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| Item Type: | Article |
|---|---|
| Title: | Domain-swapped T cell receptors improve the safety of TCR gene therapy |
| Creators Name: | Bethune, M.T., Gee, M.H., Bunse, M., Lee, M.S., Gschweng, E.H., Pagadala, M.S., Zhou, J., Cheng, D., Heath, J.R., Kohn, D.B., Kuhns, M.S., Uckert, W. and Baltimore, D. |
| Abstract: | T cells engineered to express a tumor-specific {alpha}{beta} T cell receptor (TCR) mediate anti-tumor immunity. However, mispairing of the therapeutic {alpha}{beta} chains with endogenous {alpha}{beta} chains reduces therapeutic TCR surface expression and generates self-reactive TCRs. We report a general strategy to prevent TCR mispairing: swapping constant domains between the {alpha} and {beta} chains of a therapeutic TCR. When paired, domain-swapped (ds)TCRs assemble with CD3, express on the cell surface, and mediate antigen-specific T cell responses. By contrast, dsTCR chains mispaired with endogenous chains cannot properly assemble with CD3 or signal, preventing autoimmunity. We validate this approach in cell-based assays and in a mouse model of TCR gene transfer-induced graft-versus-host disease. We also validate a related approach whereby replacement of {alpha}{beta} TCR domains with corresponding {gamma}{delta} TCR domains yields a functional TCR that does not mispair. This work enables the design of safer TCR gene therapies for cancer immunotherapy. |
| Keywords: | Autoimmunity, Cancer Immunotherapy, Protein Engineering, Receptor Biogenesis, T Cell, T Cell Receptor, Animals, Mice |
| Source: | eLife |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications |
| Volume: | 5 |
| Page Range: | e19095 |
| Date: | 8 November 2016 |
| Official Publication: | https://doi.org/10.7554/eLife.19095 |
| PubMed: | View item in PubMed |
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