MICA: Upregulation of innate immunity in the tumour microenvironment of oesophageal cancer using oncolytic virus therapy with immunotherapy

食管癌是一种高度侵袭性的癌症，五年生存率为15%。有两种主要的亚型，鳞状细胞癌和腺癌。这项研究的重点是食管腺癌，因为它是英国最常见的形式。目前的治疗方法是在手术前使用化疗和/或放疗来试图治愈这种疾病。尽管这些治疗方法取得了进展，但患者的结局仍然没有显著变化。免疫疗法为改变这些结果打开了大门。到目前为止，我们在其他癌症中看到了非常好的反应，如黑色素瘤和头颈癌，但食管癌的结果相对令人失望。我们希望增加我们对食管癌中发生的免疫反应的理解，以及我们如何改善这一点以造福患者。使用手术中收集的样本，我们将使用尖端的成像技术，多光谱免疫组织化学，来检查食管腺癌的肿瘤微环境，特别是观察肿瘤内发现的免疫细胞的数量和相互作用。我们希望我们从研究的第一部分获得的知识将使我们能够确定我们需要增加哪些免疫细胞类型的活性，以便我们的治疗将改善对食管癌的免疫反应。我们的实验室专门研究使用溶瘤病毒（“癌症杀伤”）来增加肿瘤的免疫反应，因此我们的第二个实验将使用溶瘤病毒选择性地感染和杀死肿瘤，同时不影响正常的食管组织。我们设计了一种新的联合免疫治疗策略，直接给予肿瘤本身，这将增强溶瘤病毒的作用。这种“肿瘤内免疫疗法”使用癌症作为对抗自身的疫苗，这意味着免疫系统被激活以摧毁以前无法对抗的肿瘤。肿瘤内免疫疗法还有其他优点，因为我们可以给予更高剂量的药物，因为它们在局部起作用，导致更少的副作用。一旦免疫系统被训练来杀死原发性肿瘤，它就应该在身体其他地方寻找疾病，而不需要进一步的治疗。我们的联合治疗利用溶瘤性单纯疱疹病毒-1（HSV-1）与新型免疫刺激剂（IL-15超激动剂，N-803）和免疫检查点阻断剂（抗程序性死亡-1，抗PD-1）。N-803已被证明可以增加其他肿瘤中自然杀伤细胞和效应T细胞（两者都可以杀死癌症）的水平。免疫检查点阻断剂阻止了许多肿瘤抑制这些免疫细胞破坏它们的机制，以前的工作表明，这种机制在溶瘤病毒感染后上调。我们与德国的一个研究小组建立了新的合作关系，该研究小组创造了世界上第一个食管腺癌小鼠模型。这将使我们能够在小鼠中测试我们的免疫治疗策略。我们将研究HSV-1感染对小鼠食管腺癌细胞的影响。然后，我们将使用我们的- HSV-1，N-803和抗PD-1抗体的三联免疫疗法来治疗小鼠食管肿瘤。由于本研究中使用的所有药物以前都已安全地用于患者，因此这种联合肿瘤内免疫疗法将来可以转化为人体临床试验。

Oesophageal cancer is a highly aggressive cancer with five year survival rates of 15%. There are two main subtypes, squamous cell cancer and adenocarcinoma. This study is focussed on Oesophageal Adenocarcinoma as it is the commonest form in the UK. Current treatment uses chemotherapy and/or radiotherapy prior to surgery to try to cure the disease. Despite advances in these treatments there has still been no significant change in patients' outcomes. Immunotherapy opens the door to changing these results. So far, we have seen very good responses in other cancers, such as melanoma, and head and neck cancer, however results in Oesophageal cancer have been relatively disappointing. We are looking to increase our understanding of the immune reaction that occurs in Oesophageal cancer and how we can improve this to benefit patients.Using samples collected at surgery, we will use a cutting-edge imaging technique, multispectral immunohistochemistry, to examine the tumour microenvironment of Oesophageal Adenocarcinoma, specifically looking at the number and interactions of immune cells found within the tumour. We are hopeful that the knowledge that we gain from the first part of the study will allow us to identify which immune cell types we need to increase the activity of, so that our treatment will create an improved immune response to Oesophageal cancer. Our laboratory specialises in the use of oncolytic ("cancer killing") viruses to increase the immune reaction in tumours and so our second experiment will look to selectively infect and kill the tumour using an oncolytic virus whilst not affecting the normal oesophageal tissue. We have designed a novel combination immunotherapy strategy which is given directly into the tumour itself which will augment the action of the oncolytic virus. This "intratumoural immunotherapy" uses the cancer as a vaccine against itself, meaning the immune system is activated to destroy the tumour that it was previously unable to fight. There are other advantages to intratumoural immunotherapy in that we can give higher doses of drugs, which since they are acting locally, cause fewer side effects. Once the immune system is trained to kill the primary tumour it should then hunt down disease elsewhere in the body without the need for further treatments. Our combination therapy utilises the oncolytic Herpes Simplex virus-1 (HSV-1) with a novel immune stimulating agent (IL-15 Superagonist, N-803) and an immune checkpoint blocker (anti-Programmed Death-1, anti-PD-1). N-803 has been shown to increase the levels of natural killer cells as well as effector T Cells (which both kill the cancer) in other tumours. Immune checkpoint blockers stop the mechanism by which many tumours inhibit these immune cells from destroying them and previous work has shown that this mechanism is upregulated after oncolytic virus infection. We have setup a new collaboration with a research team based in Germany who have created the first mouse model of Oesophageal Adenocarcinoma in the world. This will allow us to test our immunotherapy strategy in mice. We will examine the effect that HSV-1 infection has on cells of mouse Oesophageal Adenocarcinoma. Then we will use our triple combination immunotherapy of - HSV-1, N-803 and anti-PD-1 antibody to treat Oesophageal tumours in mice. As all the agents used in this study have been safely used in patients previously, this combination intratumoural immunotherapy could be translated to a human clinical trial in the future.