David Chung, MD, PhD
Memorial Sloan Kettering Cancer Center
Interview Date: November 19, 2018

Why do some multiple myeloma patients relapse early after stem cell transplant while others stay in remission for many years? The patient’s immune system may be a key factor.  

David Chung, MD, PhD of Memorial Sloan Kettering Cancer Center was recently selected as a Myeloma Crowd Research Initiative (MCRI) award recipient. The goal of the MCRI is to help optimize myeloma therapy for individual patients.

Dr. Chung’s research will review patients who have undergone stem cell transplant. He will study three different parts of their immune system after transplant – T cells, lymphocytes and myeloid derived suppressor cells (MDSCs) and will compare early vs. late relapse. He will then combine that immune system signature with the myeloma genetics of each patient to understand the impact they have together. 

Learn why studying the immune system may be just as important as the study of myeloma genetics and what this research can mean for you personally.

The Myeloma Crowd created the MCRI because we “Can’t Wait for a Cure.” Through the MCRI we want to help find the right treatment for the right patient at the right time. The MCRI is funding three research projects – each with a different focus – that will also integrate with HealthTree, a new tool for myeloma patients. Learn more about HealthTree here.

 

Thanks to our episode sponsor

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. Now, today is the first show in a series of three on Myeloma Crowd Radio for the Myeloma Crowd Research Initiative or the MCRI as we call it.

When we started the foundation, we asked our scientific advisory board what we could do fill gaps in research funding. The first time we did this, they unanimously said we should fund high risk research. So we did a global call for proposals to find the best high risk projects. We received 36 proposals globally and narrowed that to two that we could fund. We'd like to thank everybody - for their family members, caregivers and friends that helped contribute because we raised $500,000 for these projects. 100% of every dollar donated was given to the researchers. The first was a CAR-T therapy from the University of Wurzburg going after two CAR-T cell targets, CS1 and BCMA. The second was an immunotherapy called MILs from Dr. Ivan Borrello, who is an immunologist in myeloma.

The next year, we asked the same question, what should we be doing to fill gaps? Because there are a lot of good organizations out there already doing wonderful things. One of the doctors suggested with all the new treatments, patients could use a tool to help them identify treatment options they could consider especially if they were being seen in the local oncology setting.

Based on this feedback, we developed the HealthTree tool. With HealthTree, there are three things the patients can do. First, they can understand personalized treatments they could consider to have better discussions with their doctor. Second, they can find clinical trials that they are eligible to join. And third, we can share our myeloma story anonymously with other patients and researchers to help identify faster cures. We're so excited and thrilled that this new tool is working. Over the summer, we canvass the country in 50 cities to share the tools over 800 patients, and now over 2100 patients are using HealthTree. And we're so excited to be sharing some of these data shortly. If you'd like to join HealthTree, you can go to healthtree.org and create a patient profile.

Now, our focus for the second Myeloma Crowd Research Initiative is complementary to what we've built with HealthTree. We heard from several doctors that a small fraction of patients could possibly be cured. So we want to know who they are and how they're achieving success, so it can be replicated. The second Myeloma Crowd Research Initiative is focusing on optimizing myeloma care because so much can be done to lengthen life with today's drugs if they are applied for the right patient with the right order at the right time. We have asked all three projects that we're funding to integrate in some way with our HealthTree project.

There are some important questions. The patient outcomes, are they only related to myeloma genetics? Could it be something else like their immune system status or cells that persist after intensive treatment like transplant have an impact? Why are we so all so unique and how can we select treatments so we live as long as possible individually with myeloma with an ultimate goal of finding a cure?

Now, we have selected three projects for the second MCRI, each with a unique take on these questions. Today, we are pleased to announce three winners: Dr. David Chung from Memorial Sloan Kettering Cancer Center who we will hear from today on his work to create an immune system signature for patients; Dr. Cesar Rodriguez of Wake Forest University who is working on a new platform called organoid 3D tumor modeling to test myeloma treatment combinations against your individual tumor including your bone marrow microenvironment; and Dr. Frank Zahn of the University of Iowa who is doing work to identify myeloma stem cells that could persist after treatment and be the cause of relapse.

We'll be funding these projects for a total of another half million dollars or more and invite you to join us. You can go to http://give.crowdcare.org/mcri and create an individual or team fundraising page then share it in any way you want. You can join the local walk or run and share your page, share your page next Tuesday on #GivingTuesday on social media or share it during the holidays as a way people can support you and your efforts to speed up a cure for myeloma. You can share it by email, Twitter, Facebook or your other social media accounts because your friends and family want to know how to support you and many times, this is an excellent way of doing that. The end of the year is when the majority of donations are made. So we just encourage you to create your page and share.

With that, we'd like to welcome our guest, Dr. David Chung on today's program. We have a lot to learn from him today. Dr. Chung, welcome.

Dr. Chung: Thank you. Hello, everyone.

Jenny: It was a longer introduction that we usually have, but this is a big kick-off to the MRCI, and we're so thrilled that we're able to award you with funding for this project. Let me introduce you a little bit before we get started with questions.

Dr. David Chung is a member of the Cellular Therapeutic Center and assistant member of the Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center and Assistant Professor of Medicine at Weill Cornell Medical College as well as Assistant and Attending Physician at the Rockefeller University Hospital. He performed his medical degree and PhD at Georgetown University, his fellowship and post doc at Memorial Sloan Kettering and then another fellowship at Weill Cornell.

