A Promising Vector for TCR Gene Therapy: Differential Effect of siRNA, 2A Peptide, and Disulfide Bond on the Introduced TCR Expression.
A Promising Vector for TCR Gene Therapy: Differential Effect of siRNA, 2A Peptide, and Disulfide Bond on the Introduced TCR Expression.
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DOI：
10.1038/mtna.2012.52
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发表时间：
2012-12-18
期刊：
影响因子：
--
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使用TCR基因修饰的T淋巴细胞的连续免疫治疗是针对恶性肿瘤的有吸引力的策略。然而，内源性和引入的TCR链之间的TCR错配是主要问题，因为它们可能诱导具有未知特异性的混合TCR，并且可能降低治疗性TCR的表达。为了克服这些问题，我们最近建立了一种新的逆转录病毒siTCR载体编码小干扰RNA（siRNA）敲低内源性TCR基因的有效表达的治疗性TCR。在这项研究中，为了提高siTCR载体的功效，我们开发了基于2A肽的siTCR载体，与基于内部启动子的siTCR载体相比，其可以增加转导的TCR的表达水平。我们还评估了siTCR策略的有效性和通过半胱氨酸修饰产生的新链间二硫键的添加。我们发现半胱氨酸修饰的效果取决于TCR的变化，而siTCR策略改善了所有测试的TCR的表达。此外，siTCR和半胱氨酸修饰策略的组合效果对于某些TCR是高度显著的。因此，我们的新型siTCR技术，单独或与另一种策略相结合，可能为癌症患者的有效免疫治疗打开大门。
Adoptive immunotherapy using TCR gene-modified T-lymphocytes is an attractive strategy for targeting malignancies. However, TCR mispairings between endogenous and introduced TCR chains are a major concern, as they may induce mixed TCRs with unknown specificities and may reduce the expression of therapeutic TCRs. To overcome these problems, we have recently established a novel retroviral siTCR vector encoding small-interfering RNAs (siRNAs) to knockdown endogenous TCR genes for the efficient expression of therapeutic TCRs. In this study, to improve the efficacy of siTCR vectors, we developed 2A peptide-based siTCR vectors that could increase the expression levels of transduced TCRs compared with internal promoter-based siTCR vectors. We also evaluated the efficacy of an siTCR strategy and the addition of a new interchain disulfide bond created by cysteine modification. We found that the effect of the cysteine modification depended on TCR variations, while the siTCR strategy improved the expression of all TCRs tested. Furthermore, the combined effect of the siTCR and cysteine modification strategies was highly significant for certain TCRs. Therefore, our novel siTCR technology, in isolation or in combination with another strategy, may open the door to effective immunotherapy for cancer patients.
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影响因子：
56.9
作者：
Morgan, Richard A.;Dudley, Mark E.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
DOI：
10.4049/jimmunol.1001775
发表时间：
2011-01-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chinnasamy N;Wargo JA;Yu Z;Rao M;Frankel TL;Riley JP;Hong JJ;Parkhurst MR;Feldman SA;Schrump DS;Restifo NP;Robbins PF;Rosenberg SA;Morgan RA
通讯作者：
Morgan RA
影响因子：
4.2
作者：
Chono, Hideto;Matsumoto, Kazuya;Kato, Ikunoshin
通讯作者：
Kato, Ikunoshin
影响因子：
20.3
作者：
Kustikova, OS;Wahlers, A;Fehse, B
通讯作者：
Fehse, B
影响因子：
3.5
作者：
Hong, YT;Yu, SS;Kim, S
通讯作者：
Kim, S