Safety and efficacy of targeting CD138 with a chimeric antigen receptor for the treatment of multiple myeloma.
Safety and efficacy of targeting CD138 with a chimeric antigen receptor for the treatment of multiple myeloma.
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DOI：
10.18632/oncotarget.26792
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发表时间：
2019-03-22
期刊：
影响因子：
--
通讯作者：
Savoldo, Barbara
中科院分区：
文献类型：
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作者：
Sun, Chuang;Mahendravada, Aruna;Savoldo, Barbara
在B细胞恶性肿瘤中取得前所未有的成功之后，最近研究了嵌合抗原受体T细胞用于治疗多发性骨髓瘤。靶向T细胞的嵌合抗原受体恶性浆细胞上的B细胞成熟抗原（BCMA）在最近的试验中导致了令人印象深刻的临床应答。然而，已经观察到BCMA阴性复发，支持补充治疗策略的需要。在这里，我们探讨了靶向CD 138（syndecan-1）的可行性，CD 138是一种在正常和恶性浆细胞上表达的表面标志物。我们发现，当用CD 138特异性嵌合抗原受体转导时，来自健康供体和多发性骨髓瘤患者的T细胞可以在体外和体内消除肿瘤细胞系和原发性骨髓瘤细胞。通过Hoechst染色鉴定的推定的骨髓瘤干细胞也表达CD 138，并且这些细胞可以被CD 138特异性嵌合抗原受体T细胞消除。临床前分析未发现针对正常上皮或内皮细胞的任何靶向脱靶肿瘤细胞毒性，进一步支持了使用过继转移的CD 138特异性嵌合抗原受体T细胞治疗复发性/难治性多发性骨髓瘤患者的基本原理。
After unprecedented successes in B-cell malignancies, chimeric antigen receptor T cells have recently been investigated for the treatment of multiple myeloma. Chimeric antigen receptor targeting T cells B-cell maturation antigen (BCMA) on malignant plasma cells have led to impressive clinical responses in recent trials. However, BCMA-negative relapses have been observed, supporting the need for complementary treatment strategies. Here, we explored the feasibility of targeting CD138 (syndecan-1), a surface marker expressed on both normal and malignant plasma cells. We showed that T cells from both healthy donors and from multiple myeloma patients, when transduced with a CD138-specific chimeric antigen receptor, can eliminate tumor cell lines and primary myeloma cells both in vitro and in vivo. CD138 is also expressed by putative myeloma stem cells identified by Hoechst staining, and these cells can be eliminated by CD138-specific chimeric antigen receptor T cells. Preclinical analyses did not identify any on target off tumor cytotoxicity against normal epithelial or endothelial cells, further supporting the rationale for the use of adoptively transferred CD138-specific chimeric antigen receptor T cells for the treatment of patients with relapsed/refractory multiple myeloma.