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
一种分裂的、条件性活性的 IL-2 模拟物降低了系统性细胞因子治疗的毒性
英文原题：A split, conditionally active mimetic of IL-2 reduces the toxicity of systemic cytokine therapy.
查看英文原题
A split, conditionally active mimetic of IL-2 reduces the toxicity of systemic cytokine therapy.
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中文摘要
重组细胞因子的治疗潜力因全身给药的严重副作用而受到限制。我们描述了一种策略，通过设计两个需要共定位才能产生活性、且可被独立靶向以将活性限制于表达两种表面标志物的细胞的组分，来降低单体细胞因子的剂量限制性毒性。我们以一种先前设计的细胞因子白细胞介素-2和白细胞介素-15的模拟物——Neoleukin-2/15（Neo-2/15）——展示了该方法，既用于反式激活靶向肿瘤细胞周围的免疫细胞，也用于顺式激活直接靶向的免疫细胞。在反式激活模式中，与全身治疗相比，两个组分的肿瘤抗原靶向在同系小鼠黑色素瘤模型中增强了抗肿瘤活性并减轻了毒性。在顺式激活模式中，两个组分的免疫细胞靶向在同系小鼠黑色素瘤模型中选择性扩增了CD8 + T细胞，并在淋巴瘤异种移植模型中促进了CAR-T 细胞活化，在两种情况下均增强了抗肿瘤疗效。
展开英文摘要原文
The therapeutic potential of recombinant cytokines has been limited by the severe side effects of systemic administration.
We describe a strategy to reduce the dose-limiting toxicities of monomeric cytokines by designing two components that require colocalization for activity and that can be independently targeted to restrict activity to cells expressing two surface markers.
We demonstrate the approach with a previously designed mimetic of cytokines interleukin-2 and interleukin-15-Neoleukin-2/15 (Neo-2/15)-both for trans-activating immune cells surrounding targeted tumor cells and for cis-activating directly targeted immune cells. In trans-activation mode, tumor antigen targeting of the two components enhanced antitumor activity and attenuated toxicity compared with systemic treatment in syngeneic mouse melanoma models.
In cis-activation mode, immune cell targeting of the two components selectively expanded CD8 + T cells in a syngeneic mouse melanoma model and promoted chimeric antigen receptor T cell activation in a lymphoma xenograft model, enhancing antitumor efficacy in both cases.
论文信息
- 作者
- Quijano-Rubio A、Bhuiyan AM、Yang H、Leung I、Bello E、Ali LR、Zhangxu K、Perkins J
- 第一作者单位
- Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, USA.United States
- 通讯作者单位
- Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, USA. dabaker@uw.edu.United States
- 文献类型
- 美国 NIH 资助研究 · 非美国政府资助研究 · 美国政府（非公共卫生署）资助研究
- 期刊
- Nature biotechnology2023 Apr
- 原文标识
- PubMed 36316485 · DOI 10.1038/s41587-022-01510-z
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