Dr. Eric Bartee, MD, PhD Medical University of South Carolina Interview Date: November 14

 Dr. Eric Bartee, MD, PhD and virologist describes a new virus that seems to be a perfect fit for myeloma therapy, making the stem cell transplant process potentially more effective. A new rabbit virus called the myxoma virus can be used after the stem cells are harvested to kill residual myeloma cells in the collected stem cells before they are reinfused during transplant. Many methods have been used in the past to try to "clean up" these stem cells, but have been historically ineffective for many reasons. This is the first time a new virus is able to target the myeloma cells without hurting the healthy stem cells needed for regrowth. Dr. Bartee describes the history of this virus - over 60 years of testing in other venues. He shares why myeloma is the ideal target for this virus and how it has been used in other cancers to date. He describes the process of how the virus is used - the virus is added to collected stem cells, the stem cells are shaked, a 10-minute waiting period passes and the stem cells are reinfused. One of the challenges to other approaches was that they required the myeloma cells to be dead before they were reinfused. The time lag posed a threat to the healthy stem cells needed for regrowth and compromised a patient's chances for survival. In this approach, the myeloma cells are tagged for death and when reinfused are the "walking dead". This may also be used to treat residual myeloma cells already in the body, but it is likely to be most effective as a single-shot approach to clean up residual myeloma cells. It is likely to be best used as a combination therapy approach during the transplant process. The mPatient Myeloma Show with Dr. Eric Bartee  

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. If you'd like to receive a weekly email about past and upcoming interviews, you can subscribe to our Myeloma Crowd Newsletter on the homepage of either the Myeloma Crowd or the mPatient sites and you can follow us either place on Facebook or Twitter. Now before we get started, we'd like to give a shout out to Dana Holmes for her Mambo for Myeloma Awareness Campaign that is spreading. She just posted several videos, the IMF New York Patient Group just did a Mambo for Myeloma and there are lots of new videos posted in any style, limbos, conga lines, Rockette style, anything people can think of. So, we encourage you to make your own Mambo for Myeloma video and post it on YouTube with that title and help promote myeloma awareness. We'd also like to highlight our Songs for Life contest which has just six more days left to donate a song. So if you know musicians you can help spread the word that they can just donate their song for cancer research. We had almost 70 songs donated and they are really, really fabulous. So if you want to help choose which songs end up on the final album, you can go to songsforlife.org. We have a page with all the submissions and you can listen to those entries and like your favorites on the Facebook links. The top 20 by Facebook likes by November 30^th will be reviewed by the judging panel who will make the final selections. There is scientific evidence that music can reduce anxiety, pain, and boost mood for cancer patients and now we're going to use music to fund myeloma research as well. So we are very fortunate to have with us today an expert in virology and oncology, Dr. Eric Bartee of the Medical University of South Carolina. So welcome, Dr. Bartee.

Dr. Bartee: Thank you very much, very excited to be here.

Jenny: We're very happy to have you. Dr. Bartee, let me just give a little introduction for you. Dr. Bartee is Assistant Professor in Viral Oncology at the Medical University of South Carolina. His interests involve the study of virus-host interactions to cure diseases including hematological cancers. Now specifically in myeloma, he is studying how a rabbit-specific poxvirus called myxoma virus interacts with normal and blood cells. He won an Outstanding Journal Article of the Year at Oregon Health and Science University, is a Stop! Children's Cancer grantee, and won the Best Presentation Award at a recent Leukemia & Lymphoma Society symposium. So Dr. Bartee, let's get started. Maybe you can give us some background on your experience in virology in general and then how that applies to multiple myeloma.

Dr. Bartee: Yes. So my training, like you said, is actually in virology. I'm not really a cancer person but I'm fascinated with how viruses interact with cells and interact with their hosts and, in particular, how we can use these interactions therapeutically or in a clinical setting to try and treat a variety of human diseases. This is not a particularly new concept. The idea of using a virus to treat cancer has been around for probably 150 years and that's kind of amazing because 150 years ago they didn't even know what a virus was. But they knew that if you had a leukemia or a blood cancer and they inoculated you with what turns out to be flu, your cancer went into remission. And so clinically they were using this. A hundred, 150 years later, obviously we've gotten a little better, we know what the viruses are, we understand how they work. Basically the concept is if you take a virus that replicates better in a cancer than it does in a normal cell and you inoculate a patient with it, you will kill the cancer faster than you kill the patient and that's basically where any cancer therapy comes from. The virus in particular that we use is myxoma virus. It's effectively smallpox for rabbits. It's very, very potent as a rabbit pathogen but in humans, it's completely safe. You can drink it, you can inject it into your bloodstream and nothing happened, it's like it disappears. The one caveat for that is that it's very good for killing cancer cells. So if you put myxoma into a cancer, then you effectively give the cancer smallpox for rabbits and the cancer will die off very rapidly and the patient has basically no symptoms from the treatment. So we're really excited about that.

