中文摘要：
嵌合抗原受体 T （CAR-T） 细胞对某些血液系统恶性肿瘤显示出显着的疗效。然而，高水平表达且对肿瘤具有选择性的 CAR 靶点很少。已经提出了几种策略来解决由次优选择性引起的 CAR-T 细胞的靶向非肿瘤毒性，但这些策略很复杂，其中许多涉及双基因表达以获得特异性。在这项研究中，我们表明具有肿瘤靶向接头蛋白的可切换 CAR-T 细胞可以减轻对传统 CAR-T 细胞无法靶向的低选择性肿瘤抗原（如 CD40）的靶向非肿瘤毒性。我们的系统由抗可替宁小鼠 CAR-T 细胞和可替宁标记的抗 CD40 单链可变片段 （scFv） 组成，在淋巴瘤小鼠模型中，我们用它们显示选择性肿瘤杀伤，同时保留表达 CD40 的正常细胞，包括巨噬细胞。用自诱导性药物偶联标签简单地替换肿瘤靶向衔接子可以通过在必要时体内耗竭/清除（荷兰Liposoma巨噬细胞清除剂）可切换的 CAR-T 细胞来进一步提高安全性。总之，我们的可切换 CAR 系统可以在保持治疗效果的同时控制 CAR-T 细胞毒性，从而扩大 CAR 靶点的范围。
英文摘要：
Chimeric antigen receptor T (CAR-T) cells show remarkable efficacy for some hematological malignancies. However, CAR targets that are expressed at high level and selective to tumors are scarce. Several strategies have been proposed to tackle the on-target off-tumor toxicity of CAR-T cells that arise from suboptimal selectivity, but these are complicated, with many involving dual gene expression for specificity. In this study, we show that switchable CAR-T cells with a tumor targeting adaptor can mitigate on-target off-tumor toxicity against a low selectivity tumor antigen that cannot be targeted by conventional CAR-T cells, such as CD40. Our system is composed of anti-cotinine murine CAR-T cells and cotinine-labeled anti-CD40 single chain variable fragments (scFv), with which we show selective tumor killing while sparing CD40-expressing normal cells including macrophages in a mouse model of lymphoma. Simple replacement of the tumor-targeting adaptor with a suicidal drug-conjugated tag may further enhance safety by enabling permanent in vivo depletion of the switchable CAR-T cells when necessary. In summary, our switchable CAR system can control CAR-T cell toxicity while maintaining therapeutic efficacy, thereby expanding the range of CAR targets.
论文信息：
论文题目：Improved safety of chimeric antigen receptor T cells indirectly targeting antigens via switchable adapters
期刊名称：Nature Communications
时间期卷：15, Article number: 9917 (2024)
在线时间：2024年11月18日
DOI：doi.org/10.1038/s41467-024-53996-7
产品信息：
货号：CP-005-005
规格：5ml+5ml
品牌：Liposoma
产地：荷兰
名称：Clodronate Liposomes and Control Liposomes
办事处：Target Technology（靶点科技）
氯膦酸盐脂质体清除巨噬细胞在嵌合抗原受体T细胞(CAR-T)模型中心粒细胞功能研究，荷兰Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于Nature Communications：
ClodronateLiposomes清除巨噬细胞提高嵌合抗原受体T细胞的安全性的策略研究
Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体的材料和方法：
For cytokine neutralization experiments, anti-mIL-6 (MP5-20F3; BioXCell) and/or anti-mIL-12 p40 (C17.8; BioXCell) was administered intraperitoneally once a day for six consecutive days beginning 5 h before CAR-T cell transfer (Use 500 μg of anti-mIL-6 and/or anti-mIL-12 for the first dose, followed by 250 μg of anti-mIL-6 and/or 500 μg of anti-mIL-12 for the next 5 days). Anakinra (Kineret; Swedish Orphan Biovitrum, Sweden) was administered intraperitoneally at a dose of 600 μg once a day for 5 days, beginning 5 h before CAR-T cell transfer. For macrophage depletion, mice were treated intraperitoneally with clodronate liposome (1 mg; Liposoma, The Netherlands) for three consecutive days prior to CAR-T cell infusion.
