A new paradigm in virus-mediated immunotherapy for liver cancer

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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.