Full MCRI Show: Important Lessons Learned from the Measles Virus in Multiple Myeloma and the Next Step to Advance the Fascinating Viro Therapy with Dr. Frits van Rhee and Dr. Stephen Russell
Dr. Frits van Rhee, MD, PhD, MRCP, FRCPath, University of Arkansas Dr. Stephen Russell, MD, PhD, Mayo Clinic Interview Date: May 27, 2015 Summary The measles virus grabbed media attention with one patient's amazing outcome. Dr. Russell and Dr. van Rhee hope to expand those results into more patients with lessons learned from the first clinical trials. Phase I was a trial of six patients and now phase II is running at the Mayo Clinic for 42 patients with the measles virus alone. The proposed work for the MCRI is a collaboration between UAMS and the Mayo Clinic to treat 16 patients in a now-open clinical trial using a lower dose of the measles virus in combination with cyclophosphamide. To date, the doctors found that patients with an absence of the measles antibody and a low tumor burden responded the best to the treatment. In this show they describe how the immune system, no matter how weak, mounts a response to the measles virus given and how they would like to use the predictable cyclophosphamide in conjunction with the measles virus to buy the immune system more time and allow the measles virus to attack more myeloma cells. They will also be using imaging as a key tool to show where the measles virus is going inside of the body and how effective the treatment is. There is much to be learned from this show about a non-toxic approach to myeloma therapy. Hear more about the initial results and how the measles virus works here. The Myeloma Crowd Radio Show with Dr. Frits van Rhee and Dr. Stephen Russell
Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom, and I'm joined today by myeloma friends including Pat Killingsworth, Jack Aiello, and Cynthia Chmielewski as co-hosts. This is the last in a very important series featuring the Myeloma Crowd Research Initiative. It's been an amazing few months for this new initiative. We created an expert Scientific Advisory Board and invited well-educated patient advocates to create the first Patient Advisory Board. This is really the first time that a group of patients have been involved in voting on research that could potentially be funded. As a group, we decided to select projects for high-risk myeloma because these patients are out of options and for them, the current drugs are not working. Because we know that we all become high-risk at some point in our disease, we know that hitting the most critical target will provide benefit for us all and we've now heard how these projects could equally benefit low-risk and even smoldering myeloma patients. We called for letters of intent and received 36 high quality proposals from top investigators around the world. Our Scientific Advisory Board then scored these proposals and selected the top ten. This show is the last of the ten. After the shows are complete and full proposals have been submitted, both the Scientific Advisory Board and the Patient Advisory Board will vote to select a limited number of proposals to fund. Now, part of our very important message is that patients can and should do more than patiently wait for a cure. As Pat is fond of saying, we are on “myeloma time” and need solutions now rather than later. We need you to be involved and today, we have a very simple way for you to help do just that. Every myeloma patient, everyone diagnosed has a community of friends and family who want to love and support and help them but sometimes don't know how. Today you can go to https://mcri.myelomacrowd.org -- and notice there's no www -- to create your own fundraising page. Once you get to that link, you can click on "Build a Team". You can upload your own photo and write your own text to customize your page. We're going to wait to ask you to share that page with your family and friends when we know which projects we will be funded, but you can take ten minutes today and get that done so we are all ready to go. There's no way that we can do this without you and we are the ones for whom it matters most. As Gary said in the video, this is a way that we can cure ourselves. So we are very privileged and honored today to have with us two doctors, Dr. Frits Van Rhee of UAMS and Dr. Stephen Russell of the Mayo Clinic. Welcome, doctors!
Dr. Russell: Thank you, Jenny.
Dr. van Rhee: Thank you for inviting us.
Jenny: Well, thank you so much for joining us. This has been so valuable for patients to listen directly from the researchers themselves as they describe the research, how it operates and what they're trying to accomplish. Before we get started, let me introduce you both. Dr. van Rhee is Professor of Medicine and Director of Clinical Research with the Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences. He earned his MD at Erasmus University of Rotterdam in the Netherlands and his PhD at the University of London. He was a Fellow in Hematology and a Research Fellow at the Hammersmith Hospital & Royal Postgraduate Medical School in London. He was also a Registrar Fellow in Hematology at John Radcliffe University Hospital at Oxford and at the University Hospital in Nottingham. He is the beneficiary of a named chair, the Charles & Clydene Scharla Chair for Hematological Malignancies Research. Dr. van Rhee's research focus is on immunotherapy. He leads the Developmental Therapeutics Project in the Myeloma Institute's PO1 grant called "Growth Control in Multiple Myeloma" from the NCI. He's a member of the International Society for Experimental Hematology, International Society for Cellular Therapy, and the European Group for Bone and Marrow Transplantation. He's on the Editorial Board for Annals of Hematology, Bone Marrow Transplantation and Cytotherapy and he reviews for many journals including Blood, Clinical Cancer Research and the British Journal of Hematology including many others. Dr. Stephen Russell is a board-certified hematologist and world leader in the field of gene and viral therapy. He graduated from Edinburgh University Medical School in England having decided as medical undergraduate that he would spend his life attempting to convert viruses into powerful anti-cancer drugs. Dr. Russell moved from Cambridge to the Mayo Clinic in Rochester in 1998 to build and direct a new Molecular Medicine Program focused on the development and clinical testing of new, genetically-based therapeutics. He is a professor of Medicine with the distinction of a named professorship, the Richard O. Jacobson Professorship in Molecular Medicine. He serves as an associate medical director for the Department of Development at Mayo Clinic, Associate Director for Translational Research in the Cancer Center, and Deputy Director for Translation, Center for Regenerative Medicine in the Mayo Clinic as well. He was one of the founding board members of the European Society of Gene Therapy and a member of the board of the American Society of Cell and Gene Therapy. He serves on the editorial board with many scientific journals including Human Gene Therapy, Gene Therapy, Cancer Gene Therapy, the Journal of Gene Medicine, and the Journal of Molecular Medicine. He is also the co-author of more than 275 peer reviewed scientific publications. Thank you so much again for joining us. We have completed shows with both of you on two different topics, but as most who are listening know, there was a big, huge media splash that talked about the measles vaccine in myeloma. Dr. Russell, we can link to the show that has great detail about this, but I think it's important for you to start by giving us some research background, how you determined to do this, what you've found on your first studies, and then we'll move on from there.
