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BackgroundWith its roots in principles of basic immunology, synthetic biology and genetic engineering, the field of adoptive cell transfer (ACT) has quickly become one of the most promising and innovative approaches to treat cancer, viral infections and other immune-modulated diseases. There are currently three main types of ACT using effector cells 1 : administration of tumour infiltrating lymphocytes (TILs), and gene transfer-based strategies relying on T-cell manipulation for expression of either chimeric antigen (Ag) receptors (CARs) -composed of antibody (Ab)-binding domains fused to T-cell signalling domains -or engineered T-cell receptor (TCR) α/β heterodimers. Genetic modification of autologous T cells to target specific tumour antigens has been developed to overcome the consequences of immune tolerance and offers the possibility to endow the immune system with reactivities that are not naturally present. This approach has the additional benefit of rapid tumour eradication, which is usually observed with cytotoxic chemotherapy or with targeted therapies, and it contrasts to the delayed effects that are usually observed with vaccines and T-cell checkpoint therapies. Lasting anticancer responses have been extensively reported for CARs targeting CD19 on chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) and B-cell lymphoma 2 , and the US Food and Drug Administration (FDA) has recently approved two genetically engineered CAR T-cell products, tisagenlecleucel (Kymriah) 3 and axicabtagene ciloleucel (Yescarta) 4 , for clinical application. Although not having yet provided such a dramatic evidence of effectiveness, therapeutic TCR genemodified T cells have also shown clinical activity and significantly reduce tumour burden 2 . Furthermore, they feature particularities that render them a more suitable approach for specific types of malignancies, including solid tumours. This review will focus on the main characteristics of TCR gene-modified cells, their potential clinical application and promise to the field of ACT, basic manufacturing procedures and characterisation protocols, and overall challenges that need to be overcome so that redirection of TCR specificity may be successfully translated into clinical practice. TCR structure and signallingThe TCR is a heterodimeric protein, typically consisting of an alpha (α) and a beta (β) chain, expressed on the cell surface as part of a complex with CD3 molecules. A minority of T cells can express an alternate receptor formed by gamma (γ) and delta (δ) chains (γδ T cells). TCR activation depends on the binding to a processed intracellular peptide presented by a major histocompatibility complex (MHC) molecule (the peptide-MHC antigen) on the target cells, followed by proper signal initiation and amplification, processes that involve an array of cell surface molecules. Each αβ subunit contains variable (V) and constant (C) regions, with the latter being followed by a transmembrane region. Each V domain contains three loops which interact with the pepti...