Full MCRI Show: Remarkable approach for highly aggressive myeloma and PCL using safer allo transplant techniques in combination with immunotherapies. Dr. Guenther Koehne, MD, PhD, MSKCC
Dr. Guenther Koehne, MD, PhD Memorial Sloan Kettering Cancer Center Interview Date: April 7, 2015 Watch the Memorial Sloan Kettering Cancer Center Video about this research Thanks to our episode sponsor, Takeda Oncology Summary In our second MCRI episode featuring the top 10 proposals for high-risk multiple myeloma, Dr. Guenther Koehne explains a truly extraordinary approach for highly relapsed/refractory and plasma cell leukemia patients. First, he uses T-cell depleted allogeneic transplants to eliminate the dreaded graft vs. host side effects that are typical of allo transplant. He describes how they remove the T cells from the donors cells before infusing them into the patient. It was believed that a small level of graft vs. host was needed for good response to allo transplant, but he tells us that the data may indicate that graft vs. host may not be necessary for an anti-myeloma affect. Next, he has identified a tumor receptor called WT1 expressed on most myeloma cells from his work in leukemia. He can engineer the T cells to find that receptor and initiate cell death without side effects that are commonly found in CAR T cell approaches. As a third step, he is now working increase the effectivity by training those WT1 cells to secret Interleukin 12. IL-12 enhances the survival of these T cells and acts as a "homing" device to help the T cells find the WT1 signal, rounding up the cells that need to be eliminated. His results are truly outstanding. In his second clinical trial that included both relapsed/refractory myeloma and plasma cell leukemia patients, there are zero reported cases of graft vs. host disease and many in the trial (even those with plasma cell leukemia) are now in complete remission. This is truly remarkable because those with PCL have very poor outcomes. He is now opening up a third trial to continue this impressive work. The Myeloma Crowd Radio Show with Dr. Guenther Koehne, MD, PhD.
Full Transcript Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom, and I'm joined today by my myeloma friends including Pat Killingsworth, Gary Peterson, and Cynthia Chmielewski as co-hosts. We would like to thank our sponsor for this episode, Takeda Oncology. We're very grateful for their dedicated support for the Myeloma Crowd Radio Show. This is the second in a very important series featuring the Myeloma Crowd Research Initiative. For the first time, patients, including you, are teaming up with myeloma researchers to find and fund the ideas in myeloma that could have the greatest impact for the next generation of myeloma therapies. We decided to go after high-risk myeloma. Now, I've called this a trickle-down strategy, but a friend corrected me and said it was actually a trickle-up strategy for patients that have no viable options today either because they have high-risk features or are relapsing or refractory to existing drugs. We need new options. If we can find solutions for high-risk patients, it is highly likely that it will work in medium or low-risk patients, and ultimately we all become high-risk as the current arsenal of myeloma drugs stop working, so this series is truly for everyone. We asked researchers around the world to submit their proposals and we received back 36 high-quality letters of intent. That list was then scored by our Scientific Advisory Board including Dr. Ola Landgren, Dr. Guido Tricot, Dr. Noopur Raje, Dr. Robert Orlowski, Dr. Rafael Fonseca, Dr. Irene Ghobrial, and Dr. Mike Thompson. Ten proposals were selected and we are now holding Myeloma Crowd Radio shows so you can be involved. We would love for you to understand these proposals, so please listen in, ask questions, read the transcript after the show is posted, and share it with your myeloma friends and your caregivers and family members. This is truly critical work being done in myeloma. Now, after the full proposals are submitted, the Scientific Advisory Board and the Myeloma Patient Advisory Board will together decide on a limited number to fund through patient-driven campaign, and again, we will need your help to get the word out and share the really amazing work that's being done. We are very privileged today to have with us Dr. Guenther Koehne of Memorial Sloan Kettering Cancer Center. Welcome, Dr. Koehne. Dr. Koehne: Thank you. Thank you for inviting me. Jenny: We are so happy to have you. Let me give a brief introduction for you. Dr. Guenther Koehne is Medical Director of the Cell Therapy Laboratory in the Bone Marrow Transplantation Laboratory at Memorial Sloan Kettering. He is also Associate Member and Attending Physician in the Allogeneic Bone Marrow Transplantation Service. He is Associate Professor of the Joan and Sanford Weill Medical College of Cornell University. He leads research at the BMT Department/Immunology Program to develop adoptive immunotherapeutic strategies for post-transplant blood disorders. He has particular expertise in the creation and monitoring of antigen-specific T cell responses in these patients. He is the principal investigator in active clinical trials using adoptive cell therapy following allogeneic stem cell transplants for multiple myeloma and plasma cell leukemia patients. He obtained his medical degree at the University of Hamburg, Germany and has been at Memorial Sloan Kettering Cancer Center since 1996. Dr. Koehne, we have also with us Cynthia, and let me add Gary here who will also be asking questions. We will also open it up at the very end for patient questions, so you can press 1 on your keypad if you have a question there. Why don't you go ahead and begin with the background about this research and how it came to pass? In particular, you have one patient that has a very interesting story. Dr. Koehne: Yes. Basically, it really started out very early, as you also alluded to in your introduction, that patients were referred to me from myeloma doctors that were basically not responding to the standard chemotherapy and they had problems to treat the patients with other drug combinations. They just asked me, "Is there something you can do about it?" As you also alluded to in my introduction, I'm basically by heart a bone marrow transplant physician and secondarily, I'm really involved with utilizing the immune system to fight cancer. That idea arose then by taking on patients that had multiple relapses. They had their autologous transplant and they had relapsed disease after that. Basically, every myeloma doctor would agree that the dynamic of this disease will change once you start relapsing, and so we were really in the category where you're thinking what do you do for these patients. We have and it was known that we have a potential curative therapy for patients with multiple myeloma or even relapsed multiple myeloma, and that is the donor-derived or allogeneic stem cell transplantation. But before we could apply this, we needed to change a lot with regard of the outcome because the allogeneic stem cell transplantation