Dr. Djordje Atanackovic of the Huntsman Cancer Institute explains the difference between genetic therapy (targeting specific genes or proteins) and cellular therapy (like auto and allo transplants and CAR T cell therapy) in multiple myeloma. He stresses that these immunotherapies will likely be used in combination with other existing treatments because of the complicated nature of the disease and uses elotuzumab as a perfect example. By itself it doesn't work much, but with Revlimid, it works extremely well. He also describes cancer testis antigens, or the ability to target the interior of the myeloma cell and not just the surface of the cell. Hitting the interior of the cell means that the cell can never "trick" the treatments by hiding the target - something that happens with treatments that target the surface of the myeloma cell alone. This methodology is not as far along as the other immunotherapies, like monoclonal antibodies, but is yet another way of using the immune system to kill myeloma.  Clinical Trials Discussed in This Show NY-ESO-1  The Myeloma Crowd Radio Show With Dr. Djordje Atanackovic

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 we would like to thank today's episode sponsor, Takeda Oncology, for their support of Myeloma Crowd Radio and all they do for multiple myeloma patients. They really stand out as an organization that supports patients not just by providing life-extending drugs but supporting the patient community as a whole. Now before we get started on today's show, I'd like to share a little about our Myeloma Crowd Research Initiative campaign. This is the first time that a group of united patients have come together with top myeloma research to find potentially-curative research for high-risk myeloma. So why high-risk? These patients do not do well on today's therapies compared to other patients and we believe that it's a top-down approach that will ultimately help all patients. Our eight-month search led us to two important projects that now need our financial support and both projects are ways to use the immune system to fight myeloma. To our delight, they are just as exciting for normal and low-risk patients as they are for high-risk patients. So we invite you to help raise funds for this proposal by creating your own fundraising page that you can share with friends and family. You can go to the myelomacrowd.org website for links that you'll see at the top to create your own page. Now onto our show which is also about the new and hot topic of immunotherapy. We would like to welcome Dr. Atanackovic to talk with us about the timing and use of immunotherapies as well as other projects he has going. So welcome, Dr. Atanackovic!

Dr. Djordje Atanackovic: Thank you so much for inviting me today and I'm happy to talk a little bit about my own field of interest, which is and has always been immunotherapy for cancer. So I'm very happy to talk about this topic today.

Jenny: Okay. Well, we're very excited to hear about it. So let me first introduce you before we get started with our questions and I will just share a little bit about you. Dr. Djordje Atanackovic is Associate Professor of Internal Medicine in the Hematology/BMT division of the Huntsman Cancer Institute. He is board-certified in the Hamburg Medical Council's Oncology/Hematology division and received his education at the University Medical Center in Hamburg-Ependorf in the Oncology/Hematology/Stem Cell Transplant division and the New York branch of the Ludwig Institute for Cancer Research. His deep research focuses on blood cancer immunology. He's a member of ASH, the European Hematology Association, ASCO, and both the American and European associations for cancer research. He's a reviewer for a list of worldwide organizations including Cancer Research UK, German Cancer Aid, and cancer organizations in Austria, Belgium, Italy, and Spain. His awards include grants from the University of Hamburg for the Excellent Young Researcher Award and also from the Cancer Research Institute and German Cancer Aid. He has three patents related to myeloma and an additional patent in progress. He is editor of BMC Cancer and is a representative of the Huntsman Cancer Institute on the NCCN Multiple Myeloma Panel. Dr. Atanackovic's research interest and deep roots are in immunotherapy, as you said. So welcome again.

Dr. Djordje Atanackovic: Thank you.

Jenny: Dr. Atanackovic, maybe you want to first begin by explaining the difference between gene therapy and cellular therapy.

Dr. Djordje Atanackovic: Yes. So you mentioned gene therapy and really the traditional way of thinking of gene therapy used to be that we try to correct or repair genetic defects that cause cancer. So this was the first step of a gene therapy, to repair genetic changes that can cause cancer. And to my mind, this hasn't so far been too successful, this approach. That's why probably very recently we used gene therapy to modify the patient's immune system for example by collecting peripheral white blood cells from the patient and then used genetic approaches to make these cells tumor-specific in order to re-transfuse them into the patient for these cells to destroy tumor in the patient's body. So this I think is the general difference. So these days we're using gene therapy in order to improve cellular therapies. That's what we are doing right now.

Jenny: Can you give us some examples of gene therapies?

