Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies1–3. In this strategy, the T cell genome is modified by integration of viral vectors or transposons encoding chimaeric antigen receptors (CARs) that direct tumour cell killing. However, this approach is often limited by the extent of expansion and persistence of CAR T cells4,5. Here we report mechanistic insights from studies of a patient with chronic lymphocytic leukaemia treated with CAR T cells targeting the CD19 protein. Following infusion of CAR T cells, anti-tumour activity was evident in the peripheral blood, lymph nodes and bone marrow; this activity was accompanied by complete remission. Unexpectedly, at the peak of the response, 94% of CAR T cells originated from a single clone in which lentiviral vector-mediated insertion of the CAR transgene disrupted the methylcytosine dioxygenase TET2 gene. Further analysis revealed a hypomorphic mutation in this patient’s second TET2 allele. TET2-disrupted CAR T cells exhibited an epigenetic profile consistent with altered T cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knockdown of TET2 recapitulated the potency-enhancing effect of TET2 dysfunction in this patient’s CAR T cells. These findings suggest that the progeny of a single CAR T cell induced leukaemia remission and that TET2 modification may be useful for improving immunotherapies.Genetically engineered T cells that induced remission in a patient with chronic lymphocytic leukaemia were found to have disruption of the TET2 gene, which caused T cell changes that potentiated their anti-tumour effects.

中文翻译：

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TET2 的破坏促进了 CD19 靶向 T 细胞的治疗效果

基于遗传重定向 T 细胞的癌症免疫疗法已成功用于治疗 B 细胞恶性肿瘤1-3。在该策略中，T 细胞基因组通过整合病毒载体或编码嵌合抗原受体 (CAR) 的转座子进行修饰，这些载体或转座子可直接杀死肿瘤细胞。然而，这种方法通常受到 CAR T 细胞的扩增和持久性程度的限制4,5。在这里，我们报告了对使用靶向 CD19 蛋白的 CAR T 细胞治疗的慢性淋巴细胞白血病患者的研究的机制见解。CAR T细胞输注后，外周血、淋巴结和骨髓中的抗肿瘤活性明显；这项活动伴随着完全缓解。没想到，在回应的高峰期，94% 的 CAR T 细胞源自单个克隆，其中慢病毒载体介导的 CAR 转基因插入破坏了甲基胞嘧啶双加氧酶 TET2 基因。进一步的分析显示该患者的第二个 TET2 等位基因存在亚形突变。TET2 破坏的 CAR T 细胞表现出与改变的 T 细胞分化一致的表观遗传特征，并且在扩增的高峰期显示出中央记忆表型。TET2 的实验性敲低概括了 TET2 功能障碍在该患者 CAR T 细胞中的效力增强作用。这些发现表明，单个 CAR T 细胞的后代可诱导白血病缓解，并且 TET2 修饰可能有助于改善免疫疗法。