Anastasopoulou, Vasiliki and Schreiber, Hans and Lee, Ching-En and Kiyotani, Kazuma and Hansmann, Leo and Nakamura, Yusuke and Leisegang, Matthias and Wolf, Steven P. (2025) Mutant p53-specific CD8TCR-therapy combined with a CD4TCR prevents relapse of cancer and outgrowth of micrometastases. ONCOIMMUNOLOGY, 14 (1): 2514041. ISSN 2162-402X,
Full text not available from this repository. (Request a copy)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 inspace>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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ANTIGEN-LOSS VARIANTS; T-CELLS; GENE-THERAPY; IN-VIVO; TUMOR; ERADICATION; BYSTANDER; P53; SEQUENCE; ESCAPE; Adoptive cell transfer; metastatic tumor model; mutant p53; neoantigen; TCR-therapy |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Apr 2026 08:54 |
| Last Modified: | 23 Apr 2026 08:54 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67596 |
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