for patients with multiple myeloma had significant limitations and most of those are summarized as severe graft-versus-host disease. That's basically an immune response of the donor's T cells against healthy tissue, and the conventional allogeneic transplantation in itself had a much higher rate of graft-versus-host disease in patients with multiple myeloma compared to those that were transplanted for other diseases that required an allogeneic transplant. So what we needed to do, first step is to really reduce the risk of inducing complications for graft-versus-host disease. That initiated when I was asked to take on these patients. That initiated the idea because Memorial Sloan Kettering Cancer Center has been the pioneer of doing what we call T cell-depleted transplants. In other words, we remove the T cell from the stem cell product that's collected from the donor and with that, we reduce the risk of graft-versus-host disease significantly. This is how it started out then. The first patient was relatively young. I remember the first one that really came to me was only 36 years old and had already relapsed disease and the referring physician told me, "I really don't know what to do with him." I talked to him about the first step of introducing T cell-depleted transplants. That was frankly seven years ago now and this patient is now -- as you do the math -- is 43 years old and is still in complete remission at this point, so that was really the first step where we really got a little bit more excited about introducing the T cell-depleted transplant approach. And then later on, the second patient you alluded to then, that's my patient with a really very aggressive disease. We call this plasma cell leukemia and in her particular case, it's secondary plasma cell leukemia where everybody knows that the overall survival is extremely limited. In fact, it's somewhat between 9 and 11 weeks with best available treatment. And so, that was the next step then. After other patients that I've transplanted with the T cell-depleted approach. I knew this patient had a brother who was willing to donate or was a good match. At this point, we knew already how to generate myeloma-specific or tumor-specific T cells. This patient then underwent a T cell-depleted transplant and got infused with those myeloma-specific T cells six weeks after the transplantation. Surprisingly enough at this point, to be honest, we obtained a complete remission after we infused her with these cells and that then led to next steps to develop a strategy, how we really want to approach patients with high-risk multiple myeloma or advanced disease and treat them with a platform of transplantation, and then subsequently steps that include the immunotherapy. Jenny: There are a lot of questions around that, I think. I know Cynthia, you had a question about the T cell-depleted transplant. Do you want to ask those while we have that upfront? And then we'll move on to the immunotherapy. Cynthia: Sure. With the T cell-depleted transplant, you're taking the T cells out of this donor's stem cells. Can these transplants be done in other types of cancers or are they just specific to myeloma? Dr. Koehne: No. In fact, it started in other diseases. Initially at our place, we started to do the T cell-depleted transplant for patients with leukemia. That was really the breakthrough development when we had a national study showing that the outcome of patients undergoing allogeneic transplant for acute myelogenous leukemia or acute lymphocytic leukemia had an equivalent outcome in terms of overall progression survival, but they did not encounter the side effects which we summarized as graft-versus-host disease. In other words, there was the first time that really we could show that you do not necessarily need to have graft-versus-host disease in order to prevent relapse. That was the precursor here because those patients that came to me were not willing to undergo the old fashioned allogeneic transplant. And so, with the information we had from these initial trials for leukemia, we then opened a trial to test the hypothesis whether or not we can perform the same and achieve the same outcome of patients undergoing a T cell-depleted transplantation with multiple myeloma. In fact, the graft-versus-host disease occurrence is extremely low in all the clinical trials that I'm having right now. Cynthia: Do you take all the T cells out in a T cell-depleted transplant? Do patients need T cells in the future? Once they're depleted, do they ever grow back? Dr. Koehne: That's a key question. The first answer to the first part is what we do is we get the product that is collected from the donor, which is a bag of a liter or 1.5 liters of fluid, and that's a composition of the stem cells, which we really would like to have, and then the T cells and other cells that are in the bag. What we do is we'll attach the stem cells to an antibody that is labeled to a small magnetic bead and we'll push those through a magnetic field, and therefore, the stem cells will be pulled out and it will be enriched. All the other non-attached cells including the T cells just flush through the magnetic field and they end up in a stem cell negative fraction and will usually not be used for anything. The answer is the amount of T cells is extremely low. It's not zero, it's not negative, but it's about 2000 to 3000 T cells per kilogram body weight when we perform the transplantation, and that amount of T cells is too low to induce graft-versus-host disease in the majority of all transplants that we are performing. With regard to the second part of your question "Do you need the T cells after the transplantation?" is exactly the matter of the strategy and the scientific approach that I'm exploring. We don't know for a fact, but obviously, I transplanted a lot of patients now with relapsed multiple myeloma and we gave after the transplantation T cells from the same donor at calculated doses, which we call donor lymphocyte infusions. In some of these patients, we induced a persistent remission. In other patients that had residual disease prior to the donor lymphocyte infusion, we could induce a complete remission as a consequence of the donor lymphocyte infusion. That then raises other questions of what do we really do with the donor lymphocyte infusions and this leads then to what I think we will discuss at some point to the development of the Wilms tumor antigen or WT1-specific T cells that we're now administering. Cynthia: Okay. Thanks so much, doc. Dr. Koehne: My pleasure. Jenny: I had a question also about low levels of graft-versus-host. In other shows that I've done, some experts have said having a low level of graft-versus-host is actually good because it's a graft-versus-myeloma effect, that high levels are very poor. What I just heard you say is that might not be true. Dr. Koehne: It's a provocative statement, but I have to say I think it's time to really make this statement. You do not need to have graft-versus-host disease to prevent relapse in the majority of diseases, and myeloma is one of those where we know already for a fact that