Dr. Russell: Thanks very much, Jenny. This whole idea of virus therapy for cancer is completely different from other cancer therapies. The idea is that because viruses are known to destroy tissues in the body or different viruses destroy different tissues like hepatitis viruses damage the liver, the AIDS virus damages the immune system, and the pneumonia viruses damage the lung, the idea emerged quite sometime ago that how about if you try and make viruses that specifically damage cancer and that leave everything else unharmed in the body. People have attempted this since back in the 1950s, but typically the outcomes were a bit discouraging because the viruses were not honed in any way to target the cancer. And so, if the cancer responded, then the patient typically subsequently died. What's become possible in recent years is that we can really work with viruses and change them in such a way that they do become more specific and we really can now think in terms of viruses that specifically target and destroy cancer cells while leaving normal tissues unharmed. That's really what this is about. There are many, many viruses to choose from, probably 3500 different viruses are known, but what we've gone for is an attenuated, i.e. weakened strain of the measles virus. The history of this virus is really quite interesting because it originated in the throat of a boy named David Edmonston back in 1954 when he had a measles infection. The virus was isolated from his body because it was about that time that viruses were just beginning to be grown in the lab. It was that strain of virus that was used to develop the measles vaccines that have been used to control measles infections globally. It just so happens that that strain, the Edmonston strain of measles virus, when it's adapted to grow on cancer cells in the lab, becomes a pretty good oncolytic virus. The strain of measles that we've chosen that originated from David Edmonston's throat has been taught to grow on cancer cells and then it's been genetically modified to encode a gene that allows us to see where it's got to in the body. We can do an imaging study and we can see where the infection has got to in the body because if you think about it, giving a virus as a therapy for cancer, you expect that virus to grow and change over time. And if you want to be able to see what's going on inside the body, then you do need this type of imaging kind of snitch modification. That's the virus that we have. We did a lot of work with it in preclinical testing before we entered clinical studies. We went through the classic phase one study pathway where we start with the very low, some would say homeopathic dose of virus, and we gradually increased the dose between cohorts of three patients until finally, finally two years ago, we reached the top dose level, which was a huge amount of virus given into a vein, the purpose being for the virus to seek out, attack, infect, and destroy the myeloma cells. We got to a very top dose and the second patient that we've treated at that dose level had a remarkable response. That was Stacy Erholtz, who was at the time 49 years old. She'd had myeloma for several years. She'd had two stem cell transplants. She'd become refractory to CyborD therapy and to Revlimid plus dexamethasone therapy. Her disease was relapsing about eight months out from her most recent stem cell transplant and she had an excise tumor growing out of her left forehead, which her family had named "Evan". She had four other plasmacytomas that we could see on the PET/CT scan. She had diffused infiltration of her bone marrow, although the percentage of myeloma cells there was relatively low. Anyway, she elected to enroll in this clinical protocol and she really had the most dramatic response. A single intravenous infusion of the virus led to complete resolution of her myeloma at all sites, in the bone marrow and these plasmacytomas. About nine months after she'd received that treatment, the tumor on her forehead did start to return and was therefore irradiated. She had local radiotherapy. Subsequent to that, she's remained in complete remission. It was interesting actually because she and we alike were very worried that the myeloma would come back elsewhere, but it hasn't done that and it really was a very local relapse at the site of the plasmacytoma on her forehead. She's remarkable. She's the first patient ever anywhere with any cancer type to have such a response to intravenously administered oncolytic virus, so she sort of proved to us what is possible, what can be achieved with this totally new treatment modality. Now, the challenge that faces us is how to transform that into something reliable, reproducible that everybody can benefit from.
Jenny: That's perfect. It's such an exciting idea to be able to use a vaccine to cure cancer. It's just so exciting. We're so thrilled. Can you give us some information about what else you saw and then the barriers that you saw and what you're trying to overcome now?
Dr. Russell: Yes, of course. What we want to understand is why and how did this remarkable outcome occur and how do we make it happen in other people. There are some things about Stacy that we think are probably very important. One of those things is that she did not have detectable antibodies against the measles virus in her blood. Most of us who've had measles or been vaccinated against measles will have antibodies in the blood that can intercept and destroy the virus before it reaches the target site, so infusing a virus into the bloodstream is not going to be very effective if the virus is destroyed before it reaches the target. Now, we have various ways of addressing this problem, but when we're giving naked virus not cloaked with anything into the bloodstream, then really not having any antibody there we thought was going to be important. Actually, it turned out that Stacy did have very, very, very low levels of anti-measles antibody, so we think that's important. We don't know how important it is that she had only very low disease burden. She was relapsing and she was relatively early in her relapse at the time we treated her. We think that may be important, but we do see antibody as a barrier. It may be that very advanced disease is also a barrier, so we're exploring at the moment. We really do not know. The immune system though is something to really focus on because under normal circumstances, our immune system functions to protect us from virus infections. In this scenario, the immune system functions to protect the cancer from the damaging effect of the virus. For that reason, this study that we're proposing now with Dr. van Rhee is designed to address that problem because we know that it's sort of a race between the virus and the immune system when we initiate this treatment. The virus can infect the cancer. It can spread in the cancer. It can damage the cancer cells, but that process stops as soon as the immune system shuts the virus down. What cyclophosphamide does is it substantially slows and delays the immune response to the virus, so by giving cyclophosphamide along with the virus, which is what Dr. van Rhee's study is going to explore, we'll be slowing the immune system and giving the virus a much better opportunity to spread for a longer period of time in the cancer, thereby leading to more tumor destruction.
