Dr. David Avigan, MD Beth Israel Deaconess Medical Center Interview Date: March 11, 2016 

 "Minimal Residual Disease" is the trace amount of myeloma that can be left even after treatment is over. Dr. David Avigan of the Beth Israel Medical Center is intent on eliminating the rest of any remaining myeloma using a dendritic cell vaccine after autologous stem cell transplant. Myeloma cells can tell the immune system to shut down and dendritic cells are powerful immune system stimulants so they are a good target for practical use in boosting one's own system to go after the myeloma. To make the personalized vaccine, a patient's white blood cells are removed during a standard bone marrow biopsy and are taking these "teacher" dendritic cells and fusing them to tumor cells that it can then show to the immune system. An autologous stem cell transplant is performed and the vaccine is given to the patient with the hope that the T-Cells or fighter cells will now be turned back on to target the myeloma cells. The hope is also that the vaccine provides memory, so that if additional myeloma cells are generated, they are killed via with T cell surveillance. Dr. Avigan tells us that stem cell transplant can do more than just kill the myeloma cells. One of the goals of transplant is to debulk the tumor because vaccines don't work well when there is high tumor burden. But additionally, the stem cell transplant can help resent the immune system to get it working properly again to go after myeloma cells on its own. 

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Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. I would like to thank today’s episode sponsor, Takeda Oncology, for all they do for myeloma patients. Now, a few announcements before we get started with today’s show. We are in full swing for the Muscles for Myeloma Program and it’s never too late to join. This is a fitness challenge to get us all up and moving while helping a good cause, Myeloma Research. Doctors are segmenting patients into fit, unfit, and frail categories and are tailoring treatment based on those categories rather than by age. So our ability to handle a more difficult treatment or extended treatments also will typically give us longer overall survival. So no matter what our fitness level were at, any exercise plan is a good plan for all of us. You can check the Myeloma Crowd website and click on the link to join. And we’ll also be announcing local races across the country throughout the year as well that you can join. Now secondly, the Myeloma Crowd is working to fill gaps that exist especially for patients that need it the most. And we have particular affinity for our friends with high-risk disease. We just announced Myeloma Crowd round tables on high-risk disease. Between 15% and 25% of newly diagnosed patients will have high-risk disease. Plus, as patients become refractory to treatments or relapse quickly after transplant, their myeloma, typically, will mutate and become more aggressive over time. These round tables are daylong meetings with top myeloma experts. So we’ll cover topics that are critical for high-risk patients. Each of the meetings will cover a specific genetic mutation, as well as information that’s important to patients who has a great disease that’s aggressive in other ways, like a disease that’s not responding to currently available therapies. Our first round table will be held in Salt Lake City on May 7th with three myeloma experts, and future meetings will occur in additional cities. You could find a link to that meeting on the Myeloma Crowd website. Now, onto today’s show, minimal residual disease has been an important topic of conversation for the last few years. Patients who achieve the MRD status do better overall. Now that immunotherapies are the hot topic of the day, can they be used to help patients get to this minimal residual disease state when combined with standard myeloma therapies like stem cell transplant? With us today is Dr. David Avigan of the Beth Israel Deaconess Medical Center. So, Dr. Avigan, welcome to the show.

Dr. Avigan: Thanks.

Jenny: Let me introduce you before we get started. Dr. David Avigan is Professor of Medicine at the Harvard Medical School and Chief of the section of the Hematologic Malignancy and Bone Marrow Transplant Program at Beth Israel Deaconess Medical Center. He’s also a Director of the Cancer Vaccine Program, Director of the Allogeneic Transplant from Unrelated Donors Program, Director of the Cord Blood Transplant Program. Dr. Avigan has performed extensive research on vaccination with dendritic cell/tumor fusions, which he’ll explain in this show. He also supervises the accreditation process for the National Transplant Accreditation Program. He is Chair of the Scientific Review Committee at Dana Farber Harvard Cancer Center, is Co-leader of the Dana Farber Harvard Cancer Center Leukemia Program. He is on the Cancer Clinical Trial Investigator Oversight Committee at Beth Israel, is Director of the Hematologic Malignancy/BMT Clinical Trials Group, a member of the Hematology Oncology Division Mentorship Committee, and the Senior Advisory Committee. Now nationally, Dr. Avigan is Co-Chair of Protocol Development and National Meeting for NCI Sponsored Transplant Relapse Program Committee, and is a member of the MMRF Immunotherapy and Pipeline Development Committee. He is on the editorial board of AACR, Clinical Cancer Research, and reviews publications including Blood, JCO, Transfusion, and Oncology just to name a few. Dr. Avigan is the recipient of the American Cancer Society Fellow Award, the Clinical Scholars Award from the Sloan Kettering Institute, and dendritic cell vaccines for malignant melanoma, and the Best Abstract Award with the American Society for Bone Marrow Transplantation at the BMT Tandem Meeting. So Dr. Avigan, welcome again.

Dr. Avigan: Thank you very much.

Jenny: That was a lot to say.

Dr. Avigan: Yeah. I was going to say I wanted to cut you off there. That’s got long but thank you.

Jenny: No. You have tremendous background, and in fact, one of the reasons I would like you to join is because I attended your session at ASH and it was a very lengthy session. You went into great detail about this dendritic cell vaccine that you’re working on, and it was completely fascinating. So I wanted other patients to be able to hear what I was able to hear and learn more about this. So maybe we just want to begin by you explaining what are dendritic cells?