graft-versus-host disease is not necessarily associated with a better outcome or with a less relapse, and that holds true for acute myelogenous leukemia as well and for sure for acute lymphocytic leukemia. There's one disease that falls out a little bit, and that is the CML or chronic myelogenous leukemia where it is established outcome that graft-versus-host disease prevents relapse if you have graft-versus-host disease, but in all the other ones and the other diseases I've mentioned and primarily in myeloma, you do not need to have that. There is also a recent publication from the Europeans. It's called the EBMTR or the European Bone Marrow Transplantation Registry. They summarized the outcome of patients undergoing allogeneic transplant for multiple myeloma and just looked at those who had graft-versus-host disease versus those who had no graft-versus-host disease and there was absolutely no difference in the relapse rate. Jenny: Fascinating. If you've been doing this type of allogeneic transplant, the T cell-depleted transplant for the last seven years, why are there not more people doing this? Because if you're avoiding this, it's critical for -- Dr. Koehne: I am in total agreement. In the scientific community, the way it works is you have to show first scientifically that you are right with what you're doing or what you're thinking, and then the other centers are potentially joining. In fact, I'm right now at a stage where this trial with T cell-depleted allogeneic transplants followed by immunotherapy in the form of donor lymphocyte infusions or antigen-specific T cells will open at other centers, so I'm in strong communication with other centers that also got a little query about the fact that they had to send me all the patients. I have in particular one center in Kansas University. They sent me over 15 patients by now and asked the question why should I go to New York and why don't I do the transplant here, so that's exactly why I will open this trial, or they will open it. They are under my guidance. Jenny: Before we move on to the WT1 immunotherapy piece of it, I would like to ask if you could just give a brief overview of plasma cell leukemia because there's primary plasma cell leukemia and secondary plasma cell leukemia, and not everyone knows what that is. Dr. Koehne: Well, the development of multiple myeloma can occur in several stages. You might have heard about an MGUS stage or Monoclonal Gammopathy of Unknown Significance, and then you have an asymptomatic myeloma, and then you have multiple myeloma. At the end of this whole spectrum, you can have something that we call plasma cell leukemia, so this may be misleading. It's not necessarily a leukemia compared to a real myelogenous leukemia. It's basically really the multiple myeloma cells that are now floating around in the bloodstream and it's a very aggressive and very advanced stage of multiple myeloma. It could be sometimes that patients get diagnosed right away with plasma cell leukemia, which is called the primary plasma cell leukemia. In other circumstances, it is the development through the stages so that they had multiple myeloma for a while, for years. After that, it progressed to a leukemia transformation and then end-stage multiple myeloma. Both diseases, and really every myeloma doctor will agree, have to be looked at very differently because it's a completely different kettle of disease because the overall survival is extremely limited. Therefore, I feel like we really need to take this into account and also come up with a more aggressive treatment approach from the very beginning. Jenny: Is that what you decided to target, plasma cell leukemia, just because there are no options for these patients? Dr. Koehne: First of all, there are extremely limited options. Second of all, the antigen-specific T cells were needed to be tested in a scientific fashion. If you have a disease that is really very aggressive and you have a low threshold, then if you get patients into a longer lasting remission that exceeds the expected timeframe, then you have already something that you can show off. Basically, I really like more the trickle-down effect that you initially mentioned because if you can show that this works in these high-risk categories and is safe, you may also allow then later on to apply those two patients at an earlier stage and therefore trickle down and apply this new approach. Jenny: Absolutely. Well, maybe you would like to continue just describing the second part of this. The first part is that you're changing the way that you do the allogeneic transplant and the second part is that you're using immunotherapy to do that. Maybe you'd explain what that is and how that works. Dr. Koehne: I'd like to do that. The whole principle of stem cell transplantation or allogeneic stem cell transplantation is really the attempt to utilize the donor's immune system to treat disease. The initial stages of allogeneic stem cell transplantation, we're gearing towards high-dose chemotherapy with the goal to really eliminate every single cancer cell, if you get lucky, and then have a better outcome. It turned out to be that the high-dose chemotherapy is not really necessarily needed because it's not the treatment that treats that disease and can get somebody in long-lasting remission. The immune system of the donor and particularly T cells that develop in the patient after the transplant and gets sensitized in the bloodstream and learn to recognize tumor cells are the ones that can induce a long-lasting remission and float around and find tumor cells that escapes the strong chemotherapy. These T cells have the capacity to really walk out of the bloodstream and go into the tissue and find tumor cells, and then they have the capacity to send signals to other cells and say, "Here is where the disease still is. Come over" and they do something. This led to the development of pre-priming T cells from the donor in the laboratory to make them specific for markers that are expressed on the myeloma cells. Accidentally, I discovered by following patients that got donor lymphocyte infusions after the transplantation that the majority of these patients developed a tumor-specific response against a marker that expressed on the myeloma cells, which is called WT1 or Wilms Tumor Antigen 1. This then changed the whole strategy of how we approach patients with plasma cell leukemia by generating the T cells upfront in the laboratory to make them specific and then infused into the patient. Jenny: So you're taking out the donor T cells. You're engineering them basically to target this Wilms Tumor Antigen 1, and then you release them back into the body and they go do the attacking work, right? Dr. Koehne: Exactly right, yes, exactly right. The advantage is if you now have a disease like plasma cell leukemia where patients really have a few weeks or limited months to live, you have to act fast and you want to do the transplant or follow up with something right away afterwards. You don't want to wait until the disease is back. The advantage of these T cells that are engineered in the laboratory to