A new paradigm in virus-mediated immunotherapy for liver cancer

人们越来越清楚地认识到，利用我们自身免疫系统的力量，或称“免疫疗法”，可以为治疗其他致命的癌症带来希望。我们的免疫系统通常无法攻击癌症，因为它们是从我们自己的身体发展而来的。因此，免疫疗法欺骗免疫系统，使其忽略了通常会阻止白细胞攻击肿瘤细胞的控制，这种方法最普遍的形式基本上是“停止”我们免疫反应的“刹车”。另一种形式的免疫疗法是“按下免疫反应的加速器”，提供一种刺激，启动我们的白细胞，使它们开始攻击肿瘤。一种方法是使用一种病毒，这种病毒对我们的身体基本上是无害的，但它能够攻击癌细胞，并将它们作为免疫反应的目标。所谓的“溶瘤病毒”正被广泛使用，其中一种最近被批准作为治疗皮肤癌的药物。这种替代形式的免疫疗法是有用的，因为不是每个人都对停止治疗反应良好，原因我们还不完全清楚。我们研究的新颖之处在于，我们对溶瘤病毒进行了治疗，使其不能再在癌细胞内生长，这意味着它必须直接激活免疫反应。我们发现这种“死病毒”对实验性肝癌模型特别有效，特别是当它与肝癌患者在治疗期间已经服用的药物索拉非尼（Sorafenib）结合使用时。寻找治疗肝癌的新方法很重要，因为它是全球癌症相关死亡增长最快的原因。在这项资助的过程中，我们将使用先进的技术来确切地了解我们的死病毒和索拉非尼是如何合作的，并最终说服免疫反应杀死肝癌细胞。我们将比较各种实验系统，并将其与这些药物如何直接影响人类肝组织联系起来，这是我们在伦理许可和同意的情况下获得的，作为外科手术的副产品。这意味着我们的分析与这种疗法对癌症患者的作用有最好的相关性。一旦项目的这一部分完成，我们将通过使用某些抑制性化学物质来测试我们对反应的理解程度，这些化学物质是根据我们的结果精心选择的，以破坏肝癌疾病模型的治疗。最后，我们将使用基因表达数据库和存档的肝癌组织来询问我们的疗法产生的免疫反应的元素是否在肝癌患者中出现，这些患者往往活得更长，或者表明我们已经能够产生一种全新的，有效的抗癌免疫反应。最终，了解如何将我们的死病毒和索拉非尼结合起来杀死肝癌，可能会使未来的患者受益于一种尚未满足临床需求的疾病。

It is becoming increasingly well understood that harnessing the power of our own immune system, or "immunotherapy", can provide hope in the treatment of otherwise deadly cancers. Our immune systems aren't usually able to attack cancers as they develop from our own bodies. Immunotherapy therefore tricks the immune system into ignoring the controls that would normally stop white blood cells from attacking tumour cells, with the most widespread forms of this approach essentially "taking the brakes off" of our immune response.Another form of immunotherapy is instead to "press on the accelerator" of the immune response, providing a stimulus that kick-starts our white blood cells so that they start to attack the tumour. One way of doing this is to use a virus that is essentially harmless to our bodies, but that is capable of attacking cancer cells and highlighting them as targets to the immune response. So-called "oncolytic viruses" are becoming widely used, and one has recently been approved as a drug to treat skin cancer. Having this alternative form of immunotherapy is useful because not everybody responds well to having the brakes taken off, for reasons that we don't fully understand.The novelty of our study is that we have treated our oncolytic virus so that it can no longer grow within the cancer cells, meaning that it must activate the immune response directly. We have found that this "dead virus" works particularly well against experimental models of liver cancer, especially when you combine it with a drug that liver cancer patients already receive during their treatment, known as Sorafenib. Finding new ways of treating liver cancer is important because it is the fastest-growing cause of cancer-related death world-wide.During the course of this grant, we will use advanced techniques to understand exactly how our dead virus and Sorafenib co-operate and ultimately persuade the immune response to kill liver cancer cells. We will compare a variety of experimental systems and relate this to how these agents affect human liver tissue directly, which we obtain under ethical permission and with consent as a by-product of surgical procedures. This means that our analysis has the best possible relevance to how this therapy might act within cancer patients. Once this part of the project is complete, we will test how well we have understood the response by using certain inhibitory chemicals, carefully chosen in light of our results, to disrupt therapy in our disease models of liver cancer. Finally, we will use gene expression databases and archived liver cancer tissue to ask whether elements of the immune response generated by our therapy are seen in liver cancer patients that tend to live longer, or alternatively show that we've been able to generate an entirely novel, effective anti-cancer immune response. Ultimately, understanding how combining our dead virus and Sorafenib kills liver cancer may lead to future patient benefit in a disease of hugely unmet clinical need.