Jenny: Well, that makes sense about why you're adding the cyclophosphamide. I didn't understand that before just in reading the proposal, so that's why this is so helpful to have you describe what you're trying to accomplish. I have a follow-up question about Stacy, so she never had measles for one obviously, and she had never been vaccinated for measles?
Dr. Russell: Well, interestingly, Stacy had been vaccinated both as a child and two years following her first stem cell transplant, which was routine post-transplant vaccination protocol here at Mayo Clinic, but subsequently, she lost her anti-measles antibody and this is a very important feature of multiple myeloma, is that because it suppresses the production of antibodies, myeloma patients often lose their antiviral immunity. That did happen with Stacy. It's happened with many other myeloma patients. We have been evaluating many, many patients to determine what the antibody status is, how many of those patients have anti-measles antibody. What we've found is that about half of the myeloma patients we've tested do not have protective levels of anti-measles antibody, and about a third of the myeloma patients we've tested have virtually undetectable anti-measles antibody. And so, for the clinical trials that we're doing with naked virus, where we haven't attempted to mask the virus from the antibody neutralization, we're focusing specifically on those patients who have virtually no detectable anti-measles antibody, so a third of the patients that we screen we expect to be eligible on that basis.
Jenny: Have you seen that just across all types of myeloma or have you seen certain types of myeloma that have more of the antibody present than not?
Dr. Russell: Well, that would be really interesting to look at. We have not looked into that. We've not tried to dig deeper into the data that we have, but I think that's a good suggestion because there may be specific types of myeloma that are more likely to be associated with loss of immunity.
Jenny: How do you screen for this?
Dr. Russell: Well, there are actually two tests we do. One of them is a simple, straightforward lab test that's available pretty much in any hospital lab. It's a variation on something called an ELISA, and it's just some beads. They have measles proteins on their surface and they're mixed with the blood, and then they're tested to see whether they capture the antibody. If they have, then you know that there was anti-measles antibody in the blood. The other test that we do is we add the patient's blood to live measles virus in the lab here at Mayo and we determine whether the blood is able to neutralize the virus.
Jenny: When we first spoke about the measles virus, the Mayo Clinic was doing all the manufacturing in-house. How have you developed that process? Because it's been quite a few months since we spoke.
Dr. Russell: We have actually been working with a contract manufacturing organization and we've transferred the process to a group of scientists in that company. I'm not at liberty to state which company it is, but they have the ability to scale up the manufacture and take it to a much larger culture system than we have available at Mayo. We can reach a maximum of 75 liters, but clearly if we take it up to a thousand liters per production run, we're going to have much higher yields. The other thing we're doing is working on the cell culture system that we use to grow the virus to see if we can get high yields in the first place before we start the purification process.
Jenny: Have you made any changes in dosing or did you just determine that dose with Stacy and that's the dose that you're going to be using in the future?
Dr. Russell: Frits can maybe comment on that because Frits is going to go down to low dose. I'm going to hand it over to you, Frits.
Dr. van Rhee: I think we're going to try and see whether the cyclophosphamide suppresses the immune response to the virus and delays the emergence of the antibody. So it sets the stage for prolonged replication of the virus and perhaps it allows us to give a lower dose of the virus than is currently given. The clinical trial, which is actually now open in Little Rock, we are ready to enroll patients. It just opened. We do a dose escalation up until levels that are currently being used at the Mayo Clinic by Dr. Russell. So the hope is that we let the virus replicate longer in the body and have better efficacy and delay the immune response.
Jenny: Some questions about who can join the clinical trial, if it's open right now, are you looking at patients with just low disease burden? I know, Cynthia, you have some questions about for whom the project was for with some CD46 questions.
Cynthia: Yes, I do.
Jenny: Do you want to go ahead and ask that?
Cynthia: Yes. I was reading in the proposal that the prospective patient, there was something with the CD46 that was expressed on their cells. Now, is that something that's expressed on most high-risk patient cells? Would that be something that you would have to have to be a part of this clinical trial?
Dr. van Rhee: No, it is not an eligibility criterion and the reason for that is that CD46 is expressed on all myeloma cells, so it's not necessary to screen or test for that. The CD46 molecule is present in myeloma cells at the cell's surface and it's the protein to which the measles virus docks and gets into the cell. It is expressed in all myeloma cells and in all types of myeloma.
Cynthia: So it's always found in myeloma. Is it found on any of the normal tissues? Would the virus be attacking something that they should not be attacking?
Dr. van Rhee: That's an excellent question. The molecule is expressed -- CD46 is expressed on normal tissues, but at a very low levels. Dr. Russell has done extensive safety studies both in mice made permissible to the measles virus infection, in monkeys, and obviously we now have the human data. The safety signal is very good, which means that the low expression of CD46 on normal tissues is not a problem and does not cause illness in the patient. In other words, normal cells do not get infected, so we are not that concerned about side effects or toxicity of the virus. The main purpose is to try and get the therapy more effective.