recognize the tumor cells during this culturing process also lose their capacity to induce graft-versus-host disease. For that reason, you can give these cells at an early time point after the transplantation without having the risk of inducing graft-versus-host disease, but still fighting the disease by inducing a graft-versus-myeloma effect. Jenny: On your video -- now, you have a really nice video on the Memorial Sloan Kettering website that describes this research and we will link to that because it's really terrific, but I noticed you were saying you wanted to give them six weeks after the transplant, but not before because it had an impact on the graft-versus-host. Is that right? Dr. Koehne: That's partially correct because you need to wait a little bit until the stem cell product is really settled in the bone marrow and then you can follow up with specific T cell infusions, but you don't want to wait for too long until the disease comes back already, and the chance that it will be in the case of plasma cell leukemia is very high. Gary: Doctor, I just was wondering if you could take the T cells from the patients and make them sensitive to this marker and infuse them. Dr. Koehne: Yes. That's a very good question. Therefore, coming down again with the trickle down effect, I think it's worthwhile to try. Obviously, it's not possible to try this in patients with plasma cell leukemia because there are two aspects to it. Their own immune system already allowed the disease to develop and the disease somehow escaped the immune surveillance. Therefore, it would take way too long of a time and you don't get these patients into remission, but it may be -- and that's the trickle-down. If you have somebody with an early stage of multiple myeloma and has many more years with a controlled disease that this is a possibility. That's something that I would like to test in the future. Gary: The other question that would follow that would be you had said that these T cells from other patients or other people lost their graft-versus-host capability and as a result, could those then be just infused into a myeloma patient or end-stage leukemia patient and do the same thing without the allo or auto transplants? Dr. Koehne: The way we are doing this -- to generate these cells from a donor to infuse in a patient without an allogeneic transplant would not be possible because you would need to convert the patient -- or in this case, the recipient to donor chimerism or to the immune system of the donor before you can treat. These cells would either not do anything or they would still have the capacity to recognize the healthy tissue if you did not convert the patient to a donor immune system. Gary: Good! Thank you, doctor. Dr. Koehne: I don't want to escape or switch to a completely different theme, but there are other approaches that could potentially be considered to use the patient's cells to manipulate directly and test, but it would not be possible to use donor T cells into a patient that did not undergo an allogeneic transplantation. Gary: Okay. Cynthia: I have some questions with the WT1 cells. Can I ask them now? Jenny: Go ahead, Cynthia. Cynthia: So the WT1 cells are expressed on the malignant plasma cells. Is that correct? Dr. Koehne: Correct. Cynthia: So if by chance when you do the allogeneic transplantation, if you get the patient in a complete stringent response where there's no MRD, would they still be able to find these WT1 cells to go after if there are no myeloma cells left? Dr. Koehne: Yes. That really is another big advantage of using the donor's or the patient's immune system and using T lymphocytes that are specific for the disease in contrast to chemotherapy that has a known half life. So you take the pill or you get it infused and the drug breaks down or is broken down by the liver and you excrete it then it's over. Those T cells are just there to stay. I don't know exactly for how long the WT1 cells may be in the bloodstream, but in this particular case that Jenny also alluded to, the patient that I've transplanted for plasma cell leukemia, I know by follow-up and testing her blood that these tumor-specific T cells were in her bloodstream for more than a year and a half. At the time when she went into a complete remission and stayed negative of all disease markers, the numbers came down, but they were still there and they expressed some form of tumor surveillance. So in contrast with chemotherapy, these cells are there. They're biological weapons that are alive and they survive usually in lymph nodes. And if the disease shows up without even knowing for us because in between we didn't do the blood test, then they come out and they can go after the tumor cells again. Cynthia: That's pretty neat. Now, are there any other cells in the body that's expressed at the same WT1 receptor that these T cells may go after? Dr. Koehne: It's also an interesting development. The WT1 has been explored basically looking at all forms of cancers. For unknown reasons, nobody really looked into WT1 in multiple myeloma. I just was the first to really look into this accidentally because we have another clinical trial where we looked at WT1 in leukemia and I applied the same methodology to look into patients with multiple myeloma, and then found out that this was really very highly expressed on multiple myeloma and that patients developed a very strong immune response against this WT1 and subsequently, they have a clinical response. That was really an accidental finding. If you observe these then you exploit this, all of a sudden, you end up with a full-fledged FDA approved trial to treat patients with this disease with these T cells. Cynthia: Thank you so much. Gary: A question on the receptor. There was some information that we had seen before or talked about that you could go after this particular receptor, but sometimes it resides on other things that you don't want to mess up like for example, it could be on all your kidney cells or you can wipe out your kidneys with it. Did you see any off-target responses? Dr. Koehne: It's very interesting and a good question. We have not seen any side effects from the administration of these cells. The question with regard to kidney comes up all the time and I'm surprised by the fact that we do not see any effect on the kidney. You really brought it up because the Wilms tumor antigen is expressed although at a lot lower level than on the plasma cells, which may be the reason why you don't see side effects with regard to kidney dysfunction or anything, but we have not observed despite treating quite a good number of patients with these cells by now. Pat: Jenny, could I ask some questions? Jenny: Please go ahead, Pat. Pat: Hi, doctor! Pat Killingsworth in Florida, and I have a couple of specific questions, but first to clarify, so you can apply this principle to both allos and also autos, or just donor transplants? Dr. Koehne: At this point, we're testing them in the context of donor transplants and generate the cells from the donor that also donated the stem cells, but the question could be -- and because I've also observed