His research is focused on the development of immunotherapies for cancer with the focus on cellular therapies. One of his distinct goals is to create an immune system signature for patients to help with the development of new dendritic cell-based vaccines and other immunotherapies like checkpoint inhibitors or CAR-T treatments in myeloma. His awards include a Young Investigator Award from ASCO, the Mortimer Lacher Fellowship in the Lymphoma Foundation and Translational New Investigator Award from the Department of Defense. He received a Clinical Investigation Award for his dendritic cell works post-transplant and I hope we can incorporate some of that today as we talk.

So with the introduction, we're ready for some questions for you, Dr. Chung. Maybe you can just start out by giving us a broad assessment of what's the role of the immune system in fighting multiple myeloma?

Dr. Chung: Sure. First, I would just like to thank you again for the kind introduction and also thank you very much for the generous support for our research. In terms of your first question about the role of immune system in fighting myeloma, we know that the immune system helps control myeloma and that compromised or impaired immunity contributes to the development of active myeloma and progression. For instance, studies have shown that T-cells, which are a type of white blood cell that helps fight cancer, can recognize myeloma cells in patients who have active disease, and that the levels of these cells correlate with the amount of disease that a patient has.

Also, we know that increased numbers of T-cells that can recognize or are specific for myeloma cells after autologous stem cell transplantation and also after allogeneic stem cell transplantation (which is a kind where you get stem cells from a donor) – in both of those situations, if you have increased numbers of T-cells, patients tend to have better outcomes. In contrast to that, when there is a loss of myeloma specific T-cells, and that's been described during progression from the precursor condition for myeloma called MGUS or monoclonal gammopathy of undetermined significance, we see that there is a loss during that process. Also, myeloma cells themselves can also evade the immune system by different mechanisms including mechanisms that put the brakes on the immune response.

Overall, this provides rationale for developing or pursuing immune-based therapies to stimulate or restore anti-myeloma immunity in patients to improve outcomes. Of course, the key step in developing immune-based treatments is to better understand the changes in the immune system at different stages of the disease. It's been proposed that there are differences in immune fitness, if you will, between patients who do well versus those who don't, and that this difference influences how myeloma progresses, how it responds to standard treatments and also the patterns of relapse and progression.

Jenny: Is that why sometimes older patients might be more prone to getting myeloma because at some level, their immune system is getting weaker?

Dr. Chung: That's a hypothesis in general for cancer. We know that as we age, one of the downfalls of aging is that our immune systems tend not to be as robust. And so that could be a contributing factor.

Jenny: Well, I think this is a fascinating topic to be able to help identify that. I had a question also about when you mentioned myeloma and T-cells that are myeloma specific T-cells, what are those, and what do those look like?

Dr. Chung: When we say that a T-cell is specific for myeloma, what we're talking about is -- well, so we need to understand how the immune system works. When something foreign comes into the body for instance, the immune system has the capacity to recognize something that shouldn't be around. And then in response to that, a series of very complicated things happen and the immune system eventually triggers the soldiers of the immune system which include the T-cells to eradicate cells that have certain markers on their surfaces that make them distinct from other cells.

Then also, the immune system in addition to its basic role in terms of fighting infection, we know that the immune system also has the ability to keep cancer at bay. And then over time, in patients who eventually develop cancer, something goes awry and the ability of the immune system to keep things capped is lost, and that contributes to the progression. And then when we're talking about T-cells that are specific for myeloma, what we're talking about are specific cells that have the capacity to recognize certain markers that are on myeloma cells and think that they can recognize them and they can kill those cells.

Jenny: Okay. That makes a lot of sense. Because when something foreign comes in, your body is essentially taught to recognize and then go after it.

Dr. Chung: Correct.

Jenny: Right. So, you've done a lot of work on the immune system and the immunotherapies and on dendritic cell vaccines and things like that. Can you just give some background about your work in general so people know, understand where you're coming from?

Dr. Chung: Sure. As you mentioned in the introduction, a major goal of my research is to understand the immune system in cancer patients so that we can make more informed decisions about rational approaches to immune-based treatments for cancer specifically myeloma in my case and also optimizing vaccine-based therapies. My work on the immune system started during fellowship here at Memorial when I joined the laboratory of James Young who was also a member of the transplant service. At that time, Jim's lab was exploring how to make cancer vaccines using dendritic cells - which are a special type of white blood cells critical to turning on and controlling immune responses. The lab at that time was studying the biology of different types of dendritic cells because there is more than one type and that was done to figure out the best ways to fine-tune cancer vaccines and make them more effective.

When I joined the lab, my initial project was focused on understanding important regulatory pathways in human dendritic cells again with the ultimate goal of improving dendritic cell-based immunotherapy. One of the first things we showed when I was in the lab was that a specific subtype of dendritic cell called the monocyte-derived dendritic cell. I'm trying to avoid too much technicality but I need to include some of the terminology. But these monocyte-derived dendritic cells are the most common subtype of dendritic cell that's used in vaccine therapies for cancer. These particular subtypes of dendritic cells have high levels of an enzyme called indoleamine 2,3-dioxygenase or IDO that can actually counteract an immune response.

Under normal conditions, having this enzyme around is important to service a break to prevent uncontrolled immunity that could cause damage to our normal healthy tissue. But in situations like cancer where you want a sustained immune response against the tumor, then potentially blocking IDO, this enzyme is one way to boost the vaccine effect. So that was my initial project in the lab. And then as mentioned, there is more than one type of dendritic cell and our lab also showed that a different type of dendritic cell called a Langerhans type dendritic cell, or LC, can trigger stronger immune responses than the more commonly used monocyte-derived dendritic cell. And so that provided rationale for using the LCs in some of our most recent vaccine studies which there are two.