Dr. Avigan: Well, maybe what would be most helpful is I can talk a little bit about the background of why we are pursuing immune-based therapy in myeloma and then how that sort of applies to our specific platform that we’ve been looking into in terms of our vaccine and the dendritic cell sort of idea. I think we know that cancer is a difficult endeavor to try and come up with a strategy that will not only reduce the disease burden but really fully eradicate it. For many years, our primary approach has been with chemotherapy-type strategies where we’re often able to reduce the amount of disease and to shrink tumor sizes in the setting of myeloma with many of our new therapies. We’re really able to just reduce the disease to a minimal state at least early on. But there is resistance that ultimately does develop and that becomes a source of relapse. And these cells that come back are ones that are more intrinsically difficult to treat. We and others are very interested in how the immune system might be used in a strategy to try and target myeloma and other cancers by really harnessing power that we’ve developed evolutionarily over the many years of how our immune system basically detects and selectively eliminates invaders. So to pursue that, one has to understand what is the relationship between cancer and the immune system. And importantly, how does cancer hide from the immune system and what does it do to evade the immune system that we could try and correct. So one of the things that we know is that cancer cells and myeloma cells, in particular, have proteins on them that are foreign and which the immune system can react to. But they’re presented to the immune system in a way that’s very difficult to see. So in addition to not being fully recognized, they actually employ mechanism to shut off immunity. And so in designing immune therapy approach, what a vaccine really is trying to do is to reeducate the immune system to see, in this case, myeloma as foreign, to see those foreign proteins and other aspects of the cell that are different as not belonging, and to activate an immune response where historically, that has not been the case because of how, again, myeloma hides. So one of the key parts of this is that the proteins out of myeloma cell actually encourage the immune system to shut down. So when one wants to reverse that, one can look towards the normal way that the immune system works, which is that it uses teachers of immune system, and dendritic cells are very powerful immune stimulating cells whose normal job is to activate T-cells and to teach them to go after cells, for instance, or viruses or bacteria that don’t belong in the body. So the idea was, can we, first of all, generate those cells? And can we use them as purveyors of this material that is specific to the tumor so that the immune system can be essentially reactivated and taught to go after the myeloma cell? Dendritic cells essentially are these powerful immune educating cells that live in our bodies that normally are kind of kept silent in the setting of cancer and we’re trying to see, can we actually use them as tools to reawaken the immune response?

Jenny: And the dendritic cells, is there a difference in a healthy person versus a myeloma person with either the quantity or type of cells that are in the system?

Dr. Avigan: That is a good point, and of course the immune system is quite complicated. So there are cells that have different functions that are in different spots of the body. But it is true that within the tumor bed itself, what we call the tumor microenvironment which is in the myeloma patients typically in the bone marrow, that there is sort of a general environment there that fosters what we call tolerance, which is for the immune system to be quiet and not activated. And part of that is that dendritic cells that would normally be one set. Stimulated immune responses are discouraged from being there, and other types of dendritic cells such as plasmacytoid dendritic cells which actually foster tolerance are present in increased numbers. So the natural environment is such that the dendritic cells that could generate responses are underrepresented. Our strategy was to basically see whether we could generate what we call ex vivo, meaning, outside of the body using certain techniques. And we were able to generate large numbers of these dendritic cells that are functionally active including from patients with cancers such as myeloma or leukemia or other settings where we’ve looked.

Jenny: And I know that the research is not anything new but you’ve been working on this for a while. How did you decide to go after this as a potential target?

Dr. Avigan: Meaning myeloma?

Jenny: Well, using dendritic cells in myeloma.

Dr. Avigan: Meaning, the strategy. You know, one of the interesting things that we’ve learned in blood cancers -- and you mentioned that my background includes bone marrow transplantation. We’ve known for a long time that bone marrow transplantation has been effective in curing certain types of patients with blood cancers, including leukemia and including myeloma when one uses a transplant from a donor. Initially, the thought was that a donor transplant really just involved giving people lots of chemotherapy. The chemotherapy would hopefully cure the disease and that the transplant was more of a passive way for people to recover after the chemotherapy with so to speak clean marrow because it’s coming from a donor who’s healthy, I mean who’s a match. What was found over time, which was quite fascinating, is that it really wasn’t working that way and that it was actually the immune system of the donor that was being transplanted into the patient that was responsible for eliminating disease. And that those T-cells which are a part of the activated or what we call factor cells of immune system, the killer so to speak, have the capacity to target disease. And we call that the graft versus a disease effect, or in this case, graft versus myeloma effect. The problem is that when one uses an immune system from the donor, there are also side effects that have to do with their immune system targeting things that belong in the body. In other words, just things that are different between the donor and the recipient. So at the same time that one sees a very strong efficacy and the ability to eliminate disease, there’s also lots of side effects. So that really has kind of been a beacon for many of us in transplant to say, “Well, is there a way to harness the immune system without using a donor transplant but still taking advantage of this very powerful mechanisms that the body has?” In other words, use the patient’s own immune system to target their disease. Now, we used, as I mentioned, the dendritic cell as part of our vaccine because it has the specific expertise in stimulating immune responses. The other part of this is that we create a hybridoma or effusion with the tumor. People have done this in different ways. Sometimes they’ll load individual proteins from a tumor or peptides that go onto dendritic cell to try and stimulate responses. But we sort of have the idea that we wanted our vaccine to be a little bit cruder and more sort of general because we thought that if tumor cells are good at dodging things and that if you create just a single target for the immune system that that’s something that the tumor might evad by turning off that particular protein. But if you’re using the whole tumor cell as your donor for the initiated immune responses that you’d be targeting multiple parts of the tumor that you could target things that are also unique to that individual patient. You could target what we call neoantigens, which are proteins that are generated from specific mutations that happen in that tumor and create a much broader response that we thought would be harder for the cancer cell to evade. So in some ways, we still borrowed from the more general phenomena you see with the donor transplant but try to hone it down and make it more specific.

