T cell receptor-engineered T cells targeting the TP53R248Q neoantigen elicit antitumor effects in human cancer models
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Updated: Jan 15, 2026
A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
Lianghua Shen1,2, Ziyu Chen1,2, Jian Xu1,2
1Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Malignant tumors with TP53 mutations exhibit poor therapeutic outcomes and high recurrence rates. T cell receptor-based (TCR-based) T cell therapy shows great promise for targeting intracellular cancer neoantigens. However, the immunogenic potential of TP53 hotspot mutations remains poorly characterized. Here, we identified an immunogenic neoantigen derived from the recurrent TP53R248Q mutation, presented by the prevalent HLA-A*11:01 allele. Additionally, we isolated a TP53R248Q-reactive TCR that specifically recognized the TP53R248Q mutation without any discernible cross-activity with cognate WT TP53 or other TP53 mutants at the same codon position. Functional characterization revealed that TP53R248Q TCR-T cells exhibited selective cytotoxicity against tumor cells expressing both the TP53R248Q mutation and HLA-A*11:01 in vitro. Importantly, the adoptive transfer of TP53R248Q TCR-T cells exhibited significant antitumor activity in a clinically relevant patient-derived xenograft model engrafted with TP53R248Q/HLA-A*11:01-positive human tumor tissues. Collectively, our study validates the immunogenicity of the TP53R248Q hotspot mutation and provides a TCR with high therapeutic potential for the development of T cell therapies targeting TP53R248Q/HLA-A*11:01-positive cancers.
Insights
Researchers identified a specific neoantigen from the TP53R248Q mutation, enabling the development of a targeted T cell receptor (TCR) therapy. This TCR therapy shows promise for treating cancers with this common TP53 mutation.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- TP53 mutations are linked to poor cancer outcomes and recurrence.
- T cell receptor (TCR)-based therapies offer potential for targeting intracellular cancer neoantigens.
- The immunogenicity of TP53 hotspot mutations is not well understood.
Purpose of the Study:
- To investigate the immunogenic potential of TP53 hotspot mutations.
- To identify and characterize neoantigens derived from TP53 mutations.
- To develop a TCR-based therapy targeting specific TP53 mutations.
Main Methods:
- Identification of a neoantigen from the TP53R248Q mutation presented by HLA-A*11:01.
- Isolation and characterization of a TP53R248Q-reactive TCR.
- In vitro cytotoxicity assays of TCR-T cells against tumor cells.
- In vivo efficacy studies using a patient-derived xenograft (PDX) model.
Main Results:
- A novel immunogenic neoantigen from the TP53R248Q mutation was identified.
- A TP53R248Q-specific TCR was isolated with no cross-reactivity to wild-type TP53.
- TP53R248Q TCR-T cells demonstrated selective cytotoxicity against relevant tumor cells.
- Adoptive transfer of TCR-T cells showed significant anti-tumor activity in a PDX model.
Conclusions:
- The TP53R248Q hotspot mutation is immunogenic.
- A specific TCR targeting TP53R248Q/HLA-A*11:01 positive cancers was developed.
- This TCR holds significant therapeutic potential for treating specific cancers.
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