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

MT Bethune, MH Gee, M Bunse, MS Lee… - Elife, 2016 - elifesciences.org
MT Bethune, MH Gee, M Bunse, MS Lee, EH Gschweng, MS Pagadala, J Zhou, D Cheng…
Elife, 2016elifesciences.org
T cells engineered to express a tumor-specific αβ T cell receptor (TCR) mediate anti-tumor
immunity. However, mispairing of the therapeutic αβ chains with endogenous αβ 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 α and
β 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 …
T cells engineered to express a tumor-specific αβ T cell receptor (TCR) mediate anti-tumor immunity. However, mispairing of the therapeutic αβ chains with endogenous αβ 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 α and β 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 αβ TCR domains with corresponding γδ TCR domains yields a functional TCR that does not mispair. This work enables the design of safer TCR gene therapies for cancer immunotherapy.
DOI: http://dx.doi.org/10.7554/eLife.19095.001
eLife
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