Jenny: And I love that approach because instead of going after one particular protein on something that could evade or sometimes I know, the doctors have said, sometimes it loses that protein marker, basically. But this goes after, probably, the whole cell, it sounds like.

Dr. Avigan: Right, that’s exactly the idea.

Jenny: Well, can you explain how it works with the fusion, because I think patients might not understand, and maybe I don’t either, about how the vaccine works? And then what exactly a fusion with the tumor is doing?

Dr. Avigan: Again, the goal in all of these different types of immune therapy, and we can talk a little bit more broadly and then for just our particular vaccine, is to try and stimulate our immune response that will recognize the tumor and potentially eliminate it. And it has to do with this idea of what we call breaking tolerance, meaning that the tumor creates a safe environment for itself where the immune system has a hard time penetrating and seeing it, and we’re trying to undo that. So what we’re doing with the fusion cell is we’re taking now this powerful teacher of the immune system, the dendritic cell. We’re creating this fused cell by combining it with the tumor, so now that dendritic cell has lots of different pieces of that tumor that it gets to present to the immune system. But it’s presenting it in the way that the dendritic cell is particularly expert at which is in a very stimulatory, inflammatory kind of environment that can generate immunity. So when we vaccinate or inject the fusion into a patient, what we hope that’s happening is that they then meet up with T-cells, and those T-cells which are part of the killers of the immune system, instead of being turned off which is what the tumor does, are now being turned on and they can amplify and grow, and hopefully, work to target the disease. The other thing that we hope happens with the vaccine, and we think of this in any vaccine, whether it’s a vaccine against polio or measles, is that it’s not just that you’re creating a response for that moment, it’s also that you’re trying to create the idea of memory so that once you expand these cells, and hopefully, they attack the tumor, that they could potentially then live on to create some kind of a surveillance that would be protective against the disease, sort of acting up in the future. And that’s certainly what the long-term goal of any vaccine strategy is to both create not just a response but to also create protection. That honestly is a big hurdle. I think that people have the idea, in general, with immune therapy that it will probably work best by partnering it with other strategies. So the immune system may not do a great job in eliminating a large amount of disease. But if you’re able to reduce the disease burden down to a low level, the immune system could potentially then eliminate the leftover pieces that could otherwise cause recurrence. So I think that a lot of the immune strategies, and ours included, have been focused on trying to introduce the vaccine after the disease is either in remission or at a low point. So for myeloma, our initial study that we looked at looked at patients who had had an autologous transplant, a stem cell transplant where we know that many of these patients are in a good response afterwards. But we know that most of these patients, unfortunately, the disease will act up at some point in the future. So it’s sort of a lower point for the disease but one that maybe an immune therapy would be effective in targeting.

Jenny: Perfect. Do you want to explain kind of the ordering of the different therapies? And I think it’s important that patients know that just because immunotherapy is coming in into its own doesn’t mean that you’re not going to take existing treatments like stem cell transplant or other things and completely replace them. So this is an example of that.

Dr. Avigan: Well, I think it’s very important to say, and I’m a person who does research in this area, so I’m of course excited about it and also hopeful about it. But these areas right now are ones of exploration. So the format of how we investigate this is in the setting of clinical trials. The clinical trials have very clear goals and end points, and we hope that at the end of those trials, we can then learn whether a particular approach has evidence of it being effective or whether it goes on to the next stage of investigation. But these are, at this point, still things that are being looked at in an experimental format. I think what you said is absolutely right that in myeloma, we’ve been blessed with many new tools and many effective tools in the realm of biologic therapies such as proteasome inhibitors and immune-modulatory drugs like lenalidomide, pomalidomide, carfilzomib. And that there are many drugs now that have been very effective in reducing disease burden of giving our patients many options. And the idea here is not that immune therapy is going to sort of scuttle all of that. I mean if that was true, that would be wonderful if we had a very simple way of treating disease that didn’t involve lots of other pieces to it. But right now, what we’re talking about are trying to integrate what are other effective therapies, and transplant being one of them, into the context of an immune therapy that might be able to target a residual disease. And this is something that we’re still learning about. There are many ways to try and do this. As people may have heard, one of the areas that has gotten a lot of attention is the field of what we call checkpoint inhibitors. And these are antibodies that are being made now that block one of the main ways that cancer cells hide from the immune system. So this is an antibody targeting something called PD-1 or PD-L1 which is a pathway that is part of how cancer cells hide from the immune system. And if you block that pathway then you can stimulate immune responses. They’ve seen some very exciting results, but honestly, what you  learn as you get into the details of it is that it works well in some settings and not so well in other settings or there are certain diseases that really rely on that pathway. So by blocking it, you have a huge effect. And there are other diseases where it plays a more minor role. There’s been a lot of interest now in combining immune therapy, so to say. Well, that may be part of the story but a vaccine or a T-cell that we’d engineer might be the other part of the story. So I think that as we get to be more sophisticated in our understanding of immune therapy, we understand that it still has that same characteristic that any treatment does, which is that it’s not really a one-size-fits-all but there are different disease settings where certain things work better and worse, and that that’s part of this sort of effort to study these things carefully and learn what are the settings where things work better and what are the settings where they don’t work as well and we need to think about other approaches.

