B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres
B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres
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DOI：
10.1016/j.ebiom.2019.08.030
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发表时间：
2019-09-01
期刊：
影响因子：
11.1
通讯作者：
Dotti, Gianpietro
中科院分区：
文献类型：
--
作者：
Nehama, Dean;Di Ianni, Natalia;Dotti, Gianpietro
背景：胶质母细胞瘤（GBM）患者生存率低，迫切需要开发新的治疗方法。嵌合抗原受体T（CAR-T）细胞是一种有吸引力的策略，但GBM的临床前和临床研究表明，迄今为止靶向的抗原的异质性表达会导致肿瘤逃逸，这突出了识别新靶点的必要性。我们探索B7-H3是否是GBM中CAR-T细胞的有价值的靶标。方法：我们使用TCGA数据比较GBM中抗原的mRNA表达，并通过免疫组织化学验证B7-H3表达。然后，我们在体外和异种移植小鼠模型中测试了B7-H3重定向的CAR-T细胞对GBM细胞系和患者源性GBM神经球的抗肿瘤活性。结果：在所有GBM亚型中，相对于正常大脑，B7-H3 mRNA和蛋白在GBM中过表达。免疫组化分析的46例标本中，76%显示B7-H3高表达，22%可检测到，但B7-H3低表达，2%为阴性，与正常脑相同。所有20个患者源性神经球均显示普遍的B7-H3表达。B7-H3重定向的CAR-T细胞在体外和体内有效靶向GBM细胞系和神经球。在CD 28和4-1BB共刺激之间没有发现显著差异，尽管CD 28共刺激的CAR-T细胞释放更多的炎性细胞因子。解释：我们证明了B7-H3在GBM标本和含有推定癌症干细胞的神经球中高度表达，并且B7-H3重定向的CAR-T细胞可以有效地控制肿瘤生长。因此，B7-H3代表了GBM中一个有希望的目标。基金：Alex's Lemonade Stand Foundation; Il Fondo di Gio Onlus;国家癌症研究所; Burroughs Wellcome基金。（c）2019年作者。由爱思唯尔有限公司出版。这是一篇开放获取的文章，获得了CC BY-NC-ND许可证（http：//creativecommons.org/licenses/by-nc-nd/4.0/）。
Background: The dismal survival of glioblastoma (GBM) patients urgently calls for the development of new treatments. Chimeric antigen receptor T (CAR-T) cells are an attractive strategy, but preclinical and clinical studies in GBM have shown that heterogeneous expression of the antigens targeted so far causes tumor escape, highlighting the need for the identification of new targets. We explored if B7-H3 is a valuable target for CAR-T cells in GBM.Methods: We compared mRNA expression of antigens in GBM using TCGA data, and validated B7-H3 expression by immunohistochemistry. We then tested the antitumor activity of B7-H3-redirected CAR-T cells against GBM cell lines and patient-derived GBM neurospheres in vitro and in xenograft murine models.Findings: B7-H3 mRNA and protein are overexpressed in GBM relative to normal brain in all GBM subtypes. Of the 46 specimens analyzed by immunohistochemistry, 76% showed high B7-H3 expression, 22% had detectable, but low B7-H3 expression and 2% were negative, as was normal brain. All 20 patient-derived neurospheres showed ubiquitous B7-H3 expression. B7-H3-redirected CAR-T cells effectively targeted GBM cell lines and neurospheres in vitro and in vivo. No significant differences were found between CD28 and 4-1BB co-stimulation, although CD28-co-stimulated CAR-T cells released more inflammatory cytokines.Interpretation: We demonstrated that B7-H3 is highly expressed in GBM specimens and neurospheres that contain putative cancer stem cells, and that B7-H3-redirected CAR-T cells can effectively control tumor growth. Therefore, B7-H3 represents a promising target in GBM.Fund: Alex's Lemonade Stand Foundation; Il Fondo di Gio Onlus; National Cancer Institute; Burroughs Wellcome Fund. (c) 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).