Jenny: That's amazing, totally stunning. So how did you begin to even find this smallpox for rabbits' virus? Because I think that seems sort of out there.

Dr. Bartee: It's a little bit out there. Myxoma has been studied for 50 or 60 years. It was used initially as a bio-control agent in Australia to kill off the native rabbit population. So that's kind of where the study of the virus originated and people worked on it for 50 or 60 years in that regard. And one of the things that they really wanted to understand was that if you're going to use this as a bio-control agent to kill off rabbits, you need to understand why it kills a rabbit but doesn't kill a human. That's very important because you absolutely cannot have your bio-control agent jumping into species and causing pathology in a human host. And what they found was that the myxoma virus is very, very susceptible to host inflammatory responses particularly interferon which is a small protein that is secreted very, very rapidly upon pathogen infections. Any place that interferon is present and functional, myxoma cannot replicate. But any place that interferon is not present or not functional, the virus can replicate. Most cancers are defective in interferon signaling. So in a cancer, interferon is present but it can't block viral replication. And once people understood what was stopping myxoma from replicating in a human, this interferon response, they said "Well, we know interferon is not functional in cancer." And so it became very obvious that this bizarre virus that you would never think of actually had some pretty serious clinical potential to treat a variety of different tumors.

Jenny: And let's talk about the varieties. So it was first tested in what kind of cancer?

Dr. Bartee: They initially tested it in melanoma. It has since been tested in glioblastoma which is a brain cancer. Pancreatic cancer; it did very, very well in pancreatic cancer. They looked at it in colon cancers but it didn't behave very well there. And of course, our work looks at it there in hematopoietic malignancies particularly acute myeloid leukemia and myeloma.

Jenny: How did you come to study those two?

Dr. Bartee: We came into this as virologists and what we knew is that viruses are very, very good at killing cells in a test tube. Incredibly good. Any virus can kill any cell in a test tube to a large extent. Unfortunately, that doesn't help cancer patients very often because their cancer is not in a test tube. But it's very difficult to deliver viruses to sites of cancer in a person. And so what we wanted to do was we wanted to ask a very simple question: Are there situations that are clinically-relevant to people with cancer where we can actually use the ability of our virus to kill cancer in a test tube to improve a patient's outcome? When you look at solid tumors, that's hard to envision but when you look at blood cancers, what we found is that a lot of those cancers are treated with stem cell transplants. Particularly myeloma is the number one disease in the world that's treated with autologous stem cell transplants. Somewhere between 12,000 and 15,000 patients in America a year are treated with that. That's a very good treatment, it's the number one treatment for myeloma if you're eligible. The problem is as I'm sure your listeners are aware, you still can't cure a myeloma patient with that. The disease always comes back. Why does it always come back? It always comes back because one of two reasons: Either your treatment wasn't able to eliminate all the myeloma in the patient and so after the transplant, the myeloma comes back; or you did eliminate all that disease but you reintroduced disease when you did the autologous stem cell transplant. And if you look at what's in a stem cell transplant, it's about 1% hematopoietic stem cells but it's actually 2%-3% cancer cells. So when you do that transplant, you're reintroducing more myeloma cells back into the patient than your stem cells. So it seems to us that that's a very likely cause of myeloma relapse. But that stem cell transplant sample before you reinfuse it, that is cancer in a test tube. And we thought, we have a virus that can kill cancer in a test tube incredibly well and a clinical situation where you have cancer in a test tube. So let's see if we can take our virus and kill that myeloma in the test tube before we put it back in the patient and therefore prevent disease relapse.

Jenny: So can you talk about a little bit if there are so many cells, why hasn't this been addressed before?

Dr. Bartee: They have attempted to address it before and there's lots of literature testing how many cancer cells are in this transplant samples. And all of that research says there's definitely cancer cells in transplant samples. And clinically, what they've tried to do to address it is they've studied whether or not taking those cancer cells out of transplant samples improves patient outcome. And they've done this primarily with something that's called CD34 Positive Selection and that's an antibody-based strategy in which you take the hematopoietic stem cells which are what the transplant is designed to reintroduce and you purify those stem cells away from all the other cells in the transplant sample. And that means you purify them away from any myeloma that is present. And then when you reinfuse the purified hematopoietic stem cells, the clinicians ask, do the patients have a better outcome from that than they do from an unmodified transplant sample in which you basically know that you're reinfusing cancer? And unfortunately what they clinical trials found was that CD34 Selection really doesn't improve a patient outcome. And that was based on two or three fairly large clinical trials that were conducted maybe 15 or 20 years ago.

