The Bioinformatics CRO Podcast

Transcript of Episode 30: Matthias Gromeier

Disclaimer: Transcripts may contain errors.

Grace Ratley: [00:00:00] Welcome to The Bioinformatics CRO Podcast. My name is Grace Ratley and I’m your host for today’s show. And today I’m joined by Dr. Matthias Gromeier from Duke University. Matthias is a professor of neurosurgery and molecular genetics and microbiology at Duke. His lab studies viral cancer immunotherapies. Welcome, Matthias.

Matthias Gromeier: [00:00:19] Hello. Grateful to join you.

Grace Ratley: [00:00:21] We’re excited to have you on here. So let’s go ahead and talk a little bit about your science, because this is something that’s really cutting edge, really exciting. It has been featured on 60 Minutes two times, I believe, and it was awarded a breakthrough designation. Correct?

Matthias Gromeier: [00:00:37] Yeah. So FDA administrative action for cancer therapies, most commonly for therapies against devastating disease that show extraordinary promise.

Grace Ratley: [00:00:45] So tell us a little bit about what you’ve created.

Matthias Gromeier: [00:00:50] Yes. So even for me, it’s sometimes hard to realize just how long I’ve been doing this. So the agent we’re working with, it’s a very interesting form of the poliovirus vaccine. If you’re older than 20, that’s the very poliovirus vaccine we got as children. And I made this. This was part of a really nerdy lab experiment, very basic, just we wanted to see if it can be done in 1994. And so ever since I’ve been working on making this into a form of cancer immunotherapy. Because I’ve been doing this so long, this strategy has morphed into something completely different than what I thought it was at the beginning and actually something much better that I thought it was at the beginning. And it doesn’t have so much to do with myself, but with what’s happened outside. So there were some major breakthroughs in immunology and virology and cancer research and cancer immunotherapy research, and it all came together. It’s the purpose of my life, I could say, to make this happen. We are a very exciting stage and it was quite a journey to get to this point.

Grace Ratley: [00:01:56] Yeah. So the agent you’re working with is a polio vaccine and it’s called PVS-RIPO, if our listeners want to look into it and it’s very interesting. So it’s the poliovirus. And then you edited out some of the infectious RNA and you replaced it with a rhinovirus. So what exactly does this virus target in the body?

Matthias Gromeier: [00:02:19] Yeah. So what this recombinant is so you described it correctly. So it has the genome of what we call the oral poliovirus vaccine that was used until roughly the year 2000 in the US, is still being used in many parts of the world. So the family of viruses, that poliovirus belongs to the picornaviruses, they use a very, very sophisticated and really genial strategy to do their replication strategy, and they use a particular important genetic element that sits in their genome called Internal Ribosome Entry Site or IRES. I call it the transmission of the virus. So this is really what makes the virus succeed. And what we did, we gave the poliovirus vaccine the corresponding portion of a rhinovirus. These are related viruses. They both have these elements. They use them in the same way. But these viruses function very differently. And so we basically have now a polio vaccine with a rhinovirus transmission. The really beautiful part of this is that the virus doesn’t mind. It’s very difficult when you’re so polarized is an RNA virus just like coronaviruses is. And what we’re experiencing right now, these viruses like to mutate a lot. So whenever you design a recombinant RNA virus for a therapy purpose, you have to worry about what this virus will become. They like to change and adapt and this virus doesn’t. It’s perfectly happy with what it is. And that’s really interesting because what it has become is a truly remarkable type of virus that’s very different from what poliovirus naturally is.

