Vyriad is developing the next generation of targeted cancer therapies using engineered viruses that selectively attack cancer cells and ignite robust immune responses to prevent cancer recurrence. I sat down for a fascinating conversation with Stephen Russell, Co-founder and CEO of Vyriad, to hear about this incredible technology and its potential to transform oncology treatment forever.
Please describe your background prior to founding Vyriad.
I originally trained as an MD PhD in the UK at Edinburgh University and the University of London. While I was doing my medical degree, I decided I wanted to use viruses as cancer therapy, so I spent my life really focusing on the engineering of viruses.
I trained as a hematologist. I moved down to London and worked at University College Hospital, then I did my lab training and got a PhD in Engineering viruses at the Royal Marsden Hospital in London. Then I moved up to Cambridge for seven years, working on antibody engineering, displaying antibodies on viruses, and I completed my clinical training. Finally, I moved to Mayo Clinic in Rochester, Minnesota, to build a molecular medicine program, which focused on the engineering of viruses as a cancer therapy.
My lifelong driver has been that if viruses destroy tissue, they can be engineered to specifically destroy tumor tissue. Moving to Mayo was a golden opportunity to build a big program with 10,000 square feet of lab space with eight faculty positions. We built a great program there and generated viruses that looked like they could be used clinically. We engineered the measles virus and the vesicular stomatitis virus, manufactured them, and got all the regulatory approvals to take them into clinical trials. We started looking at what’s the next step for the development of these viruses and that’s when we formed the company to commercially develop these viruses, in 2015.
Prior to Vyriad, we formed another company called Imanis Life Sciences, a service company to provide support to anybody who was trying to develop engineered viruses as a solution for a problem that they might encounter.
Vyriad was able to use Imanis Life Sciences as a support company to provide those laboratory engineering aspects of generating new viruses, testing them, and determining what is worth taking forward for clinical testing. Imanis also assisted with the evaluation of people who were enrolled in clinical trials. We had to monitor whether the virus was persisting in those patients and whether they were generating enough antibodies. A lot of testing had to be done, and Imanis provided a lot of support for that. The two companies have developed in parallel.
What is Vyriad all about?
Vyriad is a drug development company that is developing viruses as cancer therapy, based in Rochester, Minnesota. Vyriad has grown nicely, from it’s seed financing through to its series B financing, the company has probably raised about $100 million from various sources, much of which has been non-dilutive.
We’ve recently taken over a building on the IBM campus in Rochester with about 30,000 square feet of space where we built a facility for GMP manufacturing of viruses. We have wet labs for all the virus engineering activities that Imanis performs. We have a clinical oversight team that manages our multicenter clinical trials, which are conducted using contract research organizations.
We have clinical, manufacturing, and research activities, and general administration. Altogether, we are about 70 people working on the IBM campus at the moment. This growth was partly driven by our partnership with Regeneron, which started exactly 2 years ago, in 2019.
We have a very strong partnership with Regeneron Pharmaceuticals on our lead asset, a vesicular stomatitis virus called Voyager-V1. The virus is engineered to carry two transgenes: one coding for interferon beta, which helps to inflame tumors, and the other coding for the sodium iodide symporter, which enables imaging of the sites that are infected with the virus in a patient, allowing for non-invasive reporting.
In the context of this collaboration, the Voyager-V1 virus is being co-developed with Regeneron. We are now running an ongoing clinical trial, funded by Regeneron, that combines the virus that we developed with Regeneron’s anti-PD1 antibody. That trial is going extremely well.
The other aspect of this collaboration is a strong preclinical effort wherein Regeneron is funding multiple scientists at our company to build new viruses carrying new payloads that are targeted using Regeneron antibodies. Regeneron and Vyriad scientists are working very closely together on that collaboration to generate the next wave of Oncolytic viruses. The Imanis Life Sciences support function is critically important as well.
Please explain oncolytic virotherapy to those who aren’t familiar with it.
We all know that viruses can destroy tissue. The hepatitis virus damages the liver; HIV damages the immune system; Influenza damages the lungs, and so on. If you understand what drives the specificity of these viruses for the different target tissues, then you can begin to change them so that they specifically attack cancerous tissue.
Interestingly, many of the viruses that have been grown in the laboratory over the years have become very good at attacking cancer, even though they’ve been attenuated in respect of their ability to cause disease.
For example, the measles vaccine, which has been given to billions of people safely, is actually quite good at infecting cancer cells and killing them. When it does so, it causes an inflammatory form of killing. If a virus kills a cancer cell, the immune system is very robustly woken up and comes into the tumor to rescue the tissue from the virus infection. In doing so, the immune system better recognizes the tumor and the immune response is amplified. If you then combine that virus therapy with checkpoint inhibitor antibodies, you get a synergistic effect of the two together.
Viruses are a really good complement for checkpoint antibodies which have been transforming the immunotherapy landscape in cancer. Viruses are often cancer-specific because of the way they’ve been grown in the lab, and are able to infect tumors more efficiently than non-tumorous tissue.
Tumors are not well defended against viruses. They try to hide from the immune system. When the virus gets in, the immune system isn’t immediately aware of that, so the virus can spread further in the tumor before the immune system gets woken up.
The other thing you can do with viruses is change them so that they become more selective for tumor cells. Viruses have to bind to a cell before they can go in. You can change that binding specificity to only bind to tumor cells and not the normal cells in the body. There are other tricks that you can use to make the virus selectively or specifically attack cancer cells.
Obviously, all of this is very highly regulated. You have to be certain that the changes you’re making to the viruses can be safely made. I always say you don’t want to teach a virus new tricks. Typically, we remove things from the virus or narrow its focus so that it can only hit the tumor.