Dr. Russell: We did what I think were very interesting studies in the lab where we took cells that did not have CD46 on their surface and we modified them so that they did express it on their surface in different amounts. And so, we had a whole panel of cell lines expressing different amounts of CD46 on the surface. When we put the virus on them, no CD46 meant no infection. As the amount of CD46 increased, the amount of infection increased. And then above a certain threshold level, the infected cells started to fuse with each other and die and they look absolutely dreadful. And so, the virus is really able to discriminate high from low density. And although it may give a low level of infection on cells, i.e. normal cells in the body that have low amounts of CD46, it doesn't really harm them, but once you get up to a very high CD46 level, it causes very substantial damage. We tested every myeloma patient that we've treated with the measles virus to see whether their normal bone marrow cells and their myeloma cells from the bone marrow biopsy have different amounts of CD46, and they do. And on average, it's ten times higher expression of CD46 on the myeloma cells versus the non-myeloma cells in the bone marrow.
Cynthia: Okay, so it's something that we really shouldn't be too concerned about. If for any reason something does go wrong, I guess you could just inject an anti-measles antibody to stop the reaction? Is there a way to stop this reaction once it goes through?
Dr. Russell: Well, we have that written into the protocol that if anything untoward were to happen and if the virus were to spread uncontrollably in normal tissues that we would use anti-measles antiserum. In fact, we'd probably use IVIG because that contains a lot of anti-measles antibody. But just on that safety question, because FDA was very interested in it, there have been well over a billion people vaccinated. And so, those people have been given live, attenuated, weakened measles virus that belongs to this Edmonston lineage. And so far, there have been only two cases where the virus was able to continue to grow in the patient and cause disease. So it's virtually unheard of, this scenario that you're suggesting, and we did not see any evidence of it in any of the patients who've been treated to date. I think it's probably more of a theoretical than a real concern.
Cynthia: Well, that's good to hear. I also have a question. Why did you choose cyclophosphamide as the agent to lower the amount of anti-measles antibodies that you have in your system?
Dr. van Rhee: Cyclophosphamide is a chemotherapy drug which has been around for a very long time, so its safety record is excellent and we know how to use it. It's also used as an immunosuppressive agent, for instance, for the treatment of autoimmune disorders, for graft versus host disease after allogeneic transplant, just to name a few examples. So we know that the drug dampens the immune response and it's a very well tried and tested drug, so that's why it was selected.
Cynthia: Good. So now that there's a way of lowering the amount of anti-measles antibodies in the blood, would thresholds of one-third of the people that have the undetectable anti-measles antibody, would that be able to be increased to more patients to be able to enroll in a trial like this?
Dr. van Rhee: The trial mainly aims to prevent occurrence or to delay the occurrence of the anti-measles virus antibody. It is not aimed to diminish preexisting antibody. So in fact, patients who have substantial amounts of preexisting anti-measles antibodies are not eligible for trial, so you need to have a very low level of antibody to be able to be eligible. The purpose of the cyclophosphamide is to delay the occurrence of the anti-measles virus antibody.
Cynthia: Got it. Thank you so much. I guess those are my questions for now.
Dr. Russell: I guess I'll add a little more to the answer that Frits just gave you, which is that in those patients that do have anti-measles antibody, the reason that Dr. van Rhee and I initially started discussing a collaboration on this work was that Dr. van Rhee has been using natural killer cells as a therapy for myeloma. He isolates the cells from the blood, grows them up, and then gives them back to seek and destroy myeloma cells. At the same time that he was working on that approach, we had been studying in our laboratory an approach to prevent the neutralization of measles and what we had done was to infect cells with measles virus and then put them into the bloodstream instead of putting the virus itself into the bloodstream. We found that if we did that, we could actually bypass all that neutralizing antibody. The cells would carry the virus to the target site, to the myeloma, and would release progeny viruses that would then infect and destroy the myeloma. So we thought, well, maybe we could put our approaches together and we could use Dr. van Rhee's natural killer cells and combine them with the virus and use his cells as the carriers in patients who had antibody. That is something that we still are very enthusiastic to get to, but in this first instance, we're looking at the low fruit, if you like, which is holding the immune system at bay with the cyclophosphamide and seeing how much difference that makes, but we certainly have a plan to in the not too distant future move ahead with the cell carrier approach to deliver the virus in patients who have neutralizing antibodies.
Cynthia: That sounds great. Thank you.
Jenny: Just some follow-up questions, Dr. van Rhee, do you want to walk everyone through just how the clinical trial works and the timing of everything, for example, how are the cells removed, how are they given back, when are they given back, when do you get the cyclophosphamide, and just step us through that process?
Dr. van Rhee: Maybe we should start to touch on who's eligible for the trial. The patients should have failed standard therapies and have more advanced disease, so they need to have relapsed disease. They need to have had at least one stem cell transplant and not be responding to an immunomodulatory drug or to a proteasome inhibitor. So we're looking at patients with more advanced disease. There is no specified criterion that they necessarily need to have a low disease burden. Then in terms of treatment, the patients get one dose of cyclophosphamide and the next day, they get the cyclophosphamide and they get the virus-infused, and they get for two further days cyclophosphamide-infused. So although they get four doses of cyclophosphamide and on the second day they get the virus, the four doses are chosen because we commonly use this in a regimen at our center called VDT-PACE and they are actually exactly the same doses as we use in the VDT-PACE, so we're very familiar with the toxicity of the cyclophosphamide. In addition, this dose translates back to the dose used in mouse studies by Dr. Russell where he found that this dose would suppress the emergence of the anti-measles virus antibody. After the treatment has been given, then obviously the patients are carefully followed for their well-being, for their response both in terms of clinical response and emergence of the anti-measles virus antibody. In addition, as Dr. Russell already hinted at, Dr. Russell modified this vaccine strain to allow for imaging, so we will be doing imaging studies to see where the virus goes and importantly, how long it's going to persist and that it persists at sites where the myeloma is. So one of the things that is written in our trials grant proposal is to do additional imaging studies because it is of crucial importance that the virus doesn't only have the chance to replicate and persist longer, but that it persists at the right site.