[00:03:54] It’s actually more something what a rhinovirus would do. So when I started out, poliovirus was, it is a very well studied virus. However, there are some very important gaps in our knowledge and they have been filled in gradually in the last few decades. And what we realized the biggest change in my career scientifically was when we realized that poliovirus doesn’t actually target the type of cell we thought it did. So much of the research on poliovirus has focused on the brain or on the central nervous system because that’s what the disease polio causes, paralytic poliomyelitis. That’s a disease in the spinal cord. So people looked in the spinal cord to study polio. And that’s unfortunate because this is not the primary playground, if you want, of the virus. This is more an accidental site of the infection. So the virus really lives in the gastrointestinal system. And there was a very beautiful, very, very well done study published in monkeys where people for the first time looked where the virus actually goes to, in the gastrointestinal system. Nobody else had done this before. And I saw this paper. I stumbled over this and I literally fell out of the chair in my office because what we saw was that the virus targets a type of cell with very high priority that we were not really aware of.

[00:05:16] And those are cells, myeloid cells, antigen presenting cells, macrophages and dendritic cells. This is not such a rare thing with viruses, but for poliovirus was completely unknown how important this was in a living being. And it has really shaped my view of the virus. I think it should make everybody think again when they look at these types of viruses. So for our cancer immunotherapy strategy, this changed everything because before that we had primarily regarded the virus as an agent that would infect cancerous cells. But now we realized that probably the main target we should look at are actually myeloid cells, antigen presenting cells. So these are macrophages, dendritic cells and microglia in the brain because these are the cells the virus obviously prefers to grow in. And for immunotherapy, this is a very, very momentous finding because these are the very cells, antigen presenting cells as the name say, that you need to engage for cancer immunotherapy. So this was really a turning point in my career. After this, I have become an immunologist, which I’m still not, but I’m moving in that direction. And again, so it’s remarkable how this was completely out of my work. There was the work of others. If they hadn’t done this primate study, we would never have known. So it was truly remarkable that the study done by others has turned view of our work completely upside down.

Grace Ratley: [00:06:48] It’s amazing how collaborative science can be and how serendipitous as well. Yeah. So let’s talk a little bit about how this virus is used as a cancer therapeutic. Can you tell us a little bit about the cancers that it targets and how it goes about killing these cancers.

Matthias Gromeier: [00:07:05] In cancer research, it’s probably easy to imagine why most people are obsessed with targeting the cancer cells themselves. They are the problem and we need to know how they are behaving. What are they doing? What are they like? Let’s hit them. Let’s somehow target the neoplastic cells because they are the problem. And if you work in cancer research, you intuitively lean towards this view. And here at Duke, we had a visitor James Allison, I think 2018 Nobel Prize laureate for the discovery of immune checkpoint blockade and cancer immunotherapy in general. And he gave a lecture here, and I will never forget this. The first sentence in his talk was I transformed cancer care forever and my drug doesn’t even target the cancer. So it’s true. And I just told you how we realized the past 6 or 7 years that maybe our virus really targets myeloid cells more than cancer cells themselves. And in a way, this is the breakthrough to success. So once you stop obsessing about the cancer cells themselves and open yourself up to the bigger picture, I think you are up to something promising. So most people regard cancer as an accumulation of cancerous cells or bad cells that sit in a big lump. That’s very far from the truth. So in many cancers, the cancer I’m mostly interested in glioblastoma is the case, the neoplastic cells. So the malignant cells are actually in the minority. So much of what the tumor is composed of are cells other than malignant cells.

[00:08:43] So you have blood vessel cells, fibroblasts and different things. And the number one cell, at least for glioblastoma and a very important cells for all cancers are myeloid cells. So macrophages mostly, and various shapes of antigen presenting cells that sit in the tumor and the important part is that the tumor cannot live without these non cancerous parts inside it. So it needs a supportive nest of non cancer cells. And these are cells that live in our body and they are being corrupted by the tumor to do its bidding. They’re recruited into the tumor site and they begin under the influence of the cancer to act and the cancer’s interest, if you want, for the most part. And so these cells they often referred to as stroma or tumor microenvironment. So the entirety of the stuff inside a tumor that’s not cancerous. And this is much more in terms of mass or number of cells. This is much more important than the cancerous cells themselves. So it follows that why not target this comfortable nest? These tumors build themselves rather than the cancerous cells themselves. And this has many advantages because the biggest problem in cancer, especially my research targets these horrible killer cancers where nothing works. So these cancers are known to be so heterogeneous, meaning that virtually every cancer cell has its own private genetic code. They have very specific biochemical anomalies. So it’s like a snowflake situation where you have this terrible, heterogeneous population of cancer cells. So in this situation, it’s very difficult to decide what to even target because if every cancer cell is different, how can you know what you should go after? So in that sense, it’s much more simple in a way to think about the non cancerous parts, because these are for the most part, cells that behave pretty normally.

