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一种多药耐药修饰的CAR-T细胞异体联合免疫治疗

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发表于 2015-11-4 22:27:07 | 显示全部楼层 |阅读模式
一种多药耐药修饰的CAR-T细胞异体联合免疫治疗
嵌合抗原受体修饰的T细胞(CAR-T)治疗对于多种癌症,是一个非常有前景的治疗方案。这种治疗的临床结果与效应细胞的转移、增殖和特异杀伤肿瘤细胞有紧密联系。当考虑使用异体CAR-T细胞输入,排异反应和移植物抗宿主反应必须避免,来阻止过继转移细胞的排斥和宿主组织的破坏,并且要起到明显的抗肿瘤效果。这篇文章提出解决这三个需求的方案,通过发展多耐药性T细胞受体αβ缺乏的嵌合抗原受体T细胞。我们发现这些改造的T细胞显示了明显的抗肿瘤活性,在目前临床中用于淋巴细胞治疗预处理的嘌呤和嘧啶分子类似物中,能够增殖。存在于细胞表面的T细胞抗原受体αβ,随着他们的嘌呤核苷酸类似物抵抗特性,可以防止他们的同种异体反应,能够使他们能够抵御淋巴细胞,这些能够避免它们通过HVG反应被消除。通过发展一个与异体移植兼容的T细胞的基本框架,是大规模利用CAR-T细胞治疗的基础。
A Multidrug-resistant Engineered CAR T Cell for Allogeneic Combination Immunotherapy
The adoptive transfer of chimeric antigen receptor (CAR) T cell represents a highly promising strategy to fight against multiple cancers. The clinical outcome of such therapies is intimately linked to the ability of effector cells to engraft, proliferate, and specifically kill tumor cells within patients.When allogeneic CAR T-cell infusion is considered, host versus graft and graft versus host reactions must be avoided to prevent rejection of adoptively transferred cells, host tissue damages and to elicit significant antitumoral outcome.This work proposes to address these three requirements through the development of multidrug-resistant T cell receptor αβ-deficient CAR T cells. We demonstrate that these engineered T cells displayed efficient antitumor activity and proliferated in the presence of purine and pyrimidine nucleoside analogues, currently used in clinic as preconditioning lymphodepleting regimens.
The absence of TCRαβ at their cell surface along with their purine nucleotide analogues-resistance properties could prevent their alloreactivity and enable them to resist to lymphodepleting
regimens that may be required to avoid their ablation via
HvG reaction. By providing a basic framework to develop a universal T cell compatible with allogeneic adoptive transfer, this work is laying the foundation stone of the large-scale utilization of CAR T-cell immunotherapies.

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