And then, also another thing that's important is that when a cancer vaccine is being designed, one of the key factors is choosing what you're going to target on a cancer cell. Cancer cells, as I mentioned have markers that distinguish them sometimes, not always, but markers that distinguish them from other cells in the body. And the scientific terms for this type of cell marker is “antigen”. The more unique or rare these markers are the better, because you want to target something that is not expressed commonly or is only very rarely expressed by normal cells because you don't want your immune system to attack normal cells.

And then once you've identified a marker or antigen, then you need to figure out how you're going to deliver that antigen to the dendritic cell so that they can use that to teach the immune system what to attack. The most common approach in vaccine therapy has been to pick a short fragment of a marker and give that to the dendritic cell. In a sense, you're betting that the fragments that you've chosen will be enough to generate a good immune response. There are limits to that if you can imagine. So we've been exploring other alternative approaches to this and we've decided to pursue an approach called mRNA electroporation.

Again, I don't want to get too technical with this approach. But instead of providing just a fragment of the target antigen, using this alternative approach, you are providing the entire antigen so that the dendritic cell can show multiple parts of fragments to the immune system to get a more complete immune response. So using this method of antigen delivery when making a vaccine showed better results when compared with a more traditional approach that I mentioned in our preclinical tests. For this reason, we have used this mode or method of antigen delivery in our most recent vaccine studies. One was a study, a dendritic cell study for skin cancer melanoma and the other was for myeloma.

And then not to be too long-winded, but another area of study that we've been looking at more recently is how the immune system recovers after transplant and what the immune system looks like when patients relapse after transplant. This is important because the development of rational immune-based treatments after transplant requires a full understanding of the post-transplant immune environment. In other words, it's really important to understand the status of the different components of the immune system. Are the cells that are there functional? Has the relative balance of cells changed in a way that might hinder an immune response? Etcetera, things like that.

So we recently published a study where we show that there is -- first, that there is preservation or maintenance of dendritic cell and T-cell function after transplant and we did that by taking blood samples from patients and identifying these cells and showing that they look as expected under -- with a test called flow cytometry and that they also have -- were intact functionally. And then we also showed that the early post-transplant period is a good time to try to introduce vaccines and immunotherapy and that we also identified a unique population of relatively inactive or quiet T-cells. The more technical term is exhausted or senescent T-cell and that having more of those was associated with relapse after transplant.

Jenny: They're just too tired to do their job potentially.  

Dr. Chung: Yes, exactly.

Jenny: Okay. Sorry. I didn't mean to interrupt because this is all amazing.

Dr. Chung: That's okay. That's I think a pretty good recap of the work that we've done to date.

Jenny: It's amazing. I want to ask a question too, because when you think about -- we've heard so much about precision medicine in going after specific genetic targets for myeloma. Can we find either of these point mutations like an NRAS or KRAS or something like that or go after the genetic features that people have like let's say somebody has a deletion 17 or something. But it seems to be more comprehensive than that. But it might not just be those factors. It might have a large part to do with the immune system status like you're saying after transplant, how robust are those T-cells. What's your opinion on trying to get to truly personalized medicine?

Dr. Chung: I think that the ultimate personalized medicine would be training your own immune system to get rid of your myeloma. That would be beneficial. If we can identify the right way to do this and its sort of a holy grail of cancer immunotherapy is if you can establish that within a person, then you would have -- sort of like if you get a vaccination against hepatitis or the flu or something like that. Where if you have an immune system that's intact and then receptive to a vaccine for instance, I'm not saying vaccines necessarily have to be the one and only approach. But using that as an example, if you can develop an effective vaccine, you could potentially help train a patient's immune system to recognize their tumor and to keep it under control for a very long time. So that would be the ultimate form of personalized medicine. 

Jenny: Well, I love the idea of that because a lot of these immunotherapies too don't have long term side effects that some of the chemotherapies do or even if you could reduce the burden with chemotherapy and then just maintain forever, when you have this lower burden with the immune system, that would be amazing as well.

Dr. Chung: Right. Those are some of the things that are going to be coming up in the next few years as we develop better approaches as we understand more about the best way to vaccinate people and really, the next step is going to be how are we going to combine this with other treatments to get the best response possible?

Jenny: I know earlier you mentioned that you're working primarily right now to look at patients post-transplant. But what you're saying in general is that this approach could be used for all types of patients, transplant or not, but that might be your initial focus?

Dr. Chung: Yes, that's correct, because the patient population that I see on a day to day basis are patients who have had a transplant. So they are the ones who I have that are readily accessible to contribute to our research program by donating blood and bone marrow samples. That's going to be the initial focus. And then once we've done sufficient amount of work on our proposed projects, then the goal would be to extend this to the broader population of patients who also don't undergo transplantation because I think that ultimately, a lot of these immune signatures will be relevant in those patients as well.

Jenny: Yes, absolutely. For sure. It sounds like you're looking at three different components of the immune system. Maybe you want to walk through those and we might come back to some other questions. But map it out for us, what you're looking for in trying to create this immune system signature.

