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Updated: Apr 16, 2026
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized
Matthias Obenaus1, Catarina Leitão1, Matthias Leisegang1
1Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Abstract:
Identifying T-cell receptors (TCRs) that bind tumor-associated antigens (TAAs) with optimal affinity is a key bottleneck in the development of adoptive T-cell therapy of cancer. TAAs are unmutated self proteins, and T cells bearing high-affinity TCRs specific for such antigens are commonly deleted in the thymus. To identify optimal-affinity TCRs, we generated antigen-negative humanized mice with a diverse human TCR repertoire restricted to the human leukocyte antigen (HLA) A*02:01 (ref. 3). These mice were immunized with human TAAs, for which they are not tolerant, allowing induction of CD8⁺ T cells with optimal-affinity TCRs. We isolate TCRs specific for the cancer/testis (CT) antigen MAGE-A1 (ref. 4) and show that two of them have an anti-tumor effect in vivo. By comparison, human-derived TCRs have lower affinity and do not mediate substantial therapeutic effects. We also identify optimal-affinity TCRs specific for the CT antigen NY-ESO. Our humanized mouse model provides a useful tool for the generation of optimal-affinity TCRs for T-cell therapy.
Insights
Developing optimal T-cell receptors (TCRs) is crucial for cancer adoptive T-cell therapy. This study generated humanized mice to discover high-affinity TCRs against tumor-associated antigens (TAAs), showing therapeutic potential.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Identifying high-affinity T-cell receptors (TCRs) for tumor-associated antigens (TAAs) is critical for effective adoptive T-cell cancer therapy.
- Self-tolerance mechanisms, like thymic deletion, often eliminate T cells with high-affinity TCRs specific for TAAs.
Purpose of the Study:
- To develop a novel method for identifying optimal-affinity TCRs against TAAs.
- To generate and validate TCRs with therapeutic potential for cancer treatment.
Main Methods:
- Generation of antigen-negative humanized mice expressing a diverse human TCR repertoire restricted to HLA-A*02:01.
- Immunization of these mice with human TAAs to induce T cells with optimal-affinity TCRs.
- Isolation and functional characterization of TCRs specific for cancer/testis (CT) antigens MAGE-A1 and NY-ESO.
Main Results:
- Isolated TCRs specific for MAGE-A1 demonstrated in vivo anti-tumor activity.
- TCRs identified through this model exhibited higher affinity compared to previously reported human-derived TCRs.
- Optimal-affinity TCRs specific for the CT antigen NY-ESO were also identified.
Conclusions:
- The developed humanized mouse model is effective for generating optimal-affinity TCRs for adoptive T-cell therapy.
- This approach overcomes the limitations of T-cell tolerance and offers a promising strategy for cancer immunotherapy development.
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