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

Michael T. Bethune, Marvin H. Gee, Mario Bunse, Mark S. Lee, Eric H. Gschweng, Meghana S. Pagadala, Jing Zhou, Donghui Cheng, James R. Heath, Donald B. Kohn, Michael S. Kuhns, Wolfgang Uckert, David Baltimore

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


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 a and b 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.

Original languageEnglish (US)
Article numbere19095
Issue numberNOVEMBER2016
StatePublished - Nov 8 2016

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology


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