Jenny: And it sounds like you’re trying to use that approach with this because I guess you’re shutting off all roads, all potential roads to growth when you think about adding like a PD-1 and PD-L1 checkpoint inhibitor or other therapy or whatever.

Dr. Avigan: Well, I think what was happening is that while we can stimulate an immune response -  So one question about our vaccine, just to come back to our vaccine for a minute, is can you stimulate an immune response? And we have shown now in a few studies that even in patients with more advanced myeloma where they don’t often make great immune responses against vaccines that we’ve been able, with our vaccine, to stimulate the expansion of these cells that can target myeloma. And we saw in a study that we did in conjunction with the transplant, as I mentioned earlier, that the presence of an immune response after transplant can convert some of the patients who achieve a partial response of the transplant into a complete response with this vaccine. The challenge really doesn’t stop there because you can make an immune response that is effective and you can make an immune response that maybe takes people into a better response. But in order for that immune response to have a long lasting effect, it needs to be present and stay active. And the tumor of course, over time, will try and recreate tolerance and try and essentially escape the immune response. Like in any therapy where we don’t only just look at what’s the initial effect but we look at how long lasting it is and what are the ways to make it more long lasting. That same set of questions are coming into being for these immune therapies. So we’ve been very interested in our vaccine model to combine it, as you said, with other ways to make a more durable immune response, other ways that will treat the cancer. And so for instance, we now are embarking on a national study that’s being done through the oncology cooperative groups, a group called the CTN which is a group that does transplant trials nationally. Where we’re going to take the model that we just described where patients, this is when they first start being diagnosed, are being evaluated. And if they’re eligible for this study, they will have their cells collected ideally before they start treatment. They then will undergo a standard treatment. There are many standard treatments now. They’re very effective as we start therapy for myeloma. They will have a transplant. Again, this is the patients that are appropriate and eligible for that. And then after transplant, they will be divided into two groups. One group will be treated with the maintenance therapy called lenalidomide, which we know is an immune activating drug that we think has been effective in prolonging remissions. And the other group will get that drug but also with our vaccine. And now, we will be able to compare in a very direct way what does the addition of vaccine to that post-transplant environment do. And also, the hope that the lenalidomide, which is a standard therapy for myeloma, that maybe it will also augment the vaccine effect and maybe create a more long lasting effect or help it to be more long lasting. That’s an example of a really unique endeavor and it’s being done now across the country at major cancer centers that are participating in this particular CTN trial.

Jenny: And that trial is open now?

Dr. Avigan: The trial is being opened. So it has received approval from the FDA and the central sort of structures that need to approve it, and then it is now being put in for approval at all the individual sites that will be participating and we hope it will be getting started in the next few months.

Jenny: And that’s just for newly diagnosed like you were saying?

Dr. Avigan: That is for newly diagnosed patients, yes.

Jenny: Perfect. I know other doctors have said that Revlimid actually boosts your immune system in some sense. So that’s why you chose Revlimid to be used with the vaccine and transplant?

Dr. Avigan: Yes, that’s right. So for two reasons, one is as you said this is a drug that’s known to have immune activation as one of its effects. It also, I should say, has a track record in the post-transplant period of prolonging periods of response. That’s important. And then the last piece about it is that we’ve done some pre-clinical work in the laboratory and other groups have done this also showing that it can amplify response to vaccine.

Jenny: Now, as part of this clinical trial or just the vaccine in general, it sounds like if you’re fusing it to tumor cells that it is patient-specific or very personalized. Do you want to talk about how that works or what that process looks like?

Dr. Avigan: Sure. So this is an absolutely patient-specific personalized therapy. The dendritic cell and the tumor cell come from that individual patient. The way we make our vaccine is that the tumor cells are collected typically from a bone marrow aspirate. And we have trials right now in myeloma and also in leukemia and both of those diseases that tumor tends to live in the bone marrow. So we collected tumor that way - do a normal bone marrow aspiration that’s done in the clinic in the way that we do that for just even regular purposes. And then the patients undergo apheresis, which is a collection of white blood cells in order to generate the dendritic cells. That process is really the same process that people undergo when they’re having a stem cell collection, but we don’t use Neupogen beforehand. So it’s just a regular white blood cell collection. The white blood cells are then separated into certain fractions and they’re grown in the presence of certain stimulants or growth hormones that cause these cells to turn into a population that is predominantly dendritic cells. And we can test those cells to make sure that they have the right characteristics and that they have the functional activity of dendritic cells. We then combine the patient’s tumor cell, the myeloma cells that we’ve harvested from the marrow with these dendritic cells that have grown up, and we create this, what’s called a hybridoma or fused cell. And then those cells are counted by doing special stemming to see how many cells of the preparation that we have after this fusion meet these criteria of having both part of them being part tumor and part dendritic cell. And based on those numbers, we then create our dosing that goes into the patient.

Jenny: And in your first study when you were combining that with the PD-1 or PD-L1 blocker, what did you find in your early results?

