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

  • Author(s): Bethune, Michael T;
  • Gee, Marvin H;
  • Bunse, Mario;
  • Lee, Mark S;
  • Gschweng, Eric H;
  • Pagadala, Meghana S;
  • Zhou, Jing;
  • Cheng, Donghui;
  • Heath, James R;
  • Kohn, Donald B;
  • Kuhns, Michael S;
  • Uckert, Wolfgang;
  • Baltimore, David
  • et al.

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.

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