Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsies
Abstract Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate tumor regression, including complete and durable responses, in a range of solid cancers, most notably in melanoma. However, its wider application and efficacy has been restricted by the limited accessibility, prolif...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55420-6 |
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| author | Thomas Kuilman Deborah S. Schrikkema Jules Gadiot Raquel Gomez-Eerland Laura Bies Julia Walker Robbert M. Spaapen Hanna Kok Demi Houg Milena Viyacheva Yvonne B. Claassen Manuel Saornil Oscar Krijgsman Bas Stringer Huiwen Ding Anou Geleijnse Anne C. Meinema Bianca Weissbrich Melissa Lancee Carmen G. Engele Marianna Sabatino Pei-Ling Chen Kenneth Y. Tsai James J. Mulé Vernon K. Sondak Jitske van den Bulk Noel F. de Miranda Inge Jedema John G. Haanen Jeroen W. J. van Heijst Ton N. Schumacher Carsten Linnemann Gavin M. Bendle |
| author_facet | Thomas Kuilman Deborah S. Schrikkema Jules Gadiot Raquel Gomez-Eerland Laura Bies Julia Walker Robbert M. Spaapen Hanna Kok Demi Houg Milena Viyacheva Yvonne B. Claassen Manuel Saornil Oscar Krijgsman Bas Stringer Huiwen Ding Anou Geleijnse Anne C. Meinema Bianca Weissbrich Melissa Lancee Carmen G. Engele Marianna Sabatino Pei-Ling Chen Kenneth Y. Tsai James J. Mulé Vernon K. Sondak Jitske van den Bulk Noel F. de Miranda Inge Jedema John G. Haanen Jeroen W. J. van Heijst Ton N. Schumacher Carsten Linnemann Gavin M. Bendle |
| author_sort | Thomas Kuilman |
| collection | DOAJ |
| description | Abstract Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate tumor regression, including complete and durable responses, in a range of solid cancers, most notably in melanoma. However, its wider application and efficacy has been restricted by the limited accessibility, proliferative capacity and effector function of tumor-specific TIL. Here, we develop a platform for the efficient identification of tumor-specific TCR genes from diagnostic tumor biopsies, including core-needle biopsies frozen in a non-viable format, to enable engineered T cell therapy. Using a genetic screening approach that detects antigen-reactive TCRs with high sensitivity and specificity based on T cell activation, we show that high complexity TCR libraries can be efficiently screened against multiplexed antigen libraries to identify both HLA class I and II restricted TCRs. Through the identification of neoantigen-specific TCRs directly from melanoma as well as low tumor mutational burden microsatellite-stable colorectal carcinoma samples, we demonstrate the pan-cancer potential of this platform. |
| format | Article |
| id | doaj-art-2d76c4e060a14eb1ad32c85894d62d96 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2d76c4e060a14eb1ad32c85894d62d962025-01-19T12:31:28ZengNature PortfolioNature Communications2041-17232025-01-0116111410.1038/s41467-024-55420-6Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsiesThomas Kuilman0Deborah S. Schrikkema1Jules Gadiot2Raquel Gomez-Eerland3Laura Bies4Julia Walker5Robbert M. Spaapen6Hanna Kok7Demi Houg8Milena Viyacheva9Yvonne B. Claassen10Manuel Saornil11Oscar Krijgsman12Bas Stringer13Huiwen Ding14Anou Geleijnse15Anne C. Meinema16Bianca Weissbrich17Melissa Lancee18Carmen G. Engele19Marianna Sabatino20Pei-Ling Chen21Kenneth Y. Tsai22James J. Mulé23Vernon K. Sondak24Jitske van den Bulk25Noel F. de Miranda26Inge Jedema27John G. Haanen28Jeroen W. J. van Heijst29Ton N. Schumacher30Carsten Linnemann31Gavin M. Bendle32Neogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupDepartment of Pathology, Moffitt Cancer CenterDepartment of Pathology, Moffitt Cancer CenterDepartment of Cutaneous Oncology, Moffitt Cancer CenterDepartment of Cutaneous Oncology, Moffitt Cancer CenterNeogene Therapeutics, A member of the AstraZeneca GroupDepartment of Pathology, Leiden University Medical CenterDivision of Molecular Oncology & Immunology, The Netherlands Cancer InstituteDivision of Molecular Oncology & Immunology, The Netherlands Cancer InstituteNeogene Therapeutics, A member of the AstraZeneca GroupDivision of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer InstituteNeogene Therapeutics, A member of the AstraZeneca GroupNeogene Therapeutics, A member of the AstraZeneca GroupAbstract Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate tumor regression, including complete and durable responses, in a range of solid cancers, most notably in melanoma. However, its wider application and efficacy has been restricted by the limited accessibility, proliferative capacity and effector function of tumor-specific TIL. Here, we develop a platform for the efficient identification of tumor-specific TCR genes from diagnostic tumor biopsies, including core-needle biopsies frozen in a non-viable format, to enable engineered T cell therapy. Using a genetic screening approach that detects antigen-reactive TCRs with high sensitivity and specificity based on T cell activation, we show that high complexity TCR libraries can be efficiently screened against multiplexed antigen libraries to identify both HLA class I and II restricted TCRs. Through the identification of neoantigen-specific TCRs directly from melanoma as well as low tumor mutational burden microsatellite-stable colorectal carcinoma samples, we demonstrate the pan-cancer potential of this platform.https://doi.org/10.1038/s41467-024-55420-6 |
| spellingShingle | Thomas Kuilman Deborah S. Schrikkema Jules Gadiot Raquel Gomez-Eerland Laura Bies Julia Walker Robbert M. Spaapen Hanna Kok Demi Houg Milena Viyacheva Yvonne B. Claassen Manuel Saornil Oscar Krijgsman Bas Stringer Huiwen Ding Anou Geleijnse Anne C. Meinema Bianca Weissbrich Melissa Lancee Carmen G. Engele Marianna Sabatino Pei-Ling Chen Kenneth Y. Tsai James J. Mulé Vernon K. Sondak Jitske van den Bulk Noel F. de Miranda Inge Jedema John G. Haanen Jeroen W. J. van Heijst Ton N. Schumacher Carsten Linnemann Gavin M. Bendle Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsies Nature Communications |
| title | Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsies |
| title_full | Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsies |
| title_fullStr | Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsies |
| title_full_unstemmed | Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsies |
| title_short | Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsies |
| title_sort | enabling next generation engineered tcr t therapies based on high throughput tcr discovery from diagnostic tumor biopsies |
| url | https://doi.org/10.1038/s41467-024-55420-6 |
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