The effect of castrate levels of testosterone on the host immune system: overcoming the limits of immunotherapy in prostate cancer

睾酮去势水平对宿主免疫系统的影响：克服前列腺癌免疫治疗的局限性

• 批准号: MR/X001636/1
• 负责人: Gianmarco Leone
• 金额: $ 40.64万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX001636%2F1
• 关键词: effect; castrate; levels; testosterone; host

1) Scientific/Medical contestProstate cancer is the second cause of cancer death in males in the UK, accounting for around 12000 deaths every year, which means more than 30 men die because of prostate cancer every day. In just under half of the cases, prostate cancer is diagnosed when it has already spread in other parts of the body, especially bones. This means that cancer is now metastatic and it is impossible to radically remove the tumour surgically or with radiotherapy. In this case, the treatment aims to stop or slow down the cancer growth for as long as possible. Hormone therapies are one of the best treatment options for metastatic prostate cancer. These are effective treatments that can control the cancer for many years, but unfortunately in some patients the effect only last for few months, so different approaches are needed. Immunotherapy has been a game-changing treatment for many cancer types, but its efficacy in prostate cancer is limited. It is not clear if the use of hormone therapies changes the immune system so that it prevents the immunotherapy to be effective at least in a specific subgroup of prostate cancer patients.2) What is the research trying to achieve?With this project, we are trying to understand how treatments that block the production of testosterone, which is the main goal of hormone therapies in prostate cancer, alter the immune system. In particular, we want to characterize the several cell subtypes that form the immune system and observe changes in the composition before and after the starting of the treatment. 3) Why is this important?A better understanding on how hormone therapies and the immune system interact between each other will help us develop new treatment strategies involving immunotherapy in prostate cancer. All the clinical trials investigating immunotherapy in prostate cancer have given underwhelming results and in all of them immunotherapy was combined with hormone treatments. Our hypothesis is that we can increase the efficacy of immunotherapy by administering it prior to start hormone treatments.4) Who is carrying out the research?Dr Gianmarco Leone is a clinical research fellow at the UCL Cancer Institute and UCH Macmillan cancer centre in London. He completed his medical degree and oncology training in Italy. He then moved to London as part of the PRIME team. PRIME is an international study funded by AIRC and CRUK, that aims to develop tests to be performed on blood samples that can help monitor prostate cancer. This fellowship will be carried out under the supervision of Professors Gerhardt Attard, who is an internationally recognised scientist at the top of his field and an opinion leader in prostate cancer.5) How is the research to be conducted?This type of analysis is usually performed using tumour biopsies with the aim of studying the immune cells that stay closer to the tumour cells. However, to understand the changes of these cells, we require multiple biopsies from the same patient. This can be particularly stressful for our patients and increases the risk of complications, on top of being expensive and requiring lots of resources from the hospital side. In this project we are going to mainly use immune cells isolated from simple blood samples and we hope to prove that this method can be as informative as the former. We will compare the information obtained analysing immune cells isolated from tumour biopsies to the ones obtained from blood immune cells.

1) 科学/医学竞赛前列腺癌是英国男性癌症死亡的第二大原因，每年约导致12000人死亡，这意味着每天有超过30名男性因前列腺癌死亡。在不到一半的病例中，前列腺癌是在已经扩散到身体其他部位（尤其是骨骼）时才被诊断出来的。这意味着癌症现在已经转移，不可能通过手术或放射疗法彻底切除肿瘤。在这种情况下，治疗的目的是尽可能长时间地阻止或减缓癌症的生长。激素疗法是转移性前列腺癌的最佳治疗选择之一。这些都是有效的治疗方法，可以控制癌症多年，但不幸的是，对某些患者来说，效果只能持续几个月，因此需要不同的方法。免疫疗法对于许多癌症类型来说是一种改变游戏规则的治疗方法，但其在前列腺癌中的疗效有限。目前尚不清楚激素疗法的使用是否会改变免疫系统，从而阻止免疫疗法至少在前列腺癌患者的特定亚组中发挥作用。2) 这项研究试图实现什么目的？通过这个项目，我们试图了解阻止睾酮产生的治疗如何改变免疫系统，睾酮是前列腺癌激素疗法的主要目标。特别是，我们想要表征形成免疫系统的几种细胞亚型，并观察治疗开始前后成分的变化。 3) 为什么这很重要？更好地了解激素疗法和免疫系统如何相互作用将有助于我们开发涉及前列腺癌免疫疗法的新治疗策略。所有调查前列腺癌免疫疗法的临床试验都给出了令人印象深刻的结果，并且所有这些试验都将免疫疗法与激素治疗相结合。我们的假设是，我们可以通过在开始激素治疗之前进行免疫治疗来提高免疫治疗的疗效。4) 谁在进行这项研究？Gianmarco Leone 博士是伦敦大学学院癌症研究所和伦敦 UCH 麦克米伦癌症中心的临床研究员。他在意大利完成了医学学位和肿瘤学培训。随后，他作为 PRIME 团队的一员搬到了伦敦。 PRIME 是一项由 AIRC 和 CRUK 资助的国际研究，旨在开发对血液样本进行的测试，以帮助监测前列腺癌。该奖学金将在 Gerhardt Attard 教授的监督下进行，Gerhardt Attard 教授是国际公认的该领域顶尖科学家，也是前列腺癌领域的意见领袖。5) 研究如何进行？这种类型的分析通常使用肿瘤活检进行，目的是研究与肿瘤细胞更接近的免疫细胞。然而，为了了解这些细胞的变化，我们需要对同一患者进行多次活检。这会给我们的患者带来特别大的压力，并增加并发症的风险，而且费用昂贵且需要医院方面的大量资源。在这个项目中，我们将主要使用从简单的血液样本中分离出的免疫细胞，我们希望证明这种方法可以像前者一样提供丰富的信息。我们将比较分析从肿瘤活检中分离出的免疫细胞所获得的信息与从血液免疫细胞中获得的信息。