Dr. Djordje Atanackovic: Yes, right. So I'm an immunotherapy expert so for different types of cancers we've tried to use the human immune system for a long time, for decades basically. And the first type of cellular immunotherapy at that point without gene therapy was actually the use of donor lymphocytes in patients who had an allogeneic transplant. So we would take donor-derived immune cells, infuse them in the patient in the hope that these foreign immune cells will destroy the patient's tumor. But unfortunately, this approach was very toxic in the sense that these are foreign cells which will not only attack your tumor cells but at the same time will also possibly attack your healthy tissues so donor lymphocyte infusion approach is still very toxic because a lot of patients will have developed graft-versus-host disease. So we tried to optimize the cellular immunotherapy approach, for example, by using tumor-infiltrating lymphocytes. So that's what people have done for patients with a certain type of skin cancer which is melanoma. So they resected the patient's tumors and then removed the immune cells present in the tumor tissue, expanded these immune cells and then retransfused them into the patient, the tumor-reactive cells back into the patient, and they have seem remarkable responses with this approach, with the tumor-infiltrating lymphocytes, in patients with metastasized skin cancer for example. But again, this is a very demanding approach and technically very demanding and you can't possibly do it at every center across the country or internationally. So that's why we very recently started to use gene therapy in combination with cellular immunotherapy in the sense that we will now collect the patient's immune cells just from the peripheral blood -- their own immune cells, their own white blood cells -- and then use gene therapy on these cells in the sense that by introducing a novel receptor into these cells, we will make them tumor-specific. And then we will retransfuse these genetically-modified T-cells which are CAR T-cells -- you've probably heard of this approach -- or T-cell receptor transfused T-cells, we'll retransfuse these now tumor-specific T-cells into the patients and this has also led to remarkable responses in certain types of lymphoma very recently. So this is how we, nowadays, combine gene therapy and cellular therapy.

Jenny: So it sounded like from other shows we've done that typical stem cell transplant is considered cellular therapy but what you're saying is that there are other immunotherapies that are also considered cellular therapy. Is that correct?

Dr. Djordje Atanackovic: Absolutely, that's correct. And I think this is because we've noticed and we've seen that these, like the classical autologous transplant for example and or the allogeneic transplant, there's great need for optimizing these approaches. Because as you mentioned in the introduction, these classical approaches are still not effective enough for example with patients with high-risk multiple myeloma so that's why we've used the most recent advances in the research to make your own immune system more tumor-specific and more effective in the fight against the multiple myeloma.

Jenny: Okay, perfect. I think we'll get into the tumor-specific a little bit later. So what I hear you saying and there seem to be a gene-targeted movement growing about a year or two ago and maybe it's gone on longer, to say gosh, can we find a certain protein or target on the cells and then just go after that target. And what you're saying is now you're trying to combine those two different approaches versus just one single approach. Is that what I hear you saying?

Dr. Djordje Atanackovic: Yes, exactly. I think you're absolutely right. And I think it's really still very true that we are as myeloma experts are supposed to tailor a treatment, to provide personalized treatment and that's what we will still do. I think this has been a major improvement in the field that we are now able to in a molecular fashion, define the characteristics of the disease of the patient. And even in the age of immunotherapy now, it's still very important to find out what are the genetic changes present in the patient's myeloma, for example, and then tailor the treatment not only according to the molecular characteristics of the tumor but also obviously according to the individual characteristics of the patient. So I think you're right. I think we're still these days supposed to personalize the treatment, find out what's the best treatment for this individual. But the problem is for example let's say a patient who has high-risk multiple myeloma with a deletion 17, a p53 mutation. We know that they are comparably higher risk for relapse, for example, after standard treatment including transplant but we don't know how to overcome the risk. So we're trying to overcome the risk in this patient by intensifying their treatment but we haven't been too successful in the group of patients with high-risk disease. But I think and I'm very hopeful that immunotherapy will eventually be able to overcome the risk associated with these genetic features of the patients. So I'm very hopeful and I think also our first data indicate that yes, this will become true and we will find an optimized immunotherapy even for patients with high-risk multiple myeloma.

Jenny: Well, I agree and I'm very excited for immunotherapies. And I think patients are so excited about immunotherapies just because they are still powerful but they could potentially reduce some of the need for chemo. I guess that kind of brings us to the next question. So we've had several shows where doctors have said that there are really windows of opportunity to use immunotherapies, that sometimes you might use them at a certain period of time in your treatment and sometimes they wouldn't work at all. So can you maybe explain what those windows are and then when they're best used? We've heard maybe when there is a low tumor burden or is it after transplant, is it best when you're relapsed refractory, can you even use it at that stage or maybe even for smoldering?

