CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
靶向 B 细胞成熟抗原的第三代 CAR-T 细胞治疗多发性骨髓瘤的治疗潜力
英文原题：Therapeutic potential of third-generation chimeric antigen receptor T cells targeting B cell maturation antigen for treating multiple myeloma.
查看英文原题
Therapeutic potential of third-generation chimeric antigen receptor T cells targeting B cell maturation antigen for treating multiple myeloma.
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中文摘要
多发性骨髓瘤（MM）是一种无法治愈的血液系统恶性肿瘤，其特征是骨髓内恶性浆细胞快速增殖。标准治疗常因患者耐药而失败。美国 FDA 已批准靶向 B 细胞成熟抗原（BCMA）的第二代嵌合抗原受体（CAR）T 细胞（抗 BCMA-CAR2）治疗 MM，但 CAR-T 疗法仍难以实现持久临床应答。
本研究开发了表达抗 BCMA CAR 的第三代 T 细胞（抗 BCMA-CAR3）。该 CAR 含有特异性识别 BCMA 的全人源单链可变片段（scFv），并连接 CD8 铰链区；其设计包括 CD28 跨膜结构域、两个共刺激结构域（CD28 和 4-1BB）及 CD3 信号结构域（28BB）。研究通过慢病毒技术制备改造 T 细胞，并比较其与抗 BCMA-CAR2 对抗癌症的疗效。与抗 BCMA-CAR2 相比，抗 BCMA-CAR3 对 BCMA 表达细胞（KMS-12-PE 和 NCI-H929）的细胞毒活性显著更高。在效靶比 10:1 时，抗 BCMA-CAR3 可裂解 75.5±3.8% 的 NCI-H929 细胞，抗 BCMA-CAR2 为 56.7±3.4%（P=0.0023）。
值得注意的是，培养 12 天后，抗 BCMA-CAR3 几乎清除了 BCMA 阳性细胞（残留 4.1±2.1%），而抗 BCMA-CAR2 处理后仍有 36.8±20.1% 细胞存活。
本研究显示，抗 BCMA-CAR3 对 BCMA 低表达和高表达 MM 细胞的疗效均优于抗 BCMA-CAR2，提示其可能进一步用于复发/难治性 MM 的 CAR-T 治疗。
展开英文摘要原文
Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the rapid proliferation of malignant plasma cells within the bone marrow. Standard therapies often fail due to patient resistance. The US FDA has approved second-generation chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (anti-BCMA-CAR2 T cells) for MM treatment.
However, achieving enduring clinical responses remains a challenge in CAR T cell therapy.
This study developed third-generation T cells with an anti-BCMA CAR (anti-BCMA-CAR3). The CAR incorporated a fully human scFv specific to BCMA, linked to the CD8 hinge region. The design included the CD28 transmembrane domain, two co-stimulatory domains (CD28 and 4-1BB), and the CD3 signaling domain (28BB ). Lentiviral technology generated these modified T cells, which were compared against anti-BCMA-CAR2 T cells for efficacy against cancer.
Anti-BCMA-CAR3 T cells exhibited significantly higher cytotoxic activity against BCMA-expressing cells (KMS-12-PE and NCI-H929) compared to anti-BCMA-CAR2 T cells. At an effector-to-target ratio of 10:1, anti-BCMA-CAR3 T cells induced lysis in 75. 5 3. 8% of NCI-H929 cells, whereas anti-BCMA-CAR2 T cells achieved 56. 7 3. 4% (p = 0. 0023).
Notably, after twelve days of cultivation, anti-BCMA-CAR3 T cells nearly eradicated BCMA-positive cells (4. 1 2. 1%), while anti-BCMA-CAR2 T cells allowed 36. 8 20. 1% to survive.
This study highlights the superior efficacy of anti-BCMA-CAR3 T cells against both low and high BCMA-expressing MM cells, surpassing anti-BCMA-CAR2 T cells.
These findings suggest potential for advancing anti-BCMA-CAR3 T cells in chimeric antigen receptor T (CAR-T) therapy for relapsed/refractory MM.
论文信息
- 作者
- Rujirachaivej P、Siriboonpiputtana T、Luangwattananun P、Yuti P、Wutti-In Y、Choomee K、Sujjitjoon J、Chareonsirisuthigul T
- 第一作者单位
- Graduate Program in Clinical Pathology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.Thailand
- 通讯作者单位
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT) and Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand. ptyench@gmail.com.Thailand
- 期刊
- Clinical and experimental medicine2024 Apr 29
- 原文标识
- PubMed 38683232 · DOI 10.1007/s10238-024-01347-7
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