Dr. Chung: Our plan is to compare how, again, how the immune systems of myeloma patients undergoing transplant change over time to see if there is a distinct immune biomarker signature indicative of disease status. And two, the initial studies that we're going to pursue to look at these are as follows:

The first step is we're going to look at the lymphocyte or also known as white blood cell subpopulations and function. What this will involve is taking blood and bone marrow samples at relevant times points. The major time points would be before transplant, after transplant when patients are having their standard disease with staging in which is usually around three months.And then down the line at time of relapse or for patients who don't relapse, that's sort of a similar longer-term time points. And then we're going to look at the white blood cells using initially a technic called flow cytometry. If we find that some interesting results may actually pursue more sophisticated tests, but initially flow cytometry is the test that we're going to use. What that allows us to do is to see the relative balance of each subtype of white blood cell and also to see if the individual subtypes expressed new markers over time and how the profiles of patients who do well versus those who don't do as well are different. This type of immune profiling may help us identify patients that are at higher risk for early relapse. That's the first part.

The next part is a little bit more esoteric in terms of deep dive scientific stuff. That part is looking at the T-cell diversity of a patient over time. What that is, again, it's a much more detailed study of what the T-cells are actually recognizing. With this type of test, we can measure the relative number of T-cells that recognize certain antigens and we can also see if there is the appearance or disappearance of specific cells over time and how those changes relate to disease status. For instance, is there a certain -- and we call these “specific T-cells clones”. One clone will recognize one type of antigen and then another clone will recognize another. Looking at a relative balance, we could potentially see if over time that patients who do well develop new clones that might be identifying myeloma targets versus patients who don't do well who lose these certain clones over time. You never know what you're going to find. It actually could be different. It could be the opposite of that. That's what the second step is, is to try to get a better understanding of how these clones are shifting over time, the T-cell clones that recognize markers on myeloma cells potentially.

Jenny: Can I ask you a question before you go to number three?

Dr. Chung: Sure.

Jenny: When you're saying certain clones are appearing or not appearing, are you talking about something like let's say somebody starts out with a 4;14 clone and then you're watching T-cells going after that clone, and then they develop deletion 17P later and you're assessing. Are there T-cells that are going after specifically after deletion 17? Is that what you’re talking about?

Dr. Chung: No. That's actually a separate issue. It's possible that patients with certain clones that have these cytogenetic changes that you've mentioned will have distinct markers. But as far as I know, there are no studies that really show direct correlations of certain antigens matched to certain cytogenetic changes. The clones that I'm talking all about are using this T-cell repertoire type of test. We can measure what these cells are seeing and how they change over time, how they rise and fall potentially or how they rise and sustain or how they just fall off. We can correlate that with disease outcome, but again that's separate from cytogenetic changes.

Jenny: That makes sense.

Dr. Chung: What they're actually recognizing, that would be the next step of this test would be to try to figure out the best test to try to figure out what they're actually seeing. That's the tricky part, because if you have a marker or antigen that's very commonly known, we can figure out sometimes what the T-cells are actually seeing. But if it's a new marker that's a distinct marker let's say on new myeloma cell, then we wouldn't know that beforehand. And so it would be hard to say what exactly it is identifying. But if we see certain patterns, we could make some correlative assumptions that maybe that's beneficial. Again, that's going to have to bear out over time and we're going to need a lot more information on how best to look at that type of data.

Jenny: You're looking for markers like CD38 or BCMA or something, a marker like that, is that what you're looking for or is it something totally different?

Dr. Chung: Yes. Those are kind of more markers that we would look at. But you know, cancer cells as they evolve over time can acquire different markers. I think we'll probably end up talking about the concept of neoantigens later, but that's where that comes in.

Jenny: Okay. Wow. I'm learning a lot. You were talking about the second T-cell diversity of a patient and what it's recognizing. Is there anything else on that before you want to move to the next section?

Dr. Chung: No. I think we have covered that pretty well. And then the third part of this part of the proposal is to look at a subpopulation of cells called myeloid-derived suppressor cells or MDSCs. All our terminology is pretty jumbled in medicine. But these are cells that dampen the immune response and they have been shown to be increased in the blood in bone marrow patients with active myeloma and again the cells suppressed T-cell responses.

There was one study that showed that the negative immune effect by these myeloid-derived suppressor cells can reversed with a combination of Revlimid and immune checkpoint blockade. We're going to look at this in this patient population to see the pattern of the cells and the blood and the bone marrow. These studies are going to be done in collaboration with one of my colleagues here in Memorial, Dr. Alexander Lesokhin.

Jenny: Okay. Well, that's really interesting. I would like to ask some more follow-up questions about that because there were studies earlier with Revlimid and checkpoint inhibitors that had some issues. I'm just curious about how you go about doing that.

Dr. Chung: Well, what I was saying is that that is one study that that showed that that could overcome the negative effect of these cells. But the whole issue of treating patients with Revlimid and checkpoint blockade, as you know last summer, things were halted because of the toxicity signal. As of now, there is still a lot of unknowns about how we're going to fit these treatments into the myeloma treatment regimens. But I think the point of this is to again see what the patterns are with the myeloid-derived suppressor cells in these patients that we're going to study and then also a longer term to figure out other ways to inhibit their negative effect on the immune response. What those are is still to be determined.

Jenny: Oh, I see. So you were saying that there are higher levels of these MDSC cells in myeloma patients which means it dampens the immune response even more when you have more. Is that correct?

Dr. Chung: Correct.

Jenny: Okay. And then you're trying to figure out a way to reverse that. They're just at normal levels because you want the immune system to respond and fight the cancer. Okay. Those are three important components. It just sounds like you're looking at a holistic approach, not just one part of the immune system. You're looking at it all. It's so complicated.

Dr. Chung: It is extremely complicated. Right. If we knew what the most important and most relevant components are, then we could be more focused in our studies. But just because there really is not as much known in a comprehensive way, we want to start as broad as possible and then see where the studies take us and then try to hone in once we get more information.