Dr. Djordje Atanackovic: Yes, right. That's a very good and important question I think. First of all, the question whether the human immune system can help in the fight against cancer has a very long history, I think. So they started as early as the 1920s to first experiment, even clinical experiments with patients. And I think the first approach was really cancer vaccines and that's the idea behind cancer vaccines is really to train the human immune system. So you wouldn't genetically modify, do anything outside of your own body but you administer a vaccine and try to make your immune system help in the fight against cancer by administering a vaccine. And this approach has been very effective in preventing infectious diseases as we all know. So we've tried for a long time to develop cancer vaccines and most of the time this approach has actually failed unfortunately. So this was the first type of immunotherapy which we consider active immunotherapy because this, by administering a vaccine, you basically train, as I said, your own immune system, your body would actually play an active part in the whole thing. And then later on we found out that cancer vaccines are not always effective. In fact, most of the times, these treatments failed and that's why we developed other types of immunotherapies which we call passive immunotherapies; for example, monoclonal antibodies. Antibodies, we all have antibodies in our body, they are part of the immune system. The antibodies target for example cells infected by virus, that's what antibodies can do -- they target viral infections. So we developed antibodies against different types of tumor cells because your own body, most of the time, is not capable of developing an effective immune response against the cancer cell. That's why we artificially made antibodies and gave them to the patient, which resulted in significant clinical responses in a number of cancers such as Non-Hodgkin's lymphoma where we have the antibody Rituximab, we've had this antibody for two decades basically and it's been very, very effective. Only very recently we've developed the first monoclonal antibodies for multiple myeloma. None of these treatments have been approved so far, for example, the antibody against PD-1 or the antibody against one of the surface antigens present on myeloma cells, the antibodies against CD38 so clinical results of these antibodies look very promising but they're not approved yet. I think these antibodies will receive approval very soon, hopefully early next year. And then finally, there are cellular immunotherapies I just mentioned. In this case we basically collect the patient's immune cells and modify them in a certain way, genetically for example, and then retransfuse them into the patient. So these are the things I just mentioned, these three types of immunotherapies -- vaccines, monoclonal antibodies, and cellular immunotherapies. I think these are the three major categories of immunotherapies. And I think for all of these treatments, there's a certain window of time or window of opportunity you can use but again, most of these treatments have not even been approved so they're not publicly available right now. And now I'll come back to you question, one of your questions was, can we use immunotherapies only in the case of a low tumor burden? No, I don't think so. I think that immunotherapy is for all stages and phases of multiple myeloma, there will be immunotherapies for all the different types of multiple myeloma. I think it's true that at some point in time, we thought that in the best case we'll have only very small tumor burden because this is the only thing the immune system can do, overcome minimal residual disease maybe. But that was the time when we had only vaccines available, which as I said, weren't very effective. I think these days our impression is more up-to-date, more modern versions of the immunotherapies like the genetically-modified T-cells I mentioned, the cellular immunotherapy, or the monoclonal antibodies are capable absolutely to fight large tumor burdens as well. So I would say these days we have a number of different immunotherapeutic approaches for all the different settings. I don't know if you want me to go a little more detail and explain, so I can give you an example. In a patient who has a very low tumor burden, patient after transplant, they have just minimal residual disease, a few tumor cells persisting in the bone marrow. These patients, I believe, probably at some point, can hopefully use a vaccine to keep these cells under control or maybe even eradicate these few remaining cells in the bone marrow. This would be a window of opportunity for immunotherapies that are less effective maybe but also less toxic for the patient in this particular setting. Same thing for smoldering myeloma, patients who do not have any symptoms at all, you don't want to expose them to severe toxicity so we'll have to find an immunotherapy for these patients that is not toxic. So that's the goal in these patients. And then again, a different type of patient, patients who have had relapsed disease or massive or rapidly-progressing disease maybe, in those patients you can’t wait and do something that's not effective, you have to come up with something that's very effective and will work very rapidly. So in these patients I would probably use a different type of immunotherapy, for example, one of the new antibodies that will be approved in combination with Revlimid and they've shown that these combination treatments, immunotherapy plus an IMiD is very, very effective and will work in the vast majority of the patients too. So in this case I would use a different type of immunotherapy or maybe even a cellular immunotherapy if available inside of a clinical trial. So what I'm saying is we're developing different tools, different types of immunotherapy for all the different phases of the disease -- patients with low levels of the disease, patients who have massively-progressing disease. And then again as I said previously, the plan is to individualize treatment and personalize treatment. You can pick the individual tool out of the many immunotherapies we will have available in the near future, I believe.

Jenny: Well, I think that's so exciting because I think that technology is getting there where you can target certain genetic features. In addition, we had another doctor say you really need to know your genetic features but you also need to understand that patient's immune system because what you were saying is that you can decide and pull out these tools that you're talking about and like you said, use vaccines when somebody should have low tumor burden or smoldering myeloma and monoclonal antibodies like the daratumumab and elotuzumab which are hopefully going to get approved soon in the next few months, and then the T-cell treatments that you're mentioning as well. So I think you really need a specialist who understands your disease and understands all the tools that are in that tool kit.