Jenny: And how were they purified? When they were pulling them out and purifying, how were they purifying them?

Dr. Bartee: So they do it with something called magnetic cell sorting. So you take this big transplant sample and it's a complex mixture of a whole bunch of different kinds of cells. And the cell that you really want is the hematopoietic stem cell, that's what's going to reconstitute the patient blood system after you put it back into the patient. That cell expresses a certain protein called CD34. There are antibodies to CD34 that you can label this cell with. So you take an antibody and you put on to it a magnetic marker, a bead, and then you put that CD34 bead into this mixture of cells. The antibody binds to the hematopoietic stem cells because they are the ones that express CD34. And then you just use the magnet and you purify out the bead which purifies out the hematopoietic stem cells. It's a very labor-intensive process, it's a very time-consuming process, it's a relatively expensive process. And unfortunately, it's only modestly good at removing other cells. It gets rid of about 90% of the cancer cells that are present in the transplant sample, but if you look really hard, even after CD34 Selection you can still find cancer cells present in the transplant samples.

Jenny: So just to reiterate what you just said, they tried binding something to the CD34 cells because those were the stem cells that were preferable and they are going to regenerate. But when they purified them, they couldn't get everything out so they're still reinfusing even though they're doing this probably in clinical trial and in the lab in very small sample sizes but it still didn't work. So there were residual myeloma cells is what you're saying, right, in those samples even when they tried that?

Dr. Bartee: There are a couple of problems with CD34 that people didn't appreciate 15 or 20 years ago when these trials were done. One is that there's some evidence in the last four or five years that there are actually myeloma cells that also express the CD34 protein. And so when they used this CD34 Selection to attempt to remove the myeloma cells, the new evidence would suggest that they actually purified myeloma cells along with the hematopoietic stem cells. And so that could be one reason that they didn't see any kind of beneficial patient outcomes. The other is that when you purify away CD34 cells, you get rid of more than cancer cells. You get rid of other white blood cells like T cells in particular and that opens your patient up to infections after transplant which I'm sure as you're aware is a very big problem in allogeneic or autologous transplants -- people get fungal infections, they get bacterial infections. And so they had patients dying from post-transplant infection as well. So what the trials are generally concluded to show is that those cancer cells in the transplant sample don't make any difference in patient outcome. Because when those clinicians took those cancer cells out, the patients didn't have an improved outcome. When we look at that, we see the injection of millions and millions and millions of cancer cells back into a patient. Even after [CD34] selection, you're injecting millions of cancer cells. I can't fathom that you can inject millions of cancer cells into a patient and not have it affect how that patient relapses. That just doesn't seem to make any sense to me. So what I think those trials mean is not that cancer cells in the transplant samples don't matter. It's that we need a better method to get the cancer cells out of the transplant samples because the one that they tried, that method was unsuccessful so we need to develop a better method. And that's what we think myxoma virus is. We think it is a better method to remove cancer cells from transplant samples than what was previously tried in the clinical trials.

Jenny: So maybe you want to go ahead and talk about what that process looks like. How do you do it, how long does it take, what are the steps?

Dr. Bartee: So this is one of the significant advantages of using myxoma virus in a clinical setting compared to other methods that have been used. When we were developing this, we really wanted to develop a technique that could be very easily added to what the clinicians do already. We didn't want to have some two or three-day process that was really labor-intensive, it was expensive. We didn't want that. We wanted it to be short, we wanted it to be simple. So literally the only thing that you have to do to remove the cancer cells from a graft with myxoma is take the transplant sample, add the virus to it and wait about ten minutes, and then infuse your sample just like you would have anyway. There's no washing --

Jenny: Well, they hold them anyway, right?

