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Circular mRNA-based TCR-T offers a safe and effective therapeutic strategy for treatment of cytomegalovirus infection
Molecular Therapy ( IF 12.1 ) Pub Date : 2023-11-17 , DOI: 10.1016/j.ymthe.2023.11.017 Lianghua Shen 1 , Jiali Yang 2 , Chijian Zuo 2 , Jian Xu 1 , Ling Ma 1 , Qiaomei He 3 , Xiao Zhou 3 , Xiaodan Ding 3 , Lixiang Wei 2 , Suqin Jiang 2 , Luanluan Ma 2 , Benjia Zhang 2 , Yuqin Yang 3 , Baoxia Dong 3 , Liping Wan 3 , Xueying Ding 4 , Ming Zhu 5 , Zhenhua Sun 2 , Pengran Wang 1 , Xianmin Song 1 , Yan Zhang 1
Molecular Therapy ( IF 12.1 ) Pub Date : 2023-11-17 , DOI: 10.1016/j.ymthe.2023.11.017 Lianghua Shen 1 , Jiali Yang 2 , Chijian Zuo 2 , Jian Xu 1 , Ling Ma 1 , Qiaomei He 3 , Xiao Zhou 3 , Xiaodan Ding 3 , Lixiang Wei 2 , Suqin Jiang 2 , Luanluan Ma 2 , Benjia Zhang 2 , Yuqin Yang 3 , Baoxia Dong 3 , Liping Wan 3 , Xueying Ding 4 , Ming Zhu 5 , Zhenhua Sun 2 , Pengran Wang 1 , Xianmin Song 1 , Yan Zhang 1
Affiliation
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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 killing and 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.
中文翻译：
基于环状mRNA的TCR-T为巨细胞病毒感染的治疗提供了安全有效的治疗策略
环状 mRNA (cmRNA) 由于其对核酸外切酶降解的高抵抗力而特别有用，与线性 mRNA 相比，其稳定性和蛋白质表达更高。 T 细胞受体 (TCR) 工程 T 细胞 (TCR-T) 是治疗病毒感染和癌症的一种有前景的方法。本研究旨在评估 cmRNA 在抗原特异性 TCR 发现和 TCR-T 治疗中的可行性和有效性。使用人巨细胞病毒（CMV）pp65抗原作为模型，我们发现与线性mRNA相比，转染pp65编码cmRNA的单核细胞来源的树突状细胞更有效地诱导pp65反应性T细胞的扩增。随后，我们开发了专门针对 CMV-pp65 表位的 cmRNA 转导的 pp65-TCR-T (cm-pp65-TCR-T)。我们的结果表明，pp65-TCR 可以在原代 T 细胞上表达超过 7 天。此外，杀伤模型和CDX模型都表明cm-pp65-TCR-T细胞特异性且持久地杀死表达pp65和HLA的肿瘤细胞，显着延长小鼠的存活时间。总的来说，我们的结果表明，cmRNA可以作为抗原特异性TCR分离和鉴定的更有效的技术方法，而cm-pp65-TCR-T可以为控制CMV提供安全、非病毒、非整合的治疗方法感染，尤其是接受异体造血干细胞移植的患者。
更新日期：2023-11-17
中文翻译：
基于环状mRNA的TCR-T为巨细胞病毒感染的治疗提供了安全有效的治疗策略
环状 mRNA (cmRNA) 由于其对核酸外切酶降解的高抵抗力而特别有用，与线性 mRNA 相比，其稳定性和蛋白质表达更高。 T 细胞受体 (TCR) 工程 T 细胞 (TCR-T) 是治疗病毒感染和癌症的一种有前景的方法。本研究旨在评估 cmRNA 在抗原特异性 TCR 发现和 TCR-T 治疗中的可行性和有效性。使用人巨细胞病毒（CMV）pp65抗原作为模型，我们发现与线性mRNA相比，转染pp65编码cmRNA的单核细胞来源的树突状细胞更有效地诱导pp65反应性T细胞的扩增。随后，我们开发了专门针对 CMV-pp65 表位的 cmRNA 转导的 pp65-TCR-T (cm-pp65-TCR-T)。我们的结果表明，pp65-TCR 可以在原代 T 细胞上表达超过 7 天。此外，杀伤模型和CDX模型都表明cm-pp65-TCR-T细胞特异性且持久地杀死表达pp65和HLA的肿瘤细胞，显着延长小鼠的存活时间。总的来说，我们的结果表明，cmRNA可以作为抗原特异性TCR分离和鉴定的更有效的技术方法，而cm-pp65-TCR-T可以为控制CMV提供安全、非病毒、非整合的治疗方法感染，尤其是接受异体造血干细胞移植的患者。
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