tpds影响因子（pdpdt 影响因子）

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造血干细胞移植（HSCT）是治疗白血病、重度再生障碍性贫血等血液系统疾病的重要疗法，患者在接受移植前需要接受清髓处理，呈现暂时的T细胞免疫缺陷，因此移植后人巨细胞病毒（CMV）再激活是导致患者死亡的主要原因之一。尽管来特莫韦等抗病毒药物显著降低了移植后的CMV再激活，但仍有部分患者面临死亡威胁。抗原特异性T细胞抗体（TCR）T细胞是免疫细胞疗法家族的重要成员，不同于嵌合抗原（CAR）T细胞直接靶向细胞表面抗原，TCR-T细胞需要通过组织相容复合物（MHC）来识别靶细胞，能够识别的抗原相对更为广泛，并且对于抗原更为敏感。然而验证新抗原并分离出特异性针对基因的TCRs在技术上仍然具有挑战性，部分原因在于在成熟树突状细胞（moDCs）中编码抗原的线性mRNA的生命周期相对较短。近日，研究人员在Molecular Therapy上发表论文，报道了基于环状mRNA（cmRNA）技术的TCR-T细胞疗法在对抗HSCT后CMV感染的作用。 /o:p

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cmRNA相比线性mRNA，具有更好的稳定性。研究人员利用cmRNA技术，在单核细胞衍生moDCs中表达CMV特异性抗原（CMV-pp65），为CMV-pp65特异性T细胞提供持久抗原信号，并进行更加高效的激活和扩增，显著提高TCR的筛选效率。随后研究人员测试了cmRNA编码的外源TCR基因在原代T细胞中表达时长，在电转7天和11天后，仍然有约80%和50%的T细胞表达外源TCR，显著延长TCR表达时长。小鼠体内杀伤功能检测实验表明，基于cmRNA技术的cm-pp65-TCR-T在两周输注一次的情况下有效清除表达CMV-pp65抗原的靶细胞。综上，该研究证实了基于cmRNA技术的TCR-T细胞疗法，不仅为HSCT后CMV感染提供了新的治疗策略，也为其他抗病毒/肿瘤TCR-T疗法拓宽了思路。 /o:p

推荐阅读原文： /o:p

Circular mRNA-based TCR-T offers a safe and effective therapeutic strategy for treatment of cytomegalovirus infection. /o:p

Circular mRNA (cmRNA) is particular useful due to its high resistance to degradation by exonucleases, resulting in greater stability and protein expression compared to linear mRNA. T cell receptor (TCR)-engineered T cells (TCR-T) represent a promising means of treating viral infections and cancer. This study aimed to evaluate the feasibility and efficacy of cmRNA in antigen-specific-TCR discovery and TCR-T therapy. Using human cytomegalovirus (CMV) pp65 antigen as a model, we found that the expansion of pp65-responsive T cells was induced more effectively by monocyte-derived dendritic cells transfected with pp65-encoding cmRNA compared with linear mRNA. Subsequently, we developed cmRNA-transduced pp65-TCR-T (cm-pp65-TCR-T) that specifically targets the CMV-pp65 epitope. Our results showed that pp65-TCR could be expressed on primary T cells for more than 7 days. Moreover, both in vitro killing and in vivo CDX models demonstrated that cm-pp65-TCR-T cells specifically and persistently kill pp65-and HLA-expressing tumor cells, significantly prolonging the survival of mice. Collectively, our results demonstrated that cmRNA can be used as a more effective technical approach for antigen-specific TCR isolation and identification, and cm-pp65-TCR-T may provide a safe, non-viral, non-integrated therapeutic approach for controlling CMV infection, particularly in patients who have undergone allogeneic hematopoietic stem cell transplantation.

编辑：伍婷

美编：王乐

审核：辛嘉平