that patients with multiple myeloma get sensitized, so they have very low frequencies of Wilms tumor antigen specific T cells in their bloodstream. Therefore, the question could be can you use those, take them out of the blood, grow them up in the laboratory to higher numbers, and reinfuse? That's something that we'd like to test in the future. Pat: Okay. That's interesting. Now, I watched the video. Have you been able to duplicate that success yet with the patient that we see in the video, for example, at the clinic? They had some phenomenal results with the measles virus, but in their second cohort, they haven't been able to duplicate this success. Dr. Koehne: I totally agree and I appreciate your comment. The answer is "yes", so I have other patients with plasma cell leukemia primary and secondary plasma cell leukemia that are still in persistent, complete remission. There are a few now that are more than a year out, which is a good timeframe to say that's more than expected. Pat: Oh, that's wonderful, so the implication is if you can treat plasma cell leukemia, myeloma should be easier? Dr. Koehne: That would be my conclusion as well. And so, the next clinical trial that we're going thinking ahead because this plasma cell leukemia trial is coming to a closure because the accrual rate is just complete. We'll open up to patients with less aggressive disease, so showing the safety of these cells, it would be certainly a good approach to use patients that have relapsed multiple myeloma and treat them with the same approach. Pat: Yes. That would be great. I have a specific question. Being one of those patients, what I've learned -- I've now relapsed three times. What I've learned is I'm becoming a non-secretor and that a lot of late stage patients are non-secretors. Are you able to include non-secretors in your trials? I'm finding just when I need a trial, I'm excluded from like 95% of the trails. Dr. Koehne: Yes. Non-secretors are not excluded from the trial. You just have to monitor the response by bone marrow studies, which is obviously a little bit more painful to the patient who have a bone marrow every single time to see whether or not the cells are working or that the treatment is working, but in general, they're not excluded from this approach. Pat: Well, that's great. Hey, I'm getting ready preparing for a modified salvage autotransplant. How soon do you start accruing patients, myeloma patients? Dr. Koehne: For the autotransplant, I'm not sure this will happen within the next two or three years. We really have to test whether or not they're equally effective. Right now, all I can say and I know scientifically that the donor-derived T cells can have a very good effect. Pat: Sure, but aren't you starting to accrue for a donor transplant? Dr. Koehne: Oh yes, that's in full swing. The donor transplant, that's with the antigen specific -- T cell infusions are in full swing. Pat: Maybe I should look at doing that instead. My insurance approved an auto or an allo, so maybe I should look into that. Dr. Koehne: Yes. I'd like to talk to you here in person. Pat: Wonderful! Thank you, doctor. Dr. Koehne: My pleasure. Jenny: I had a question. In some of the literature, when I was reading about it, it talked about the Wilms Tumor 1 Antigen and they were secreting IL-12. Can you explain what IL-12 is and why is that beneficial or what that does? Dr. Koehne: That's already the next step that we try to think about how we can do better. The Interleukin 12 basically is a substance. We call it a cytokine. It's a small molecule that is excreted by certain types of cells that we call antigen-presenting cells that are at the site of the disease. That's an interesting substance that's produced in the body at the site of disease. The Interleukin 12 has the capacity to change the environment around the tumor site and also can stimulate and send signals to T cells to come to the site, so it's really a very interesting substance that could enhance the survival of the T cells at the site and could also improve the recruitment to the tumor site, something we call "homing" to the site. All in all, there is a good chance that the T cells will be there at more numbers and they will be around that site at longer time periods. Knowing that, it introduced the idea of whether or not you can just armor those Wilms tumor antigen specific T cells with a gene that allows the T cells to produce Interleukin 12 at the site. And so, the next step that we're thinking about to introduce is to modify the Wilms tumor antigen specific T cells with a gene that allows to produce Interleukin 12, and that may even have a better effect than the Wilms tumor specific T cells that I'm utilizing now. That, in fact, will also be testable in the autologous setting because if you now can use the T cells from the patient to make them tumor-specific for WT1 and introduce the Interleukin 12 gene and reinfuse those, then we may ask the question, "Is this an effective treatment that does not require the allogeneic transplant?" or it could at least utilize to find out whether or not it's safe and how strong the immune response is that you can achieve with this approach. Gary: So the IL-12, that specifically armors the T cells so it can't be eliminated. Is that right? Dr. Koehne: Yes. Gary: I had a feeling that it was like a mini-bomb attached to the T cell. Dr. Koehne: You can say it like that definitely. It's something that changes the environment. We call it an inflammatory or a proinflammatory cytokine that once the T cells home to a site in your body where the disease is present, then it gets released and the T cells get more active. There are inhibitory cells around the tumor site, and so there is something that is called immune escape. The tumor cells are usually a little bit smarter than we just think they are, so they can shut down the response to immune response, to T cells, and this Interleukin 12 would be able to reverse the effects so that they are not protected. Gary: It's like a little detonator. Dr. Koehne: Exactly. That's exactly how we can look at it. Gary: Okay. Thank you. That's pretty neat. Dr. Koehne: Yeah. We have to test whether or not it's as effective as we hope, but we have some evidence and some background that that is very promising. Jenny: Well, could you take us through your process? You're building upon what you've learned already and now you're trying to, it sounds like, just super boost what you're already doing. Can you walk us through the original single patient in the clinical trial, the clinical trial that you just recently ran, what you have planned in the future? Dr. Koehne: Yes. It's basically a learning process that we have been through. Every time we'll treat a patient or more than one, we learn something. There are some scientific results that always surprise us and we take notice of it. We just try to take advantage and then build this into the program. First step really was the T cell-depleted transplant for patients with multiply relapsed myeloma. They underwent the transplant. They got unmodified T cells or donor lymphocyte infusions from the same