Dr. Avigan: The studies that I talked about initially were with the vaccine alone. One was just with patients with myeloma who had more advanced disease, and then one was a study where we had patients getting vaccinated after transplant as we sort of described. We’ve been also conducting a study looking at drugs that augment the immune system in other ways. You mentioned the PD-1 antibodies are one approach to that. And we’ve been doing a study where we combine the vaccine with that drug, with a drug that is about to stimulate the immune system in that way. We’re still in the process of analyzing and following those patients early on. So I don’t have results to present yet in a kind of finished format. We have been able to see that there are nice immune responses and we’re now kind of trying to get a sense about how the patients are doing over time. So that’s still very much in the mix. But that idea of combining a vaccine with a checkpoint inhibitor of PD-1 blockade or CTLA-4 blockade is another. Those negative checkpoints I think have gained a lot of attention and is interesting and we’re hoping that that will augment responses. One of the potential concerns if you just use a PD-1 antibody by itself is that what it does is it activates T-cells that are being put to sleep by the tumor. In order for it to be effective, it would make sense that you need those T-cells around. You need those sort of sleepy T-cells around in order to wake them up and cause activity. And in some of these diseases, myeloma being one of them, there aren’t a lot of T-cells that are there in the bone marrow. So you might have to do something first to sort of introduce those T-cells. And that’s what we think our vaccine potentially could do. So the idea of combining those things has a lot of theoretical, I think, appeal and we’ll have to see what the studies show us.

Jenny: I know myeloma patients have very suppressed immune systems. So when you say you’re growing up dendritic cells, how much do you grow them? How do you know what amount is appropriate for each patient?

Dr. Avigan: So most myeloma patients, particularly once they’re on treatment, will have a normal white blood cell count. And we generate these cells from their white blood cell fraction. So I would say that there are some situations where patients have little counts and it’s hard to generate. But most of those folks, you can generate these cells without a lot of problem using their white blood cells, and then training them in the test tube, so to speak, to take on the role of the dendritic cells. So we generally are able to come up with enough dendritic cells per patient. The process of generating the vaccine takes about ten days. And then there’s a series of testing for sterility and other things that are acquired as per FDA standards which takes another couple of weeks. So the whole process takes about a month from start to finish.

Jenny: And you can be processing the vaccine while they’re going through this transplant process, correct?

Dr. Avigan: Well, what we’ve done for our study that was completed is that patients had the vaccine made while they were getting their other treatments, and then it was sort of ready for them in the freezer after they finish their transplant. In the current study, we have a similar thing, and here we’re going to be making the vaccine in the earlier period after transplant when they’re sort of waiting and then they start a lenalidomide maintenance around day 100, then the vaccine hopefully at that point is ready.

Jenny: Okay. And what’s the difference between a dendritic cell vaccine and other myeloma vaccines that we’ve heard about that are peptide vaccines?

Dr. Avigan: So there are different ways to try and basically stimulate the immune system and to reverse, as we talked about, tolerance. One approach is to just take a piece of the tumor. So a peptide is basically a part of a protein that you think is presented to the immune system. And you introduce that with, let’s say an immune stimulating chemical, and hope that the dendritic cells that live inside the patient will come and gobble up that protein or peptide and stimulate the immune system. So some peptide or protein vaccine is involved just that, just the peptide with maybe what we call an adjuvant which is a chemical that stimulates the immune system. In general, the peptide approach in cancer has not been terribly successful, and it probably has to do with the fact that it just doesn’t stimulate enough of a response. People have used dendritic cell approaches of the peptide. So they’ve taken dendritic cells and loaded them with peptides, for instance, and use that as a vaccine, or what we call, let’s say, lysates which are the tumor kind of dropped into pieces. And those have been used in the setting of myeloma. One thing that people have looked at is something called the idiotype. That’s the protein, the M protein that is very unique to the patient because it’s made by their particular myeloma clone, and you can basically generate that protein and use that for a vaccine. But that also, as a standalone, has been a little bit less successful. People have looked at that both for myeloma and certain kinds of lymphoma. And there’s been some success, but again, like any type of treatment, it’s like using the general term chemotherapy, how effective a particular type is or isn’t has to do with the potency of that individual approach. So what I was saying was just that the idiotype is very specific to the tumor. But again, probably, strategies that are going to make a better immune response than just using the protein or peptide by itself are needed. Dendritic cells are one approach to that. You know, another way of explaining that is that people may have heard about CAR T-cells which are another type of immune therapy where people take T-cells from patients with cancer, and myeloma is one of the areas that people are looking at right now. And they grow them up and change the T-cell or engineer them so that they now have a tail on them that binds to a protein on the tumor. So it will bring the T-cell and bind it to the tumor cell, in this case, let’s say a myeloma cell. Now, when that was used as a therapy without any further bells and whistles, it didn’t really work that well. The T-cells, basically, weren’t that activated. They didn’t really kill so well. So then a second innovation was made that they inserted into the T-cell a stimulatory factor, something that activated the cell. And after that happened, they started to see dramatic responses in certain diseases in particular, for instance, leukemia. And they’re now working on that strategy in myeloma as well, and further trying to refine it. So all of that is to say that all of these strategies, whether it’d be a vaccine or a T-cell strategy or it’s about how these things combine well with each other, are all still very much in a learning phase where we’re seeing some activity, we’re seeing some promise but still need to work out how to best approach this and how it might be different in different patients.

Jenny: And I love the part that this is so personalized and just you need each individual patient because most of us now, most myeloma patients can present with multiple types of myeloma.

Dr. Avigan: I think that’s a very good point and we call that, the technical term for that is called a tumor heterogeneity which just as a way of saying that within a tumor, there are multiple different types of clones. And you’re right, you have to try and ultimately target all of them if you’re going to be successful in the long-term. So I think that that is very encouraging as a strategy. We now have to see how well it works and whether we really accomplish that goal. One of the things that happened with personalized therapy, for many years, people I think, and particularly drug companies, were scared about it because it seemed very kind of unwieldy to have to make a different thing for each patient. We’ve been doing that for many years in the setting of bone marrow transplantation, but there wasn’t really a lot of experience in doing that in a larger context. But I think with some of the successes that have been seen and the drive to make this into an effective therapy, there has been more effort to try and come up with strategies to do personalized therapies that are also accessible and less boutique-like.