Jenny: Going back to what you were talking about earlier when you're studying patients who are post-transplant. What are the most broad things that you've noticed about the immune system for those patients and talk about neoantigens a little bit later?

Dr. Chung: Okay. We did a study where we had myeloma patients and did some of these studies that I mentioned on those patients. What we've seen is that, at least in terms of the immune system, that one, the early post-transplant period might be a good time to introduce vaccines in other immune-based treatments for several factors. It's a little bit technical, so I'm not going to go into that. But basically, it's a receptive environment where you can -- for instance, if you bring in a vaccine-based treatment, you could potentially generate a more effective immune response.

We've also shown that -- one of the concerns was that in patients with cancer and specifically with myeloma is that if you're going to do cell-based treatments like vaccines from a patient, are their cells actually functional? Can you use those cells and generate effective therapies or are the cells not functional? What we showed was that we could grow dendritic cells from the blood of patients with myeloma and also that the T-cells that we isolated before and after transplant retain many of their basic functions so that you have a component where you can take dendritic cells to make vaccines and then that the cells that are in patients can respond to some degree.

And then in terms of the immune response and relapse, we identified as I mentioned earlier a unique population of relatively inactive or quiet or sleepy T-cells and that this is associated with relapse after a transplant. We also observed that there is an increased number of regulatory T-cells which is a type of white blood cell that's similar to the myeloid-derived suppressor cells can damp into immune responses. And then we also showed that there is decreased natural killer or NK cells which again this is another type of white blood cell that plays a role in fighting tumors and cells incepted with viruses. Having increased numbers of regulatory T-cells and decreased numbers of NK cells are both associated with relapse after transplant. Those are some of the preliminary findings that we've found in the post-transplant setting. I think that these findings again underscore the role of the immune system in providing some degree of benefit to prevent relapse.

Jenny: Absolutely. I was talking to another immunologist about transplant. He was saying it's kind of an ideal time because your immune system is regenerating. And so it's proliferating. I like that you're looking at this time period. Another question, are your dendritic cells vaccine personalized? That kind of made me think that we were talking about it that you're personalizing these vaccines for people when you were saying you're testing them to see if their T-cells are exhausted or not.

Dr. Chung: Yes. They're not off the shelf. The dendritic cell vaccines that we've been doing are personalized where we take either stem cells from their bone marrow which for the transplant population is relatively simple because when they undergo their standard stem cell collection, we take a portion of that and we can make dendritic cells. Either that way or the alternative ways to get blood for patients and you can use the blood to grow up dendritic cells in the lab also. And then it's personalized in a sense that the dendritic cell that's being given back is the patient's own cells. And then on top of that, the vaccine product, itself depends on how you're -- what's going into the product, but it's unique in the sense that -- for instance, it might make sense if I talk about two of the vaccine studies that we have.

Jenny: Yes, sure.

Dr. Chung: The first one is an in-house study using the Langerhans type dendritic cells that I mentioned earlier which are the more potent type, at least in studies in our lab. With this particular vaccine, what we're doing is we're introducing the full length of the antigen. So remember I talked about how we can do it either with the fragment or the full length? What we're doing is we're introducing the full length of three different antigens that have been identified in myeloma cells. How it works is so patients gets their stem cells collected. We take a portion of that and we grow up the LCs or the Langerhans cells. And then, when the cells are mature, what we do is we give them the three antigens.

And then what happens is that the cell takes up -- after it's taken up those three antigens, it does a lot of complicated in the cell type of manipulation of these proteins and then shows bits and pieces of multiple bits and pieces to the immune system. It's kind of a random process so that even from one patient, what parts of a protein are shown on one cell within the vaccine can be different from another. And so, in a sense, this is a very personalized process where the patient's own cell is processing this and then showing what it decides it's going to show. And then that's given back as a vaccine. The study just completed accrual earlier this year and we're currently doing the immune response assessments and hope to have some results soon. You can see how that this is a personalized vaccine.

And then the second study we have is a dendritic cell myeloma fusion vaccine. Some of the listeners may have heard of this already, but this is a multi-center national trial conducted through the Blood and Marrow Transplant Clinic Trial's Network or BMTCN. For those who are interested in this study, the number is 1401, but it is close to accural, but if people are just interested in reading about it. I have been fortunate to serve as one of the national study chairs along with David Avigan from Israel in Boston whose group did the initial studies leading -- his group did the initial studies leading to these multicenter trials. And then our other national co-chair is Nina Shaw in the University of California at San Francisco.

As I mentioned, this study recently closed to accrual and patients in the study are going through the treatment process. It's still too early to comment on results. But this vaccine again is a personalized vaccine where when patients are enrolled in -- for patients who are enrolled on the study, before they started treatment, they underwent a tumor harvest. Basically, the myeloma cells from their bone marrow were taken up. And then those cells are later -- when the vaccine is given, fused with dendritic cells that are grown up from the patient's blood. This type of vaccine is different from what I've mentioned a little bit earlier where instead of predetermining which antigens you want to target, you're actually just taking the entire myeloma cell and letting it fuse with a dendritic cell and then that's the vaccine product that you give back. And what this vaccine product has is potentially every marker that your tumor has.

Jenny: Wow.

Dr. Chung: You can see the advantage of that potentially. That study is -- again, it enrolled extremely quickly and close to accruall I think last month and we're eagerly awaiting results.

Jenny: That's amazing. Are you going to have ASH results?

Dr. Chung: No. Not this year.