Dr. Bartee: They thaw them, they probably keep them on ice for a couple of hours. You could do this while the transplant sample was on ice. Basically you just have to add the virus and shake once or twice and that's it. And the reason for that is that the only thing that you really need the virus to do before you infuse the sample into the patient, is to bind the cancer cells. You don't need it to infect the cancer cells, you don't need it to actually kill the cancer cells. Once the virus is on the cancer cells, those cells are going to die. Nothing you do will save them at that point. So if you inject that cell into the patient, even if the cell is actually still alive when you inject it, it's basically been loaded with a little viral time bomb and that time bomb is going to go off and it's going to kill the cell. You don't have to wait for the cells to die and that's what most of these other techniques need, they need the cells to be dead. Because if you inject them into the patient, whatever you're doing to kill them goes away if you're treating with a drug or if you're treating with an antibody, all those treatments go away as soon as you inject the cells into the patient. The virus doesn't go away. It hangs on those cancer cells like a little tick. And regardless if you put those cells back into the patient, whatever you do with them, the virus is still there and it's going to kill the cells.

Jenny: And you haven't seen any kind of interaction on the back end of that virus at all so it's harmless basically from what you've seen.

Dr. Bartee: We can inject as much virus as we can synthesize into whatever animal you would like except rabbits, and the virus just disappears. And one of the nice things about myxoma is when they used it as a biocontrol agent in Australia [1950's], they did a lot of work to prove to the public that it was safe. And part of that was actually to inject it into live volunteers and it disappears.

Jenny: I don't know if I'd have signed up for that.

Dr. Bartee: No, I wouldn't do it either and you can't do it now obviously. But it's been done historically and it's a completely and utterly safe virus. It will not do anything. And it evolved that way. We didn't make the virus safe. We didn't change myxoma virus to get these properties, this is how it already was when we started this work. So there's no chance that it's going to change and become dangerous because the virus has had thousands and thousands of years to do that and it never had. As a safety thing goes, it's completely safe. There's basically no chance that you're going to get sick from myxoma.

Jenny: Okay. And how did you use this in AML because usually with AML, the transplant is a donor transplant, right?

Dr. Bartee: Yes. And the reason that AML is usually done with allogeneic transplants is that autologous transplants, just like in myeloma patients, autologous transplants from AML are contaminated with cancer cells. But in AML, the clinicians know that the reintroduction of those cancer cells into patients directly causes patient relapse in the clinical trials. And in that case the clinical trials showed that you if you take out the cancer cells, the patient does better. So the reason that they use allogeneic transplants in AML is that autologous transplants can't be done because they're all contaminated with cancer cells and there is no good way to remove them. So we said can the virus remove the cancer cells in AML that would let you use autologous transplant? And the virus did remove the cancer cells from the one patient that we tried and this is all animal studies at this point. There are no clinical trials yet on this.

Jenny: Maybe you want to help us understand the stage where you are now and then what comes next.

Dr. Bartee: We think we're nearing the end of our animal work. We've shown in the animals that if you take a sample that's contaminated with cancer cells and you treat it with myxoma for ten minutes and then you inject it, you prevent the disease from developing in those animals. We've showed that the virus is perfectly safe. It doesn't cause pathology in the animals and more importantly, we showed that the virus doesn't affect the hematopoietic stem cells. It doesn't kill those cells, it doesn't bind to those cells at all, it doesn't prevent the reconstitution of a patient blood system after the transplant. And those are the two things that we think were really important coming in. did it kill the cancer and did it kill the stem cells. And it turns out it does kill the cancer, it doesn't kill the stem cells. So it looks good. The next step we think is take this and do a clinical trial. Undoubtedly it will be a phase I safety trial. But to do that, we need to generate a clinical-grade virus and I know you talked to Stephen Russell about GMP-grade measles virus. That quality of virus is very difficult to produce, it's very expensive. And so that's where we are currently. We're trying to find a method to get that high quality clinical-grade virus so that we can start a clinical trial for removal of myeloma from transplant samples.

Jenny: And at the Mayo Clinic, they were developing their own virus, right, and they were sort of constrained with how much they could produce at the same time. Would you try to do it yourself or is that something that you outsource or how do you go about doing that?

Dr. Bartee: You can do it both ways. My lab personally is not really geared up to make clinical-grade virus. It's a very heavily-regulated and rigorous process. I don't think that we're capable of doing it so we will probably have to outsource it somewhere else. And unfortunately, that costs a lot of money. The Mayo Clinic is a little larger. Dr. Russell has some more resources in that regards than we do so we're not really able to do it. Just like his treatment though, our treatment is very much dose-dependent. It takes a lot of virus to remove all the cancer cells from a transplant sample. And that's one of the things that we're trying to work on right now, to see if we can  make the virus a little bit better so that we can use less virus which that would definitely speed up the clinical process.

Jenny: Just because you'd have to produce less.

Dr. Bartee: Yes. And even with a virus like myxoma which has a very long, very rigorous safety record, people get a little leery when you tell them you're going to pump them full of tens and hundreds of billions or replicating viral particles. It's a bit of a stigma. And so if you can reduce that number, you make people a lot less leery about what you're doing. So it serves multiple purposes.

