MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity
Background The development of chimeric antigen receptor (CAR)-T cell therapies for solid tumors has attracted considerable attention, yet their clinical efficacy remains limited. Therefore, various efforts have been made to improve the efficacy of CAR-T cell therapy. As one promising strategy, incor...
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| Language: | English |
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BMJ Publishing Group
2024-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/11/e010248.full |
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| author | Naoko Imai Hiroshi Shiku Yoshihiro Miyahara Linan Wang Takuma Kato Hiroshi Fujiwara Hiroshi Miwa Meiou Liu Yasushi Akahori Kohei Negishi |
| author_facet | Naoko Imai Hiroshi Shiku Yoshihiro Miyahara Linan Wang Takuma Kato Hiroshi Fujiwara Hiroshi Miwa Meiou Liu Yasushi Akahori Kohei Negishi |
| author_sort | Naoko Imai |
| collection | DOAJ |
| description | Background The development of chimeric antigen receptor (CAR)-T cell therapies for solid tumors has attracted considerable attention, yet their clinical efficacy remains limited. Therefore, various efforts have been made to improve the efficacy of CAR-T cell therapy. As one promising strategy, incorporating the T-cell receptor (TCR) machinery into CAR structures has been reported to improve the efficacy of CAR-T cells in studies using conventional CARs targeting such as EGFR. However, in the case of peptide/major histocompatibility complex (pMHC)-targeted CARs, the advantages of exploiting TCR machinery have not been fully elucidated. We recently developed MAGE-A4-derived pMHC (MAGE-A4 pMHC)-targeted CAR-T cells (MA-CAR-T cells) using a highly specific human scFv antibody against MAGE-A4p230-239/HLA-A*02:01. We aimed to determine whether MAGE-A4 pMHC-targeted CAR-T cells using the TCR machinery (Hybrid MA-TCR-T cells) exhibit superior functionality without compromising antigen specificity.Methods We constructed a retroviral vector expressing Hybrid MA-TCR where MAGE-A4 pMHC-specific scFv are fused to human TCR constant chains.Results Hybrid MA-TCR-T cells demonstrated superior in vitro functions compared with MA-CAR-T cells, while maintaining strict antigen specificity. In addition, functional superiority of Hybrid MA-TCR-T cells to MA-CAR-T cells became more pronounced on repetitive antigen stimulation. In particular, Hybrid MA-TCR-T cells significantly inhibited tumor growth in an immunodeficient mouse model more effectively than MA-CAR-T cells. Ex vivo analyses indicated that their enhanced therapeutic efficacy might result from higher infiltration of functionally active, less differentiated Hybrid MA-TCR-T cells in tumor tissues.Conclusions These findings suggest that leveraging the TCR machinery is a promising strategy for enhancing pMHC-targeted CAR-T cell therapy for solid tumors, potentially leading to more effective treatments. |
| format | Article |
| id | doaj-art-1c5183fed7f0440b97fad57c7417232e |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-1c5183fed7f0440b97fad57c7417232e2025-08-20T02:49:02ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-11-01121110.1136/jitc-2024-010248MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificityNaoko Imai0Hiroshi Shiku1Yoshihiro Miyahara2Linan Wang3Takuma Kato4Hiroshi Fujiwara5Hiroshi Miwa6Meiou Liu7Yasushi Akahori8Kohei Negishi9Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu, JapanPersonalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu, JapanPersonalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu, JapanHematology and Oncology, Mie University Graduate School of Medicine, Tsu, JapanImmunology, Nagoya University Graduate School of Medicine, Nagoya, JapanPersonalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu, JapanPersonalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu, JapanPersonalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu, JapanPersonalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu, JapanPersonalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu, JapanBackground The development of chimeric antigen receptor (CAR)-T cell therapies for solid tumors has attracted considerable attention, yet their clinical efficacy remains limited. Therefore, various efforts have been made to improve the efficacy of CAR-T cell therapy. As one promising strategy, incorporating the T-cell receptor (TCR) machinery into CAR structures has been reported to improve the efficacy of CAR-T cells in studies using conventional CARs targeting such as EGFR. However, in the case of peptide/major histocompatibility complex (pMHC)-targeted CARs, the advantages of exploiting TCR machinery have not been fully elucidated. We recently developed MAGE-A4-derived pMHC (MAGE-A4 pMHC)-targeted CAR-T cells (MA-CAR-T cells) using a highly specific human scFv antibody against MAGE-A4p230-239/HLA-A*02:01. We aimed to determine whether MAGE-A4 pMHC-targeted CAR-T cells using the TCR machinery (Hybrid MA-TCR-T cells) exhibit superior functionality without compromising antigen specificity.Methods We constructed a retroviral vector expressing Hybrid MA-TCR where MAGE-A4 pMHC-specific scFv are fused to human TCR constant chains.Results Hybrid MA-TCR-T cells demonstrated superior in vitro functions compared with MA-CAR-T cells, while maintaining strict antigen specificity. In addition, functional superiority of Hybrid MA-TCR-T cells to MA-CAR-T cells became more pronounced on repetitive antigen stimulation. In particular, Hybrid MA-TCR-T cells significantly inhibited tumor growth in an immunodeficient mouse model more effectively than MA-CAR-T cells. Ex vivo analyses indicated that their enhanced therapeutic efficacy might result from higher infiltration of functionally active, less differentiated Hybrid MA-TCR-T cells in tumor tissues.Conclusions These findings suggest that leveraging the TCR machinery is a promising strategy for enhancing pMHC-targeted CAR-T cell therapy for solid tumors, potentially leading to more effective treatments.https://jitc.bmj.com/content/12/11/e010248.full |
| spellingShingle | Naoko Imai Hiroshi Shiku Yoshihiro Miyahara Linan Wang Takuma Kato Hiroshi Fujiwara Hiroshi Miwa Meiou Liu Yasushi Akahori Kohei Negishi MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity Journal for ImmunoTherapy of Cancer |
| title | MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity |
| title_full | MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity |
| title_fullStr | MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity |
| title_full_unstemmed | MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity |
| title_short | MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity |
| title_sort | mage a4 pmhc targeted car t cells exploiting tcr machinery exhibit significantly improved in vivo function while retaining antigen specificity |
| url | https://jitc.bmj.com/content/12/11/e010248.full |
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