A novel mouse model for checkpoint inhibitor-induced adverse events.
A novel mouse model for checkpoint inhibitor-induced adverse events.
复制标题
DOI：
10.1371/journal.pone.0246168
复制
发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Mor A
中科院分区：
文献类型：
--
作者：
Adam K;Iuga A;Tocheva AS;Mor A
免疫检查点抑制剂在治疗多种癌症中表现出显著的疗效，然而其治疗潜力受到难以理解的免疫相关不良事件的限制。目前，不存在检查点通道诱导不良事件的稳健动物模型。建立这样一个模型将提高我们对这一过程的机械理解，这反过来又将为改进治疗的设计提供信息。我们开发了一种小鼠模型，以确定在存在同源肿瘤的情况下响应于双重检查点阻断的炎症毒性。来自易感遗传背景的小鼠接受腹腔内注射抗小鼠PD-1和CTLA-4抗体。监测小鼠的体重减轻和炎症的组织学证据。采集血液用于基础代谢检查和抗核抗体滴度。同时，小鼠也用泼尼松龙治疗，泼尼松龙通常用于治疗癌症患者中的免疫相关不良事件。在所有遗传背景中，用抗CTLA-4和抗PD-1抗体处理的B6/lpr小鼠发展出更多实质性肝炎、胰腺炎、结肠炎和以免疫细胞的器官浸润为特征的肺炎。发生组织浸润的小鼠表现出高血清葡萄糖水平和高滴度的抗核抗体。最后，虽然给予泼尼松龙预防了炎症不良事件的发生，但它也消除了检出抑制剂的保护性抗肿瘤作用。遗传背景和治疗方式共同改变了荷瘤小鼠的炎症不良事件，表明检查点通道相关炎症的复杂机制。未来的研究将评估其他遗传易感性因素，并将检查其他抗炎药物的可能作用。
Immune checkpoint inhibitors have demonstrated significant efficacy in the treatment of a variety of cancers, however their therapeutic potential is limited by abstruse immune related adverse events. Currently, no robust animal model exists of checkpoint inhibitor-induced adverse events. Establishing such a model will improve our mechanistic understanding of this process, which in turn will inform design of improved therapies. We developed a mouse model to determine inflammatory toxicities in response to dual checkpoint blockade in the presence of syngeneic tumors. Mice from susceptible genetic backgrounds received intraperitoneal injections of anti-mouse PD-1 and CTLA-4 antibodies. The mice were monitored for weight loss and histologic evidence of inflammation. Blood was collected for basic metabolic panels and titers of anti-nuclear antibodies. In parallel, mice were also treated with prednisolone, which is commonly used to treat immune related adverse events among cancer patients. Among all the genetic backgrounds, B6/lpr mice treated with anti-CTLA-4 and anti-PD-1 antibodies developed more substantial hepatitis, pancreatitis, colitis, and pneumonitis characterized by organ infiltration of immune cells. Mice that developed tissue infiltration demonstrated high serum levels of glucose and high titers of anti-nuclear antibodies. Finally, while administration of prednisolone prevented the development of the inflammatory adverse events, it also abrogated the protective anti-tumor effect of the checkout inhibitors. Genetic background and treatment modalities jointly modified the inflammatory adverse events in tumor bearing mice, suggesting a complex mechanism for checkpoint inhibitor-related inflammation. Future studies will assess additional genetic susceptibility factors and will examine possible contributions from the administration of other anti-inflammatory drugs.
登录
查看更多内容
DOI：
10.1097/ppo.0b013e318250c001
发表时间：
2012-05
期刊：
Cancer journal (Sudbury, Mass.)
影响因子：
--
作者：
Iorio MV;Croce CM
通讯作者：
Croce CM
影响因子：
3.7
作者：
Kochupurakkal NM;Kruger AJ;Tripathi S;Zhu B;Adams LT;Rainbow DB;Rossini A;Greiner DL;Sayegh MH;Wicker LS;Guleria I
通讯作者：
Guleria I
影响因子：
8.4
作者：
Ali, Omar Hasan;Berner, Fiamma;Flatz, Lukas
通讯作者：
Flatz, Lukas
影响因子：
3.1
作者：
Matsuya, Taisuke;Nakamura, Yasuhiro;Yamamoto, Akifumi
通讯作者：
Yamamoto, Akifumi
影响因子：
4.6
作者：
Corneth, Odilia B. J.;Schaper, Fleur;Lubberts, Erik
通讯作者：
Lubberts, Erik