Jenny: Well, we did a post on Stacy Erholtz and how she got the measles vaccine for myeloma. And I think that virus was enough for 10,000 people or something. It worked for her, it worked great. So she's still in remission.

Dr. Bartee: That was a really exciting result in virus therapy. The whole field was really excited about Dr. Russell's result. To get this to work in patients, particularly since the patient gets tested on or usually multiply relapsed, really, really high risk, to get anything that works on those patients is really exciting.

Jenny: Well, this is huge. I think this is a huge idea. So when I was reading your paper, you mentioned something about CD138 cells and I know that a lot of times those cells are related to myeloma. What's the relationship with those cells in your work?

Dr. Bartee: So myeloma is a disease of plasma B cells that secrete antibody. The protein that is used by scientists to define a plasma B cell is this protein called PD138, so almost all myeloma cells are PD138-positive. So when we look at the ability of virus to kill myeloma, how we were looking at it was the ability of the virus to eliminate cells that express PD138. And we think one of the reasons that myxoma might be so good at this particularly in regards to myeloma is that there might be some relation between the virus binding to myeloma cells and those cells' expression of PD138. The more of that they express, the better the virus binds. And we haven't formally proven that yet but that's our hypothesis that myxoma works so well against myeloma specifically because the cancer is defined by this expression of a protein that the virus likes to bind to.

Jenny: We've talked about pulling this out [stem cells] and using the virus in the stem cells that are being prepared for transplant. And you said at the beginning that there were two possible causes for myeloma to return. One is that you don't fully eliminate the disease or it's hiding somewhere in the bone marrow niche or wherever. Can this virus be used in any way to eliminate any of that residual cancer that might still be there?

Dr. Bartee: We would definitely like to think so. That's actually an area that we're working really hard on right now. And one of the added features of using the virus to remove cancer cells from transplant samples, our protocol does not wash the virus away. So the virus that we put into the transplant sample is then immediately injected back into the patient. So if we do that in a mouse and we give a mouse myeloma and we then inject the mouse with a whole bunch of myxoma virus. No transplant sample, no removal of cancer. This is just does the virus affect residual disease? What we see is that just one intravenous injection of myxoma will get rid of 95% of the residual disease in an animal quite rapidly. It takes two or three days' result. There's a caveat to that though. Myxoma has one very large drawback in the treatment of multiple myeloma. The virus kills the cancer so fast it doesn't get a chance to replicate. So most viruses including measles, when you put them into cancer cells, they replicate tens of thousands of more viruses that then go out and kill more cancer cells. So it's a self-amplifying treatment. Myxoma does not do that in myeloma because the virus kills the cells so fast, it never gets a chance to produce new virus. And so instead of a self-amplifying treatment, it's a single shot. Whatever you put in, that's what you get. So the virus is very good at eliminating residual disease or at least knocking it down but it's probably not going to be a one-shot you're going to cure residual disease. It probably isn't going to work what way unfortunately.

Jenny: So maybe a combination of things. I know they're working on lots of things in the bone marrow microenvironment to make it really unfriendly. I mean you have dual or triple strategies now so that might just be something.

Dr. Bartee: I'm sure you're familiar with this one. One of the problems with myeloma is that it's a very heterogeneous disease. The cancer cells are all a little bit different from each other. None of the treatments work as well mono therapies. Even the new drugs Bortezomib, historically people use melphalan. They didn't use melphalan, they used melphalan and prednisone and radiation because the single drugs simple don't work very well. Myxoma's probably going to be like that. It's a new drug; it works on completely different mechanisms. But I would envision trying to use it to treat minimum residual disease in the bone marrow probably as one part of a combination therapy would be the most clinically-successful way to go. And that's going to be true for any cancer treatment for any cancer. The combination therapies just seem to work a lot better.

Jenny: Right. You're hitting it from all sides.

Dr. Bartee: Yes. And the more sides, the better it works.

Jenny: Right. So is this something you could get over and over again or you just use it…? I mean the measles vaccine was a one-shot deal you said because you develop an antibody towards that vaccine. So is this similar or could you give it -- let's say you knock the disease down by giving some of these and then a year later you give more or even a few weeks later or something to keep killing those cells. Would that work or no?