Jenny: Okay. I'm taking notes. That makes me think about the question, how long can this vaccine stay in the body and be effective?
Dr. van Rhee: Well, it is a virus and even patients who are heavily pretreated and have a dysfunctional immune system mostly due to the myeloma and their treatment will eventually mount an immune response. A foreign virus is a very potent stimulant even of a somewhat crippled immune system, so we do anticipate that a neutralizing antibody will appear albeit in a delayed fashion.
Dr. Russell: Yes. If I just add a little more to that, the way the virus works -- and it's true of other oncolytic viruses -- is that in the first step of the therapy, the virus infects the cancer cells and kills them. That process continues for as long as it takes the immune system to stop the virus. At the end of that killing spree where the virus has been killing tumor cells and which ends when the immune system has got control of the virus, there are typically going to be still tumor cells that have survived. And so, the virus is now gone and there are still some myeloma cells that need to be marked up. It's at that point that the immune system, having destroyed the virus-infected cancer cells, is now much better able to recognize the uninfected myeloma cells. And so, there's an immunotherapeutic phase to the treatment and this we know from the mouse studies that we've done. We know that it works in these two component stages and we think that that is what is going on with Stacy because Stacy has very long-term control even after that brief relapse of her cancer. We think that the immune system has been responsible for controlling the disease over the longer term whereas the immediate, early destruction of the tumor was due to the virus replicating, spreading in the cancer, and destroying it. The virus may not persist long-term in the body, but the immune system learns during the virus infection to attack the myeloma cells.
Jenny: So it's kind of like resetting your immune system back to what a healthy individual might look like. Is that a good way of saying it or no?
Dr. Russell: That is -- but it's more than that. It's not only resetting the immune system in that way, but it's also teaching the immune system to recognize cancer. That's a huge and very important aspect of modern cancer therapy with the development of the checkpoint inhibitor antibody approach. And so, we do envisage that down the road, it's going to be a very potent combination of mixing oncolytic viruses with checkpoint inhibitor antibodies.
Jenny: And continuing that idea of combination therapy in myeloma. Now, in one of our previous interviews, one of the doctors was saying that on average, a general myeloma patient might have five separate types of myeloma clones in myeloma cells, but you're saying they all express the CD46; so hypothetically, they would all be wiped out. And then if there are others, that vaccine kills off the first set and then teaches the immune system. It can go after those others. Is that correct?
Dr. Russell: Yes, that is correct. I think it's different from a small molecule in that here, you have a fairly complex biological therapy that works in more than one way and that recruits different parts of the immune system to help it do its job. So it may be that this will be a better way to overcome that heterogeneity that you're talking about where there are multiple different clones of myeloma cells, which all need to be controlled by the same therapy.
Jenny: Well, we hope it could be controlled by the same therapy because it'd be great if something didn't grow up later.
Dr. Russell: Absolutely. That's the goal. I think we still have a long way to go, but the dream is absolutely on fire at the moment. I think the fact that Stacy Erholtz is doing so well two years out from that initial therapy is really quite an inspiration to us to continue with this work. She actually asked me to mention that she's half Dutch and she wanted Dr. van Rhee to know that.
Jenny: It's good. It's all good. I'm so thrilled for her and I'm so thrilled for you that this is something that you've studied for so long and you're seeing the fruits of some very hard work, I'm sure. Jack, did you have some questions? I know you did.
Jack: I have a couple of follow-ups. I think a lot of the original questions I had have been asked and answered, which I'm really appreciative of. Just following up on the eligibility or ineligibility criteria, are there any related to either age or secretion or high-risk? Hello?
Jack: Should I ask the question again or do you want to try to answer, Dr. Russell?
Dr. Russell: Yeah, I can answer. Dr. van Rhee was going to answer this question, so if he does call back in, then we'll certainly have him respond. The patients to be enrolled in this study will by definition be high-risk because they will have become resistant to other myeloma therapies and that in itself puts you into a high-risk category. So high-risk in this context isn't really going to be defined according to the cytogenetics or whether it's plasmablastic disease or whatever. It's going to be defined according to the stage of the disease in relation to the therapies that have been administered.
Jenny: Dr. van Rhee, I think you're back.
Dr. van Rhee: Yes. I got cut off.
Jenny: The question that Dr. Russell was answering is the eligibility criteria, what you consider to be high-risk.
Dr. van Rhee: Effectively, most of these patients will be high-risk because they will fail the standard therapies. In addition, patients who have extramedullary disease growing outside the bone marrow will be eligible. Patients with abnormal cytogenetics are eligible, so we are looking at a high-risk population.
Jenny: I know this would be Pat's question, too. How about secretion, if you're non-secretory myeloma patient, would you qualify?
Dr. van Rhee: Yes, you would. You don't need to make the myeloma protein. In fact, many of the patients with more advanced disease don't make much myeloma protein or sometimes they're entirely non-secretory and we have to follow them by imaging. We use MRI or PET scanning to do that. Going back to the prior discussion briefly, one point that I would like to make about the immune response is that in my lab, we've actually looked for myeloma-specific T cells, which are myeloma-specific immune cells. The majority of myeloma patients do have these, so the measles virus sets the stage for cell death and creating an immunogenic environment, and the myeloma proteins, the tumor proteins will be presented to the immune system. And then there's already a pool or reservoir of myeloma-specific immune cells which then hopefully can expand and add to the therapeutic effect. And that has in humans not been looked at and that's one of the things that we're hoping to do with the viral therapy in our research proposal, so we're going to look at the reactivation of the immune response and see if the myeloma-specific immune cells expand and kill myeloma.
