Codon modification of T cell receptors allows enhanced functional expression in transgenic human T cells

Immunotherapy with TCR-Redirected T Cells: Comparison of TCR-Transduced and TCR-Engineered Hematopoietic Stem Cell–Derived T Cells

“…Owing to the fact that we used a nonoptimized P14 TCR in these experiments, mispairing can presumably be further reduced by utilizing a codon-optimized and cysteinized TCR (15,40,41). The application of more recently described methods such as RNA interference-mediated silencing or zinc finger nucleases-promoted disruption of the endogenous TCRa/b-chain genes could potentially avoid the formation of mispaired TCRs entirely (42,43) and improve the therapeutic efficiency of TCR-transduced T cells.…”

“…Recent technical advances aim to reduce these issues to a negligible level. For example, increased surface expression of the transgenic TCR was achieved by codon optimization of the TCR genes (15). Also, improved transgene cassettes in which TCR a-and b-chain genes are linked by 2A peptides instead of an internal ribosomal entry site confer improved TCR function (16,17).…”

Engineered Drug Resistant Cell-Mediated Immunotherapy

“…Bicistronic viral vectors encoding cDNA sequences for both α and β chains have been successfully incorporated into retroviral based strategies to transfer αβ transgenic TCR into T lymphocytes (Yang et al, 2008). The functional efficacies of the engineered CTLs have also been improved by codon optimizing α and β sequences that result in increased surface expression of the transgenic TCRs (Jorritsma et al, 2007;Scholten et al, 2006). The chimeric αβ T cells can be rapidly expanded ex vivo to produce sufficient quantities of tumor reactive cells and after adoptive transfer to patients display potent MHC-restricted cytotoxic activity against tumor cells expressing the specific epitope.…”

Genetic engineering of virus-specific T cells with T-cell receptors recognizing minor histocompatibility antigens for clinical application

“…Several approaches are currently under investigation to increase the efficiency of TCR surface expression after retroviral gene transfer, including increased transcription by selecting optimal retroviral vectors, 28 enhanced translation by codon optimization, 29 selection of TCR with higher affinities 30,31 and prevention of chain mispairing by modification of the TCR constant regions. 32,33 Our findings, however, indicate that adoptive transfer of lymphocytes selected for appropriate surface expression of the transgenic TCR, either by selection of permissive lymphocytes prior to retroviral transduction or by purification of lymphocytes with transgenic TCR surface expression after retroviral transduction, may be an effective alternative approach to improve the clinical efficacy of TCR gene therapy.…”