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Elife. 2016 Nov 8;5. pii: e19095. doi: 10.7554/eLife.19095.

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

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
2
Program in Immunology, Stanford University School of Medicine, Stanford, United States.
3
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
4
Department of Immunobiology, University of Arizona, Tucson, United States.
5
The BIO5 Institute, University of Arizona, Tucson, United States.
6
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States.
7
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States.
8
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, United States.
9
Institute of Biology, Humboldt-Universität zu Berlin, Berlin, Germany.

Abstract

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.

KEYWORDS:

T cell; T cell receptor; autoimmunity; cancer immunotherapy; human biology; immunology; medicine; mouse; protein engineering; receptor biogenesis

PMID:
27823582
PMCID:
PMC5101000
DOI:
10.7554/eLife.19095
[Indexed for MEDLINE]
Free PMC Article

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