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| Home > Publications database > Mutant p53-specific CD8TCR-therapy combined with a CD4TCR prevents relapse of cancer and outgrowth of micrometastases. |
| Home > Publications database > Mutant p53-specific CD8TCR-therapy combined with a CD4TCR prevents relapse of cancer and outgrowth of micrometastases. |
| Journal Article | DKFZ-2025-01225 |
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2025
Taylor & Franics
Abingdon
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Please use a persistent id in citations: doi:10.1080/2162402X.2025.2514041
Abstract: 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.
Keyword(s): CD8-Positive T-Lymphocytes: immunology (MeSH) ; Tumor Suppressor Protein p53: genetics (MeSH) ; Tumor Suppressor Protein p53: immunology (MeSH) ; Mice (MeSH) ; Animals (MeSH) ; Mutation (MeSH) ; Humans (MeSH) ; Neoplasm Micrometastasis (MeSH) ; CD4-Positive T-Lymphocytes: immunology (MeSH) ; Receptors, Antigen, T-Cell: immunology (MeSH) ; Receptors, Antigen, T-Cell: genetics (MeSH) ; Immunotherapy, Adoptive: methods (MeSH) ; Neoplasm Recurrence, Local: prevention & control (MeSH) ; Neoplasm Recurrence, Local: immunology (MeSH) ; Cell Line, Tumor (MeSH) ; Female (MeSH) ; Antigens, Neoplasm: immunology (MeSH) ; Neoplasms: therapy (MeSH) ; Neoplasms: immunology (MeSH) ; Neoplasms: pathology (MeSH) ; Neoplasms: genetics (MeSH) ; Adoptive cell transfer ; TCR-therapy ; metastatic tumor model ; mutant p53 ; neoantigen ; Tumor Suppressor Protein p53 ; Receptors, Antigen, T-Cell ; Antigens, Neoplasm
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