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。
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。
推荐阅读原文：
Circular mRNA-based TCR-T offers a safe and effective therapeutic strategy for treatment of cytomegalovirus infection.
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.
审核：辛嘉平
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