CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
整合素α4 抑制可延长移植 CD19 阴性 CAR-T19 后复发 B-ALL 的 NSG 小鼠的生存期
英文原题：Integrin Alpha 4 Inhibition Prolongs the Survival of NSG Mice Engrafted with CD19-Negative Post-CART19 Relapsed B-ALL.
查看英文原题
Integrin Alpha 4 Inhibition Prolongs the Survival of NSG Mice Engrafted with CD19-Negative Post-CART19 Relapsed B-ALL.
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中文摘要
尽管治疗取得了进展并改善了患者预后，抗CD19CAR-T 细胞（CAR-T19）治疗后因抗原丢失导致的复发/难治性B细胞急性淋巴细胞白血病（r/r B-ALL）仍然是一个关键的未满足临床需求。
在本研究中，我们发现整合素α4在CAR-T19前后均稳定表达于B-ALL细胞上。CRISPR/Cas9介导的原代B-ALL细胞CD19敲除并未改变整合素α4的表达，进一步表明整合素α4的表达稳定且不依赖于CD19，是一个稳定的靶点。使用美国食品药品监督管理局（FDA）批准的抗整合素α4抗体natalizumab（NZM），我们证明了其能够有效破坏白血病细胞与VCAM-1（整合素α4的主要配体）以及基质OP9细胞的黏附，从而关键性地减少与白血病支持性微环境的相互作用。最重要的是，与对照组相比，NZM治疗显著延长了移植CAR-T19后复发B-ALL的NSG小鼠的生存期。
我们的工作确立了整合素α4作为识别接受CAR-T19治疗患者白血病细胞的理想标志物。
展开英文摘要原文
Despite therapeutic advancements and improved patient outcomes, relapsed and refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) after anti-CD19 chimeric antigen receptor T-cell (CART19) therapy due to antigen loss remains a critical unmet clinical need. In this study, we identify that integrin α4 is consistently expressed on B-ALL cells before and after CART19. CRISPR/Cas9-mediated CD19 knockout in primary B-ALL cells did not alter integrin α4 expression, further suggesting stable integrin α4 expression independent of CD19 a stable target.
Using the United States Food and Drug Administration (FDA)-approved anti-integrin α4 antibody natalizumab (NZM), we demonstrated effective disruption of leukemia cell adhesion to both VCAM-1, the primary integrin α4 ligand, and to stromal OP9 cells, thereby critically reducing interactions with the leukemia-supportive microenvironment. Most importantly, NZM treatment markedly extended survival in NSG mice engrafted with post-CART19-relapsed B-ALL compared with controls.
Our work establishes integrin α4 as an ideal marker for identifying leukemia cells in patients receiving CART19.
论文信息
- 作者
- Kim HN、Hurwitz S、Fourfouris T、Lee KJ、Le J、Ogana H、Friedmann R、Zarrabi M
- 第一作者单位
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Pediatrics, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA.United States
- 通讯作者单位
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Pediatrics, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA. Electronic address: ymkim@chla.usc.edu.United States
- 期刊
- Experimental hematology2026 Sep
- 原文标识
- PubMed 42336130 · DOI 10.1016/j.exphem.2026.105471