Dr. Bartee: It's going to be a lot like the measles vaccine. You're going to generate an antibody response against the myxoma virus and that's going to severely limit how well repeat therapies work. You probably have a window of three or four days is about it and during that period, you could inject it multiple times. But after a week or a year or five years, if a patient relapses, probably a second round of myxoma treatment would not be very successful. You could still use it. If they got a tandem autologous transplant, you could use the virus to purge the transplant sample a second time and that would work. But treatment of residual disease, probably it's a one-shot deal. But unlike measles, nobody has existing antibody responses to myxoma. So you don't have to select your patient population as well and make sure that they're immunosuppressed or they never got the measles vaccine or they never got the smallpox vaccine which would restrict vaccinia which is another oncolytic virus. Everybody is a candidate for myxoma treatment officially.

Jenny: That's interesting. Because yeah, that was one of the caveats in the measles vaccine was that people who have had measles before couldn't really use it. Are there any pros or comparisons you want to make between this vaccine and the measles vaccine?

Dr. Bartee: The two are very, very different and this is true of any viral treatment. There are probably a dozen different viruses that are really being studied as treatments for cancer. They all have very different properties. In particular with measles versus myxoma, measles is very potently lytic. It gets into a cancer cell, it kills the infected cancer cell very, very well. It's not as good at getting the patient's own immune system revved up to come back and eliminate whatever cancer cells the virus misses. Basically it kills whatever cancer cells it infects and it's really the strength of that treatment. Myxoma kind of works on a different principle. It kills myeloma pretty well, really well, but it does a much better job than measles at getting the patient's own immune system revved up to kind of come back in and clean up whatever cancer cells the virus misses. And it does that actually specifically because it's a rabbit virus. And every virus has defenses to kind of counteract the host's immune system. Measles defenses are all designed to counteract human immune systems and they're very good at it. Myxoma's defenses are all designed to counteract the rabbit immune system and it turns out, most of them don't work on the human immune system. So the human immune system gets to do whatever it wants to myxoma and so that makes it very good at revving up this big patient immune response that then gets targeted towards the cancer. So is that better than something like measles? No, it's definitely not. Is it worse? No, it's just different. And the clinicians will have to move forward with clinical trials to see does this work better than measles, how do you use myxoma virus clinically compared to measles? You should think of it as two different drugs and they work different ways. Neither one is better than the other but they are distinctly different.

Jenny: Okay. A follow up question on that and thank you for that great explanation. There seems to be kind of a relationship in myeloma, myeloma patients are particularly susceptible to getting shingles or it's particularly bad for them so get shingles. And that whole disease family -- measles, mumps, Rubella, smallpox -- one of these viruses, they're being used now to treat the cancer but could any of these viruses cause the cancer? I know that's sort of a strange question but you're a virologist so I have to ask it when you're on.

Dr. Bartee: So the viruses that are studied as cancer treatments, the researchers are very careful in picking which viruses they use. And one of the things that they look for is that the virus is put into the patient and it does what it does, it kills the cancer and then it goes away. And after a month or two months, the viruses that they use in these treatments are gone and pretty much any cell that they infect is gone so there's no store of the virus left. When you look at something like shingles which is caused by chicken pox, varicella zoster virus, that virus does not leave the body. When you get chickenpox, you have that virus in you for the rest of your life and that's called a latent infection or a persistent infection. Viruses that cause those long-term infections, they're the ones that cause cancer, they're the ones that gives you recurring disease. When you look at the viruses used to treat cancer, nobody studies viruses that have persistent infections or latent infections specifically because you would run the risk of them causing cancer. Measles is not going to cause cancer, myxoma is not going to get cancer. Potentially you can get some acute effects. A lot of times people treated with this get flu-like symptoms. They say, "Oh, I feel like I have a bad cold." That's the acute virus treatment. But long-term, no. There's no evidence that you're going to get cancer from these treatments.

Jenny: Well, a follow up question, have other sanitizing or purifying methods been used to I guess wash or purify these stem cells before transplant that you're aware of?

Dr. Bartee: People have actually tried a lot of different methods. And the fundamental problem with most of them is that they need the cancer cells to be dead before transplant. People have looked with treating the transplant samples with chemotherapeutics, treating them with drugs, treating them with radiation to remove cancer cells. But all of those treatments work you have to kill the cancer cells before infusion. And chemotherapeutics, radiation, those things take days to kill cancer cells. That means that those treatments are slow, they're very laborious, they're very time-consuming. And the more that you do to those transplant samples, the more that you damage the hematopoietic stem cells. And if you hurt the hematopoietic stem cells, your patient dies. You cannot do that. And so a lot of those techniques, they've been very, very difficult to use in human patients because they hurt the stem cells. They're too long, they're too laborious. Myxoma treatment is ten minutes. You put the virus on and you go. And the reason for that is we don't need to have the cancer cells actually be killed when we infuse them. They're the walking dead. We've killed them, they just don't know it yet. And so that makes the myxoma treatment much, much faster and much easier which we think will help it translate into human patients.