Dr. Djordje Atanackovic: Yes, I think so. I think you're absolutely right. But this has always been to a certain degree the case for multiple myeloma. I think the first thing as you all know, the most important thing really in the treatment of multiple myeloma is understand who's the patient. And I'm not talking only about the molecular characteristics of the tumor cells but also who is this individual, what's their background, what are their comorbidities, even the social background -- everything. So you really have to find out who's this patient, what does that tumor look like and then you'll have to define a goal. And these days it includes the whole spectrum of treatment with immunotherapies as well but it has always been the case that you'll have to get a detailed picture of whom are you dealing with basically.

Jenny: And it sounds like that the monoclonal antibodies coming up and it seems like all the T-cell research is right behind it but a little bit further behind and it looks really promising. Would you look at using those two things together? I know you'll have to test them by themselves first but are there stages where you would say well, at this stage I think a monoclonal antibody like the SAR or the daratumumab or the elotuzumab is a better choice and then later on we're going to give you CAR T-cell or we're going to start with the CAR T-cell stuff and then… I mean all the CAR T-cell stuff is in clinical trials like you were saying but I'm just wondering how you would determine what and when to use it especially with the current drugs that we have.

Dr. Djordje Atanackovic: Yes, right. I think that's a very good question. So for multiple myeloma, I think one of the hallmarks for multiple myeloma which really makes it very different from other tumor types is that you have enormous immunosuppression in the bone marrow environment of the multiple myeloma cells. And we've done a lot of research on this aspect, that's what multiple myeloma is actively doing. It's creating its own immunosuppressive environment in the bone marrow to protect itself from an immune attack. You could say it's fascinating too, how this disease creates its own comfortable environment in the bone marrow; attract for example immunosuppressive cells into the bone marrow to protect itself from an immune response and it produces all kinds of immunosuppressive soluble factors so there's a huge network of immunosuppressive factors around the multiple myeloma cells in the bone marrow. And that's why I think it will turn out that it's not that easy for multiple myeloma compared for example to non-Hodgkin's lymphoma. I think for multiple myeloma the solution is really you'll have to combine different approaches. For example, combine a cellular immunotherapy genetically modified T-cells with an antibody against PD-1 immunosuppressive surface molecule in the bone marrow. So combine different treatments or as you've mentioned the novel antibodies, the daratumumab or the elotuzumab, has been shown to be very effective but mainly when given in combination with an iMiD just like Revlimid which will change the bone marrow environment. So I think that's really the solution, the key point for multiple myeloma, you'll have to probably combine different types of immunotherapies in order to fight the disease effectively.

Jenny: And what you're saying with the CAR T-cell stuff versus the monoclonal antibodies, would you see one being better than the other? Like with a high tumor burden, is one going to be more powerful than the other or will they be just kind of combined?

Dr. Djordje Atanackovic: Yeah, I think that's really what it is. So for the antibodies they are a little farther ahead. So the antibodies have been tested in large clinical trials like the daratumumab, the elotuzumab and has been proven that they are very effective even in the setting of a large tumor burden, patients who've had a number of previous treatments and who are basically resistant to other types of treatment. The antibody when given in combination for example with Revlimid will still be very effective. So this has been shown in very large trials and will lead to the approval of the first monoclonal antibodies very soon. For the cellular immunotherapies, I would say it's still a little early because we don't have too many clinical results right now. So it's a little too early to say what's the role of cellular immunotherapies. I'm actually hoping for and I think it's very possible that these approaches will turn out to be very effective but it's just that it's a little early right now to determine exactly the role of these cellular novel immunotherapies for multiple myeloma. But if you ask me, same thing -- I think we'll end up combining for example antibodies with the cellular immunotherapies and that will probably be the most effective approach for multiple myeloma.

Jenny: In today's environment, let's say these monoclonal antibodies get approved, what do you see as standout combination treatments right now and for which stage of disease?

Dr. Djordje Atanackovic: I think right now as of today I would say it's probably the antibodies and the novel antibodies -- and there are more antibodies under development right now -- but the novel antibodies given in combination with the standard treatments just like Revlimid. And this is very fascinating because for some of the monoclonal antibodies like the elotuzumab, they tried them as a single agent. So they administered the antibody to patients with relapsed multiple myeloma and it didn't work, there was no response at all. So with the elotuzumab, a single agent, and then somebody luckily came up with the idea to combine the antibody with Revlimid in patients who had previously had the Revlimid already and maybe even failed it. But they combined it because they thought this is called an immunomodulatory drug, that's what the IMiD is, so why not combine it and give it a try? And then they observed enormous responses when given as a combination as an antibody plus the Revlimid. I think it's really, really fascinating. It just shows important the tumor microenvironment, the bone marrow, the immunosuppression in the bone marrow is really. But you really need to overcome the immunosuppression in the bone marrow environment before you will see a response to any of the new treatments. So I would say this has been the most dramatic change and achievement I think in the past few years. I think it's the monoclonal antibodies and the effect that we found out luckily that you need to combine them with a standard treatment like an IMiD for example.