[00:10:47] They’re not malignant, so it’s not an easy target, but they’re more well behaved if you want. So we learned that through our work spanning all these years that the tumor microenvironment really is what our virus targets. Now, PVS-RIPO does infect, malignant cells, too. It can replicate in these malignant cells. It can kill them. And we believe that infection of the cancerous cells and damage of cancerous cells and possibly also killing is part of our strategy. But it’s just one component that contributes to a much bigger series of events. But killing the cancer cells with the virus itself is not the objective of our therapy. So the more important mechanisms that what our virus does and we know this from important animal studies that were recently published and some that are coming out soon hopefully, that it’s the inflammatory wave that is created when the virus infects the non cancerous cells and the tumor. And based on our study, the number one cell by far that’s targeted by the virus are the macrophages inside the tumor, which makes sense because we know from this monkey gastrointestinal work that it is those cells that the virus naturally prefers. So it makes sense that in the tumor it would do the same thing.

Grace Ratley: [00:12:16] Yeah. This concept of activating the immune system in order to generate anticancer effects. I mean, it’s not necessarily a new idea. Observations even back in like the 1800s where people had cancers and they had some sort of infection like influenza infection, where their immune system was stimulated in such a way that it ended up killing the cancers within their bodies. Can you maybe speak a little bit to other forms of immunostimulatory anticancer drugs?

Matthias Gromeier: [00:12:46] Yes. What you’re saying is true. So there have been all kinds of usually anecdotal observations where people had infections, sometimes coincidentally, and this helped them fight off their cancer. Let me draw a very important distinction in the way we approach this phenomenon compared to a lot what you see out there. So that is true. Sometimes my colleagues tell me this is completely anecdotal. This is not a scientific study, but it is an unfortunate complication of brain surgery that sometimes a patient develops a brain abscess. And I’ve heard some of our colleagues tell that such patients do better when they have a brain tumor just because the infection creates some antitumor effect. We don’t want people to have brain abscess, but there’s a lot of these coincidental observations that suggest that having an inflammatory process helps. That’s true. However, attempts to leverage this in a more systematic fashion so to make this a safe kind of intervention that you can give to many patients in a way that it has a therapy effect and a clinical study, that has been very difficult. So while there are these anecdotal observations of inflammatory processes, having anticancer properties, that’s one thing. But turning this into a real drug that performs in a trial has been very difficult and there have been so many attempts in this direction. There are too many to really list. Some of them terrible, some of them really unsafe. And this has never quite really worked.

[00:14:28] What is necessary and this is what we are pursuing because we have made so much progress in immunology that we now know what may be behind these antitumor effects mechanistically, what it is about an infectious process that could turn into an antitumor effect, that we can begin to devise cancer therapies that are both safe and that have more of a reliable antitumor effect in a clinical trial. So the mainstay of cancer immunotherapy, we know this now is something called the CD8 T cells. So these are cytotoxic T lymphocytes. And they are so important in cancer immunotherapy because they are the obvious part of the immune system capable of recognizing, attacking and killing cancer cells. Ultimately, you’re going to have to kill some cancer cells to fight the tumor. And it is the CD8 T cells that can do it. So for our approach with the recombinant poliovirus, we do not think that the poliovirus itself kills off significant amount of cancer cells. It is the immunologic reaction, the CD8 T cell response against the tumor that does this job. So how do you get a CD8 T-cell response against the tumor? How do you make that happen? And here comes the idea of the infectious agent. So our immune system is not primarily an anti cancer system. It is mostly that has to do with evolution. It has mostly an antimicrobial type of machine. So the immune system is really designed and geared to fight viral and bacterial infection and other infectious challenges.

