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首页> 外文期刊>Cell discovery. >Enhancement of the in vivo persistence and antitumor efficacy of CD19 chimeric antigen receptor T cells through the delivery of modified TERT mRNA
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Enhancement of the in vivo persistence and antitumor efficacy of CD19 chimeric antigen receptor T cells through the delivery of modified TERT mRNA

机译：通过传递修饰的TERT mRNA增强CD19嵌合抗原受体T细胞的体内持久性和抗肿瘤功效

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Chimeric antigen receptor T cell immunotherapy is a promising therapeutic strategy for treating tumors, demonstrating its efficiency in eliminating several hematological malignancies in recent years. However, a major obstacle associated with current chimeric antigen receptor T cell immunotherapy is that the limited replicative lifespan of chimeric antigen receptor T cells prohibits the long-term persistence and expansion of these cells in vivo , potentially hindering the long-term therapeutic effects of chimeric antigen receptor T cell immunotherapy. Here we showed that the transient delivery of modified mRNA encoding telomerase reverse transcriptase to human chimeric antigen receptor T cells targeting the CD19 antigen (CD19 chimeric antigen receptor T cells) would transiently elevate the telomerase activity in these cells, leading to increased proliferation and delayed replicative senescence without risk of insertion mutagenesis or immortalization. Importantly, compared to conventional CD19 chimeric antigen receptor T cells, after the transient delivery of telomerase reverse transcriptase mRNA, these CD19 chimeric antigen receptor T cells showed improved persistence and proliferation in mouse xenograft tumor models of human B-cell malignancies. Furthermore, the transfer of CD19 chimeric antigen receptor T cells after the transient delivery of telomerase reverse transcriptase mRNA enhanced long-term antitumor effects in mouse xenograft tumor models compared with conventional CD19 chimeric antigen receptor T cell transfer. The results of the present study provide an effective and safe method to improve the therapeutic potential of chimeric antigen receptor T cells, which might be beneficial for treating other types of cancer, particularly solid tumors.
机译：嵌合抗原受体T细胞免疫疗法是治疗肿瘤的一种有前途的治疗策略，证明了其近年来消除多种血液系统恶性肿瘤的效率。然而，与当前的嵌合抗原受体T细胞免疫疗法相关的主要障碍是，嵌合抗原受体T细胞的有限复制寿命限制了这些细胞在体内的长期持久和扩增，潜在地阻碍了嵌合体的长期治疗作用。抗原受体T细胞免疫疗法。在这里，我们表明，将编码端粒酶逆转录酶的修饰mRNA瞬时递送至靶向CD19抗原的人嵌合抗原受体T细胞（CD19嵌合抗原受体T细胞）会瞬时提高这些细胞中的端粒酶活性，从而导致增殖增加和复制延迟。没有插入诱变或永生化的风险。重要的是，与常规的CD19嵌合抗原受体T细胞相比，在端粒酶逆转录酶mRNA的瞬时传递后，这些CD19嵌合抗原受体T细胞在人B细胞恶性小鼠异种移植肿瘤模型中显示出改善的持久性和增殖。此外，与传统的CD19嵌合抗原受体T细胞转移相比，在端粒酶逆转录酶mRNA瞬时递送后CD19嵌合抗原受体T细胞的转移增强了小鼠异种移植肿瘤模型的长期抗肿瘤作用。本研究的结果提供了一种有效和安全的方法来提高嵌合抗原受体T细胞的治疗潜力，这可能对治疗其他类型的癌症（尤其是实体瘤）有益。

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