Jenny: Just as a quick follow-up question before Jack -- I know Jack has more questions -- when you say myeloma-specific T cells exist, is that in blood or in the bone marrow cells?
Dr. van Rhee: We've looked in the blood, but these cells also traffic to the bone marrow, so they undoubtedly will be in the bone marrow as well. In fact, we've proposed to look in the bone marrow in this study.
Jenny: Okay. Jack, what else did you have?
Jack: Still along the criteria. I know you said patients had to have had an autotransplant as well as be non-responsive to iMiDs and proteasome inhibitor. Are there any other ineligibility criteria that might surprise a patient, maybe they're too old, or anything that is out of the ordinary, I guess?
Dr. van Rhee: Well, we would exclude patients who are medically not fit, so like in all clinical trials, you can’t enroll patients who have multiple other diseases and excluding them from treatments.
Jack: Yeah, I understand that, comorbidities and such, but otherwise, it seems like it's a relatively inconclusive trial.
Dr. van Rhee: Correct.
Jack: Any concerns with cyclophosphamide -- which I'll call Cytoxan because it has fewer syllables and other listeners might want to know they're the same -- any concerns with Cytoxan infusions inhibiting the effectiveness of viral therapy? I don't know if there could be any unsynergistic outcomes here.
Dr. van Rhee: No, we would not anticipate that the cyclophosphamide would affect the efficacy of the measles virus at all. We don't anticipate any negative effects in that regard.
Jack: And regarding Stacy's wonderful outcome, I think you mentioned she was one of three that were treated at the same dosage level and such. Is there something that distinguished her from the other two, which I assume did not have a favorable response?
Dr. Russell: Actually, in the phase one trial, there were six patients treated at that top dose level. She was the star of the show. One other patient had very, very extensive disease and had a transient response. She had many plasmacytomas in the muscles of her legs and her abdominal wall that had become refractory to everything. The plasmacytomas started to hurt about a week after the virus had been infused and the free light chain dropped to less than half its starting level. On day eight, the imaging study that we did showed that the virus was basically cooking in all of those plasmacytomas and we were very excited, but within about four weeks of receiving the virus, all of the imaging signal had faded. The tumors were no longer painful and the free light chain level was rising again. Now, the other four patients did not respond. When we looked at the anti-measles antibody levels in those six patients, two of the six were measles antibody negative and those were Stacy, number one, and this patient that I just described to you, number two. So that made us think that a critical factor was the anti-measles antibody.
Jack: The eight patients that you mentioned in the phase two where you gave a single Cytoxan injection, did they have higher levels of the measles antibodies?
Dr. Russell: No. In the phase two study, we're moving to patients who do not have anti-measles antibody. We didn't give them a single Cytoxan injection because we have not been using the combination of Cytoxan with measles in phase two. It's single agent measles administered intravenously, but the patients that we were treating for initially in that study had very advanced treatment refractory disease. The difference between those patients and Stacy is that if Stacy had been at the time of her relapse given Velcade, Revlimid, carfilzomib, pomalidomide, cyclophosphamide, additional melphalan, bendamustine, and had continued to grow through all of those and had reached the point of having very bulky disease, then that is the situation that most of the patients we've treated in the phase two have been in. We think that that is too advanced. And so, we've modified the entry criteria for the phase two study that's going on at Mayo Clinic so that we will be treating patients with earlier stage disease and with less disease burden.
Jack: The letter of intent though, I think I read that in a cohort of eight patients, we see the virus infusion along with the single dose of Cytoxan. Is that correct?
Dr. Russell: That was very early on in the phase one trial at a much lower dose level. The dose of cyclophosphamide administered was very low. We abandoned it because at that point, we had a breakthrough with the manufacturing and we were therefore able to push the dose up to a much higher level. And so, we decided that rather than pursue cyclophosphamide combination therapy at that point, we would pursue dose escalation. Meanwhile, we completed additional studies on the combination of cyclophosphamide with virus therapy and discovered in the course of doing those studies that the dose of cyclophosphamide needed to be substantially higher in order to have the desired impact. That is the cyclophosphamide regimen that Dr. van Rhee is using in the study that has just opened at Arkansas.
Jack: I understand. Thanks very much. I wish you the very best of success with this subsequent trial.
Dr. Russell: Thank you. We're very excited.
Jenny: Well, I think it's so exciting and I think it's fabulous that you have imaging studies that you can really watch what's happening and see where it's effective and when it loses its effectivity. It's amazing.
Dr. Russell: Yes. The imaging is critically important for this because cyclophosphamide does have known activity against multiple myeloma. The ability to be able to independently track the propagation of the virus in the body using the imaging study is therefore crucial. So when we see responses, we'll know what the relative contributions of the cyclophosphamide in the virus therapy are.
Jenny: Well, it's totally fascinating. Two other questions that I have and then I want to still allow some time for caller questions, is first, how many patients are you working to enroll in this phase two trial?
Dr. van Rhee: Well, we want to enroll altogether around 16 patients.
Jenny: And that's just at UAMS, right? This is a study primarily there, but you're working together on the construction of the study?
Dr. Russell: Yes. The UAMS trial is the combination of measles virus with cyclophosphamide. In the ongoing phase two study of virus alone at Mayo Clinic, it's up to 42 patients.
Jenny: And those are just going to run simultaneously, right?
Dr. Russell: They'll be running simultaneously, yes.
