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.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
HDAC 抑制剂 (SAHA) 增强 B7-H3 特异性 CAR-T 细胞对软骨肉瘤细胞的细胞毒性疗效并延长原位小鼠模型生存
英文原题：HDAC inhibitor (SAHA) enhances B7-H3-specific CAR T cell cytotoxic efficacy against chondrosarcoma cells and prolongs survival in an orthotopic mouse model.
查看英文原题
HDAC inhibitor (SAHA) enhances B7-H3-specific CAR T cell cytotoxic efficacy against chondrosarcoma cells and prolongs survival in an orthotopic mouse model.
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中文摘要
高级别软骨肉瘤（II级、III级及去分化型）是一种侵袭性原发恶性骨肿瘤，肿瘤组织呈透明软骨样，但目前缺乏有效的全身治疗。局限性疾病采用完整手术切除并确保切缘阴性治疗。
然而，高级别软骨肉瘤常发生全身播散，总生存率仅为29%。这些临床结果凸显了开发更有效全身治疗的迫切需求，CAR-T 细胞疗法便是其中一种。
本研究以肿瘤相关抗原B7-H3为靶点；该抗原在软骨肉瘤细胞中高表达，而在正常组织中表达受限。结果显示，B7-H3特异性CAR-T 细胞可在体外有效杀伤软骨肉瘤细胞，并在免疫缺陷小鼠中减缓肿瘤生长，从而延长荷瘤小鼠生存期。为增强B7-H3 CAR-T 抗肿瘤活性，研究者在体外使用低剂量伏立诺他（SAHA，一种组蛋白去乙酰化酶〔HDAC〕抑制剂）处理肿瘤细胞或CAR-T 细胞；SAHA可上调多种实体癌细胞及CAR中的B7-H3转录和表达。研究结果表明，SAHA处理B7-H3 CAR-T 细胞或软骨肉瘤细胞，均可在体内外增强CAR-T 抗肿瘤细胞毒活性。
展开英文摘要原文
High-grade Chondrosarcoma (Grades II, III, and dedifferentiated) is an aggressive primary malignant bone tumor characterized by hyaline cartilaginous neoplastic tissue without any effective systemic therapy. Localized disease is treated with a complete surgical resection with negative margins.
However, high-grade chondrosarcoma often spreads systemically, leading to low overall survival rates of 29 %. These clinical findings emphasize the urgent need for improved systemic therapies. Among them is chimeric antigen receptor (CAR) T cell therapy. In this study, tumor-associated antigen B7-H3, which is highly expressed in chondrosarcoma cells but has a restricted expression in normal tissues, is targeted with B7-H3-specific CAR T cells.
Our results show that these CAR T cells are effective in killing chondrosarcoma cells in vitro and retard chondrosarcoma tumor growth in immunodeficient mice, which resulted in prolonged survival of tumor-bearing mice. To enhance the antitumor activity of B7-H3 CAR T cells, tumor cells or CAR T cells were treated ex-vivo with a low dose of vorinostat (SAHA), a histone deacetylase (HDAC) inhibitor that upregulates B7-H3 transcription and expression in several types of solid cancer cells as well as the chimeric antigen receptor.
Our results demonstrate that treatment of B7-H3 CAR T cells or chondrosarcoma cells with SAHA enhances CAR T cell antitumor cytotoxic activity in vitro and in vivo.
论文信息
- 作者
- Osei-Hwedieh DO、He L、Wang K、Fan S、Ferrone S、Wang X、Schwab JH
- 第一作者单位
- Departments of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA; Orthopaedic Oncology Service, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA; Department of Orthopaedic Surgery, Cedars Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.United States
- 通讯作者单位
- Departments of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA; Orthopaedic Oncology Service, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA; Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA; Department of Orthopaedic Surgery, Cedars Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA. Electronic address: joseph.schwab@cshs.org.United States
- 期刊
- Translational oncology2025 Dec
- 原文标识
- PubMed 41037832 · DOI 10.1016/j.tranon.2025.102538
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