Jenny: Well, this is absolutely fascinating and it gives you a lot to think about. I want to leave some time for caller questions. This is really amazing to hear about and we're so thankful that you're here with us today. So if you would like to ask a question of Dr. Bartee, call 347-637-2631 and press 1 on your keypad. And we have our first question, go ahead.

Caller: Hi Jenny. Good morning, Dr. Bartee, thanks so much for taking your time out to speak to Jenny and share all these information with the myeloma community. It's always very, very helpful to hear it straight from the horse's mouth.

Dr. Bartee: My pleasure.

Caller: Yeah. I'm a smoldering multiple myeloma patient so I'm wondering do you see your researches having a future utility for the precursor stages of myeloma when the disease burden is lower and perhaps is more susceptible and has less genomic instability?

Dr. Bartee: So genomic instability, that's one of the hallmarks of myeloma, that's one of the big problems with the chemotherapeutic treatments. Myxoma virus actually doesn't care very much about genomic instability. It will kill a myeloma cell regardless of what the genetic looks like. In terms of smoldering myeloma, those patients are not going to be getting transplants, most of the time the clinicians take a wait-and-see approach. I don't know that myxoma's going to behave well enough at treatment of minimum residual disease to make it a frontline treatment for smoldering myeloma. It certainly could, we haven't really looked into it but I would suspect it's probably not going to be the way to go for those patients.

Caller: Are you working on any research or focusing on any of the precursor states whether it be smoldering or MGUS?

Dr. Bartee: We have not looked particularly at those. The thing that we would be most interested in in terms of myeloma precursors would be identifying the myeloma stem cell that actually it's the fundamental cause of disease and no one really knows what that stem cell is yet. So that would be something that we would definitely be interested in.

Caller: Do you have an opinion about early treatment intervention in the smoldering patient population? Do any of the smoldering clinical trials stand out to you as having a good potential as a curative approach at this stage, in your opinion?

Dr. Bartee: Unfortunately my background is not as a physician. I'm coming at it from the virus side of things so I really don't have the knowledge to answer that question with anything except wild guesses.

Caller: Okay. I appreciate that and would certainly welcome any opportunity that you would offer to smoldering patients to really kind of look at our disease state too and see how you can stop it in its tracks because during that awful watch-and-wait situation, it's not an easy situation to be in. You don't want to jump the gun and obviously overtreat but you certainly would like to be able to intervene before any of the damage that this disease causes to show its ugly face.

Dr. Bartee: Cancer treatment of any kind, the earlier you catch it, the earlier you treat it, the better your patient outcome is going to be. So down the road it's certainly something that we will have to look at but right now, we haven't gotten around to it yet.

Caller: Well, great. I look forward to that and hope I can keep smoldering until you do.

Dr. Bartee: I hope you do, too.

Caller: Thanks. Thanks so much for taking the questions in the call.

Jenny: Thanks. Okay, our next caller, go ahead with your question.

Caller: Hi! This is a patient that is still shocked at hearing the stem cells are being reintroduced that have cancer in them. Is that common knowledge among all doctors that stem cells that are being reintroduced have cancer in them?

Dr. Bartee: It's certainly the consensus from the scientific literature, that the vast majority of the transplant samples are contaminated with cancer cells. Whether the physicians are aware of it or not, I'm not sure. Most of them are familiar with the clinical trials that were done that showed the removal of the cancer cells with CD34 Selection didn't improve outcome. And none of the other methods that have been used or suggested to remove cancer cells have really progressed into a clinical trial yet. So for people that are right now getting transplants or have gotten transplants, the physicians unfortunately don't have anything that they can tell you, "Well, this is what we're going to do to remove those cancer cells because we know it will help you." All they've got is stuff that they know doesn't work. It sounds bad but even if the physician knows there's cancer cells there, there's not much he can do about it right now.

Caller: I have a follow up question to that. Let's move to the economics of this. What comes with the cost to produce this virus?

Dr. Bartee: We have never tried to produce it on a scale that would be relevant to a human clinical trial. We use research-type scales. They're much, much smaller. It's unfortunately probably not an inexpensive process. It's a lot of virus and the testing required by the FDA to validate that the virus is of sufficient quality to put in a patient is quite rigorous. So I don't know exactly what it would cost a patient to get a treatment like this but it's going to not be in the hundreds of dollars. I don't think.

