B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma.
B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma.
复制标题
DOI：
10.1158/1078-0432.ccr-12-2422
复制
发表时间：
2013-04-15
期刊：
影响因子：
--
通讯作者：
Kochenderfer JN
中科院分区：
文献类型：
--
作者：
Carpenter RO;Evbuomwan MO;Pittaluga S;Rose JJ;Raffeld M;Yang S;Gress RE;Hakim FT;Kochenderfer JN
多发性骨髓瘤(MM)是一种通常无法治愈的浆细胞恶性肿瘤。多发性骨髓瘤迫切需要新的治疗方法。表达嵌合抗原受体(CAR)的T细胞过继转移是治疗恶性血液病的一种很有前途的新疗法，但表达CAR的T细胞治疗多发性骨髓瘤的理想靶抗原尚未确定。B细胞成熟抗原(BCMA)是一种B细胞系细胞(包括MM细胞)选择性表达的蛋白。我们的目标是确定BCMA是否是表达CAR的T细胞的合适靶点。我们用流式细胞术、定量聚合酶链式反应和免疫组织化学方法对BCMA在正常人组织和MM细胞中的表达进行了评估。我们设计并测试了新型的反BCMA汽车。BCMA具有限制性的RNA表达模式。除浆细胞外，正常人体组织中未检测到BCMA蛋白的表达。在原代人CD34+造血细胞上未检测到BCMA。我们在5例患者的原代MM细胞上检测到均匀的BCMA细胞表面表达。我们设计了第一个报道的抗BCMA CARS，并用编码这些CARS的慢病毒载体转导T细胞。这些汽车使T细胞具有识别BCMA的能力。抗BCMA-CAR转导的T细胞具有BCMA特异性功能，包括细胞因子的产生、增殖、细胞毒作用和体内肿瘤清除。重要的是，抗BCMA-CAR转导的T细胞识别并杀死原代MM细胞。BCMA是表达CAR的T细胞的合适靶点，过继转移抗BCMA-CAR的T细胞是治疗MM的一种有前景的新策略。
Multiple myeloma (MM) is a usually incurable malignancy of plasma cells. New therapies are urgently needed for MM. Adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a promising new therapy for hematologic malignancies, but an ideal target antigen for CAR-expressing T cell therapies of MM has not been identified. B-cell maturation antigen (BCMA) is a protein that has been reported to be selectively expressed by B-lineage cells including MM cells. Our goal was to determine if BCMA is a suitable target for CAR-expressing T cells. We conducted an assessment of BCMA expression in normal human tissues and MM cells by flow cytometry, quantitative PCR, and immunohistochemistry. We designed and tested novel anti-BCMA CARs. BCMA had a restricted RNA expression pattern. Except for expression on plasma cells, BCMA protein was not detected in normal human tissues. BCMA was not detected on primary human CD34+ hematopoietic cells. We detected uniform BCMA cell-surface expression on primary MM cells from 5 of 5 patients. We designed the first anti-BCMA CARs to be reported, and we transduced T cells with lentiviral vectors encoding these CARs. The CARs gave T cells the ability to specifically recognize BCMA. The anti-BCMA-CAR-transduced T cells exhibited BCMA-specific functions including cytokine production, proliferation, cytotoxicity, and in vivo tumor eradication. Importantly, anti-BCMA-CAR-transduced T cells recognized and killed primary MM cells. BCMA is a suitable target for CAR-expressing T cells, and adoptive transfer of anti-BCMA-CAR-expressing T cells is a promising new strategy for treating MM.