Development of a 'humanised' model for renal cancer

开发肾癌“人源化”模型

• 批准号: MR/T024097/1
• 负责人: Sarah Welsh
• 金额: $ 41.02万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT024097%2F1
• 关键词: Development; humanised; model; renal; cancer

Immune checkpoint inhibitors (ICPIs) are a type of cancer treatment that boosts the body's immune system to fight cancer. ICPIs are revolutionising cancer treatment as they can lead to years of control of cancers in up to 50% of patients. However, unfortunately less than 50% of kidney cancer patients benefit from treatment with these costly drugs (1year treatment up to £90,000), yet up to 80% of patients experience side effects relating to 'over-activation' of their immune system which can attack their normal organs. Therefore, there is an urgent need to accurately predict which patients will benefit from treatment whilst providing alternative treatment options for patients who do not. Normally such studies can be performed using laboratory models to prevent patients being unnecessarily exposed to sub-optimal drugs (and combinations) and their side effects, but models for testing ICPIs in kidney cancer are limited as they lack immune cells that work like a human immune system. However, a new genetically engineered mouse has been developed (called a NSG MHC I/II knockout (KO) mouse) which can grow a human immune system when immune cells from patients' blood (called peripheral blood mononuclear cells; PBMCs) are injected into the mouse, to generate a so-called 'humanised' mouse. The goal of my project is to develop a new 'humanised' mouse model for kidney cancer. The specific objectives are:1) To generate 'humanised' mice by injecting PBMCs from kidney cancer patients into NSG MHC I/II KO mice, plus transplant RCC and normal kidney tissue from patients having surgery to remove their kidney cancer to generate a new 'humanised' mouse model for RCC2) To test the new model to determine the extent to which it reflects patient responses by comparing immune and cancer responses in kidney cancer patients vs 'humanised' mice treated with ICPIs3) To provide preliminary (pilot) data for a future large grant (called a Clinician Scientist grant) To do this I will inject PBMCs from kidney cancer patients into the new strain of mice to create 'humanised' mice. I will also implant kidney and normal kidney tissue (obtained when those patients have surgery to remove their kidney cancer) into the mice. This will create the new 'humanised' model for kidney cancer which has both the immune system and kidney cancer that the patient has (acting like an 'avatar'). We will do this for up to 30 patients as some work will be needed to optimise the procedures to make sure that the PBMCs, cancer and normal kidney cells grow properly in the mice. I will then test the model and see how well it mirrors patient responses to ICPI treatment. The mice will be treated with ICPI for 4 weeks and their immune, tumour and normal tissue responses will be compared to the same responses in kidney cancer patients who receive the same drugs in the clinic as part of their normal treatment. This data will form essential pilot data for my future Clinician Scientist application which will aim to fully assess and validate the model with arrange of different drugs for a longer time period. It could then be used to identify the most effective novel therapies and combinations of different drugs (with the least side effects) for kidney cancer patients which can then be tested in clinical trials, rather than testing all treatments and combinations in patients as currently happens. This would save significant time and cost. It could also identify markers from blood or tumours that could predict which patients are likely to respond or have very serious side effects to new treatments so those patients who would not benefit from a particular treatment could be spared treatment or side effects and offered an alternative treatment. The model will also be useful to many academic and commercial researchers worldwide who can use it to streamline drug development (as above) but also to investigate how the immune system interacts with kidney cancer (and vice versa).

