Mutant p53-specific CD8TCR-therapy combined with a CD4TCR prevents relapse of cancer and outgrowth of micrometastases
Relapse remains challenging in the treatment of metastatic cancers. More than 50% of human cancers harbor mutant p53 (mp53) as a cancer-specific target. We present the spontaneously metastasizing tumor model Ag104A to advance mp53-specific T cell receptor engineered T cell therapy (TCR-therapy). We...
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Taylor & Francis Group
2025-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2025.2514041 |
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| author | Vasiliki Anastasopoulou Hans Schreiber Ching-En Lee Kazuma Kiyotani Leo Hansmann Yusuke Nakamura Matthias Leisegang Steven P. Wolf |
| author_facet | Vasiliki Anastasopoulou Hans Schreiber Ching-En Lee Kazuma Kiyotani Leo Hansmann Yusuke Nakamura Matthias Leisegang Steven P. Wolf |
| author_sort | Vasiliki Anastasopoulou |
| collection | DOAJ |
| description | Relapse remains challenging in the treatment of metastatic cancers. More than 50% of human cancers harbor mutant p53 (mp53) as a cancer-specific target. We present the spontaneously metastasizing tumor model Ag104A to advance mp53-specific T cell receptor engineered T cell therapy (TCR-therapy). We identified in Ag104A an autochthonous p53D256E mutation as neoantigen recognized by a TCR isolated from CD8+ T cells (CD8TCR). Cloning of the Ag104A cancer revealed mp53 expression in >99% of cancer cells. Targeting mp53 by CD8TCR-therapy was initially therapeutic, but tumors escaped as cancer cells with reduced or lack of antigen expression. Therefore, we determined whether escape could be prevented by combining the mp53-specific CD8TCR with a CD4+ T cell-derived TCR (CD4TCR) recognizing a mutant antigen presented on the stroma of the cancer. No relapse occurred when the mp53-specific CD8TCR was combined with the stroma-recognizing CD4TCR. The combination therapy also prevented the development of macrometastases from cancer cells that had already spread to the lung at the time of TCR-therapy. Macrometastases were only observed after monotherapy. Thus, in a spontaneously metastatic model, tumor relapse and development of macrometastases can be prevented by combining a CD8TCR targeting an autochthonous p53-mutation with a mutation-specific CD4TCR recognizing tumor stroma. |
| format | Article |
| id | doaj-art-ad16966f7eae471181f5fa0ec3eac3e8 |
| institution | DOAJ |
| issn | 2162-402X |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-ad16966f7eae471181f5fa0ec3eac3e82025-08-20T03:20:59ZengTaylor & Francis GroupOncoImmunology2162-402X2025-12-0114110.1080/2162402X.2025.2514041Mutant p53-specific CD8TCR-therapy combined with a CD4TCR prevents relapse of cancer and outgrowth of micrometastasesVasiliki Anastasopoulou0Hans Schreiber1Ching-En Lee2Kazuma Kiyotani3Leo Hansmann4Yusuke Nakamura5Matthias Leisegang6Steven P. Wolf7Institute of Immunology, Charité – Universitätsmedizin Berlin, Berlin, GermanyDavid and Etta Jonas Center for Cellular Therapy, The University of Chicago, Chicago, IL, USADepartment of Pathology, The University of Chicago, Chicago, IL, USALaboratory of Immunogenomics, Center for Intractable Diseases and ImmunoGenomics (CiDIG), National Institute of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki-shi, Osaka, JapanDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyLaboratory of Immunogenomics, Center for Intractable Diseases and ImmunoGenomics (CiDIG), National Institute of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki-shi, Osaka, JapanInstitute of Immunology, Charité – Universitätsmedizin Berlin, Berlin, GermanyDavid and Etta Jonas Center for Cellular Therapy, The University of Chicago, Chicago, IL, USARelapse remains challenging in the treatment of metastatic cancers. More than 50% of human cancers harbor mutant p53 (mp53) as a cancer-specific target. We present the spontaneously metastasizing tumor model Ag104A to advance mp53-specific T cell receptor engineered T cell therapy (TCR-therapy). We identified in Ag104A an autochthonous p53D256E mutation as neoantigen recognized by a TCR isolated from CD8+ T cells (CD8TCR). Cloning of the Ag104A cancer revealed mp53 expression in >99% of cancer cells. Targeting mp53 by CD8TCR-therapy was initially therapeutic, but tumors escaped as cancer cells with reduced or lack of antigen expression. Therefore, we determined whether escape could be prevented by combining the mp53-specific CD8TCR with a CD4+ T cell-derived TCR (CD4TCR) recognizing a mutant antigen presented on the stroma of the cancer. No relapse occurred when the mp53-specific CD8TCR was combined with the stroma-recognizing CD4TCR. The combination therapy also prevented the development of macrometastases from cancer cells that had already spread to the lung at the time of TCR-therapy. Macrometastases were only observed after monotherapy. Thus, in a spontaneously metastatic model, tumor relapse and development of macrometastases can be prevented by combining a CD8TCR targeting an autochthonous p53-mutation with a mutation-specific CD4TCR recognizing tumor stroma.https://www.tandfonline.com/doi/10.1080/2162402X.2025.2514041Adoptive cell transfermetastatic tumor modelmutant p53neoantigenTCR-therapy |
| spellingShingle | Vasiliki Anastasopoulou Hans Schreiber Ching-En Lee Kazuma Kiyotani Leo Hansmann Yusuke Nakamura Matthias Leisegang Steven P. Wolf Mutant p53-specific CD8TCR-therapy combined with a CD4TCR prevents relapse of cancer and outgrowth of micrometastases OncoImmunology Adoptive cell transfer metastatic tumor model mutant p53 neoantigen TCR-therapy |
| title | Mutant p53-specific CD8TCR-therapy combined with a CD4TCR prevents relapse of cancer and outgrowth of micrometastases |
| title_full | Mutant p53-specific CD8TCR-therapy combined with a CD4TCR prevents relapse of cancer and outgrowth of micrometastases |
| title_fullStr | Mutant p53-specific CD8TCR-therapy combined with a CD4TCR prevents relapse of cancer and outgrowth of micrometastases |
| title_full_unstemmed | Mutant p53-specific CD8TCR-therapy combined with a CD4TCR prevents relapse of cancer and outgrowth of micrometastases |
| title_short | Mutant p53-specific CD8TCR-therapy combined with a CD4TCR prevents relapse of cancer and outgrowth of micrometastases |
| title_sort | mutant p53 specific cd8tcr therapy combined with a cd4tcr prevents relapse of cancer and outgrowth of micrometastases |
| topic | Adoptive cell transfer metastatic tumor model mutant p53 neoantigen TCR-therapy |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2025.2514041 |
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