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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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2025-12-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2025.2514041 |
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| Summary: | 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. |
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| ISSN: | 2162-402X |