Jenny: So that brings up another question. Do you ever see immunotherapies replacing ever the traditional drugs like the proteasome inhibitors or the IMiDs, or they'll always be used in combination you think with those because they help boost the path, I guess.

Dr. Djordje Atanackovic: Yes, I think that's the point. I think as of today just looking at the data we have, at the most recent clinical trial, it doesn't look like the immunotherapies will replace all the standard treatments. But on the contrary it looks like you need to combine the standard treatments, the IMiDs for example with a novel immunotherapy and that's when the treatment will be most effective. So I'm not sure, I can't predict with certainty, but right now it looks a little more like the appropriate way to develop new treatments is to combine them. Combine different versions of immunotherapies with standard treatments like an IMiD or a proteasome inhibitor. And this may very well change but I'm talking about what the data tells us right now.

Jenny: Right, and you have to work with what you have right now. And it's tough because when you look at something new you're not looking at in combination, you're just looking at it by itself first.

Dr. Djordje Atanackovic: Exactly, and that's how it is -- it could have perfectly failed. When they had the first results with the elotuzumab antibody and they found out it doesn't work, somebody could have said let's just forget about it, let's not invest any more money in this, let's just forget about it. And then someone came up with the idea to combine it and it was successful. So this is really very fascinating and on the other hand, I think you are right. And I think probably, that's how it's always been in medicine. Novel treatments at some point in time will probably replace all the types of treatment, I think. For example, I'm not so sure we'll do as many standard autologous transplants ten years from now because we will probably and hopefully have less toxic and more effective types of cellular immunotherapy just like the CAR treatment I just mentioned. So I'm sure that some types of treatment will be replaced at some point in time.

Jenny: Well, I think everybody would be excited to just get to a cure no matter what combination that would be.

Dr. Djordje Atanackovic: Yes.

Jenny: So I see that you have done research on cancer testis antigens and I know this has to do with immunotherapy. So maybe you would like to describe what that is and how it works because I'm not sure what that is.

Dr. Djordje Atanackovic: First of all, it's a certain family of proteins present inside of the tumor cells. So we just mentioned all the different antibodies which target proteins present on the surface of the cell. That's the only thing an antibody can do, it can target something present on the surface of a tumor cell. These proteins, the cancer testis antigens, are present mostly inside of the cell, you can't find them on the surface of the cell. But that's fine because there are all kinds of things the immune system can recognize inside of the cell because that's what cells do, many of the proteins present inside of them, they present them on the surface in the context of HLA molecules. And the purpose of this is to show, to demonstrate for example in case of a virus infection, that cell will present certain parts of the virus to the immune system on the surface saying "That's me, I'm infected. Please kill me." So that's the purpose of this whole thing. So intracellular proteins are presented on the cell surface in the context of HLA molecules, that's what evolution has developed. So that's what we can use, we can actually target proteins present inside of a tumor cell. Cancer testis antigens are intracellular proteins which play very important role, I think. They are only expressed in tumor cells, no cancer testis antigens expressed in normal cells which is good I think, because this is what we want. We want to target a structure that's not present on healthy tissues obviously because we don't want any toxicity. And we think that these proteins, the cancer testis antigens, play also a very important role in the development and progression of multiple myeloma. My group has shown that there's practically no multiple myeloma without a cancer testis antigen inside of the cell. And these proteins, if you remove them or suppress them, myeloma will stop growing, so this plays a very important role. It's not only a target for immunotherapy but these types of protein play a very important role in the progression of the disease too. And that's very important too I think because this way the tumor can't afford to just down-regulate or get rid of the protein in order to evade the immune control because the tumor cell can't survive without cancer testis antigen. That's why we continue to express antigens and we will be able to continuously target these structures inside of the cell. How can you do it, how can you target these intracellular proteins? You could do it for example by using genetically-modified T-cells. Again, T-cells are little bit different from the CAR T-cell approach you just mentioned. So you would have to genetically modify these T-cells in the case of cancer testis antigen by introducing different types of T-cell receptor. That's how probably we'll be able to effectively target cancer testis antigens expressed in multiple myeloma. And I can tell you there's a number of trials ongoing and a number of genetically-modified T-cells under construction right now that will target cancer testis antigens in multiple myeloma. Multiple myeloma is the one tumor type that shows the most frequent and strongest expression of cancer testis antigens out of all the different tumor types.

Jenny: Oh, that's fascinating. So what you're saying is if you can get inside the cell, maybe you can do a few things -- you can make sure that just because it has it on its surface, sometimes you're saying the cancer cells lose that signature because they get tricky and they lose the signature even though they're still developing myeloma. So by going on the inside of the cell you're kind of killing it at the origin, that's what it sounds like. Is that correct?

