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
抗 TACI 单靶点与双靶点 CAR-T 细胞克服多发性骨髓瘤中的 BCMA 抗原丢失
英文原题：Anti-TACI single and dual-targeting CAR T cells overcome BCMA antigen loss in multiple myeloma.
查看英文原题
Anti-TACI single and dual-targeting CAR T cells overcome BCMA antigen loss in multiple myeloma.
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中文摘要
靶向B细胞成熟抗原（BCMA）的嵌合抗原受体（CAR）T细胞可使多发性骨髓瘤患者获得深度应答，但多数患者无法达到长期完全缓解。此外，近期证据提示，高亲和力结合BCMA可能导致基底节区“靶向肿瘤但伤及正常组织”的作用，并引发致命的帕金森样疾病。本研究开发了靶向多发性骨髓瘤的CAR-T 细胞，采用结合跨膜激活剂和钙调亲环素配体相互作用分子（TACI）的结合分子，并设计单靶点和抗BCMA双靶点形式。这些CAR在体内外均具有强效抗原特异性活性。研究还显示，TACI RNA在基底节区表达有限，可能避免部分近期报道的BCMA CAR毒性。因此，单靶向TACI CAR可能具有更安全的毒性特征；靶向BCMA和TACI的双特异性CAR-T 细胞则可能避免单一抗原靶向所导致的抗原逃逸。
展开英文摘要原文
Chimeric Antigen Receptor (CAR) T cells directed to B cell maturation antigen (BCMA) mediate profound responses in patients with multiple myeloma, but most patients do not achieve long-term complete remissions.
In addition, recent evidence suggests that high-affinity binding to BCMA can result in on-target, off-tumor activity in the basal ganglia and can lead to fatal Parkinsonian-like disease.
Here we develop CAR T cells against multiple myeloma using a binder to targeting transmembrane activator and CAML interactor (TACI) in mono and dual-specific formats with anti-BCMA. These CARs have robust, antigen-specific activity in vitro and in vivo.
We also show that TACI RNA expression is limited in the basal ganglia, which may circumvent some of the toxicities recently reported with BCMA CARs.
Thus, single-targeting TACI CARs may have a safer toxicity profile, whereas dual-specific BCMA-TACI CAR T cells have potential to avoid the antigen escape that can occur with single-antigen targeting.
论文信息
- 作者
- Larson RC、Kann MC、Graham C、Mount CW、Castano AP、Lee WH、Bouffard AA、Takei HN
- 第一作者单位
- Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA.United States
- 通讯作者单位
- Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. mvmaus@mgh.harvard.edu.United States
- 文献类型
- 美国 NIH 资助研究
- 期刊
- Nature communications2023 Nov 18
- 原文标识
- PubMed 37980341 · DOI 10.1038/s41467-023-43416-7
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