Targeting non-small cell lung cancer with personalised doggybone DNA vaccines (db-PCV)

癌症免疫疗法已经导致了癌症治疗的里程碑式的变化，可以提供长期的无癌生存，甚至可能治愈晚期癌症患者。然而，即使在免疫疗法有效的癌症类型中，如肺癌，也只有少数患者受益。目前最好的工具，如检查点抑制剂，通过“唤醒和激活”癌症反应性免疫细胞来治疗癌症，这些免疫细胞天然存在于癌症组织中，数量足够。我们现在知道，只有20-30%的癌症是这种情况，这也是为什么我们现有的治疗方法似乎已经达到了临床效益的上限的关键原因。克服这一限制的合理方法是训练患者的免疫系统产生更多的T细胞，这些T细胞可以识别和攻击癌细胞。疫苗接种是一种成熟的工具，用于训练免疫系统对新目标变得活跃，越来越多的证据表明疫苗可以成功地用于对抗癌症。非常有希望的免疫攻击目标是突变，它将癌细胞与健康细胞区分开来。现在可以“读出”这些差异，然后将这些突变用作疫苗的模板。在这里，我们将把这种方法与我们在癌症患者中制造和测试DNA疫苗的长期专业知识结合起来。一种新型的DNA疫苗，称为“狗骨DNA疫苗”，将用于为每个病人量身定制新疫苗。这种方法非常快速，将使我们能够及时制造出定制的疫苗。我们将评估在临床实践中，在开始标准免疫疗法（pembrolizumab）治疗晚期肺癌后的几周内生产疫苗的现实性。我们将重点关注肺癌，因为这是最常见的癌症之一，也是大多数晚期疾病患者无法通过手术切除的癌症之一，仍然死于癌症。我们将测试：疫苗是否能激活血液中正确的免疫细胞，以及这些免疫细胞是否能在接种疫苗后进入癌组织并在那里富集。我们将收集有关这种方法安全性的信息，尽管我们不预测我们会引起超出标准免疫疗法的副作用。我们将收集有关疫苗是否改善标准免疫疗法益处的早期信息。如果成功，我们将开展一项更大规模的研究，以调查我们在这里测试的原则是否适用于所有类型的癌症以及处于癌症旅程不同阶段的患者，这可能会导致我们使用免疫疗法的方式发生里程碑式的变化。

Cancer immunotherapy has led to a landmark change in cancer treatment and can offer long term cancer free survival, and possibly a cure, even to patients with advanced cancer. However, even in cancer types, such as lung cancer, where immunotherapy can work, only a minority of patients benefit.The current best tools, such as checkpoint inhibitors, treat cancer by 'waking up and activating' cancer-reactive immune cells that are present in the cancer tissue naturally in sufficient numbers. We now know that this is the case in only about 20-30% of cancers, and this is a critical reason why we appear to have hit a ceiling in clinical benefit with existing treatments.The logical way of overcoming this limitation is by training the patient's immune system to produce more T cells that can recognise and attack cancer cells. Vaccination is a well-established tool for training the immune system to become active against new targets, and a growing body of evidence suggests vaccines can be used successfully against cancer. Very promising targets for immune attack are the mutations, that distinguish cancer cells from healthy cells. It is now possible to 'read out' these differences and then to use these mutations as templates for vaccines. Here we will to bring together this approach with our long-standing expertise in making and testing DNA vaccines in cancer patients. A new type of DNA vaccines, called 'doggybone DNA vaccines' will be used to make a new vaccine tailored for each patient. This method is remarkably rapid and will allow us to make a bespoke vaccine in a timely fashion.We will evaluate how realistic it is in clinical practice to produce a vaccine in a small number of weeks after starting the standard immunotherapy (pembrolizumab) treatment for advanced lung cancer. We will be focussing on lung cancer as this is one of the most common cancers and one where most patients with advanced disease, that cannot be removed by surgery, still die from the cancer. We will test: if the vaccine can activate the right immune cells in the blood, and whether these immune cells can travel to the cancer tissue and become enriched there after vaccination. We will collect information on how safe this approach will be, although we do not predict that we will cause side effects beyond those from the standard immunotherapy. We will collect early information on whether the vaccine improves the benefit of standard immunotherapy. If successful, we will develop a larger study to investigate if the principles we are testing here are applicable to all kinds of cancer and for patients at different steps of their cancer journey, potentially leading to a landmark change in the way we use immunotherapy.