T cell receptor (TCR) gene therapy provides patients with autologous T cells that are genetically engineered with TCRalphabeta chains and constitutes a promising approach for the treatment of tumors and virus infections. Among the current challenges of TCR gene therapy is the optimization of TCRalpha and beta transgene pairing to enhance the functional avidity of therapeutic T cells. Recently, various genetically modified TCRs have been developed that enhance TCR pairing and minimize mispairing, i.e. pairing between transgenic and endogenous TCR chains. Here, we classify such receptors according to their CD3-dependence for surface expression and review their abilities to address functional T cell avidity. In addition, we discuss the anticipated clinical value of these and other strategies to generate high-avidity T cells.
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