show promise in other diseases, including autoimmune disorders and cardiac injury. However, broader application, particularly in solid tumours, is limited by challenges such as antigen escape and tumour heterogeneity. This study aimed to develop an anti-FLAG CAR capable of engaging FLAG-tagged secondary reagents, providing a flexible and adaptable targeting strategy.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We engineered a humanised anti-FLAG CAR to engage FLAG-tagged secondary reagents. The initial construct exhibited tonic signalling, which was addressed through structural optimisation. Therapeutic efficacy was assessed in solid tumour mouse models expressing either FLAG or a FLAG-tagged secondary targeting reagent.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>The initial anti-FLAG CAR showed functional activity but exhibited tonic signalling and exhaustion, limiting its therapeutic utility. Structural optimisation significantly reduced exhaustion and improved T cell persistence and functionality. The optimised CAR T cells effectively inhibited tumour growth in models using either FLAG- engineered tumour cells or a FLAG-tagged secondary targeting reagent.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>Our findings underscore the importance of CAR design in minimising exhaustion and enhancing therapeutic efficacy. This work supports a modular CAR T cell platform with the potential to overcome tumour antigen heterogeneity and immune evasion in solid cancers.</p>\n </section>\n </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 8","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70046","citationCount":"0","resultStr":"{\"title\":\"Optimised modular anti-FLAG CAR T cells for solid tumor therapy\",\"authors\":\"Xiaomeng Zhang, Rachel Xu, Dmitry Zorin, Evan G Pappas, Jiawei Tang, Yuchen Bai, Vicky M Qin, Bianca von Scheidt, Ruihong Huang, Weronika Kulakowska, Charbel Darido, Phillip K Darcy, Michael H Kershaw, Clare Y Slaney\",\"doi\":\"10.1002/cti2.70046\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Objectives</h3>\\n \\n <p>Chimeric antigen receptor (CAR) T cell therapies have transformed the treatment of B cell malignancies and show promise in other diseases, including autoimmune disorders and cardiac injury. However, broader application, particularly in solid tumours, is limited by challenges such as antigen escape and tumour heterogeneity. This study aimed to develop an anti-FLAG CAR capable of engaging FLAG-tagged secondary reagents, providing a flexible and adaptable targeting strategy.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>We engineered a humanised anti-FLAG CAR to engage FLAG-tagged secondary reagents. The initial construct exhibited tonic signalling, which was addressed through structural optimisation. Therapeutic efficacy was assessed in solid tumour mouse models expressing either FLAG or a FLAG-tagged secondary targeting reagent.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>The initial anti-FLAG CAR showed functional activity but exhibited tonic signalling and exhaustion, limiting its therapeutic utility. Structural optimisation significantly reduced exhaustion and improved T cell persistence and functionality. The optimised CAR T cells effectively inhibited tumour growth in models using either FLAG- engineered tumour cells or a FLAG-tagged secondary targeting reagent.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion</h3>\\n \\n <p>Our findings underscore the importance of CAR design in minimising exhaustion and enhancing therapeutic efficacy. This work supports a modular CAR T cell platform with the potential to overcome tumour antigen heterogeneity and immune evasion in solid cancers.</p>\\n </section>\\n </div>\",\"PeriodicalId\":152,\"journal\":{\"name\":\"Clinical & Translational Immunology\",\"volume\":\"14 8\",\"pages\":\"\"},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2025-08-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70046\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical & Translational Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/cti2.70046\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical & Translational Immunology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cti2.70046","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Optimised modular anti-FLAG CAR T cells for solid tumor therapy
Objectives
Chimeric antigen receptor (CAR) T cell therapies have transformed the treatment of B cell malignancies and show promise in other diseases, including autoimmune disorders and cardiac injury. However, broader application, particularly in solid tumours, is limited by challenges such as antigen escape and tumour heterogeneity. This study aimed to develop an anti-FLAG CAR capable of engaging FLAG-tagged secondary reagents, providing a flexible and adaptable targeting strategy.
Methods
We engineered a humanised anti-FLAG CAR to engage FLAG-tagged secondary reagents. The initial construct exhibited tonic signalling, which was addressed through structural optimisation. Therapeutic efficacy was assessed in solid tumour mouse models expressing either FLAG or a FLAG-tagged secondary targeting reagent.
Results
The initial anti-FLAG CAR showed functional activity but exhibited tonic signalling and exhaustion, limiting its therapeutic utility. Structural optimisation significantly reduced exhaustion and improved T cell persistence and functionality. The optimised CAR T cells effectively inhibited tumour growth in models using either FLAG- engineered tumour cells or a FLAG-tagged secondary targeting reagent.
Conclusion
Our findings underscore the importance of CAR design in minimising exhaustion and enhancing therapeutic efficacy. This work supports a modular CAR T cell platform with the potential to overcome tumour antigen heterogeneity and immune evasion in solid cancers.
期刊介绍：
Clinical & Translational Immunology is an open access, fully peer-reviewed journal devoted to publishing cutting-edge advances in biomedical research for scientists and physicians. The Journal covers fields including cancer biology, cardiovascular research, gene therapy, immunology, vaccine development and disease pathogenesis and therapy at the earliest phases of investigation.
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