Dr. van Rhee: I think obviously, if our study proves to be successful, we hope that we can expand it and treat more patients, but the initial plan is for 16 here at UAMS.
Jenny: Absolutely. Maybe my last question would be can you outline the different milestones that you have with the timeline and then expected budget requirements to do what you would like to do?
Dr. van Rhee: One of the major milestones obviously is to see that the cyclophosphamide will hamper the occurrence of the anti-measles virus response, so we'd like to see the measles virus antibodies generated later and we'd like to see that there's prolongation of the viral replication in the blood, and hopefully we're also going to see with the repeated studies, the imaging studies, that it's actually replicating at tumor sites. In the first four patients, we're going to go through dose escalations, so we're going to start at a lower dose before we reach those levels currently used at the Mayo Clinic. The next patients will be treated at much higher levels and hopefully we are going to see major milestone responses. And as Dr. Russell already pointed out, this occurrence of an immune response may prove very important in maintaining responses and maintaining remission. Another milestone would be that we could actually detect the tumor-specific immune cells and that we can see that they multiply in the patients. Obviously, we can demonstrate in the labs that they have the ability to kill myeloma cells, so those are the major milestones.
Dr. Russell: The other non-scientific milestone, which is the real goal, is we want to see another Stacy and then we want to see another Stacy, and then again. That's the goal of this obviously, is to see those dramatic responses, but clearly these scientific milestones are really critical in enabling us to reach that ultimate goal.
Jenny: Well, we love that goal. We love the research and we love that goal. Is there an estimated cost per patient like for manufacturing costs or just overall to do the project?
Dr. van Rhee: Well, obviously these therapies are not necessarily cheap in terms of manufacturing. If you cost out the whole clinical trial, it adds up to a significant amount of money per patient. What we obviously are seeking support for is the additional studies both in terms of imaging and in terms of understanding what happens with this therapy both with the anti-measles virus neutralizing antibody and the immune response.
Dr. Russell: Yes, so the cost of manufacturing I don't think is something that we are seeking through the Crowd Initiative. Manufacturing clearly is a potentially very substantial part of the cost of performing these studies, but if it does prove to be the case in the study that Dr. van Rhee is doing that a lower dose of virus is much more effective when combined with cyclophosphamide, then that could be a huge advantage in respect to the long-term costs of manufacturing a dose for a patient, but at the moment, we have other sources of funds that are taking care of the manufacturing costs.
Jenny: Great! Well, I don't want to take all the time. I want to open it up for caller questions, so if you have a question for the doctors, please press 1 on your keypad. I know we're a little past our time, but we're going to keep you just for a few more minutes, if you don't mind.
Caller: All right. Thank you for taking my call. My question is I had a stem cell transplant and I have gotten the measles vaccine since the transplant. If that makes me ineligible for this kind of treatment, would you suggest perhaps that a patient have another transplant and wipe the slate clean? Would that make someone eligible for this treatment that isn't potentially at the moment?
Dr. van Rhee: I think obviously, you need to have effective therapy for your myeloma. I don't think that that should be a strategy. It should be directed at purely eliminating the measles virus antibody. The other point to make is I don't know what treatments you've had following your transplant, but if you've had maintenance therapy with some drugs, it might be that you haven't had a good response to the vaccine and that you have not had antibodies generated. So even with the fact that you've been vaccinated, in my view, it might still be worthwhile just to see whether you've got anti-measles virus antibodies if you have had maintenance treatment.
Caller: Okay. I have, so that's definitely worth looking into.
Dr. Russell: It's a very important point you're making and I would make a very strong plea to any patients who are listening not to aim for strategies that will get rid of anti-measles antibodies. This is not a proven, effective therapy. This is experimental therapy and it's just wrong to change your treatment plan in order to make yourself eligible for this treatment. If and when it's proven and we've ironed out all the problems and we do have a reliable, reproducible, effective therapy, then maybe it would be the time to consider that sort of thing, but it would just be completely wrong for us to say to you, "Go ahead and have a second transplant to see if you can get rid of the anti-measles antibody." That's absolutely not appropriate.
Caller: Okay. What is the commitment to participate in the trial, how much travel, how much time, for example?
Dr. van Rhee: You will spend -- essentially, you'll be at the first month in Arkansas and then you will be coming every three months here for at least a year, so this requires some time and travel and dedication.
Caller: Okay. I also have my mother here with me. She was my caregiver and she has a question, if that's okay.
Caller: I understand you are in phase two of your work and I was wondering for us that are eager, of course, in this situation, how long do you anticipate before we hear your plan, if your system is giving positive results? Would you say a year or two or three?
Dr. van Rhee: Well, we're enrolling at UAMS -- the plan is to do 16 patients and we're hoping to enroll about one a month. So realistically, we're looking at one and a half years before enrollment is completed, but we should be able to get an idea about the efficacy of the therapy in the next two years, or at least the efficacy of the approach of combining cyclophosphamide with the virus.
Dr. Russell: I would agree with that assessment. I think we need two years. I would be delighted if we were able to shout something from the rooftops sooner than that, but I think it's reasonable to think in terms of two years before we have a much better fix on how effective the virus is and under what circumstances.
Caller: I know this is somewhat of a difficult question for you doctors to answer, but compared to all the other treatments that are being developed right now -- and I'm sure you're familiar with all of them -- would you say yours is extremely promising at this point as opposed to others?
Dr. van Rhee: I want to say something first. One of the exciting things about this therapy is that it's not dependent on the risk profile of the myeloma or the genetics of the myeloma, so this viral therapy approach could overcome potentially nasty mutations in the myeloma clone, and that makes this type of approach so exciting. Steve, maybe you want to elaborate on that.
