肿瘤细胞治疗研究
英文原题：TET2 downregulation enhances the antitumor efficacy of CD19 CAR T cells in a preclinical model.
TET2 downregulation enhances the antitumor efficacy of CD19 CAR T cells in a preclinical model.
我们的研究表明，在临床前模型中，shRNA介导的TET2敲低是一种有前景的策略，可增强CD19 CAR T细胞的抗肿瘤活性。
嵌合抗原受体（CAR）T 细胞疗法已在血液系统癌症患者中显示出显著的临床疗效。然而，长期随访研究表明，三年后仅 50% 的患者仍处于完全缓解。为克服这些局限性，我们研究了一种通过基因修饰增强 CAR T 细胞抗肿瘤活性的策略。基于既往研究结果——即与常规 CAR T 相比，TET2（一种甲基胞嘧啶双加氧酶）被破坏的 CAR T 细胞表现出增强的抗肿瘤作用——我们开发了通过 TET2 shRNA 下调 TET2 的 CAR T 细胞。在筛选的 TET2 特异性 shRNA 中，TET2-shRNA-1 被确定为基因沉默最有效的序列。使用该序列，我们构建了一个共表达 CD19 CAR 和 TET2 shRNA 的 all-in-one 载体。体外研究表明，与常规 CD19 CAR T 细胞相比，TET2 敲低 CD19 CAR T 细胞对 CD19 阳性癌细胞的溶细胞活性相当。然而，有趣的是，在使用 NSG 小鼠的异种移植小鼠模型中，TET2 敲低 CAR T 细胞与常规 CAR T 细胞相比显示出显著改善的抗肿瘤活性。我们的研究表明，shRNA 介导的 TET2 敲低是一种在临床前模型中增强 CD19 CAR T 细胞抗肿瘤活性的有前景的策略。
Chimeric antigen receptor (CAR) T cell therapy has demonstrated significant clinical efficacy in patients with hematologic cancers. However, long-term follow-up studies indicate that only 50% of patients remain in complete remission after three years. To overcome these limitations, we investigated a strategy to enhance the antitumor activity of CAR T cells through gene modification. Based on previous research results demonstrating that CAR T cells with disrupted TET2, a methylcytosine dioxygenase, exhibit enhanced antitumor effects compared to conventional CAR T, we developed CAR T cells in which TET2 is downregulated by TET2 shRNA. Among the screened TET2-specific shRNAs, TET2-shRNA-1 was identified as the most effective sequence for gene silencing. Using this sequence, we constructed an all-in-one vector co-expressing CD19 CAR and TET2 shRNA. In vitro studies demonstrated that TET2 knockdown CD19 CAR T cells exhibited comparable cytolytic activity against CD19-positive cancer cells compared to conventional CD19 CAR T cells. However, interestingly, in xenograft mouse model using NSG mice, TET2 knockdown CAR T cells showed significantly improved antitumor activity compared to conventional CAR T cells. Our study demonstrates that shRNA-mediated knockdown of TET2 is a promising strategy to enhance the antitumor activity of CD19 CAR T cells in a preclinical model.
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