Stephen J. Russell, MD, PhD

Stephen J. Russell, MD, PhD, moved from the United Kingdom to the Mayo Clinic more than 20 years ago and has never looked back. He is a Professor of Medicine at Mayo and also President and CEO of Vyriad. His passion remains oncolytic virotherapy. Some remarkable successes in the clinic give Russell—and his commercial and pharmaceutical partners, including Regeneron—the belief that this can become an increasingly important aspect of cancer therapy.

Kevin Davies recently spoke to Russell – who is also serving as the 2021 president of the American Society of Gene & Cell Therapy — about his passage to America, his research and clinical successes, and his hopes for the future of oncolytic virotherapy. (This interview has been lightly edited for length and clarity.)

GEN Edge: When did you come over to the United States? Clearly you have resisted any temptation to go back.

Stephen Russell: I graduated from Edinburgh University back in 1982. I decided while I was at medical school that I wanted to use viruses to treat cancer—that has been a lifelong passion… After I got my PhD, I moved to Cambridge into Greg Winter’s laboratory and completed my hematology training there. I became a consultant hematologist and got a laboratory of my own in the Center for Protein Engineering. I was hell bent on staying in the United Kingdom and building my career at Cambridge…

Then I got a call from Mayo Clinic saying we have this big new program in molecular medicine that we would like to build. We have seven faculty positions to fill, 10,000 square feet of laboratory space negotiated by previous (candidates) who decided not to go. I think they were scraping the barrel, but anyway, they asked me, do you want to come and direct the program? Given that I wanted to do oncolytic viruses in a translational mode, they were throwing down the gauntlet. I absolutely had to come. It was a phenomenal opportunity, a wonderful move [in 1998].

GEN Edge: You mentioned oncolytic viruses. What got you switched on to knowing that that was what you wanted to do?

Russell: It was in medical school. I had just been told after my microbiology final examination in the third year that I was coming back for a distinction oral—and the following day I got a phone call to say to my sister had died in a house fire. I went home on the train from Edinburgh to the south coast and I just lost myself in virology because I needed something to take my mind off what had happened. I realized, just reading about viruses, that it was the last untapped bioresource. We should use them to destroy something we need to get rid of. I decided I am going to do viruses for cancer. Once you realize the destructive power of viruses can potentially be harnessed, it is quite addictive.

The whole idea of oncolytic virotherapy is that viruses destroy different tissues. For HIV, it is the immune system; hepatitis, the liver; encephalitis, the brain. What is the basis of that tissue tropism and can you engineer viruses to make them highly specific for tumors? It turns out you can. The targeting strategies that you can use are not just at the level of entry, which is targeting viruses by antibody display on surface proteins (engineered to destroy their natural binding), where we have had a lot of success. They can also be targeted inside the infected cells, where they are good biosensors because, once the viral genome is inside the tumor cell, it can register whether appropriate transcription factors are available, or other parameters needed to complete its life cycle.

We also developed a micro-RNA targeting strategy—if you have a virus that damages normal tissue, and you want to remove that tropism, then you can stitch into the viral genome a micro-RNA target, such that the genome is destroyed in the tissue you do not want to damage. We did it first for a picornavirus, with a muscle tropism that we wanted to get rid of, and there are plenty of muscle-specific micro-RNAs. So targeting is absolutely central to the whole oncolytic virotherapy field.

GEN Edge: What are one or two of the most successful examples of oncolytic virotherapy?

Russell: The biggest event in my life as an oncolytic virotherapy person was a patient named Stacy Erholtz, whom we treated at the Mayo Clinic 7 years ago with a measles virus. She had multiple myeloma, she had had two stem cell transplants, and she was resistant to all available myeloma therapy. She had rapidly relapsing disease after a second transplant and a large tumor on her forehead. Her PET-CT (positron emission computed tomography) scan showed four other tumors and she had diffuse infiltration of her bone marrow.

We gave her a single infusion of this oncolytic measles virus at the top dose level—it was a very high dose 1×1011. Within a few days, she noticed that the tumor on her forehead was disappearing. She went into complete remission and remains in complete remission today, seven and a half years out. That illustrated that with oncolytic virotherapy, you can hit disseminated disease targets by intravenous administration of a virus. And you can get rid of diffuse infiltrating disease in the bone marrow and it can be durable.

We were very excited when we achieved that and thought “Aha, we’ve unlocked the secret to this.” We have subsequently discovered that it is not so easy — there were some special things about Stacy that led to her responding. One factor was she had no anti-measles antibodies in her bloodstream… She did, however, have anti-measles T cells, and so the virus could get to the tumor and the anti-measles T cells could then enhance the immune response to those infected tumor cells. Also, when we compared her with other myeloma patients, she had a higher mutational burden than the vast majority of myeloma patients that were in the public databases.

