ClodronateLiposomes清除巨噬細(xì)胞提高嵌合抗原受體T細(xì)胞的安全性的策略研究

中文摘要：

嵌合抗原受體 T （CAR-T） 細(xì)胞對某些血液系統(tǒng)惡性腫瘤顯示出顯著的療效。然而，高水平表達(dá)且對腫瘤具有選擇性的 CAR 靶點(diǎn)很少。已經(jīng)提出了幾種策略來解決由次優(yōu)選擇性引起的 CAR-T 細(xì)胞的靶向非腫瘤毒性，但這些策略很復(fù)雜，其中許多涉及雙基因表達(dá)以獲得特異性。在這項(xiàng)研究中，我們表明具有腫瘤靶向接頭蛋白的可切換 CAR-T 細(xì)胞可以減輕對傳統(tǒng) CAR-T 細(xì)胞無法靶向的低選擇性腫瘤抗原（如 CD40）的靶向非腫瘤毒性。我們的系統(tǒng)由抗可替寧小鼠 CAR-T 細(xì)胞和可替寧標(biāo)記的抗 CD40 單鏈可變片段 （scFv） 組成，在淋巴瘤小鼠模型中，我們用它們顯示選擇性腫瘤殺傷，同時(shí)保留表達(dá) CD40 的正常細(xì)胞，包括巨噬細(xì)胞。用自誘導(dǎo)性藥物偶聯(lián)標(biāo)簽簡單地替換腫瘤靶向銜接子可以通過在必要時(shí)體內(nèi)耗竭/清除（荷蘭Liposoma巨噬細(xì)胞清除劑）可切換的 CAR-T 細(xì)胞來進(jìn)一步提高安全性。總之，我們的可切換 CAR 系統(tǒng)可以在保持治療效果的同時(shí)控制 CAR-T 細(xì)胞毒性，從而擴(kuò)大 CAR 靶點(diǎn)的范圍。

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.

論文信息：

論文題目：Improved safety of chimeric antigen receptor T cells indirectly targeting antigens via switchable adapters

期刊名稱：Nature Communications

時(shí)間期卷：15, Article number: 9917 (2024)

在線時(shí)間：2024年11月18日

DOI：doi.org/10.1038/s41467-024-53996-7

產(chǎn)品信息：

貨號(hào)：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes and Control Liposomes

辦事處：Target Technology（靶點(diǎn)科技）

氯膦酸鹽脂質(zhì)體清除巨噬細(xì)胞在嵌合抗原受體T細(xì)胞(CAR-T)模型中心粒細(xì)胞功能研究，荷蘭Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes見刊于Nature Communications：

ClodronateLiposomes清除巨噬細(xì)胞提高嵌合抗原受體T細(xì)胞的安全性的策略研究

Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體的材料和方法：

Macrophage depletion in vivo

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.