Retroviral transfer of a dominant TCR prevents surface expression of a large proportion of the endogenous TCR repertoire in human T cells

Mixed T cell receptor dimers harbor potentially harmful neoreactivity

“…On average, we conclude that approximately one of 10 mixed TCR dimers will harbor potentially hazardous neoreactivity. The results demonstrate that selecting strong competitor TCRs could not avoid occurrence of neoreactive mixed TCR dimers, as has been proposed previously as a strategy to acquire single TCR expression on transduced T cells (21). For example, introduction of a strong competitor CMV-TCR into weak competitor pp50-specific T cells resulted in HLA-B58-restricted neoreactive mixed TCR dimers.…”

Selected Murine Residues Endow Human TCR with Enhanced Tumor Recognition

“…Murinization of human TCRs has been demonstrated to improve their function and expression (15,23). However, the potential risk of immunogenicity that might be triggered by such xenogenic sequences might preclude their clinical use in TCR-gene transfer treatments.…”

“…Recently, we also described an additional strategy based on the swapping of the human C regions with murine ones or "murinization" (23), because it was observed that murine TCRs are better expressed than (and can replace) human TCRs more efficiently on the surface of human lymphocytes (24)(25)(26). This also translated in improved cytokine release and cytotoxicity mediated by murinized TCRs (8,15,23,27) and was associated with an improved pairing of the TCR chains as well as a stronger interaction with the CD3 complex (23).…”

“…9) or to enhance the affinity of the transferred receptor by point mutations (10)(11)(12). Alternatively, various approaches have been devised to augment the number of TCRs on the surface of transduced cells, such as the engineering of the expression vector (9,13), the use of codon-optimized TCR sequences (14,15), the elimination of glycosylation sites (16), and the improved pairing of the introduced TCR chains. The latter is also of clinical importance to prevent or lower the risk for potential autoimmunity because of the generation of mixed-chains TCR dimers occurring between the introduced TCR chains and the endogenous ones (17,18).…”

Progress and prospects: graft-versus-host disease

“…Current strategies, aimed at promoting preferential pairing and expression of exogenous TCR, and at reducing the rate of mispairing, exploit murine TCR constant regions-dominantly expressed in human lymphocytes but possibly immunogenic-and molecular modifications of the TCR constant regions (such as inclusion of a set of additional cysteins to promote disulfide bonds) finalized to increase their reciprocal affinity. [62][63][64] This strategy aims at increasing the proportion of gene-modified T cells expressing the exogenous tumor-specific TCR at high levels, while avoiding the production of functionless and potentially autoreactive T cells.…”