Jenny: Just kind of a side question. But this approach work, I know you say that post-transplant is an optimal time. But would it work for patients who were in remission and just kind of want to extend their remission?

Dr. Chung: I think that that's the next step is to figure out the best way to time this. I think that it's a logical extension of the studies that we've done. Again, you mentioned earlier that when you had spoken with a transplant or who mentioned the potential advantages of introducing a vaccine during the post-transplant period because of immune system recovering in a lot of cells dividing and potentially you could skew a response in a beneficial way. So you would lose that component of the vaccine administration, but I think that if we learn a little bit more about vaccinations and the way to help boost them, you could give a vaccine in almost any kind of setting and get a response. I think that's something that's going to be coming down the line.

Jenny: It's just a miracle that's happening right now in myeloma in my opinion. Smart people like you or really moving the field. So we're just so grateful for all you're doing. It's amazing.

Dr. Chung: Oh, thank you.

Jenny: Well, so you're looking at a three component of the immune system. And then you were going to do some DNA and RNA sequencing or whole exome sequencing to find certain things. Can you explain that and then you may want to explain neoantigens because you might be mentioning that term.

Dr. Chung: Right. I think it makes most sense to explain what a neoantigen is. When cancer cells divide to make new cancer cells, they're very prone to developing a lot of mistakes or mutations. When this happened, some of the mutations altered the normal amino acid sequence of peptides in a cell. The amino acids are what provide the instruction to the cell of how to make a protein. It's like a guide. When new mutations occur, a peptide or antigen is converted from its normal status to a new or neoantigen. Neoantigens can serve as very specific immune targets because they're completely new. There is nothing else in the body that's similar to that. The presence of neo antigens and cancer cells and their absence in normal cells make some again very attractive targets for cancer therapy because you have almost basically eliminated the -- you have increased the specificity and you have eliminated the potential for off target affects.

Jenny: Right.

Dr. Chung: Again, this directing immune system toward neoantigen offers a new level of patient and tumor specificity that again might translate into improved patient outcomes. And so, what we're interested in doing is -- and this is the second part of the proposal is to look at patients who relapse. When they relapsed, try to get good bone marrow samples so that we could isolate their myeloma or plasma cells and sequence them to look for neoantigens. And then once we have identified neoantigens, do a screen to figure out which of those that we identify might be the best targets for a vaccine. And then to ultimately carry that over to a vaccine therapy for patients at who've relapsed. That's the second part.

Jenny: Okay, that's amazing. Yeah. What a great strategy. That's truly amazing. I know you could just customize it for that patient for whatever neoantigens their body is making post relapse.

Dr. Chung: Correct.

Jenny: In this first initial phase where you're looking at patients post-transplant, you sort of separated that amount between early relapse versus late relapse. Maybe you want to go into some of the study methods and why you're looking for patients with less than two-year relapse or greater than four-year relapse and how you divide people out and then how many patients are you looking for or samples that you're going to study as well?

Dr. Chung: Okay. Again, the goal of study is to compare the immune profile or landscape of myeloma patients undergoing transplant and keep time points to identify immune biomarkers signatures of disease status and to optimize our chances of detecting differences in immune signals that are characteristic of disease outcome. We wanted to initially focus on patients at clinical extreme. And so we decided (it's somewhat arbitrary to have a cut off) but we decided that patients who relapsed less than two years after transplant versus those who remain progression free more than four years would be a pretty good way to separate them.

And again, this is simply a way to try to see if there is a more easily identifiable signal if we choose these two patient populations. The current numbers are that if you have a patient who undergoes a transplant and then goes on Revlimid maintenance which is standard at most centers, then the average progression free survival is a little over four years. And so, that also helped guide us in terms of how we were picking our time points. Again, we'll be using blood and bone marrow samples from before transplant. The best response after transplant, again, that's usually about at the three-month mark where restaging is done and then at the time of progression or relapse. That's what we're going to be doing.

Jenny: If you're looking for patients who are out four years and are relapsing after that, are you just going back to your existing patients and trying to find patients who qualify for that section asking them if they want to participate or you're just doing it from here on out? You know what I'm saying?

Dr. Chung: Well, for patients who are here, the goal is to follow them for as long as possible and then to capture them even if they relapse farther out than four years. Sorry. I was going to say we haven't put a cap on when we're going to stop sample acquisition as long as patient is willing to provide a sample.

Jenny: Can somebody from, not at Memorial Sloan Kettering contribute to this research?

Dr. Chung: For now, that would be very difficult because getting samples -- the logistics of just getting samples would be difficult because there is special tubes and things that we need and there is also processing and getting samples here within a certain period of time. I would say that for now, it's really going to be based on patients who are here.

Jenny: And you have a lot of patients are there. You should be fine.

Dr. Chung: We do see a fair number of patients. Oh, and then -- you did ask in terms of how many patients we were going to look at. At the outset, at the beginning, we're going to try to look at 30 to 50 patients in each of the two groups. And then we'll see what we see with those results and then go from there in terms of pursuing additional patients if needed.

Jenny: How long will it take? Will you have to wait the four years or you'll have this before because you'll be able to look at patients who are out four years already?

Dr. Chung: We do have some samples from patients like that because my -- our practice here has been to -- if patients are willing to contribute to the research program, we sign them up and we collect samples along the way. And so we have a fair number of patients for whom we already have samples. And so clearly, we would want to take advantage of that. When we start doing these studies, we would start with the ones that are already banked. And then we're also in addition to that as patients come through we're collecting samples prospectively in real time and we'll continue to do that for as long as we can to try to really get the best samples and to see if we can see a clear signal.