Dr. Russell: Relative to other myeloma therapies, obviously I'm going to have a very optimistic perspective. I totally believe in this approach to therapy. And having seen the dramatic response that Stacy Erholtz had, I now know that it can be effective. We really just need to determine how. The other treatments that we have available work, the new iMiDs, the new proteasome inhibitors, the monoclonal antibodies against CD38, they definitely have anti-myeloma activity. Putting all those drugs together is going to give us better and better outcomes. The problem I see with our approach to myeloma therapy is that we keep people on treatment for a long period of time and that's a very high penalty paid in terms of toxicity for the treatment that we do give. Actually, one of the things that Stacy said to me was that of all her myeloma therapies to date, this was the one that gave her the best remission because she was off all therapy, and it was a single intravenous administration of virus and then no therapy other than the local radiotherapy for the next two years. So for her anyway, it was far preferable to being on Revlimid maintenance or on cyclical chemotherapy every week with the CyborD and then with the Velcade maintenance. I think if it does prove to be the case that we can determine how best to use it, it could be a game-changer and it could be much preferable to the existing approaches.
Caller: And you are pretty positive that this possibility exists?
Dr. Russell: Yes, I am, but you've got that health warning on that statement that I'm the person who developed the measles virus in the first place.
Jenny: You might be a little biased, but we're excited that you are. We have time for one more caller question.
Caller: Good afternoon, Dr. Russell and Dr. van Rhee. I really appreciated hearing your ultimate goal, that being we want to see another Stacy and another Stacy. I can't agree with you more. Stacy is a member in our online support group and we have been cheering her on. It's really just such a unique opportunity to have her in our group and as patients, we can actually see and hear how she's doing. A question, if successful, if this treatment is successful in the relapsed stage, the high-risk stage, I guess the aggressive stage, do you see moving this approach into newly diagnosed myeloma patients who are treatment-naïve, those who perhaps at the early stage of myeloma have a lower tumor burden and have a less aggressive, mutated level stage of the disease, or is it too toxic for someone like that?
Dr. van Rhee: Well, that is actually probably one of the good things about this therapy. The studies that Dr. Russell and his colleagues have done at the Mayo Clinic shows that the therapy so far has proven quite safe and non-toxic. Dr. Russell made a very important point that patients require prolonged therapy at this moment in time. In Arkansas, we use the dreaded Total Therapy Approach, which means two cycles of chemo, two transplants, two further cycles of chemo, and three years maintenance, which is an enormous amount of treatment. The results are very good, but if you actually could achieve the same with a very limited treatment approach upfront, I think that that will be truly exciting and truly innovating. Obviously, we hope that viro therapy can achieve this and Dr. Russell is obviously pursuing multiple avenues to try and get these therapies as effective as possible, and maybe Dr. Russell would like to expand on this.
Caller: Thank you, Dr. van Rhee.
Dr. Russell: Well, on the toxicity front, I think it would be -- at least on what we know, remember at the moment, we're early stage, so the information we have about toxicity is somewhat limited. But generally, what we see is that during the infusion, there may be a headache. In fact, Stacy got a pretty bad headache. The infusion was stopped. She had some Benadryl and the infusion was restarted. Most patients don't get the headache, but sometimes they do. Post-infusion, everything was quiet for an hour, two hours, sometimes four hours, and then the shaking begins, the rigors as the temperature increases. And so, body temperature goes up typically to around about 40 degrees by late afternoon on the day of the infusion, and there may be some vomiting. We haven't reached the point yet where we pre-empt that and we give therapy to prevent it. We almost like to see it because then we know the patient has actually received the virus.
Caller: And having a response to it.
Dr. Russell: And then overnight, the fever typically resolves. And so, by the morning, the temperature is back down to the normal level and it may bounce up and down a little for the next week or so, but it's really that early -- you certainly know when you've been infused with this treatment. But I think it's manageable and it's acceptable toxicity provided this ends up being an effective therapy, so we could envisage bringing it as a frontline treatment for myeloma if we really do iron out all the issues with how best to use it.
Caller: Hypothetically, Dr. Russell, if you did iron them all out, let's say within that two-year timeframe, would you move into the newly diagnosed patient right away or would you continue to test it in that relapsed setting just to more or less validate it and test it further?
Dr. Russell: Well, that is a question that I have not really thought through. I think you're now getting into the territory of what is the best drug development path in order to get FDA approval of a new drug for the treatment of myeloma patients. It seems that very often, the best approach is to demonstrate that it's beneficial in patients who did not have other treatment options because then FDA will ultimately say, "Okay. We approve." It's typically after that's happened that drugs are used earlier and earlier in the course of the disease, so I don't know. I don't know whether that would be different for a drug like this, but I think we'll cross that bridge - we hope to cross that bridge when we get there.
Caller: Well, thank you, Dr. Russell. I'm actually a smoldering patient, so I have time to wait and I'll walk that bridge with you hopefully someday. All right. Thank you both very much for taking the call. I appreciate it.
Jenny: Thank you so much for your question. Well, doctors, we are so happy to have you on. This is such an exciting project. We love that you're collaborating. We love that you're making refinements and changes along the way as you learn more. I think that's just part of the whole process. We're excited that you're looking at something that could be applicable for all myeloma patients and are just very grateful for all the work that you're doing.
Dr. Russell: Well, thank you very much and thank you so much for giving us the opportunity to appear on the show and discuss the myeloma viro therapy approach.
Dr. van Rhee: I absolutely second that. Thank you very much.
Jenny: We are learning so much from you, so thank you so much. Thank you to our listeners for listening to Myeloma Crowd Radio and the new MCRI series. We believe that patients can help support the discovery of a cure and we encourage you to become involved.