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Cell Journal، جلد ۱۶، شماره Suppl ۱، صفحات ۸-۸
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عنوان انگلیسی Is-8: Cancer Immunotherapy with Genetically Modified T Cells
چکیده انگلیسی مقاله Adoptive T cell therapy is an innovative therapeutic approach aimed at providing effective and long-lasting tumor-reactive T cells to cancer patients. Unfortunately, T lymphocytes able to recognize tumor cells with sufficient avidity are often deleted or tolerized because tumor antigens are usually self-antigens. New technological gene transfer tools allow today to enforce natural T cells, enabling to generate high numbers of genemodified tumor-reactive T cells from virtually every cancer patient. T cells have been manipulated ex vivo with viral vectors coding for tumor specific Receptors or “suicide” genes to potentiate their efficacy and minimize toxicity. The genetic transfer of a tumor-specific T cell receptor (TCR) in mature T cells has yielded promising clinical results in cancer patients. Nevertheless, the expression of a novel TCR into polyclonal T cells holds some limitations. In particular, the tumor-specific α and β TCR chains are expressed in lymphocytes that already bear an endogenous TCR on cell surface. Genemodified cells thus express at least two different TCRs that compete for binding to the CD3 complex, and this bottleneck results in mutual TCR dilution and reduced avidity. Furthermore, since TCRs are heterodimers, the α and β chains of the endogenous and transgenic TCR can mispair to produce a new hybrid TCR, with unpredictable and potentially harmful specificity. To permanently remove the expression of the endogenous TCR and the risk of TCR chain mispairing, we developed a TCR gene editing approach, based on the combination of somatic knockout of the endogenous TCR genes (by transient expression of Zinc Finger Nucleases - ZFNs specific for the endogenous α and/or β TCR chains) and introduction of tumor-specific TCR genes by lentiviral vectors (Provasi, Genovese et al. Nat. Med. 2012). Challenges and opportunities of TCR gene transfer and TCR gene editing will be discussed.
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نشانی اینترنتی http://celljournal.org/journal/article/abstract/302
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