Dr. Djordje Atanackovic: Yeah, that's absolutely correct.

Jenny: And how is this being done and then how, if you could compare it please to like the monoclonal antibody work and the CAR T-cell work, where is this at in terms of development?

Dr. Djordje Atanackovic: Right, that's a very good question. So the general difference between CAR T-cells, for example, and monoclonal antibodies, versus the vaccine approach or the T-cell receptor transduction approach is really that antibodies and CAR T-cells target surface molecules expressed on myeloma cells for example. The problem with these approaches is that very often you won't be able to find a surface molecule present only and specifically in multiple myeloma cells or you won't be able to find a molecule that's expressed on all the different myeloma cells in every single patient. So that's the problem of surface because they're very often not specifically enough expressed on the tumor cells, you won't be able to find a perfect tumor antigen expressed on the surface. So that's why for example let's say the novel antibodies, the daratumumab which targets CD38 on the surface of multiple myeloma cells, will at the same time kill all kinds of plasma cells, all the normal plasma cells probably which are also positive for CD38 and the number of T-cells and so forth. So I'm just saying there is probably no perfect surface molecule, you will always also at the same time target healthy tissues. And that's not the case for intracellular proteins like the cancer testis antigens. We have identified a number of proteins that are only and specifically expressed only in tumor cells and that's why approaches targeting these proteins will hopefully be less toxic and more effective. But right now, as of today, the antibodies and the CAR T-cells targeting surface molecules are very close to the clinic and will be approved very soon while the other approaches targeting intracellular proteins are still under development. I'm only aware of one large trial that was very recently published that used target as the cancer testis antigen using genetically modified T-cells. So this still needs a lot of time for development.

Jenny: Can you explain how it works? Like what will the treatment look like in that trial or in a trial that uses the antigens?

Dr. Djordje Atanackovic: Again, this is a very fascinating approach. As you probably know, they've recently combined two different approaches. So they've combined an autologous transplant so high-dose chemotherapy, high-dose melphalan followed by an autologous transplant. And then on day 15 after transplant which you know is the point in time when most patients will show recovery of their blood cell counts, on that day they gave the patients CAR T-cells, for example. And I think that's a very reasonable design of a clinical trial to combine it with the transplant. I think that's not what most people have in mind when they talk about immunotherapy but I think that for now is probably very reasonable design. I think that's what a number of trials will do to combine it with an autologous transplant and give these cancer testis antigen-specific cells, for example, within the framework of an autologous transplant for a number of reasons. Because one of the reasons is that you will have an empty bone marrow, you will have a lot of space in the peripheral blood. So these newly developed T-cells, they can easily expand and grow in the bone marrow, in the peripheral blood of the patient and then multiply and fight the myeloma more effectively. So I think this would probably be one of the possible designs for such a study.

Jenny: Okay. So we were doing a show about infiltrating lymphocytes and it sounded like that sample, let's say you were going to do an immunotherapy on a patient. That sample was from a bone marrow and most of these others are coming out of the blood. So what do you use for this cancer testis antigen approach, you just take it out of the blood and then how do they engineer it to target inside of the myeloma cells? I think that's really fascinating.

Dr. Djordje Atanackovic: Yes, right. So for a T-cell in general to recognize intracellular approach, we have millions of different types of T-cells in our blood which basically patrol the blood 24 hours a day. They will look for their specific little piece of a protein they can recognize. So one T-cell can only recognize a certain little piece of a protein, let's say a viral protein, or a cancer testis antigen. That's why we have millions of different T-cells in our blood. And that's what makes it generally a little difficult for the immune system to find tumor cells in the first place because the number of preexisting T-cells specific for the given antigen is just simply too low. So to a certain degree it's just a number that's the problem really. The basic idea was why don't we collect all the patient's T-cells and make all these cells specific for a given cancer testis antigen. That's actually how we do it. So you can collect a patient's white blood cells including all the T-cells, then you expand them, grow them in the lab, and then introduce a new T-cell receptor, a receptor that's specific for the given cancer testis antigen. Make all the patient’s T-cells specific for this given target basically so I'm talking about let's say 500 million cells. And then you will retransfuse these T-cells with a new T-cell receptor into the patient's peripheral blood and then these cells will be able to recognize all of the cells, 100% of the 500 million cells will be able to recognize and kill cells expressing the given cancer testis antigens.

Jenny: That's amazing that you can train them all to go after one kind. So let's say a patient has different types of myeloma cells in their body, does it just go after one of those kinds or you're training it to go after all the kinds that that particular patient has in their system?

