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Domain-swapped T cell receptors improve the safety of TCR gene therapy

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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. and Gee, M.H. and Bunse, M. and Lee, M.S. and Gschweng, E.H. and Pagadala, M.S. and Zhou, J. and Cheng, D. and Heath, J.R. and Kohn, D.B. and Kuhns, M.S. and 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
Publisher:eLife Sciences Publications
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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