Experimental Transplantation and Immunology Branch; Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 2013 Apr 15;19(8):2048-60. doi: 10.1158/1078-0432.CCR-12-2422. Epub 2013 Jan 23.
PURPOSE: Multiple myeloma is a usually incurable malignancy of plasma cells. New therapies are urgently needed for multiple myeloma. 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 for multiple myeloma 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 multiple myeloma cells. Our goal was to determine if BCMA is a suitable target for CAR-expressing T cells. EXPERIMENTAL DESIGN: We conducted an assessment of BCMA expression in normal human tissues and multiple myeloma cells by flow cytometry, quantitative PCR, and immunohistochemistry. We designed and tested novel anti-BCMA CARs. RESULTS: BCMA had a restricted RNA expression pattern. Except for expression in 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 multiple myeloma cells from five of five 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 multiple myeloma cells. CONCLUSIONS: 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 multiple myeloma.
目的:多发性骨髓瘤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。嵌合抗原受体(CAR)表达 T 细胞的过继转移是血液恶性肿瘤的一种很有前途的新疗法,但尚未确定用于多发性骨髓瘤 CAR 表达 T 细胞治疗的理想靶抗原。B 细胞成熟抗原(BCMA)是一种已被报道在包括多发性骨髓瘤细胞在内的 B 细胞谱系细胞中选择性表达的蛋白。我们的目标是确定 BCMA 是否是 CAR 表达 T 细胞的合适靶标。
实验设计:我们通过流式细胞术、定量 PCR 和免疫组织化学评估了正常人类组织和多发性骨髓瘤细胞中的 BCMA 表达。我们设计并测试了新型抗 BCMA CAR。
结果:BCMA 的 RNA 表达模式受到限制。除了在浆细胞中表达外,BCMA 蛋白在正常人类组织中未检测到。BCMA 未在原代人类 CD34+造血细胞上检测到。我们在来自五名患者的原代多发性骨髓瘤细胞上检测到均匀的 BCMA 细胞表面表达。我们设计了第一批据报道的抗 BCMA CAR,并通过慢病毒载体转导 T 细胞以编码这些 CAR。这些 CAR 赋予 T 细胞特异性识别 BCMA 的能力。抗 BCMA-CAR 转导的 T 细胞表现出 BCMA 特异性功能,包括细胞因子产生、增殖、细胞毒性和体内肿瘤清除。重要的是,抗 BCMA-CAR 转导的 T 细胞识别并杀死原代多发性骨髓瘤细胞。
结论:BCMA 是 CAR 表达 T 细胞的合适靶标,过继转移抗 BCMA-CAR 表达 T 细胞是治疗多发性骨髓瘤的一种很有前途的新策略。
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