[00:16:11] And the CD8 T cell response, so the very response that we want to have to fight the tumor really is an antiviral function. Because CD8 T cells, their natural job in an immunology sense is to fight viruses that sit inside of cells. So CD8 T cells kill cells that have a virus in them. And typically it’s an RNA virus like poliovirus. And you see where I’m going with this, use a virus that can provide the signals and the stimuli to get CD8 T cells going, to turn that against the cancer. And so in that sense, what started as a primitive idea to infect cancers with God knows what, things are often very unsafe things. Can we maybe have a sophisticated strategy to design infectious agents so we get the good part of the immune response? And so that’s where we are now, I think, in the field. And that’s very much where my research is going. So we are trying to understand when our PVS-RIPO virus infects the macrophages inside a tumor and it generates a very, very substantial inflammatory program, how does this program contribute to making anti-tumor CD8 T cell response? We now know how it can work. We know the mechanism, and we have to figure out how to best get there. So that’s where we are currently. But you’re absolutely right. There’s this long history of infectious agents being lobbed against cancers.

Grace Ratley: [00:17:46] Yeah, but despite this long history of viruses potentially being used against cancers, there was still a lot of pushback to your study for good reasons, but it did slow down the research process for you. Can you speak a little bit to that?

Matthias Gromeier: [00:18:02] Yes. So the long delay, 1994 to 2021, this is mostly because of what you mentioned. And that’s not a bad thing. People sometimes think these regulatory processes are bad because they prevent progress. I don’t see it this way, and I’m probably one of the most regulated scientists around because we inject people with live poliovirus into their brain. Research is so far ahead in the US, partly because we have regulatory agencies that have the knowledge, the experience and they’re equipped to provide regulatory insight. So I know from some of my colleagues who don’t have an FDA in their home countries. They can’t even do the type of research I do because there’s nobody there who can certify that what they’re proposing is safe. So regulation is a very necessary part. Of course it’s challenging. You’re being pushed and the demands are extremely high. And I’ve dealt with this forever. I still do and always will. And it’s just part of what we do. And if we didn’t have this, we would see horrible, unsafe things move to the clinic. And I don’t think there’s a better system than that what we have in the US. So I have a very positive experience working with the FDA. It took a very long time. It was very demanding, but that’s good. We want to be safe. We have to be. And I had very positive interaction with them. It really helped me also to make our strategy better. Yeah, there was a lot of pushback of course. You have to work yourself through the regulatory concerns. So one concern for us was does your virus change when it replicates? And this is something we will always deal with and you have to answer this through science. This is why we carry out research to make sure what we’re doing is safe. And also is it efficacious? This is a very, very big part of my career, my life to answer the regulatory agencies. And I think I found a very good way of working constructively through this. There’s no other option, really. So I’ve seen how productive this can be to engage in these regulatory interactions.

Grace Ratley: [00:20:08] Yeah, but despite all of the hoops you had to jump through, it’s been incredibly successful. PVS-RIPO was in late phase two for clinical trials in glioblastoma and it’s being applied to melanoma as well. To what extent do you think PVS-RIPO could be applied to other cancers?

