When we think of viruses, we often think of diseases, pandemics and death. Our impression of viruses is that they are “bad”. But viruses could also be a possible cure for the deadliest disease in modern history: cancer. The therapeutic effects of “good” cancer-killing oncolytic viruses have been documented over a century ago. Records from as early as 1904 described a 42-year old woman with acute leukemia who experienced temporary remission after an influenza infection. Other early reports showed spontaneous remission of Hodgkin lymphoma and Burkitt’s lymphoma after natural infections with the measles virus.
Despite the long history, oncolytic viruses have only recently gained momentum in the scientific community. Dr. Aldo Pourchet, CSO and co-founder of Omios Biologics—a biotech startup in the San Francisco Bay area—is determined to harness the power of oncolytic viruses to develop a new generation of cancer immunotherapy.
How Oncolytic Viruses Work
“One thing that we know for sure is that you need the immune system to fight the cancer,” says Pourchet. “You need to recruit the immune system, and probably the best thing we know for recruiting the immune system is viruses. Our immune system evolved to detect them immediately. That’s why we are still on Earth. It’s because we have been able to fight deadly viruses.”
When oncolytic viruses are introduced into tumors, two things happen. First, the viruses begin replicating and killing the cancer cells, which is a direct lytic effect. Next, the cell killing triggers an inflammatory response, recruiting our own immune cells to destroy the cancer cells. Our immune system now recognizes the tumor antigen as an enemy and will be able to find and destroy metastasis that occur anywhere else in the body. In this sense, oncolytic viruses work just like vaccines.
“Viruses are amazing at dealing with the immune system. They developed function to control, modulate, influence the immune system and are a great reservoir of function,” says Pourchet. “So what can viruses give us? They’re going to give us a lot of tools to manipulate our immune system and make our immune response more efficient. Our immune system can get rid of cancer. We just have to help it.”
A Better in vitro Model Platform
Although oncolytic viruses show great potential for cancer therapy, Pourchet believes that the lack of a good model platform has been a huge obstacle for the field. Viruses behave differently in different species, so using animal models, such as mice, would not generate results entirely relevant to humans. To move forward, they needed a more complex in vitro model that uses human cells and integrates the human immune response. This was the first thing that Pourchet wanted to achieve.
To enable the large-scale study of oncolytic viruses, Pourchet’s team has built an in vitro platform that integrates the primary events of human immune responses and extracellular responses, including cytokines and other secreted factors. Early events that lead to the priming of the immune system are important to Pourchet because he believes that the therapy will be most efficient by acting very early on.
Of course, the platform would be useless without good, quantitative cell-based assays for measuring various biomarkers to evaluate the effectiveness of treatment. “Immunotherapy is a chain of events. It’s complex and evolves over time. To study complex biological processes, one approach is to combine multiple assays and to do that in a clever way. These assays need to be fast, easy, reliable and quantifiable,” says Pourchet.
Assays for Real-Time Monitoring of Cellular Responses
One outcome of the oncolytic virus treatment that Pourchet want to measure is immunogenic cell death, the process that cancer cells undergo when they die. An important biomarker for measuring immunogenic cell death is the release of extracellular ATP (eATP). There are many existing methods for measuring eATP, but most of them can only measure one time point, meaning that you could miss the precise timing of when immunogenic cell death occurs. What Pourchet needed was an assay that could continuously measure eATP over time. With help from Promega representatives, he found the perfect assay for his needs: the RealTime-Glo™ Extracellular ATP Assay, which uses bioluminescence to kinetically monitor ATP release. Using this assay, he was able to determine the timing of when immunogenic cell death begins and the duration of the effect.
The therapeutic effect of oncolytic viruses can happen in just a day or two, and changes occur every minute. Therefore, precise monitoring of cellular responses over time is essential when developing this type of immunotherapy. “The real-time monitoring you can have with the Promega assays is something that is absolutely necessary,” says Pourchet. “When you look too late and with just one time point, you do not see the same thing.” Besides the extracellular ATP assay, Promega has a whole portfolio of live-cell kinetic assays that allow continuous measurement of the same sample plate over time. These assays are based on highly sensitive and quantitative bioluminescent technology, with simple add-mix-measure protocols. “I’m a big fan of using luciferase technology for drug development and immunotherapy. As a startup, you don’t have so much time. You are under pressure. If you have a reliable product that you can directly use, that’s great!” says Pourchet.
The Future of Immunotherapy
Pourchet believes the next step for developing more effective oncolytic viruses is to make them better at recruiting our own immune system and make immunomodulation the central strategy for cancer therapy. New, complex in vitro human models and cell-based assays are key to achieving this goal. “I think that now with new tools, new assays, and new models, we are accelerating this research,” says Pourchet. “It’s a great time for oncolytic viruses. I think that they are going to be the best therapy against cancer.”
Larson, C. et al. (2015) Going viral: a review of replication-selective oncolytic adenoviruses. Oncotarget. 6: 19976-19989