Jenny: Now, a question that’s a follow-up to that, does a vaccine work regardless of genetic features people may have like, for example, deletion 17p or a 14;16 translocation? Have you seen them have similar impact to outcomes of “low-risk patients”?

Dr. Avigan: So those are very important questions, and at this point, as I mentioned, we are still learning about what is the nature of the response, who benefits and who doesn’t, what is the degree of benefit. So part of the question that we hope to address when we look at this larger trial that I mentioned is to start asking questions like that, which is to say, “Well, let’s look. Are there particular subtypes of patients that seem to be benefiting and ones that is not benefiting?” You know, it’s hard to do that kind of thing when you’re dealing with initial studies that are small. If you have 20 patients in the study, you’re not going to really be able to pair into -- well, how did this type of patient versus that type of patient did. But as these studies are becoming larger and they’re becoming multi-centered, those are the kind of questions we hope to be able to answer.

Jenny: Now, a question, I know that we actually have a mailed in question for one of these. I know you’re using autologous transplant to get the tumor burden down. Is there any other purpose of the transplant besides just debulking of tumor for the transplant? And then are there situations where a vaccine like this would work alone like if you’re in complete remission or you’re  a smolderer?

Dr. Avigan: So that’s a great question. Firstly, the transplant is something that offers a unique kind of platform. I think that the initial idea that people had was that chemotherapy might be effective but it seems to kind of knock down the immune system. So the idea of combining chemotherapy, whether it’s a vaccine or a T-cell approach, seemed a bit counterintuitive. But what we learned actually is that the effects on the immune system are more complicated. And that one of the things that transplants seem to do is to reset the immune system a little bit so that patients who have all of these factors in their immune system that cause tolerance and cause the tumor to be harder to see and detect, those things also get disrupted. So there is essentially this transient breaking of tolerance that may allow vaccines to be actually a bit more successful in that period of time after transplant. So it’s not just that the tumor bulk is down, as you said, but that there may be some immune effects that actually favor a vaccine strategy after transplant. The same could certainly be potentially true for other approaches. And as we are doing in our study and others are doing as well, combining immune therapy with a drug like an immune-modulatory drug or checkpoint inhibitor, those kinds of things could set a stage that would potentially be more effective. And the question about a smoldering disease is also an excellent one. There is a thought that in smoldering disease, maybe the immune system is not as debilitated as it is when patients have more advanced disease. And maybe that is a great time to intervene and see whether you could disrupt the progression towards myeloma. And there are a bunch of studies now with other vaccines. We haven’t pursued that so much with our vaccine at least to date. But there have been other vaccine strategies, peptide strategies, that I know of where they looked at that question, or I should say are looking at that question to see whether there’s an effect in that particular setting.

Jenny: Now, I know that if I were newly diagnosed, something like this just seems to be such an easy decision because you take something that already is kind of “standard therapy.” And then you add something that’s potentially even going to make it better. To me, that’s just such an easy choice. I know a lot of patients don’t understand about clinical trials or how they work but it really is exciting when you’re combining just a standard therapy that many patients or most patients will go to, anyway, and you’re adding something completely unique to them.

Dr. Avigan: Right. You make a good point. I mean I think that there are different types of trials, and some trials are of new drugs that there’s not a lot of experience with. They’re often let’s say used in patients with more advanced disease. Other trials are using more standard therapies but maybe in a different combination. This is sort of a third kind where you’re taking a standard therapy and you’re still giving that to the patient but you’re adding an extra piece to it. I think like any study; the hope is that the study offers an advantage. In this case, in the particular studies that we’re doing with the cooperative group, there is a randomization where some patients get the vaccine, some patients don’t. But it is true that anytime you’re involved in an experimental therapy, there is always the chance that there would be a side effect or that there’s some toxicity from the vaccine, and we can talk about that in a moment, that you could get. And the other side effect, so to speak, is that these things take time and involve investment of people’s effort and time. So I agree that we are very excited about these studies and encourage patients to participate, but understand that it is still something to ask the folks to participate in the study where not everything is totally defined yet.

Jenny: Well, let’s talk about side effects for a minute. Have you seen any?

Dr. Avigan:  So the toxicities that we’ve seen so far have been pretty manageable in terms of what we’ve reported on in our papers. Some patients have had some, what I would call vaccine-like reactions like they’ll get redness at the side of the vaccine. That was one of the common things we saw. We saw some patients who got sort of transient muscle aches or flu-like symptoms or fever. This tended to be mild and transient. There was always we’re on to look out for what we call autoimmune reactions, meaning that you stimulate the immune system in a way that causes normal tissues to be targeted. And you know, I think that that’s something that in any new therapy remains on the horizon of things to watch for. On one hand, a sign of potency of an immune therapy is that it does cause some side effects because it’s stimulating the immune system. For instance, in CAR T-cells, in some of the successful trials where they’ve seen effects against a tumor, there has been a fair amount of side effects just because of the T-cells, as they get activated, can cause certain hormones get released that cause side effects.   So I would say in general, so far with our vaccine, the side effects have been pretty manageable and mild, but we can only keep looking for the possibility of whether there could be more substantive issues. Or even as we combine these treatments, they may make better immune responses that could make a bit more in the side effect area. So these are things that are we are actively studying.  