Matthias Gromeier: [00:20:27] Yeah, the longest program we have going on is in brain tumors is a recurrent glioblastoma. So these are brain tumors that have failed standard of care. Standard of care is surgery. It is a form of chemotherapy and radiation therapy that all patients get when they’re first diagnosed. Unfortunately, this treatment is not effective. So virtually everybody recurs. So the tumor returns, and at that point, patients become eligible for our trial that’s currently ongoing with PVS-RIPO. This is a horrible disease. It’s invariably lethal and it’s very problematic for somebody who’s interested in immunotherapy like myself, because chemotherapy and radiation more or less destroys the type of immune cancer relationships we require for the virus to do its job. So it’s a very, very tough challenge. We have to make progress in this area. So the mission of my life is to get rid of chemotherapy and radiation and replace it with something safer and more efficacious. That’s very difficult to do because you have to design trials that are acceptable to the establishment. So you can’t just stop chemo. So we have to work through this and we are in the process. So glioblastoma, that’s my scientific home, a very big focus for us and we’re very excited about the future there however slow it is. Melanoma is an easier tumor if you’re an immuno therapist because there’s very little use of chemo and radiation in that disease. So in general, dealing with patients who have a better immune status and melanoma is in the skin or close to the skin, there’s metastatic lesions often, but there’s usually tumor you can treat with an intratumoral inoculation where you don’t need surgery to administer your drug. So it’s a little bit easier. They’re not as many safety issues with the tumor growing where melanoma grows.

[00:22:23] We published our first very exciting clinical results just in March, I believe, and there’s a very exciting trial ongoing in multiple hospitals in the US now. We are in the preparation for a trial in bladder cancer that may enroll its first subject this summer, if I’m not mistaken. So these are again, patients who have failed everything else. And it’s a new protocol that I’m very excited about because of how the virus is being used to give patients a shot at immunotherapy where they otherwise wouldn’t have any options. There’s other trials in preparation. We are talking to many physicians who are head and neck carcinoma experts. There is discussions about colorectal cancer and then further down the line, ovarian cancer, hepatocellular cancer and various other diseases. We can’t treat any cancer with this, not blood cancers. So leukemias, that’s not an option as long as there’s a tumor we can inject. And so here you see the attraction. If you don’t target the cancer cells themselves so much, but it’s more about the macrophages and antigen presenting cells. So they sit in every tumor. It doesn’t really matter what kind of cancer this is, because these immunologic processes are the same, at least in principle are the same regardless of the tumor of origin. This is a very lengthy process to find out which cancers can be injected because they have to be physicians that are willing to do this. They don’t do what I say. So there has to be an interest in the clinical community and what we have to offer and you have to design a trial for patients that are suitable subjects for this kind of treatment. That takes some time. But we are very, very aggressively moving forward towards other types of cancers.

Grace Ratley: [00:24:12] Where do you think this technology is is going to go? I know I’ve read mention of it potentially being used as a cancer vaccine. Can you maybe speak a little to that as well?

Matthias Gromeier: [00:24:22] Yeah. So cancer vaccine, that’s a kind of dirty word. So when you say cancer vaccine, typically that means conventionally just like an antiviral vaccine. You pick out a feature in a particular cancer that is an antigen and you make an immune response against that antigen. And this largely has been unsuccessful. And the main reason is this terrible heterogeneity that I already mentioned. So there’s just not a whole lot of antigens that are common to many cancers, let alone to all the cells inside a cancer. So it’s extremely challenging to come up with a vaccine idea. So the way you could describe a virus is what we call an in-situ vaccine. What that means is rather than picking out something, deciding what to target, you throw the virus into the tumor and you let the virus basically reveal whatever is in this particular patient’s tumor with all the heterogeneity. So anything that’s present in a one particular patient gets presented to the immune system as an antigen. So the idea is rather than you picking what should be targeted, it’s the in situ situation that reveals what’s there. So in that sense, you could call this a vaccine, although I don’t like this word because it gets associated with these other failed ideas. Mainly what we need to learn is how to use it properly. And it sounds silly, but you wouldn’t believe how many questions there are. So we are combining the virus with another drug that’s approved for cancer therapy called anti-PD-1. This is a very logical combination for us. So certainly there’s a lot to be learned from that. So the trials that I described that are ongoing are in combination with that drug. There’s a large number of similar drugs we could combine the virus with.