donor. And with these T cells, we could observe immune-specific responses. That then led to the detection of the Wilms tumor antigen expression on the myeloma cells and the discovery of immune-specific T cells that are derived from the donor lymphocyte infusion. As a consequence, we developed a second clinical trial that then integrates the administration of T cells that are specifically generated in the laboratory to recognize WT1. This trial now is applicable for patients with what we call relapsed or refractory multiple myeloma or plasma cell leukemia, as discussed. Both these trials are coming to an end because they reached the accrual pretty soon. So now, what we learned now is that the WT1 specific T cells are safe, so we will apply this approach to patients with multiple myeloma at an earlier stage because they seem to be effective, they're safe, and the risk of graft-versus-host disease is really low. Now, while we are doing the next step of clinical trial, we'll plan to improve upon this even further by saying if we now have the capacity to transduce these T cells that are recognizing WT1 with a gene that produces the Interleukin 12, then we have the detonator at the time that will hopefully lead to a better outcome with the same risk profile and the same amount of limited side effects. The overall goal is very simple. We want to cure these diseases and the allogeneic transplant as a platform has certainly the potential to cure a disease, but if we now build immunotherapeutic approaches specifically targeting these tumor cells, then I think we have a shot to do that. Jenny: Well, we love that goal as patients. We love that goal to cure it and it's not a chronic disease. Now, with patients in the second set, when will you begin this clinical trial or recruiting for that, and then if you're able to now avoid some of the common pitfalls of graft-versus-host, do you have any age restrictions or physical restrictions on that clinical trial? Dr. Koehne: Well, there are two aspects to this. Obviously, you'll think a little differently talking to a patient that is 45 years old and with standard of care. You have another three years to give with drugs compared to somebody who is 75 years old and can be having a really good quality of life for another three to five years with drugs. You could tell a 35-year-old patient, "With the best drug combinations because you have high-risk cytogenetics, the risk of relapse is very high, I can give you three years," he will just say, "That is not good enough." So from that aspect, there are some limitations. The tolerance of this transplant itself or the age limit on my clinical trials I just raised at to 72 years old because it was really very well tolerated, which speaks in itself also, but I've also taken into consideration that the tolerance is better in patients that are younger. All in all, what the overall results now is showing on all the patients transplanted is that the outcome of this transplant is better if you don't wait for four or five relapses. You'd want to do this relatively early. Again, in the beginning of our conversation, I pointed out that the disease dynamic changes once we have a relapsed multiple myeloma after, for example, an autologous transplant. That's where you'll want to start thinking differently. There are drugs that can keep you in remission after that, not everybody, and that's really critical for me to point out at this point. Not everybody should have an allogeneic transplant with our approach here, but those who had multiple relapses who have high-risk cytogenetics, are stable, and their kidney function, their lung function, and their heart function is fine, should start thinking about this rather than to wait for another two or three relapses that will ultimately occur. Jenny: Let's talk about cytogenetics. Are there any other high-risk features that you see this as being particular good for? If it's plasma cell leukemia, but a gene deletion 17p or -- Dr. Koehne: Exactly right, so there are markers that predict that the disease will have a high potential and propensity to come back, the P53 gene or the deletion 17p. There are other markers, 1q25, 1q23, t(4;16) are all indicators that you want to start thinking about this at an earlier time point. A part of my clinical trial where we do T cell-depleted transplants is what we call an upfront transplant where the patients are really young, less than 55 years, and have this high-risk cytogenetics. You know that with standard of care and an autologous transplant, the disease will come back sooner than later. Therefore, we now transplant those patients after the autologous transplant, if we have appropriate donors, with the T cell-depleted allogeneic transplant. Jenny: We were asking this question -- our last show was about CAR T cells that are targeting the CS1 protein. Gary asked some relevant questions about pricing, how much it costs to be able to do this type of research. Can you talk about different milestones that you might see on the horizon and how much those milestones cost to achieve? Dr. Koehne: Yes. The good news now is for patients who undergo allogeneic transplantation, the transplantation is covered by the insurance company with the exception of Medicare. They haven't done that step yet, but in the beginning, I've had some problems to get this approved. Right now, most of the patients can get this covered by their insurance, so those costs are already accounted for. For us, it's really the laboratory costs and the experimental strategy that we have to generate these T cells, to monitor the immune responses that require skilled personnel in the laboratory, that requires research study, assistance, and so on. The generation of the T cells itself is inducing some costs, so if I had a clinical trial now with T cell-depleted transplant and performing the administration of WT1-specific T cells, depending on the amount of patients you enroll, let's just say 30 patients, you may talk about $500,000 for a trial like this that has to cover all the other costs to generate the cells, to infuse the cells, to cover for the expenses and personnel. Jenny: Okay. Well, it's interesting learning about that from a patient perspective because we usually don't think about that part. Dr. Koehne: And the patients don't get charged. The hospital, as long as it's experimental trials, my funds in the hospital has to -- basically it has to cover the strategy and the idea to do this. Therefore, these funds in the bank are really important before you can open this trial. Gary: All we need is one Sam Walton to get sick and we'll have plenty of money. Dr. Koehne: That's right, but that's not -- Jenny: No, we don't wish it on anybody, do we? Dr. Koehne: That's right. Jenny: So since you're here, Pat, do you have any follow-up questions? I'm sure you do. Pat: No, I'm good. This has been very enlightening and it's hopeful and encouraging. We appreciate your hard work, doctor. Dr. Koehne: Thank you very much. I hope I made it understandable. I'm not really sure how lifted off I sometimes give my answers, but I try to keep it on an understandable