We think that high neo-antigen burden was probably contributory. When you give oncolytics, it is a two-stage therapy. Stage one is the virus infects and kills tumor cells—inflammatory killing. Step two is that you get long-term immune control because you have amplified the tumor-specific cytotoxic T lymphocytes in the context of that reaction against the virus.

GEN Edge: The case study that you just mentioned, was that published?

Russell: We put it in the Mayo Clinic Proceedings.1 We submitted (the article), while we had two patients who responded, to the New England Journal of Medicine. They came back saying, “we want a third patient.” Given I was working at Mayo Clinic, I thought, let us put this in Mayo Clinic Proceedings. It was probably one of the biggest media events that Mayo Clinic had had. The attention that it attracted was phenomenal, which made it all the more dismaying that we could not just repeat it…

I think systemic oncolytic virotherapy is where we need to get to. Because of the anti-measles antibodies we moved to the vesicular stomatitis virus (VSV). It is a virus that causes a blistering illness in hoofed animals. It is endemic in Central America and the southern United States. Most people have no pre-existing exposure or antibody and you can easily grow it to high titer. We shifted our attention to that virus and we have been running it in intravenous clinical trials. It is starting to look very promising. We have unpublished data—we have a complete remission and a very deep partial remission in some patients.

GEN Edge: Have there been other successful clinical treatments during the past 5 or 10 years?

Russell: There is very little on systemic—I am not aware of other comparable cases. As I said, last year we had a patient that we treated with VSV who had extensive treatment refractory disease, who went into complete remission and remains in complete remission almost a year out from therapy. We think we are back there, but we had to take a deep dive and develop the VSV as a therapy and then go through the dose escalation. I have not seen comparable results from others. I think most of the success has been with intra-tumoral delivery and in the context of melanoma where it is an immunogenic tumor.

GEN Edge: Does oncolytic virotherapy have the chance to become a bigger and bigger part of the oncologist’s armory?

Russell: There is massive interest in it from big pharma at the moment. The hunt is on for something that can be used fairly generically in combination with checkpoint inhibitor antibodies. If you think about all the different approaches that have been taken in combination therapies, many of them are intratumoral delivery of something that inflames the tumor. The idea is, if you can inflame tumors then the checkpoint inhibitor antibodies are going to have something to work on, because you will have a lot of T cells.

So what is the best innate agonist or vaccine approach? If you think about oncolytic virotherapy it can come in destroy tumor cells and provoke a response against unknown tumor antigens. So it is an antigen-agnostic vaccine that can be used in conjunction with checkpoint inhibitor antibodies. That is really where everybody is going—all the pharma companies that have bought or entered into collaboration with oncolytic virotherapy companies, it is because of that.

At Vyriad, we have a major partnership with Regeneron Pharmaceuticals and a multicenter multi-indication phase II clinical trial combining intravenous VSV coding for interferon beta and NIS, in combination with the anti-PD1 antibody. So far, so good—it is looking pretty promising. The combinations are synergistic between the virus and the checkpoints preclinically. That study got underway fairly recently. We have 10–12 patients accrued so far out of a total expected of 140.

GEN Edge: You are President and CEO of Vyriad. Why did you launch the company?

Russell: I’ve spent my life in academic medicine until the launch of Vyriad. I have been committed to developing oncolytic virotherapy, no matter what it takes. At Mayo Clinic in the academic environment it could go so far—we could make lots of different viral constructs, test in mouse models, take through manufacturing on a small scale, and start local clinical trials. But accrual would always be slow because it is a single center.

Mayo was never going to become a pharmaceutical company and start developing product. We knew we needed a company. Mayo changed the rules back in 2013 about faculty getting involved in companies, starting an employee entrepreneurship program. As soon as they fired that starting gun, I was on it, because I have been desperate to get involved in that way.

We were able to put the technologies that we were developing at Mayo Clinic into the Vyriad and start thinking about multicenter clinical trials and moving things more aggressively. For me it has been a real eye opener to understand how things really work. In academic research you are often working on something to get it into the clinic. But you do not really think beyond that. There is so much more that has to happen for a product to finally get approved.

GEN Edge: Is Regeneron your biggest partnership to date?

Russell: Yes. It is a substantial partnership—we finally signed the Regeneron contract in October 2019, after a 2-year negotiation. It is a very strong collaboration with two components to it—this multicenter clinical trial that combines their antibody with our virus. There are frequent meetings to discuss how that is going, whether to add new arms, what indications we are chasing down.

Then there is a preclinical component in which we are engineering new configurations of VSV. It is so much bigger than anything I ever did in academia, because they have huge scientific firepower at their headquarters. They have a lot of their scientists working on this, we have 15 scientists working on it on our end. It is a very different approach to the development of the new oncolytics. By having the scale, you march through everything, nothing is left to chance. Any question that anyone raises leads to another animal experiment, defining things mechanistically. I have been impressed with the next-level science that it is taking me into.

This interview is adapted from Human Gene Therapy (February 2021).