[00:26:20] So we need to figure out which is the ideal combination. Generally in cancer, you don’t see a lot of drugs that are used alone. It’s too hard. So almost everything we do is some kind of combination. We need to figure out dosing. The advice I get from many of my immunologist colleagues is please give repeat treatments because that’s how our immune system works. We call this a boost. That’s how we give vaccines. You get your Covid shot twice. That’s how you stimulate the immune system. So this is something we have to fully learn. There’s all kinds of ideas about where to inject it, what kind of tumor, in what organ and what sequence, how many times. So there’s all these questions to be answered. But ultimately, where we want to be, of course, is that we want to give as many cancer patients that chance of immunotherapy so that they do mount and enter tumors once, I think we can. It is amazing to see, for example, in the melanoma space, basically it’s all immunotherapy or mostly. So cancer therapy has moved on from these horrible cytotoxic regimen to something that I think is a much better choice. And I think that we can reach this for many cancers. That will require a lot of clinical trials, a lot of work, but that’s where we want to be. That’s my mission. So my own mother passed away from gastric cancer a long time ago, and she she got standard of care chemotherapy. And she told me that the chemotherapy was worse than the cancer. It’s just this sticks with you. And if you have an opportunity like I do now, this is where I think I need to invest my energy.

Grace Ratley: [00:28:01] You’d be hard pressed to find a person whose life hasn’t been affected by cancer, whether it is them themselves or a family member or a friend. And it’s really unfortunate that we have so many incredible advances in the biomedical space, and yet we still face this monster of a disease with so few treatments.

Matthias Gromeier: [00:28:22] Yeah, well, these things just take a long time. Whether this is good or bad, I don’t know. It just does. I’ve made peace with this, and I’m glad we came as long as we did. But you have to think in decades. So when you hear these people talk about how they are going to make a big change in the year or two and all these fast track, quick, forget that. That usually doesn’t bode well. So you have to have a long horizon with these things. And this is how you make progress. It is this long, steady learning that gets you to places, not this quick action.

Grace Ratley: [00:29:00] Do you hope to see, I hate to say, a cure for cancer because as you’ve mentioned, cancer is extremely heterogeneous. But do you see it at least dropping off of our top ten killers in the world in our life?

Matthias Gromeier: [00:29:14] Hard to say. It’s more like a chipping away at it at the edges for now. I think it may remain this way, but if you just look at breast cancer. So my experience back in the 80s, it’s completely different now. There’s so many good treatment options and patients live very long times and many times they remain cancer free. And it came gradually, but it did achieve amazing things. This is more how it’s going to happen, this gradual improvement, and it’s never just one thing. So most of these breast cancer things are. It’s not one solution for everyone, but there’s just a lot of options. So whatever problem that’s presented, there is another option available to deal with it. So it’s not one thing, but a whole lot of complementary system. And I think this is what should happen in most cancers just to have a better choice for the physician. So in brain tumors, it’s depressing. It’s almost nothing. And so I think immunotherapy could provide great options there because there are some good openings provided that it’s done correctly. But it’s going to be a slow chipping away at it and improving things. And I think it has been shown for breast cancer and that was a horrible disease and it’s much less so now because of all the options that have become available. So that’s how I see it.

Grace Ratley: [00:30:36] So I want to get into what inspired you to study this virus and what inspired you to go into cancer. So maybe you can tell us a little bit about your path to science.

