A Potent Tumor-Reactive p53-Specific Single-Chain TCR without On- or Off-Target Autoimmunity In Vivo
| Autor: | Edite Antunes Ferreira, Carina Lotz-Jenne, Jutta Petschenka, Hakim Echchannaoui, Ralf-Holger Voss, Matthias Theobald, Beate Hauptrock |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Genetically modified mouse
Adoptive cell transfer medicine.medical_treatment Genetic enhancement T-Lymphocytes Receptors Antigen T-Cell Autoimmunity Biology 03 medical and health sciences Mice 0302 clinical medicine Antigen Cancer immunotherapy Drug Discovery HLA-A2 Antigen Genetics medicine Animals Humans Molecular Biology 030304 developmental biology Pharmacology 0303 health sciences T-cell receptor Immunotherapy Genetic Therapy Tumor antigen 030220 oncology & carcinogenesis Cancer research Molecular Medicine Original Article Tumor Suppressor Protein p53 |
| Popis: | Genetic engineering of T cells with a T cell receptor (TCR) targeting tumor antigen is a promising strategy for cancer immunotherapy. Inefficient expression of the introduced TCR due to TCR mispairing may limit the efficacy and adversely affect the safety of TCR gene therapy. Here, we evaluated the safety and therapeutic efficiency of an optimized single-chain TCR (scTCR) specific for an HLA-A2.1-restricted (non-mutated) p53(264–272) peptide in adoptive T cell transfer (ACT) models using our unique transgenic mice expressing human p53 and HLA-A2.1 that closely mimic the human setting. Specifically, we showed that adoptive transfer of optimized scTCR-redirected T cells does not induce on-target and off-target autoimmunity. Furthermore, ACT resulted in full tumor protection and led to a long-lived effective, antigen-specific memory T cell response in syngeneic and xenograft models. Taken together, the study demonstrated that our scTCR specific for the broadly expressed tumor-associated antigen p53(264–272) can eradicate p53(+)A2.1(+) tumor cells without inducing off-target or self-directed toxicities in mouse models of ACT. These data strongly support the improved safety and therapeutic efficacy of high-affinity p53scTCR for TCR-based immunotherapy of p53-associated malignancies. |
| Databáze: | OpenAIRE |
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