Jenny: And I know you probably haven’t gotten this far yet because you’re just still at the early stages. But when you’re thinking about combining different immunotherapy approaches like you were talking about, could you use vaccines together or could you kind or what’s the downside, I guess, of adding other things like the monoclonal antibody or what other drugs that are considered to be immunotherapy approaches?  

Dr. Avigan: I think that there’s a lot of interest in that. For instance, monoclonal antibodies which sometimes is somewhat sort of interestingly, we don’t always really know why they work. But why would an antibody binding to a cell kill it? So that may be a direct consequence of the protein that’s being bound. But we think that one of the main mechanisms is that when antibodies bind to cells that they attract immune cells to kill that. So it would be an easy thing to understand why then an antibody would work in concert with another strategy that helps stimulate the immune system and generates more of those killer cells.   I think one of the things we’re interested in is also seeing, for instance, how engineered T-cells like CARs might interact with vaccines because maybe the two together would actually boost each other’s function. And there’s some reason to think that that might be true with some exciting data that folks have started to generate. So I think that the idea of combining these strategies makes a lot of sense, but of course you have to think about how to do that in the rational way.   Certain strategies may work together, certain strategies may work in counter-purpose to each other. Certain strategies may be so powerful when you put them together that they just create lots of side effects. So I think that it’s a mixture of the pre-clinical experiments that we do in the laboratory, and also then doing thoughtful design of clinical trials where you are testing something, seeing what it looks like and then deciding whether it goes further or not.

Jenny: And how long does that process typically take when you say, “Okay, we’ve got something new, let’s say, in our phase one or early phase two or something clinical trial”? It’s going to take some time for it to get advanced and mature a bit before you know some of these answers that you’re talking about. So how long until we see those different types of vaccines playing out and how they compare one with another - you know which is better?

Dr. Avigan: The process of doing a trial, of course it depends on how big the trial is. There’s always a regulatory process for us where you introduce the idea and it’s reviewed and you have to get approval from the different regulatory bodies which typically involves both the FDA and the Institutional Review Board of your institution. So that process of designing a trial and getting approval takes at least a number of months but maybe longer. Then the trial itself, depending on how quickly patients are enrolled and what the level’s interest is, usually, it would take a couple of years to enroll a medium-sized study and have a chance also to analyze how long, how well people are doing. Unfortunately, it does take time. We would like things to go quickly because we are obviously very motivated to figure out what’s the best way to do this and to help bring this help to patients. So we try and both optimize which trials we want to do so that we’re not wasting time in a dead end or getting caught in a place that’s not as helpful. And also, trying to move them as speedily as possible, but it is unfortunately slow.

Jenny: Well, you have to be thorough, and I understand that. So we’re excited to see what you come up with. A couple of follow-up questions from something you talked about earlier. You talked about transplant being the most ideal time to kind of reset the immune system. Ultimately, as you see this progress, if someone had a low tumor burden, could you ultimately use this with some form of chemo - maybe not the high dose needed for transplant or is it going to always be the best time?  

Dr. Avigan: No. I think that’s a good question, and people are asking that question. For instance, when we use T-cell therapy, we also generally use it with some kind of chemotherapy. So CAR T-cells are generally given after chemotherapy is used to reset the clock, as I mentioned. And people are looking at what kinds of chemotherapy work best, and ideally, you’d like to use something that doesn’t have lots of side effects in and of itself. So transplant happens to be a therapy that we kind of do in many patients, anyway. We’re then taking advantage of that time after transplant to introduce, let’s say an immune therapy that we hope will target the residual disease, whether it’s a T-cell, whether it’s a vaccine. But you’re right that there are other settings that you’d want to explore, and there may be kind of more mild forms of either chemotherapy or other immunomodulatory drugs that will partner well with the vaccine that don’t require, certainly, transplant.

Jenny: Okay. Another question about that is, can patients -- I know you’re using it in a nearly diagnosed situation, right now. Can patients ultimately having maybe a prior transplant take advantage of this treatment option if  they need to go to transplant again?

Dr. Avigan: Well, I think that it just depends on the study on how it’s designed. The particular strategy that we’re talking about in this trial that I mentioned is for patients having a first transplant. There are studies that have involved second transplant. I think one of the CAR T-cell studies that was being done involved the second transplant. So I think it just depends. If you’re asking what’s the best setting or where will this be effective, you know, we are still learning about all those things. These are exciting ideas. We’re trying them in different settings. But honestly, we’re still in a mode now where we’re learning about, is this effective? How effective? What’s the right setting? We don’t know all those answers yet.

Jenny: And then when you think about producing the vaccine, how is the work in vaccines replicated? Let’s say you complete your study and this becomes a popular treatment option. If this is personalized, how do you standardize that process so that they can be used for multiple facilities?  

Dr. Avigan: Right. So there are different ways to approach that. One would be, as you said, to essentially train other facilities and do it the way we kind of do bone marrow transplant, and that’s the model at least for this individual trial that we’re doing. But I think this has happened, for instance, with some of the T-cell therapies. It also may be that if this therapy shows effectiveness and the final version of them becomes sort of clear, there may be central production. And certain companies have done that where they started to make a vaccine, where people send cells to them and then they generate the vaccine and send it back. So I think that’s another very important question for this field, which is what is the best way to do it and what’s the best model. And I think both of those are potentially doable and are being sort of explored.

Jenny: And at the beginning of the show, you talked about minimal residual disease and why you’re trying to basically mop up the rest of the disease that’s not killed with standard stem cell transplant or the other standard therapies. So for our patients that might not know what is minimal residual disease an important indicator, and then can you give this vaccine in multiple dosage over time to keep extending the life of it?