Matthias Gromeier: [00:30:46] Sure. So I’m German. I was born in Germany, and when I was born, you had to go to the army. You could either do that so train with weapons or you could work in a civil sector. That’s what I did. So for 20 months I worked in a hospital in a big university center for women’s cancer, and I was very young. I was 18. We were very lowly, so low in the hierarchy. So we were abused. I say so for all kinds of really low jobs. So I was an assistant in the O.R. and the anesthesia division there. I had a lot of contact with patients. Most of the patients there were breast cancer patients and ovarian cancer patients. And this was around 1984, 1985, 1986. So it’s a long time ago. And back in those days, cancer care was very different from now. It was very doctor focused, so nobody cared what patients felt or what they thought. They had to do what they were told. The treatment was completely inadequate. It was awful. Breast cancer then was a more or less a death sentence.

[00:31:54] And so my overall experience was I was quite depressed about this because it was this doctor centric world where people use these completely ineffective, very toxic treatments that really didn’t help patients. And there was just this feeling of authority that patients had to swallow this and just deal with it because that’s how it was. So I was really turned off by that. And while I was fascinated with this medical apparatus, I wasn’t really excited about what it meant for the people working there. I finished there. I had very good grades from high school. I didn’t know what I wanted to do. And my father without asking me enrolled me in the equivalent of MCAT in Germany. So I went there. I didn’t want to go to med school. I didn’t prepare for it or anything and I did amazing, probably because I didn’t really want to go. So everybody was very nervous. I was completely relaxed. So I got a really high score and I got into med school and I said, Why not? So I went and I was immediately drawn to research because of my earlier experience of the inadequacy of the medical establishment. I went to med school with the intent to not do what I experienced there. So research was my way out of this. And in Germany, to get an MD degree, you have to do a thesis which is not a PhD type, but more like a master’s, maybe a body of work. And I wanted to work with viruses. I can’t tell you why. They fascinated me. And this was around 1989. So back then it was all HIV. So I was looking for a virus lab that would take me and nobody would from the HIV side. But I found a guy who was a polio guy who said, I’ll take you. And I had absolutely zero interest in polio, but I went because that was the only guy who would take me. And he was a very nice man. And I did an interesting project. That’s how I got to polio. So my advice just go with the flow. And sometimes what you don’t expect works out really amazingly well. So this is not what I had planned, but I immediately caught the interest. I was very, very excited to be in the lab. It just worked out right from the beginning and it was the right thing to do. And after I finished there, then instead of becoming a doctor, I did get an MD degree. I came to United States and embarked on a research career. So I joined the laboratory of a very famous polio researcher, and that’s where I started this cancer work.

Grace Ratley: [00:34:41] And why did you choose the United States?

Matthias Gromeier: [00:34:43] In Germany, you either go to the US, it’s like 90% of the UK, about 10%. Back then I had a fellowship to come to the US that paid for three years of postdoctoral support in the US and then go back to Germany, which I never did. Research is just much better organized, better funded. There’s a better structure here than anywhere else in the world, in my opinion. It’s just you can’t beat this. And especially for the type of work I do, this type of research really is not possible anywhere else, I would say, at least not easily. The FDA actually is a big part of this. The Europeans are trying to copy something similar just to create an infrastructure where you can do clinical trials of innovative approaches better. But for now it’s unmatched in the US.

Grace Ratley: [00:35:36] So you mentioned that you developed this poliovirus while you were working as a postdoc. So what was that like? Why were you making chimeric poliovirus and rhinovirus?

Matthias Gromeier: [00:35:48] For no reason. That had something to do with the structure of this element we were studying. It’s a very complicated RNA element that’s hard to study because you can’t do a whole lot of things to it without destroying it. So we just thought maybe we should flip it out. This was actually somebody else’s project. So I got involved in it because I had an idea of how to clone this. Cloning was more complicated than. It’s a joke now, but back then it was more of an effort. And I had a good idea how to make it. This is actually the virus we’re using now. This is how I got to this. You see, it’s all coincidences and serendipity.

Grace Ratley: [00:36:27] Go with the flow, it is.

Matthias Gromeier: [00:36:30] This is how I teach my students. This idea that you can make a plan and this is not how it works.