Dr. Djordje Atanackovic: That's a very, very good question. So I mentioned a number of characteristics that we think are positive for a given tumor antigen. We think it's an advantage if your target plays a role in the progression of the disease because that way the tumor can't afford to lose its expression. So that's the one thing. And then what you want, did I mention that too, is really you want to target antigens that's only expressed in or on tumor cells but not on any healthy tissues because this way you will avoid toxicity. And then the third criteria in which you just mentioned is we would like to come up with a tumor antigen that is expressed in all the patient's tumor cells, so homogenous expression not just in 95% of the patients but an expression in all, 100% of the patient's tumor cells. And then another advantage would be to have an expression or the presence of the given antigen in all the different myeloma patients so 100% of the myeloma patients in an ideal world and in all of their tumor cells. And that's not the case for too many targets these days but there are a number of cancer testis antigens, for example, which are expressed in 90% of the patients and in all of their tumor cells. So I think this way we wouldn't even have to test the patients -- if we think it's expressed in 100% of the patients, you wouldn't even have to test them. But for the clinical trial for example, the one I just mentioned which targeted a certain cancer testis antigen named NY-ESO-1. So they tested the patients. You can collect their bone marrow and then test the expression, evaluate the expression of the target antigen in the patient's bone marrow, in the patient's tumor cells, that's how they did it for that trial. And I think it turned out that 20% of the patients only expressed the antigen of interest.

Jenny: And that was my next question, how do you test for this? So it's part of a bone marrow biopsy?

Dr. Djordje Atanackovic: Yes. Since the tumor cells in the case of multiple myeloma are primarily present in the bone marrow, that's why you have to do a bone marrow biopsy. That's what we've done for hundreds and hundreds of patients in the past. We've collected their bone marrow and then you can apply a number of assays to determine the expression of the antigen of interest. For example you can do a PCR or you do immunohistochemistry, you could even do a gene array, you can do all kinds of things to evaluate the expression of a given antigen in a particular patient. I don't remember how they did it for that trial but it's not that difficult, the only thing is you have to do a bone marrow biopsy.

Jenny: Well, that's fascinating because I've seen all these approaches to target the surface of the cell and I haven't heard much about this at all. That's amazing.

Dr. Djordje Atanackovic: So recently -- I think if I'm correct it was in NIH, I'm not very sure but they completed a large trial with TCT, transduced T-cells targeting the cancer testis antigen, NY-ESO-1, and they achieved some remarkable responses. It's not that easy if you don't have a large trial and not a randomized trial to clearly demonstrate that it's the new approach because they combined it with chemotherapy so it's hard to say in such a trial how effective was the cellular immunotherapy, the whole framework of the whole approach. But that's how they did it for the trial so it was recently published only.

Jenny: Wow, okay, that's exciting. So we look forward to hearing more about that. Now there were two other topics that I saw that you were doing research on and we probably have time to just talk about one. I'm looking at the time, the time goes by so fast. So I know that we'll be hearing more about PD-1 and PD-L1 from ASH and it is considered an immunotherapy and I know you're working on that and you're also working on CAR CD229. So maybe you want to pick what you would like to talk about.

Dr. Djordje Atanackovic: Yes, I can explain briefly. I think the anti-PD-1 approach, antibodies are very fascinating things because it's not targeting, like the antibodies I just mentioned I told you so these antibodies they target a molecule present on the surface of the tumor cell. So they target these tumor cells directly while these new antibody doesn't even target the tumor cells but it targets the immunosuppressive environment of multiple myeloma cells. So what the anti-PD-1 antibody does, it doesn't kill the tumor cells but it helps the immune system and it removes the brake -- that's how they call it -- from an effective immune response on T-cells. So it's actually targeting the immunosuppressive environment of multiple myeloma. So it's an antibody as well but the whole approach is very different from classical antibodies, very, very fascinating. I'm very optimistic that will result in a very nice response. And our own group, we defined again another molecule present on multiple myeloma cells which we're on the process of developing an immunotherapy targeting this molecule which is CD229. It's expressed on all the patients' multiple myeloma cells. Unfortunately it seems like it's also expressed on some healthy cells, normal cells, as it is the case for most surface antigens. But we're very hopeful that we will still don't see too much of the toxicity and this approach will be very effective in multiple myeloma. Actually we're making CAR T-cells targeting CD229 right now in the lab and we'll test it very shortly in vivo and find out.

Jenny: Wow, that's fascinating. So where will your research take you next primarily? With all these different immunotherapy approaches and with a background in immunotherapy, what do you see as the most exciting and promising and how do we get it out the door faster or in combination? Because as a patient I listen to you talk and I say "Gosh, well I would like to use the PD-1 and the PD-L1 to take the brakes off my immune system but I'd also like to kill the tumor burden that I already have:, so how do you prioritize as an immunotherapy expert?

