Sun Chuang, Mahendravada Aruna, Ballard Brandon, Kale Brandon, Ramos Carlos, West John, Maguire Todd, McKay Katie, Lichtman Eben, Tuchman Sascha, Dotti Gianpietro, Savoldo Barbara
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX, USA.
Oncotarget. 2019 Mar 22;10(24):2369-2383. doi: 10.18632/oncotarget.26792.
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.
在B细胞恶性肿瘤治疗中取得前所未有的成功后，嵌合抗原受体T细胞最近被用于多发性骨髓瘤的治疗研究。在恶性浆细胞上靶向B细胞成熟抗原（BCMA）的嵌合抗原受体在最近的试验中已产生令人印象深刻的临床反应。然而，已观察到BCMA阴性复发情况，这表明需要补充治疗策略。在此，我们探讨了靶向CD138（多配体蛋白聚糖-1）的可行性，CD138是一种在正常和恶性浆细胞上均有表达的表面标志物。我们发现，来自健康供体和多发性骨髓瘤患者的T细胞，在用CD138特异性嵌合抗原受体转导后，在体外和体内均可消除肿瘤细胞系和原发性骨髓瘤细胞。通过Hoechst染色鉴定的假定骨髓瘤干细胞也表达CD138，这些细胞可被CD138特异性嵌合抗原受体T细胞清除。临床前分析未发现对正常上皮或内皮细胞的任何脱靶肿瘤细胞毒性，这进一步支持了采用过继转移的CD138特异性嵌合抗原受体T细胞治疗复发/难治性多发性骨髓瘤患者的理论依据。
