A new paradigm in virus-mediated immunotherapy for liver cancer
Lead Research Organisation:
University of Leeds
Department Name: School of Medicine
Abstract
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.
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.
Technical Summary
Oncolytic viruses (OV) are increasingly recognise to achieve anti-cancer efficacy through both cancer-specific replication resulting in cellular lysis, as well as via their pro-inflammatory nature comprising diverse pathogen-associated molecular patterns (PAMP). The balance between how these aspects of OV function result in therapy likely varies according to the virus in question, as well as the tumour against which they are directed.
We have established a new paradigm for OV therapy, whereby uv-inactivated human Orthoreovirus (uv-Reo) achieves superior therapy compared with live virus in preclinical models of hepatocellular carcinoma (HCC). Furthermore, uv-Reo is synergistic with Sorafenib in preclinical models, whereas this is again not the case for live virus. Combined with additional preliminary data, we hypothesise that uv-Reo comprises a unique PAMP, the response to which is enhanced by the immune-specific effects of Sorafenib to achieve cancer-limiting immunity.
We aim to combine transcriptomic, phenotypic and functional analysis of both human and preclinical murine hepatic/immune cells to define the hallmarks of the response to uv-Reo + Sorafenib. This will be undertaken using ex vivo stimulation of fresh human liver tissue combined with refined orthotopic HCC preclinical models capable of incorporating hepatic fibrosis. Processivity will be enabled through use of the Nanostring transcriptomic and Vectra high throughput IHC systems.
Next, we will attempt to validate therapy by blockade of immune-associated kinases, chemokines, or other immune regulators within in vivo models and human liver tissue, with targets determined by preceding transcriptomic, phenotypic and functional analyses. Finally, we will determine retrospectively whether elements of the immunological signatures defined by analysis of successful therapy can be detected in longer-lived HCC patients, or if instead uv-Reo + Sorafenib generates a novel anti-HCC response.
We have established a new paradigm for OV therapy, whereby uv-inactivated human Orthoreovirus (uv-Reo) achieves superior therapy compared with live virus in preclinical models of hepatocellular carcinoma (HCC). Furthermore, uv-Reo is synergistic with Sorafenib in preclinical models, whereas this is again not the case for live virus. Combined with additional preliminary data, we hypothesise that uv-Reo comprises a unique PAMP, the response to which is enhanced by the immune-specific effects of Sorafenib to achieve cancer-limiting immunity.
We aim to combine transcriptomic, phenotypic and functional analysis of both human and preclinical murine hepatic/immune cells to define the hallmarks of the response to uv-Reo + Sorafenib. This will be undertaken using ex vivo stimulation of fresh human liver tissue combined with refined orthotopic HCC preclinical models capable of incorporating hepatic fibrosis. Processivity will be enabled through use of the Nanostring transcriptomic and Vectra high throughput IHC systems.
Next, we will attempt to validate therapy by blockade of immune-associated kinases, chemokines, or other immune regulators within in vivo models and human liver tissue, with targets determined by preceding transcriptomic, phenotypic and functional analyses. Finally, we will determine retrospectively whether elements of the immunological signatures defined by analysis of successful therapy can be detected in longer-lived HCC patients, or if instead uv-Reo + Sorafenib generates a novel anti-HCC response.
Planned Impact
Primary liver cancer, mainly comprising hepatocellular carcinoma (HCC) is the fastest growing cause of cancer deaths worldwide; it is currently ranked 3rd despite only being the 7th most common form of cancer, with over 700 000 deaths reported worldwide in 2008. The vast majority of HCC cases (~70%) are associated with infection by either hepatitis C or B viruses (HCV, HBV), with lifestyle choices, particularly alcohol increasingly apparent. UK HCC incidence has tripled since 1975, due primarily to an increase in HCV seroprevalence, currently estimated at ~0.5 million. The UK 5 yr survival rate for HCC is less than 5%, reflecting the fact that the majority of tumours are discovered after the stage when potentially curative surgical intervention is advised.
Treatment for advanced HCC is largely ineffective, with best results achieved from hepatectomy followed by transplant, although only a minority of tumours are treated this way. Conventional chemotherapy and other interventions (e.g. TACE) generally provide only palliative benefit. The tyrosine kinase inhibitor (TKI) Sorafenib remains the first line treatment for non-resectable HCC, yet generally only extends life by a matter of months and is associated with often severe toxicity leading to dose reductions or cessation in many cases.
Sorafenib was only recently approved by NICE for the treatment of advanced HCC after many years of rejection and availability solely via the controversial "cancer drugs fund", established by the former coalition government. Approval was conditional upon a considerable discount from the $69000 pa list price from Bayer. Indeed, in 2014, the Bayer CEO was quoted as saying that Nexavar (Sorafenib trade name) is for "western patients who can afford it" in response to an Indian company's bid to manufacture a generic version of the medicine. Thus, any means by which the benefit of Sorafenib might be improved is of high priority.
Our research, if successful will provide a much-needed new avenue by which to develop new therapies for HCC which, importantly, synergises with Sorafenib. In addition, limited trials using immune checkpoint inhibitors for HCC show some promise, and again will potentially be complementary to the therapeutic potency of uv-Reo + Sorafenib. Finally, our functional and gene expression analyses may provide further additional targets that could be exploited for HCC therapy via drug repurposing or novel agents under development for other tumours.
Treatment for advanced HCC is largely ineffective, with best results achieved from hepatectomy followed by transplant, although only a minority of tumours are treated this way. Conventional chemotherapy and other interventions (e.g. TACE) generally provide only palliative benefit. The tyrosine kinase inhibitor (TKI) Sorafenib remains the first line treatment for non-resectable HCC, yet generally only extends life by a matter of months and is associated with often severe toxicity leading to dose reductions or cessation in many cases.
Sorafenib was only recently approved by NICE for the treatment of advanced HCC after many years of rejection and availability solely via the controversial "cancer drugs fund", established by the former coalition government. Approval was conditional upon a considerable discount from the $69000 pa list price from Bayer. Indeed, in 2014, the Bayer CEO was quoted as saying that Nexavar (Sorafenib trade name) is for "western patients who can afford it" in response to an Indian company's bid to manufacture a generic version of the medicine. Thus, any means by which the benefit of Sorafenib might be improved is of high priority.
Our research, if successful will provide a much-needed new avenue by which to develop new therapies for HCC which, importantly, synergises with Sorafenib. In addition, limited trials using immune checkpoint inhibitors for HCC show some promise, and again will potentially be complementary to the therapeutic potency of uv-Reo + Sorafenib. Finally, our functional and gene expression analyses may provide further additional targets that could be exploited for HCC therapy via drug repurposing or novel agents under development for other tumours.