It’s a very big field now. 40 years ago, Racaniello and Baltimore discovered that you can recover polio virus from DNA in the lab. That was the beginning of the era of engineering viruses. Nowadays, you can change the genome of just about any virus in a DNA construct, and recover the virus with the corresponding changes.
That technology was more difficult for some classes of viruses than for others, but now, pretty much any virus can be subjected to these changes through reverse genetics systems, where a DNA construct can be used to generate a recombinant virus.
How are viruses administered to patients in immunotherapy?
One virus, a recombinant herpes virus, has been approved for the treatment of melanoma here in the US. It is administered by repeat intratumoral injection that is given every two weeks for a period of six months. That is not the most convenient therapy for patients with cancer because it requires regular attendance for intratumoral injection.
Realizing the full potential of viruses as a cancer therapy depends on the ability to deliver them intravenously and reach multiple metastatic sites of cancer at places where it has spread from its initial primary site.
If you’re administering the virus systemically, you cannot give repeat dosing without running into antiviral antibodies. If you receive an intravenous dose of the virus, you quickly make antibodies to that virus, so the next dose that goes into your bloodstream is neutralized by the antibodies that you’ve made before it can ever reach the target site.
As for the viruses that we are developing, we currently give them as a single injection. They reset things, so a single intravenous dose of the virus will attack the tumor. It probably will not completely eliminate the tumor, but it will certainly do some damage. In doing so, it will activate the anti-tumor immune response, which can be further boosted by giving longer-term therapy with anti PD1 or other immune checkpoint antibodies that will drive that immunotherapy.
How is immunotherapy better than the current standard practice?
The way things are today, many cancer patients are not cured. Mortality from cancer is pretty high. The treatments that we have available are great if the tumor is localized. You cure it with surgery or radiotherapy. But if it spreads more systemically, if there are metastases elsewhere, you’re going to need a more systemic therapy. That’s where chemotherapy and later antibody therapies came in as ways to attack cancers wherever they are in the body, but they ultimately failed in many cases.
Immunotherapy was the next thing that came in. It harnesses the individual’s own immune system to eliminate cancer everywhere. If you can activate the immune system, it will carry on fighting.
The current problem with immunotherapy is that for most cancers, only 15% of patients are going to have a response to immunotherapy. Those patients may or may not be curable, so eventually the immune system will be outwitted by the tumor.
We have given the Voyager-V1 virus to quite a large number of cancer patients and have seen a range of different outcomes; from no response whatsoever to a complete resolution of treatment-refractory disease.
We know that the virus can, as a single intravenous infusion, without anything else given, induce complete or partial remission of treatment refractory cancer. We also know that in the majority of cases, that does not occur. That’s where combination therapies like our program with Regeneron become critically important.
How do you explain such a wide range of outcomes?
We do a lot of preclinical studies to work out how to best combine the drugs, and we take those lessons into the clinic.
You can take a tumor biopsy and do an RNA seq and look at the entire transcriptome to determine which genes are expressed at a high level and which at a low level. That’s one way we’ve been working to try and understand the differences between different tumor types.
We do know from those studies that certain tumors have very significantly impaired antiviral defenses. We know what genes need to be on in order to be in an antiviral state. Some tumors have a strong anti-viral gene signature.
It’s too early to say whether there’s a definitive correlation there, but the early signs are that it’s quite an informative approach to understanding which tumors are going to be susceptible to virus attack, and which tumors are going to be less susceptible.
Another factor that we’ve been studying extensively pre-clinically is that the payload you introduce into the virus can have a very major impact on the magnitude of the immune response that you get in a tumor. In the case of a virus that infects the tumor weakly, and only a few tumor cells get infected, it carries the right payload that may induce a very strong anti-tumor immune response, so even a weak virus infection can be a potent immunotherapy.
There’s a balance there, because you may, by equipping the virus with these immune-activating proteins, diminish its ability to damage tumors. You have to find the right genes to insert into the virus in order to maximize the therapeutic outcome.
What do you think is required in order to standardise this kind of therapies?
I’m optimistic that viruses will be increasingly recognized as a valuable addition to the armamentarium and become much more widely used in the next 10 years or so.
Of course, virus therapy is not the only way forward. There are people developing cancer vaccines and other immune stimulatory agents that are injected into tumors. There’s a great deal of optimism based on preclinical mouse studies, but the transition from mouse to human is often disappointing. It takes a while before you really understand how to best use the drug that you have in humans to make it work.
The regulatory pathway is pretty clear. From a high-level strategic perspective, you have to prove the therapy is beneficial over and above whatever the other therapeutic options are. You can only do that in the context of fairly large randomized clinical trials that prove that the outcomes are better when you combine the virus into the therapy than when you don’t. Alternatively, you can take the type of cancer where there are no real options.
For example, you can take a group of patients who have been heavily pretreated with all known active drugs for that particular type of cancer. You can administer the therapy to them, and if you see tumors shrinking, and the quality of life improving, and you have data on the durability of those responses, then the FDA may accept that and give a provisional approval, provided you can continue to definitively demonstrate the efficacy of your product. That’s how you get into the drug approval position.
Typically, cancer drugs are initially approved for people with advanced treatment-refractory cancer, but then there are additional trials that have to be done to show that they can be beneficial when used as part of frontline therapy.
What I would love to see for the virus that we’re developing is that cancer patients would generally have a single infusion of the virus from the get-go, before they start their immunotherapy. The virus may impact their tumor and will help boost the efficacy of their immunotherapy treatment Protocol. We still have a long way to go to get to that point, but that is our ultimate goal.