Caller: Do you have funding for this initiative right now?

Dr. Bartee: Yes, we do. We have funding for the research. We don't have funding to translate it clinically. That's something that we definitely need.

Caller: This might be an interesting project for me may be crowdfunding. I know that there are a group of patients are going get it the same way. What can they do to accelerate research in different areas and find promising prospects?

Dr. Bartee: Yes. I've looked into crowdfunding this. Crowdfunding a clinical trial would be very, very difficult. Those trials cost millions and millions of dollars and getting that kind of money from crowdsourcing is just… unless you have a couple really wealthy people that are going to donate big chunks, it's just really hard to crowdsource anything. Preclinical work you can definitely crowdsource but the actual clinical trial, I think that currently is not feasible.

Caller: All right. By the way, as I develop at my questions, you did a great job, you just kept answering in detail, that's the next thought I would have. And so there's one more follow up I'd like to have, it doesn't have to do with myeloma, it has to do with AML. My brother passed away from AML. At the beginning, I would say I don't understand why this could be used in myeloma but not used in AML. And then you said later in the interview, you said that it does react. The AML does react to this. So could you clarify what is the reaction in AML and why this wouldn't be an equally interesting treatment to AML?

Dr. Bartee: It probably is an equally interesting concept for AML. The problem with AML is that it's a very diverse type of disease. Myeloma, it's got a lot of genetic defects, a lot of heterogenic, but in terms of epicellular level, myeloma represents one type of cell, it's a plasma cell, a plasma B cell. That's the only type of cell that gives you myeloma. Myxoma behaves very, very well against plasma cells so regardless of what the exact genetics of your myeloma are, you have a very, very good chance that your myeloma is going to be susceptible to myxoma. When you look at AML, AML is a phrase used to describe anything in the myeloid lineage -- monocytes, macrophages, intrinsic cells, neutrophils -- it's a whole huge range of different cells types. Whether or not the virus is effective against one or more multiple or all of those cell types, we don't know. It behaves very, very well against the one patient sample that we tested but that was just one form of AML.

Caller: That's a good point because there different types of proteins that are present in different types of AML. My brother had CD34 present and you're talking about 138 so I could see that… if you had gotten to that point, if you tested the person, you had a specific type of AML that they had then you could, "So this works in this subtype."

Dr. Bartee: Yes. The key here is virus binding to the cancer. Just like myeloma, you don't have to kill AML probably to remove it from a transplant sample. And whether or not the virus binds is a very easy test to do. So we could certainly go on a patient-by-patient basis. Is this patient going to be treatable with myxoma therapy?

Caller: Because I don't have it personalized. You have a much higher probability of surviving an autologous transplant as opposed to having host-versus-graft disease. That's pretty significant. It will be worth a personalized medicine test that you could qualify for that.

Dr. Bartee: It's another thing that we should look at AML. AML would be a very nice disease for purging because it would be used with autologous transplant if you could remove those cancer cells.

Caller: Yeah, but you can't do autologous obviously with AML so that's not even a question.

Dr. Bartee: No, that would make it a little more difficult to get the therapy adapted because instead of having a physician to simple put your virus on for five minutes in a treatment, he's already going to do anyway. You have to ask a physician to take a treatment that he knows is going to benefit the patient allogeneic transplant and completely ignore that treatment and go with a treatment that he thinks is probably not going to help the patient unless this part that you're adding to it works. So that's asking the physician to take a lot on faith. It's going to get a lot more difficult to get adapted into clinical practice.

Caller: That's interesting and doctors can't do that because they have to follow a standard  of care so you have to figure out it's a significant trial to pull it off.

Dr. Bartee: Yes, you would need a lot more work in AML to convince the treating physicians that this will be better than what they're already doing. That will be hard hurdle.

Caller: Well, you have significant progress in myeloma and that shows that this is working to be promising then branch out into other areas.

Dr. Bartee: Yes, it would certainly help.

Caller: Great interview. Thanks for taking the question.

Dr. Bartee: Thank you very much.

Jenny: Okay, thank you so much. Well, Dr. Bartee, we are out of time. We are just so grateful that you joined us today. We feel really enlightened and sort of shocked though. But we're thankful for all that you're doing and hope that your research continues to impact us and make a huge difference for myeloma patients.

Dr. Bartee: Thank you for giving me the opportunity.

Jenny: Well, thank you so much. So thank you for listening to another episode of Innovation in Myeloma. Join us for our next interview as we learn more about how we, as patients, can help drive to a cure for myeloma by participating in clinical trials