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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.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at email@example.com.
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