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靶向TSLPR癌蛋白的嵌合抗原修饰的T细胞技术用于B-ALL的根除

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发表于 2016-1-5 23:18:15 | 显示全部楼层 |阅读模式
Eradication of B-ALL using chimeric antigen receptor-expressing T cells targeting the TSLPR oncoprotein.
Adoptive transfer of T cells genetically modified to express chimeric antigen receptors (CARs) targeting the CD19 B cell-associated protein have demonstrated potent activity against relapsed/refractory B-lineage acute lymphoblastic leukemia (B-ALL). Not all patients respond, and CD19-negative relapses have been observed. Overexpression of the thymic stromal lymphopoietin receptor (TSLPR; encoded by CRLF2) occurs in a subset of adults and children with B-ALL and confers a high risk of relapse. Recent data suggest the TSLPR signaling axis is functionally important, suggesting that TSLPR would be an ideal immunotherapeutic target. We constructed short and long CARs targeting TSLPR and tested efficacy against CRLF2-overexpressing B-ALL. Both CARs demonstrated activity in vitro, but only short TSLPR CAR T cells mediated leukemia regression. In vivo activity of the short CAR was also associated with long-term persistence of CAR-expressing T cells. Short TSLPR CAR treatment of mice engrafted with a TSLPR-expressing ALL cell line induced leukemia cytotoxicity with efficacy comparable with that of CD19 CAR T cells. Short TSLPR CAR T cells also eradicated leukemia in 4 xenograft models of human CRLF2-overexpressing ALL. Finally, TSLPR has limited surface expression on normal tissues. TSLPR-targeted CAR T cells thus represent a potent oncoprotein-targeted immunotherapy for high-risk ALL.
靶向TSLPR癌蛋白的嵌合抗原修饰的T细胞技术用于B-ALL的根除
靶向CD19 的嵌合抗原修饰的T细胞过继移植技术已经在复发性/难治性B淋巴细胞白血病(B-ALL)患者的治疗中展示了潜在的治疗活性。 并不是对所有的病人都有效,能够观察到CD19阴性逃逸的现象。在成人和儿童B-ALL患者细胞表面高度表达胸腺基质淋巴细胞受体(TSLPR;CRLF2编码),这种疾病有较高的复发风险。最近的研究表面TSLPR信号的功能很重要,预示着TSLPR可能是一种理想的免疫治疗靶点。我们构建了短的和长的CARs,靶向TSLPR,并且测试其对抗CRLF2过度表达的B-ALL细胞的有效性。在体外实验中,所有CARs显示了抗癌细胞活性,但是只有短链的CARs会介导白血病的回归。体内试验中,短链的CARs的活性也与表达CART细胞的持久性有关。短的TSLPR CAR-T细胞处理表达TSLPRALL癌细胞,会导致白血病细胞毒性,这与CD19 CAR-T细胞的疗效相媲美。短链的TSLPR CAR- T细胞也能对过度表达CRLF2ALL癌细胞产生消灭作用。最终,TSLPR已经限制在正常的组织细胞表面的表达。因此,TSLPR靶向的CAR-T细胞代表着一个潜在的对抗高危ALL患者的免疫治疗方案。
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