Jenny: Right. I know sometimes in myeloma is getting tricky because when you're running these studies, you might not have results for ten years and that's why they're looking for other things like minimal residual disease or something to be early markers or indicators.

Dr. Chung: Right.

Jenny: As you're testing these samples, how long do you want it to take basically to do the analysis on a number of patients that you're looking for so you kind of have an idea of where you want to go from there?

Dr. Chung: Well, I would think that within 12 to 18 months, we'll have preliminary results that would help us figure out what we need to do next. And if we need to extend certain aspects of the study. But I think that we'll have some signal within a year, a year-and-a-half that that's my help at least. You never know where a research will take you, but yes.

Jenny: Well, I'm amazed by what you all do. And then will you include -- well, it sounds like the dendritic cell vaccine trials at Memorial Sloan Kettering are closed. But would you do anything related to the vaccines on these same patients or that would be a completely different body of work?

Dr. Chung: That would be a different project. We do envision that a vaccine-based approach either a dendritic cell or other formulation could be used to prime or boost patient's immune responses? Again, probably in combination with other therapies. But this particular study would be separate from that. It would hopefully be informative so that we could figure out, okay, if we're going to give a vaccine to this type of patient with this type of immune profile, we would probably want to tweak the therapy in a certain way. That would be the best-case scenario if we could actually really tailor therapy.

Jenny: Yes, it's totally amazing. It's just completely amazing to me in what's happening. In the ability to look back closely at an individual patient and really target timing and therapies and staging and all of that to an individual. Last couple of questions. How will you use the funds and then how would you integrate this with HealthTree? And then I'll open it up for just some short caller questions.

Dr. Chung: The funds will be used to perform the two aims of the study that I have described and those costs are sample acquisition processing research, supplies including costs related to sequencing and some salary support for the research technicians in the lab who are doing the actual work. And then in terms of how this might be integrated into HealthTree, upon validation, you can envision that we would be able to include a biomarker, immune-based biomarker panel within the patient portal where you could use that as a compliment to the other markers like cytogenetics and stage a diagnosis and other factors that have been validated to provide a more comprehensive snapshot of each patient's unique myeloma disease profile and that ultimately, that might be a way to guide patients toward the most optimal therapy.

Jenny: Amazing. Well, I want to open it up for caller questions. So if you have a question for Dr. Chung, you can call 347-637-2631 and press 1 on your keypad. We don't have a lot of time left. I'm so sorry for that, but there was so much to talk about. I have so many more questions. So we might have to do a follow-up show as this progresses but it's truly amazing. Go ahead with your question.

Caller: Hi, Jenny. It's Dana Holmes. Thanks so much for taking my call. I appreciate it. Hi, Dr. Chung. Congratulations on being awarded an MRCI research grant. It's terrific. The work you're doing is so exciting.

Dr. Chung: Thank you.

Caller: I'm actually a Sloan Kettering patient, but I'm smoldering. So right now, I'm under that watch and wait mode. Who knows, maybe someday, I'll be crossing your path as well. Question to you, is the work that you're doing with the immune system signature similar to what the Spanish group, myeloma group research group has done to date?

Dr. Chung: I think that it's similar in a sense that they are looking at different subsets of the immune system. Although in their work, they did not do some of the things that we have been looking at more recently. They may be actually doing that work and just haven't published it yet. But a lot of people are interested in really understanding the immune system in myeloma so that we can develop better treatments. I wouldn't be surprised if they're doing it. They just haven't published all the exact same things.

Caller: Oh, absolutely. I'm thrilled to see that because honestly, I think that that's where our answer may lie on -- you know, these neoantigen vaccines are very intriguing as well, and there is actually -- well, there is one that MD Anderson is actually developing for smoldering patients and Dana Farber is going to be as well. I don't know if they're similar, different. I'm not quite sure because I'm still trying to understand what that is yet. Do you foresee Sloan Kettering doing something along those lines for smoldering myeloma patients? Because I'm thinking earlier in the disease, the disease perhaps is less complex. Would it be more specific? Would it be more successful in the earlier lines of disease?

Dr. Chung: Right. I think you raised some very, very important points. I think that it makes sense to pursue some form of therapy in that setting I think that we're still trying to figure out the best approach and we have had discussions of doing a study in a vaccine-based study. It's just, we haven't figured out exactly how we're going to do that because we want to get as much information possible before we launch into this because as you can imagine --

Caller: For smoldering patients?

Dr. Chung: Right.

Caller: Oh, that's exciting. Okay.

Dr. Chung: Yeah. As you can imagine, there is a lot that goes into designing and executing clinical trials.

Caller: Oh, absolutely. And I would imagine what you're going to learn from this study that you could then hopefully transfer into smoldering population.

Dr. Chung: Right, exactly.

Caller: That's exciting. Okay. I'm already onboard with the research and banking everything at Sloan Kettering. Anytime I get blood draws -- because I find every research study that I could possibly find at this point. So you guys definitely have some bankable data on me already. That's exciting to hear. I don't want to take up all of the time, but one last question that I'm really just trying to understand a little bit better and it has to do a T-cell exhaustion I guess is the term that's being used. And I found it interesting that you explain that those immune suppressor cells seems to be more present after a stem cell transplant. Is that because part of the immune system is either getting a bump up or having additional damage done to it let's say perhaps due to the alkylating agent like melphalan and the cytoxan. Am I even conceptually understanding any of this?

