CSPG4-Specific CAR T Cells for High-Risk Childhood B Cell Precursor Leukemia
CSPG4-Specific CAR T Cells for High-Risk Childhood B Cell Precursor Leukemia
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DOI：
10.3390/ijms20112764
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发表时间：
2019-06-01
影响因子：
5.6
通讯作者：
Schaft, Niels
中科院分区：
文献类型：
--
作者：
Harrer, Dennis C.;Schuler, Gerold;Schaft, Niels
cd19特异性嵌合抗原受体（CAR） T细胞的出现已被证明是急性淋巴细胞白血病和某些B细胞淋巴瘤的癌症免疫治疗武器库中的强大资产。然而，相当一部分接受CD19-CAR - T细胞治疗的患者复发为cd19阴性癌细胞，这就需要寻找备用抗原。硫酸软骨素蛋白多糖4 （CSPG4）在白血病细胞中表达，MLL 11q23重排是不幸的。我们旨在探索使用cspg4特异性CAR - T细胞对抗混合谱系白血病(MLL)-重排白血病原细胞，使用前体B细胞白血病细胞系KOPN8 （MLL- mllt1易位）作为模型。首先，我们证实了CSPG4在KOPN8细胞上的表达。与KOPN8细胞共培养后，经编码cspg4特异性CAR的mRNA电穿孔的大块T细胞上调活化标记物，并以抗原特异性的方式分泌Th1细胞因子TNF和IFN。更重要的是，cspg4特异性CAR - T细胞对KOPN8细胞表现出特异性脱粒，并在铬裂解实验中特异性裂解KOPN8靶细胞。CSPG4是皮肤黑色素瘤中一个公认的CAR靶点。在这里，我们为使用cspg4特异性CAR - T细胞治疗mll易位性白血病提供了原理证明数据。
The advent of CD19-specific chimeric antigen receptor (CAR) T cells has proven to be a powerful asset in the arsenal of cancer immunotherapy of acute lymphoblastic leukemia and certain B cell lymphomas. However, a sizable portion of patients treated with CD19-CAR T cells relapse with CD19-negative cancer cells, necessitating the quest for back-up antigens. Chondroitin sulfate proteoglycan 4 (CSPG4) expression has been reported on leukemic blasts bearing the ill-fated MLL 11q23 rearrangement. We aimed at exploring the use of CSPG4-specific CAR T cells against mixed-lineage leukemia (MLL)-rearranged leukemic blasts, using the precursor B cell leukemia cell line KOPN8 (MLL-MLLT1 translocation) as a model. First, we confirmed CSPG4 expression on KOPN8 cells. Bulk T cells electroporated with mRNA encoding a CSPG4-specific CAR upregulated activation markers and secreted the Th1 cytokines TNF and IFN in an antigen-specific manner upon co-culture with KOPN8 cells. More importantly, CSPG4-specific CAR T cells evinced specific degranulation towards KOPN8 cells and specifically lysed KOPN8 target cells in chromium lysis experiments. CSPG4 is a well-established CAR target in cutaneous melanoma. Here, we provide proof-of-principle data for the use of CSPG4-specific CAR T cells against MLL-translocated leukemias.