Domain-swapped T cell receptors improve the safety of TCR gene therapy
AuthorBethune, Michael T
Gee, Marvin H
Lee, Mark S
Gschweng, Eric H
Pagadala, Meghana S
Heath, James R
Kohn, Donald B
Kuhns, Michael S
AffiliationUniv Arizona, Dept Immunobiol
MetadataShow full item record
PublisherELIFE SCIENCES PUBLICATIONS LTD
CitationDomain-swapped T cell receptors improve the safety of TCR gene therapy 2016, 5 eLife
Rights(CC) Copyright Bethune et al. This article is distributed under the terms of the Creative Commons Attribution License.
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AbstractT 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.
NotePaid Open Access after January 2017*
VersionFinal published version
SponsorsNational Institutes of Health [5P01CA132681-5]; Prostate Cancer Foundation [15CHAL02]; Jane Coffin Childs Memorial Fund for Medical Research; Pew Charitable Trusts