Dr. Chung: The immune suppressor cells like the myeloid-derived suppressor cells and the regulatory T-cells that I mentioned, they're not necessarily higher at after transplants for everyone. What I meant to convey if I didn't do so properly --

Caller: Well, you might have. I just probably didn't understand it.

Dr. Chung: The point was that the inpatients who relapsed, we have noticed -- other groups have also have noticed that there is a higher fraction of regulatory T-cells, and that that might be contributing to the immune dysfunction that again might be contributing to relapse.

Caller: Obviously, stem cell transplant is standard of care. Until something better comes along, I understand that it remains standard of care. But is it something that a patient who is either newly diagnosed or someone like in my shoes that I hopefully got a little bit more time to hold off on actual treatment to think about using those DNA damaging type drugs to perhaps preserve some of these important immune cells.

Dr. Chung: Right. It's a complicated situation. We don't have direct test comparing the impact of different treatment types on the immune cells, because a lot of times we use combination therapies. Sort of delving through that and figuring out is it this drug or this drug that's causing more immune dysfunction in patients who actually have immune dysfunction based on some screening that we might do in a research setting that that's hard to say. But it's possible and -- again, the other thing that you brought up is that when myeloma progresses from the precursor state to active disease, there is loss of immune function. Your point is well taken that if we can develop interventions at an earlier stage where someone's immune system is more intact and potentially more receptive to an immune-based treatment, you might have a better result.

Caller: If you were to develop and move along with these neoantigens or any vaccine trials for smoldering patients, would it be limited to just your patients or would it be open to all of the myeloma group at Sloan Kettering?

Dr. Chung: Oh, when we open studies for myeloma, it's open to all patients who are eligible based on the study.

Caller: Okay. Because I was going to make the phone call today and start transferring my care.

Dr. Chung: No. If you're eligible otherwise based on the basic criteria for a study, you can get the treatments here.

Caller: Great. Dr. Chung. Thank you for your time. Thank you for your research. Jenny, thank you for the platform as always.

Jenny: Oh, yes. Thank you, Dana. We have two other couple quick questions for you. We have just a few minutes more. Go ahead with your question.

Caller: Hi. I am at patient at Memorial. I opted not to do the transplant, but I am MRD negative status right now. I just never hear anything really about, it's always about the stem cell transplant. I'm just wondering the process if you were MRD negative.

Dr. Chung: If I'm understanding the question correctly, you're asking should you have a transplant if you're MRD negative or not?

Caller: I did see someone about the transplant, but then I opted not to do it. After that, I have reached the MRD negative status, and I've had another bone marrow which is negative also. It's been about a year now. I feel great. I don't feel sick at all. You just never see research with it, with the non-transplant.

Dr. Chung: Right. What we know is that reaching MRD negative status is a good thing. In general, patients who achieve a deeper response especially the deepest response that we have based on current tools is the MRD negativity that the likelihood of a better outcome is increased. Whether or not that is enhanced with a transplant, once you've already achieved MRD negative status is still not completely known. I think ultimately that is a discussion that you're going to have to have with your myeloma physician about the potential pros and cons. I would say that at the very least that -- have you already had your stem cells collected?

Caller: Yes, I did. I did everything I was supposed in the beginning, yes.

Dr. Chung: Okay. We recommend that to all patients who are potentially transplant eligible because even if you don't pursue a transplant upfront, you want that as a potential option in the future in case you need --

Caller: In case I needed it at some point.

Dr. Chung: Right, exactly.

Caller: Okay. All right. Well, thank you very much. You're very informative, yes.

Jenny: Well, thank you so much for your question. One more call. Go ahead with your question.

Caller: Good morning, and thanks very much, Jenny. This is Eric Hansen. I have kind of gotten lost possibly, but could you talk a little about -- we know that myeloma mutates and changes over time. But do individual's immune systems mutate or not mutate but change characteristics in terms of suddenly developing a pool of exhausted cells or different types of white cells so that you need to continually update on what's going on with a person's immune system or is that a static thing once you've got a fix on a person's immune characteristics, is that good to go for a period of time?

Dr. Chung: Right. That's the goal of the study is to really look at this in more detail to figure that out. What I can tell you is that in some of the patients that we've already looked at that there are some patients who -- it looks like even before they start transplant that their immune systems are kind of pooped out or exhausted and that over time, they remain that way and those happen to be some of the patients who have relapsed. We need more patients and more numbers to really validate this because there is some variability. Every once in a while, you'll see someone whose immune system looks pooped out with more exhausted cells, but they have had a great response and they're in a good category. That really emphasizes the fact that we need to look at more patients to get a more complete look at how things are changing and what that actually means over time.

Caller: Thank you.

Dr. Chung: Sure. You're welcome.

Jenny: Yes, thank you. Dr. Chung, this has just been very enlightening. We're just so appreciative for all the work you're doing. We're just thrilled to be able to support it and hope you can come to your conclusions quickly. We're so excited to learn what you're learning. 

Dr. Chung: Well, I think we're all in the same page if you want to get some fast results and so that we can move on and develop better treatments for myeloma patients. Again, thank you very much for having me and for the generous support.

Jenny: Well, we're thrilled at what you're doing and we're so grateful that you think about myeloma every day for us. Thank you so much. And to all our listeners and supporters during the Myeloma Crowd Research Initiative, again, we encourage you to share this with your family and friends and people who love you and want you to live longer with multiple myeloma. We encourage you to listen in next time for our next Myeloma Crowd Radio program and learn more about the MRCI projects and also how this research can benefit you. Thanks for listening.