Dr. Djordje Atanackovic: I think the thing is really we don't have the time to prioritize, we'll have to do everything at the same time to evaluate. So we'll have to determine what's the efficacy and the toxicity of all the different treatments used as a single agent and then we'll have to start to do combination trials in parallel. I think this is the only way how we can speed up the process by doing studies in parallel to single agent and then combination treatment because that's what we've seen in the past, combination treatments are more effective than single agent immunotherapies. So that's how in general I would do it. Then we just started to develop something here which is a very novel approach. So we have something called platform for cellular immunotherapies here at the Huntsman and at University of Utah. The idea is really let's say if you were a physician treating patients with multiple myeloma you could come to us and you could tell us "I have so many patients who are in need of these novel treatments and I don't have any clinical trials going on because I'm not a researcher, I'm just treating patients." And then we would help you to develop your own type of immunotherapy and develop the whole product really and provide you with a product you can use in your own clinical trial for your patients within a few months only. So that's what we're building right now here at the university and that's the other way of how I think hopefully we'll be able to get there faster I think.

Jenny: Well, that's a very new approach and a way of thinking about it because you have all these local oncologists who are trying to treat myeloma when they're not necessarily a specialist and now you have combinations and more combinations and immunotherapies and new drugs coming out. Wow, that's a challenge for them to properly treat myeloma.

Dr. Djordje Atanackovic: Yes, right, and I think this is really how we should do this. I think we shouldn’t focus too much just on our own lab and groups and things like that. So the goal is really to provide new treatments faster and more effectively for different diseases, different tumor types and different clinical investigators.

Jenny: Okay. Last question will be before we open it up to caller questions is what's the value to you of patients joining clinical trials?

Dr. Djordje Atanackovic: That's the key issue. So we really should make very clear particularly also for multiple myeloma, I think numbers of patients treated within clinical trials are still way too low. So this is what we have to do, we have to raise awareness and make very clear there won't be any advances without clinical trials. I think for multiple myeloma we should try to treat the majority of our patients within clinical trials. Unfortunately that's not the case today but this is of major importance, I think.

Jenny: Well, that's terrific. We're really excited that you're working on this. So we would like to open it up for caller questions and if you have a question for Dr. Atanackovic, you can call 347-637-2631. Please go ahead with your question.

Caller: Hi, thanks for taking my call. In the past, Huntsman has done tandem transplants. Are you guys continuing to do the tandem transplant therapy or is that not a therapy that you are pursuing?

Dr. Djordje Atanackovic: It's true that the Huntsman in the past treated most of the patients, the vast majority, with a tandem approach and this was based on the total therapy approach developed in Arkansas. We don't do that anymore. I think we're part of the NCCN network and we should adhere to our own guidelines which are really based on clinical trials and there's really no solid evidence so far that the tandem approach is the optimal approach for all the different types of multiple myeloma. So we are actually not performing tandem transplant on a routine basis for all of our patients. We still do it for a minority of patients who do not respond well enough to their first transplant but for the majority of transplant-eligible patients, we'll only do one transplant probably.

Caller: Okay. And then I have a follow up question if that's okay. How long do you think it will take to get the CAR T-cell into clinical research?

Dr. Djordje Atanackovic: It's already in clinical studies and that's already the case nowadays. I think for the first CAR T-cells to be FDA-approved, I think the time and also of the companies involved, I think the plan is to have the first ones approved in 2018. And for multiple myeloma I can't give you a specific date. I know right now there are a number of studies going on, different places with different antigens. So there are a number of clinical trials with CAR T-cells actively recruiting multiple myeloma patients as of today but I can't give you a specific date on when exactly will these agents be approved.

Caller: Awesome, thank you so much. Great interview and thanks for all you're doing there. Welcome to Utah!

Dr. Djordje Atanackovic: Okay, thank you.

Jenny: And I have a follow up question to that. So when you say it's about 2018, I know they're just entering clinical studies right now, it's really early, what would you say for the cancer testis antigens, like maybe three to five years? Because it seems to be a step behind that, what do you think?

Dr. Djordje Atanackovic: That's what I would hope for. I would say five years is probably real, that's what I'm hoping for.

Jenny: Well, I think at that point you'll have a really good idea about how these work and how they work together. Dr. Atanackovic, we're so grateful for your participation on the show today. We're very excited about what you're doing and know that these immunotherapies are giving patients more options and better options, so we are just thrilled.

Dr. Djordje Atanackovic: Thank you. So we are thrilled too. I'm very, very optimistic to know that we'll be able to further improve the survival of the patients. I think the goal is really to use these immunotherapies to also maybe hopefully in few years from now be able to achieve cures for the first time in multiple myeloma.

Jenny: I know. We're so excited you're saying that word. It's a great word. So thank you so much for participating and thanks for all you're doing.

Dr. Djordje Atanackovic: Thank you so much.

Jenny: Thank you for listening to Myeloma Crowd Radio. We believe that patients can help support the discovery of a cure through our initiative and we are grateful for all that researchers are doing to make this possible.