level. Gary: You made it much easier than reading that presentation that you provided. Dr. Koehne: Okay. Gary: And our ability to ask the questions, that clarifies that, so we really do appreciate that. I have a couple of questions, one of which is based on be the match. Memorial Sloan Kettering Cancer Center does a pretty good job. Their one-year survival for the allo is 70.3% and compared to other people, that's pretty darn good; that's 30%. If you applied this kind of strategy, that 30% who die, is that usually due to graft-versus-host? Dr. Koehne: No, that's basically -- but that's exactly the point that I was making earlier. The 70% outcome is really as good as it can get because we avoid graft-versus-host disease. This 70% alludes to all patients transplanted. This is not particularly multiple myeloma. So that basically is because the rate at one year is lower because patients die of graft complications from graft-versus-host disease. Since we can avoid that, we are really up there. There are still obviously two aspects that can reduce it by 30% and the one is that you have a really advanced disease. No matter what you do, you relapse. That's one part of this patient cohort. Another group is another complication that we encounter, complications with regard to infections that develop. That is also a really key aspect of it, if patients with advanced leukemia or multiple relapses of leukemia get transplanted. They are more prone to get complications of viral infections and so forth. Therefore, you would take this into account and the dropout rate is about 30%. Gary: Okay. In your analysis, you said something about 18% was infection related mortality. Dr. Koehne: Yes. This is specifically now for patients undergoing transplants for multiple myeloma. I'm about to submit a manuscript to summarize the clinical outcome of 44 patients transplanted with multiple relapsed disease and some of these or most of these patients in fact had more than five lines, up to ten lines of treatment because they relapsed six times and more. What this shows is that the graft-versus-host disease rate on all patients transplanted is only 2%. That is unheard of. And so, the biggest complication frankly is what's called chronic graft-versus-host disease, which leads to complications like dry eyes, dry mouth, stiff skin. The quality of life of these patients is really not good if you have chronic graft-versus-host disease and they sometimes wonder whether or not they really benefit from a longer life, but not so good quality of life. In my study, there is not one patient with chronic graft-versus-host disease and that's 0%. This makes the point again that you do not need to have this to prevent relapse. The 18% you alluded to are the ones that have complications from infectious complications of all patients transplanted. It's 18%, but we also had within these cohort unfortunate situations that basically are unavoidable. Two patients got infected with flu from visitors and couldn't recover from it early post-transplant. One patient just decided to go overseas despite of medical advice not to do so and came back with a really bad infection and did not survive that. Those situations are hard to avoid. Usually with the T cell-depleted transplant, we have what we call a non-transplant related mortality, which includes the infections of approximately 10%. Gary: Okay, versus the 30% that you have for all allo transplants? Dr. Koehne: That includes also the patients that die of relapsed disease, so that's the 10% -- Gary: Well, that's still remarkable. I was trying to surmise because I've looked at some of your data and it says 31% of the patients at two years, which is 5 of 16 are alive at two years. That didn't quite equate to your 18%, so I can't -- because to me, that was -- unless they all died in the second year -- Dr. Koehne: I'm not sure which data -- where these are or what they're applied to. Gary: It was in your report. It was 31% of all patients at two years, or five -- Dr. Koehne: But this includes all transplant recipients for all diseases. That is not specifically for the patients with multiple myeloma. That is all the diseases. Gary: Okay. That was the other one -- Dr. Koehne: And that's a broader spectrum, yes. Gary: This was just in your analysis. It stated this and I was a little confused trying to make that equate to your 18% or make it equate to the 16 patients, five of which had plasma cell leukemia and didn't even make it to T cell infusion. Dr. Koehne: Yes, so that's important to point out that at this point, not everybody who has plasma cell leukemia has complete remission and a long-lasting response because the disease is really that aggressive. A lot of patients or some patients come back with the disease after the allogeneic transplant before you have a chance to give the T cells because it is such an aggressive disease. That leads really to the next question. That's why the IL-12 may come down with some benefits, but also how early would be best to administer these T cells, so maybe we should not wait six weeks or eight weeks because there was already a 30% drop-off of patients that relapsed within the short time period. Gary: Are all 16 patients plasma cell leukemia patients? Dr. Koehne: Of the 16, there were seven patients with plasma cell leukemia and the rest had what we call relapsed or refractory multiple myeloma. Gary: Okay, so you had much better luck with myeloma than you did with plasma cell leukemia. Dr. Koehne: No. In fact, the patients with primary and secondary plasma cell leukemia, half of them are in complete remission and it's a really impressive response. Cynthia: I have a question. Does everyone that you give the WT1 T cells to shows some kind of immune response to them or are there some non-responders? Dr. Koehne: That's a really good question also and that leads back to the answer, is not everybody did, but those who do are doing clinically well. Those who do not have a detectable T cell response are not benefitting from the T cells. Cynthia: And we don't know why -- Dr. Koehne: That is not entirely clear at this point, but that's also under investigation. It gets a little bit more in detailed immunology. Sometimes, some of the peptides that are derived from WT1 are more immunogenic in the context of what we call HLA that is the markers. We look for donor and patient matching, so some of them present this peptide stronger to the T cells than others. Therefore, the ones who have the appropriate HLA typing have a stronger and better immune response. These are all questions and really important aspects of it that arise off of all this work that we are doing right now. Cynthia: Right. It's great. Great work, what you're doing. Also, what kind of side effects have the patients experienced once they saw an immune response to the T cells? Dr. Koehne: Interestingly enough, no side effects, just clinical responses. There are no side effects, particularly we have not observed any cytokine release syndrome, which the CAR T cell therapy can do or any kidney dysfunction, or acute or chronic graft-versus-host disease. Cynthia: Because