不适合移植的大 B 细胞淋巴瘤二线使用 axicabtagene ciloleucel：ALYCANTE 最终分析
Second-line axicabtagene ciloleucel in large B-cell lymphoma ineligible for transplantation: ALYCANTE final analysis.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
CD20 表达调控 B 细胞淋巴瘤中的 CD37 水平——对免疫治疗的启示
英文原题：CD20 expression regulates CD37 levels in B-cell lymphoma - implications for immunotherapies.
查看英文原题
CD20 expression regulates CD37 levels in B-cell lymphoma - implications for immunotherapies.
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中文摘要
利妥昔单抗（RTX）联合化疗（R-CHOP）作为淋巴瘤一线治疗后，约 40% 患者会复发。因此，针对侵袭性淋巴瘤的新治疗方法正在受到广泛研究。研究人员已建立多种 RTX 耐药（RR）细胞系，作为研究 R-CHOP 耐药的替代模型。
本研究发现，RR 细胞中 CD37 显著下调；CD37 是目前正在探索的免疫治疗靶点。我们利用 CD20 基因敲除（KO）细胞系证实 CD20 和 CD37 可形成复合物，并推测 CD20 的存在可稳定细胞膜上的 CD37。
因此，在 RR 和 CD20 KO 细胞中，抗 CD37 单克隆抗体（mAb）介导的补体依赖性细胞毒作用均减弱，但可通过抑制溶酶体而部分恢复。另一方面，与对照组相比，CD20 KO 细胞对抗 CD37 mAb 的内化速率增加，提示抗体药物偶联物（ADC）的疗效可能不受影响。
重要的是，即使 CD37 水平大幅下调，也不会削弱靶向 CD37 的嵌合抗原受体（CAR）T 细胞疗效。总之，本研究提出了一种新的 CD37 调控机制，并揭示了其对抗 CD37 免疫疗法应用的进一步影响。
展开英文摘要原文
Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of the patients.
Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP.
Our study reveals that RR cells are characterized by a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate that CD20 and CD37 form a complex, and hypothesize that the presence of CD20 stabilizes CD37 in the cell membrane.
Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates (ADCs).
Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies.
论文信息
- 作者
- Bobrowicz M、Kusowska A、Krawczyk M、Zhylko A、Forcados C、Slusarczyk A、Barankiewicz J、Domagala J
- 单位
- Department of Immunology, Medical University of Warsaw, Warsaw, Poland.Poland
- 文献类型
- 非美国政府资助研究
- 期刊
- Oncoimmunology2024
- 原文标识
- PubMed 38846084 · DOI 10.1080/2162402X.2024.2362454
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