Grace Ratley: [00:36:36] So after your post-doc, when did you know that this technology was going to be really important and useful in cancer?

Matthias Gromeier: [00:36:44] About two years ago. It takes a long time, because what we’re doing is so different from anything else. I know there’s other viruses studying being studied for cancer immunotherapy. Ours is very different from the others. And there comes this moment when you really know. We had some hopeful signs when we began our first clinical trial in brain tumor patients. There were some very hopeful signs, but we just didn’t have enough mechanistic information about the immune effects of what we were doing. Our research hadn’t caught up yet, but now I know. So I’d say in the last few years we really got the certainty that we’re on the right track. We are nowhere near to where we need to be with cancer, you never are. That’s not one of these things you can finish. It’s a constant challenge, but it took an extremely long time. And this is healthy. You never want to be too sure of yourself because that leads to dangerous developments. It’s good to have doubts. And of course, we had that. Research just takes time. And then there’s these events that are outside your control what I just told you about these studies going on elsewhere. There was a lot of work in the immunotherapy field with which we couldn’t have done what we are doing now. So it’s never one person charting the course. It’s a very complicated story where a lot of different influences flow together to make something happen. And I think we’re on the more exciting edge of that. But it took a long time to get there.

Grace Ratley: [00:38:20] I would say very exciting, definitely. So your work has been used in the biotechnology space, a company called Istari. So why did you end up staying in academia to continue this research?

Matthias Gromeier: [00:38:33] Yeah. So full disclosure, I’m a co-founder of Istari. I own equity in them. I’m a paid consultant to them. So in the type of work I do and the very first clinical trials we put up where what we call academic clinical trials, and that’s very difficult to put up because clinical trials are expensive. They are very involved. There’s a lot of red tape. Moving forward, these trials that are currently ongoing, it would be impossible to make this happen through an academic setting. So this has to be done in the commercial space because they have completely different resources and means to do this. So this is the natural way it happens. PVS-RIPO is still in a developmental phase, so we still are learning a tremendous amount of information about its mechanisms. So my objective is to make it a success for patients. That’s why I work on it. I want to make sure it can reach the most patients in the best way possible. And right now, the best way to make sure is for me to continue my basic research. Of course, I absolutely want these trials to succeed. And I’ll do anything to make this happen in the interest of everybody involved, especially the patients. But you have to decide for yourself where your best places and where you most need it because it has so many activities, infects cancer cells. It infects antigen presenting cells. It does really interesting things in them in terms of inflammation, the way it engages T cells. This is what makes it attractive. But this is also makes it very complicated from a research perspective. So as long as we must learn about its mechanism, then there is a need to maintain a basic research effort on it.

Grace Ratley: [00:40:23] So to aspiring scientists or people who are interested in going into oncology or virology, what advice would you give to these people as they go about their journey?

Matthias Gromeier: [00:40:35] From my own experience, be open to the unforeseen. Don’t be too strict with your plan. Have a little bit more creativity and freedom about your career. You never know where something really interesting may come from. What is very important and something like not just cancer, but in these big challenges like Alzheimer’s. And there was so much discussion about this controversial drug being approved. A career doesn’t mean to get other people to agree with you or to please the leadership or the establishment. You have to challenge existing paradigms and move to the unknown territory. That’s very risky. I can’t tell you how many times I got very close to complete elimination of my career, but that’s part of the story. You can’t change paradigms without risk. Somebody has to take this risk. There was the biggest fun in hindsight. It wasn’t so much fun going through it, but in hindsight just to challenge existing norms and existing lazy thought. So that’s what I’m trying to do and I think we need more of that. That’s what being a scientist means. It means not being satisfied with the status quo. That would be my advice.

Grace Ratley: [00:41:53] Well, thank you so much Matthias for coming on. You were really an inspiring scientist and it’s been a pleasure to talk to you about your career in the science.

Matthias Gromeier: [00:41:59] Thank you for having me.