with the CAR T cells, they were seeing some of those side effects. They were talking about the CAR T cells, once they're infused in your body, there's an expansion of them. Does the same thing happen with the WT1 T cells? Do they expand once -- Dr. Koehne: Absolutely, and that gets back to the biology of these T cells and the difference between a chemotherapy and a drug. The chemotherapy drug just gets eliminated over time. In fact, the T cells can expand over time in the system. Therefore, you get more over time. Cynthia: And they just come out when you need them and then they go away when you don't? Dr. Koehne: They do their business. They kill the tumor cells and then they disappear. If there is a tumor cell that develops over time or can be found, then they have the capacity to come out. That's basically the reason why the principle is the vaccination of viral against viruses or you were exposed as a child to a specific measles virus for example and then you get exposed again later during your life. You're not going to get a second wave of measles because your immune system is on standby and is just able to eliminate the virus before it can make you really sick. That's what we hope. I've observed it in some patients. I cannot generalize this at this point, but the principle surely could apply to exactly the same approach. We have them, they survive, and they come out, and they do the tumor surveillance. Cynthia: It sounds great. Thanks. Jenny: Now, we have some write-in questions and you may have covered some of this already, but from Jack, he was asking, "Is there a way that you could ultimately give the therapy without transplant maybe a very good partial remission from induction therapy?" and then proceed -- you've covered this a little already. Dr. Koehne: Yes. At this point, it's difficult to predict, but we will certainly test this. We talked a little bit about the CAR T cell's approaches. That would be more an approach to utilize in the autologous setting or to treat the disease with the patient's own cells. Whether or not that's applicable to the WT1 specific T cells clearly needs to be tested. There is no scientific evidence at this point that it is possible, but certainly we have the capacity and the ability to generate these cells from the patient and we will certainly test this. If this has a comparable outcome than the CAR T cell therapy, then we will develop clinical trials to expand this. Gary: Would you do it in a mouse model at first or no? Dr. Koehne: From scientific aspects, it's always good to do this, so we have three phases basically. You do the laboratory work and then you test it on the mouse, and then you go to clinical trials in human beings. That is a watertight approach. We did a lot of mouse experiments and I'm not really sure we have to do it in every single circumstance, but it does recapitulate work that we have done before. Obviously, since this is untouched ground, it would be worthwhile to have T cells from an individual in a mouse, in the humanized mouse model that allows you to show that the T cells really go to the tumor and that we'd like to test in this circumstance. Gary: Yeah. Your research has historically shown that what happens with the mouse also happens in your human trials. I mean, is it pretty good at doing that? Dr. Koehne: If you talk to a mouse doctor who is focusing on laboratory work, he will say "yes". If you talk to somebody who applies this more into the human beings -- the environment obviously is very different in the human beings, so it's not necessarily transferable in every single circumstance, but basically the principle is to show that the cells have the capacity to go through the bloodstream and to home to the tumor. If you can show that, then I think it's worthwhile to get it to the next level and administer these cells in the human being. Gary: Well, Dr. Hoffmeister did show that and with some remarkable results with those CAR Ts, so that's why I asked that question. Dr. Koehne: Absolutely, no question about that. Jenny: Jack's second question was, "This proposed next upcoming trial is for primary plasma cell leukemia, secondary plasma cell leukemia, and relapsed/refractory myeloma, correct?" Dr. Koehne: That's the plan, yes. We would target this high-risk category of diseases first. Jenny: Okay. Well, unless anyone has any other -- Cynthia: I have one last. Jenny: Okay. Go ahead, Cynthia. Cynthia: I do have one last question. Would there be any way in the distant future that this type of therapy does prove to work to have a factory manufactured type T cell so that you don't need to make it individual per person and cut down the expenses? Dr. Koehne: Wonderful question and in fact, companies are now heavily involved to look into this market. We are right now at our place at Memorial Sloan Kettering in intense negotiation with companies that would like to do exactly what you're suggesting, to take over the patent, to license it, generate these cells, and then make it basically open to the market. Right now, all the patients that would need this treatment have to come to our place for the treatment of it, but if it gets licensed and it can be expanded, then we have the capacity to ship these cells to centers that can administer these cells. That is in fact not just in the future anymore. Cynthia: Okay. Great! That sounds exciting, too. Dr. Koehne: Yes, very nice. Jenny: It's remarkable. Dr. Koehne, we're just so impressed that you've been able to see results in plasma cell leukemia patients. I think that alone is just stunning to be able to see that kind of response in plasma cell leukemia patients who really have no options and a few weeks to live. It's just truly stunning. Dr. Koehne: Yeah. I'm also very happy and really honored to observe this and have the contact to my patients and having a discussion and talk about the limited time that is left, and then two or three years later, you still are able to see them in remission and talk to them. It just puts you in a completely different category and the question of why you're doing all of this. It's just a wonderful experience. Gary: It's truly remarkable, doctor. Dr. Koehne: Thank you. Jenny: That is why you're doing this and that's why we're loving that you're doing it. Dr. Koehne: Thank you. Thank you very much. Jenny: We're just so thrilled. Well, we are so grateful for you that you joined us today. Thank you so much for explaining your research in such great and easy to understand terms. Dr. Koehne: Thank you for including me and for inviting me to give me a chance to talk about it. I'm very honored to do that. Jenny: Well, we're very appreciative. We will be providing the full transcript as we are finished in a few days, so watch for that and then we'll include the link to the video so you can learn a little bit more about that. We're just very thankful. Dr. Koehne: Thank you. Gary: It's truly remarkable, doctor. Jenny: Thank you for listening to Myeloma Crowd Radio and the new Myeloma Crowd Research Initiative Series. We believe that patients can help support the discovery of a cure and we encourage you to become invo