eLife 5: e19095 (2016-11-08)

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.; Baltimore D.

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

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

Type: Article

PubMed: 27823582
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