Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma.
Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma.
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DOI：
10.1016/j.immuni.2016.05.014
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发表时间：
2016-06-21
期刊：
影响因子：
32.4
通讯作者：
June CH
中科院分区：
文献类型：
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作者：
Posey AD Jr;Schwab RD;Boesteanu AC;Steentoft C;Mandel U;Engels B;Stone JD;Madsen TD;Schreiber K;Haines KM;Cogdill AP;Chen TJ;Song D;Scholler J;Kranz DM;Feldman MD;Young R;Keith B;Schreiber H;Clausen H;Johnson LA;June CH
表达嵌合抗原受体 (CAR) 的转基因 T 细胞表现出针对血液癌症中谱系限制的非必需靶标的强大反应。然而，在实体瘤中，CAR T 细胞疗法的全部潜力受到具有足够癌症特异性表达的细胞表面抗原的可用性的限制。大多数 CAR 靶标是可有可无的造血组织上的正常自身抗原或过度表达的共享抗原。在这里，我们确定异常的自身抗原可以作为肿瘤排斥的靶标。我们开发了一种 CAR，可以识别 MUC1 的癌症相关 Tn 糖型，MUC1 是一种在多种癌症中表达的新抗原。抗 Tn-MUC1 CAR T 细胞在 T 细胞白血病和胰腺癌的异种移植模型中表现出靶点特异性细胞毒性并成功控制肿瘤生长。这些发现证明了针对 Tn-MUC1 的 CAR T 细胞的治疗功效，并呈现异常糖基化抗原，作为工程化 T 细胞肿瘤治疗的一类新型靶标。
Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.