A new paradigm in virus-mediated immunotherapy for liver cancer

人们越来越清楚地认识到，利用我们自己的免疫系统的力量，或“免疫疗法”，可以为治疗致命的癌症提供希望。我们的免疫系统通常不能攻击癌症，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，使其忽略通常会阻止白色血细胞攻击肿瘤细胞的控制，这种方法的最广泛形式本质上是“解除”我们的免疫反应的刹车。另一种形式的免疫疗法是“按下免疫反应的加速器”，刺激我们的白色血细胞开始攻击肿瘤。其中一种方法是使用一种对我们身体基本无害的病毒，但这种病毒能够攻击癌细胞并将其作为免疫反应的目标。所谓的“溶瘤病毒”正在被广泛使用，其中一种病毒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，因为并不是每个人都对刹车失灵有很好的反应，原因我们还不完全清楚。我们研究的新奇在于，我们已经处理了溶瘤病毒，使其不再在癌细胞内生长，这意味着它必须直接激活免疫反应。我们发现这种“死病毒”对肝癌实验模型特别有效，特别是当你将其与肝癌患者在治疗期间已经接受的药物（称为索拉非尼）联合收割机结合使用时。寻找治疗肝癌的新方法非常重要，因为它是世界范围内癌症相关死亡增长最快的原因。在此资助期间，我们将使用先进的技术来确切了解我们的死亡病毒和索拉非尼如何合作，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脏组织联系起来，这些药物是在伦理许可和同意下作为外科手术的副产品获得的。这意味着我们的分析与这种疗法如何在癌症患者中发挥作用具有最佳相关性。一旦该项目的这一部分完成，我们将测试我们如何通过使用某些抑制性化学物质来理解这种反应，这些化学物质是根据我们的结果精心选择的，以破坏我们的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治疗产生的免疫反应的元素是否在倾向于活得更长的肝癌患者中看到，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，了解我们的死亡病毒和索拉非尼如何结合杀死肝癌可能会导致未来患者在一个巨大的未满足的临床需求的疾病中受益。

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.