免疫检查点抑制剂（ICPIs）是一种癌症治疗方法，可以增强人体的免疫系统以对抗癌症。ICPIs正在彻底改变癌症治疗，因为它们可以在高达50%的患者中控制癌症多年。然而，不幸的是，只有不到50%的肾癌患者从这些昂贵的药物治疗中获益（1年治疗高达9万英镑），但高达80%的患者会出现与免疫系统“过度激活”相关的副作用，这些副作用可能会攻击他们的正常器官。因此，迫切需要准确预测哪些患者将从治疗中受益，同时为不受益的患者提供替代治疗选择。通常，可以使用实验室模型进行此类研究，以防止患者不必要地暴露于次优药物（及其组合）及其副作用，但用于测试肾癌中ICPIs的模型有限，因为它们缺乏像人类免疫系统一样工作的免疫细胞。然而，已经开发出一种新的基因工程小鼠（称为NSG MHC I/II敲除（KO）小鼠），当将来自患者血液的免疫细胞（称为外周血单核细胞; PBMC）注射到小鼠中时，该小鼠可以生长人类免疫系统，以产生所谓的“人源化”小鼠。我的项目的目标是开发一种新的“人源化”肾癌小鼠模型。具体目标是：1）通过将来自肾癌患者的PBMC注射到NSG MHC I/II KO小鼠中来产生“人源化”小鼠，加上移植RCC和来自进行手术以去除其肾癌的患者的正常肾组织，以产生用于RCC的新的“人源化”小鼠模型2）通过比较肾癌患者与用ICPIs治疗的“人源化”小鼠中的免疫和癌症应答来测试新模型以确定其反映患者应答的程度3）为未来的大资助（称为临床科学家资助）提供初步（试点）数据为此，我将来自肾癌患者的PBMC注射到新小鼠品系中以产生“人源化”小鼠。我还将把肾脏和正常的肾脏组织（当这些患者接受手术切除肾癌时获得）植入小鼠体内。这将为肾癌创造新的“人性化”模型，该模型具有患者的免疫系统和肾癌（就像一个“化身”）。我们将为多达30名患者进行这项工作，因为需要进行一些工作来优化程序，以确保PBMC，癌症和正常肾细胞在小鼠中正常生长。然后，我将测试该模型，看看它如何反映病人对ICPI治疗的反应。将用ICPI治疗小鼠4周，并将其免疫、肿瘤和正常组织反应与在诊所接受相同药物作为其正常治疗一部分的肾癌患者的相同反应进行比较。这些数据将为我未来的临床科学家应用程序提供必要的试点数据，该应用程序旨在通过更长时间的不同药物排列来全面评估和验证模型。然后，它可以用于确定最有效的新疗法和不同药物的组合（副作用最小），然后可以在临床试验中进行测试，而不是像目前这样在患者中测试所有治疗和组合。这将节省大量的时间和成本。它还可以识别血液或肿瘤中的标记物，这些标记物可以预测哪些患者可能对新治疗产生反应或产生非常严重的副作用，因此那些无法从特定治疗中受益的患者可以免于治疗或副作用，并提供替代治疗。该模型也将对全球许多学术和商业研究人员有用，他们可以使用它来简化药物开发（如上所述），但也可以研究免疫系统如何与肾癌相互作用（反之亦然）。

项目成果

The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro

• DOI: 10.3390/biology9040074
• 发表时间: 2020-04
• 期刊: Biology
• 作者: R. Al‐Lamki;N. Hudson;J. Bradley;A. Warren;T. Eisen;S. Welsh;Antony C. P. Riddick;Fiach C. O’Mahony;A. Turnbull;T. Powles;A. Reverter;D. Harrison;G. Stewart

The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro.

舒尼替尼治疗肾癌细胞的疗效与体外 PHAX 蛋白有关。

• DOI: 10.17863/cam.51161
• 发表时间: 2020
• 作者: Al-Lamki R

Advantages of multi-arm non-randomised sequentially allocated cohort designs for Phase II oncology trials.

• DOI: 10.1038/s41416-021-01613-5
• 发表时间: 2022-03
• 期刊: British journal of cancer
• 影响因子: 8.8
• 作者: Mossop H;Grayling MJ;Gallagher FA;Welsh SJ;Stewart GD;Wason JMS
• 通讯作者: Wason JMS

Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.

• DOI: 10.1056/nejmoa2103425
• 发表时间: 2021-11-25
• 期刊: The New England journal of medicine