Dr. Avigan: Right now, the way that studies are generated have to do with making a certain batch of vaccines, typically, three vaccines. But you’re right, other investigators have shown that there may be some advantage in giving boosting vaccinations later in the course as a way of trying to keep up some kind of protection, and I think that is something that people are exploring in the setting of studies. I think that minimal residual disease has this appeal because we think that when a tumor is sort of down and out but still not 100% gone that maybe there’s a mop up that can be done by the immune system. And when there’s less tumor around and it’s growing more slowly, that might also give you the time for the immune response to have an effect because the immune system works in a somewhat steady and deliberate way but not necessarily in a fast way. So you don’t want to get in a situtation where disease is rapidly growing and you’re just trying to vaccinate that situation, I think that probably doesn’t work as well. But honestly, we’re still learning.

Jenny: No. It’s early. This is so early but you’re doing great work to learn those important lessons. Well, one of my last questions will be what can patients do to help you speed up your work? What can they do to support you or help you?

Dr. Avigan: Well, I think the bottom line is that when I sit with patients and talk about whether they’re interested in the study or not or the standard care, that’s a very individualized decision. And I think patients are often very generous in thinking about studies not just sometimes for themselves but also some folks like to participate in the field as a way of growing it. But it’s a very personal decision and I think patients just need to kind of try and inform themselves as well as possible and find out the options and then make decisions they think are going to work best for themselves and their families. That’s really all that we ask from them. We want essentially to be a tool or help to them, and we understand that people have to be careful and thoughtful about how their individual situation applies to any of this kind of potential opportunities. So we’re grateful that folks are willing and generous to be part of studies. We also know that’s not right for everybody. So we kind of have a very personal discussion with each person. Jenny: Yeah. It’s an important decision and combinations are just exploding. Dr. Avigan: Right, and I think ultimately, it can be a bit dizzying. And what I would always recommend to the patient is to ultimately use a physician who they trust and have the relationship with to help guide them through what are a lot of different choices, and that that relationship should be one that is an ongoing one. It may be that they’re referred to a specific site or specific center for a very specific treatment, but that the physician and patient relationship is critical for helping to guide people through and talk through the options in a way that feels comfortable. Jenny: And we’re very big proponents of having patients see myeloma specialists even if they get local care by local oncologist. Having a specialist to understand all the different nuances of this disease is just, there’s so much to consider. I want patients to know that you can always go and get tested or get some care directed by a myeloma specialist and then go and have that care implemented in a local office. Dr. Avigan: It’s right. Jenny: Dr. Avigan, we’re so grateful that you’re working on this. We’d like to open it up to caller questions. So if you have a question for Dr. Avigan, please call 347-637-2631 and press 1 on your keypad. And while we’re waiting for callers with questions, we had another one from Dana Holmes about smoldering myeloma. She says, "Do you have any recommendations for those with smoldering myeloma and specifically which of the trials may get the biggest impact? Do you see any of those things potentially curative or more to just slow progression down? And how efficacious would these trials be for the smoldering patients who already have some immune system dysfunction?" Dr. Avigan: Again, I think that the decisions when patients have smoldering disease are complicated because one option if the disease is quiet is to of course just watch and to not jump into therapy right away. There’s a greater understanding now of patients that may be at high risk for the disease acting up sooner rather than later. And often, many of the studies focus in that direction. So let’s say that patients with smoldering disease will have certain characteristics are the ones that are the subject of a particular study. And that’s something that is very important when one sits with their physicians to know where they are in their smoldering situation and what are the level of concerns about activation of the disease because I think that will help also sometimes shape people’s understanding of what might be helpful or even whether it makes sense to think about a study or not. Honestly, I don’t know that we have, because the question with smoldering disease is still, does early intervention make a difference and does it help in the longer term? How much does it help? Those are all the questions that studies are asking. I don’t know that we know the answers yet. So I think that if somebody has a high-risk profile and they’re interested in doing a study, that makes a lot of sense to me. I can’t say, unfortunately, like, “Here is the study that works and here’s the one who doesn’t” because I think if you go to a good center and you have a physician that you trust, I would talk through what the options are with them. There are some vaccine studies in smoldering disease but we’re not sure how will they work yet, and there are some other approaches including using maybe certainly the immune-modulatory drugs, lenalidomide-based therapy sometimes maybe with checkpoints. But we don’t know what the winner is so to speak at this point. They’re just being sort of thought about.

Jenny: Well, there’s a lot to consider as you think about your care trying to plan ahead. I know a lot of people try to plan ahead. At every stage, whether they’re newly diagnosed, there’s an opportunity you don’t have to plan ahead. You just kind of have to forge ahead and then move forward. But with smoldering myeloma or in remission is a great time to take a break and plan ahead. Well, Dr. Avigan, we have kept you over time. So I just want to thank you so much for your participation on the show and helping us understand this dendritic cell vaccine. We are thrilled that you have dedicated your work and your life to helping us survive. We’re so very grateful for all your doings for patients.

Dr. Avigan: Well, it’s certainly my pleasure, and again, I feel that this is a partnership that we feel quite privileged to be part of.

Jenny: Well, we’re grateful and we hope you will keep us posted on your progress.

Dr. Avigan: That sounds great. Thank you very much.

Jenny: Okay. Thank you so much.

Dr. Avigan: Take care. Bye-bye.

Jenny: Thank you for listening to another episode of Myeloma Crowd Radio. We hope you join us for our next show and to learn more about how we, patients, can help drive a cure for myeloma by joining clinical trials and learning as much as we can about the research that benefits us.