CAR T cell therapies are an exceptionally exciting non-transplant therapy future option for blood cancer patients, including multiple myeloma. CAR T cells are an engineered product, so selecting the best one and engineering it in the best way is of critical importance. Drs. Einsele and Hudecek share their deep experience in the use of CAR T cells and the lessons learned to increase the effectivity while also boosting safety measures. They describe how T cells are removed from a blood sample, engingeered to target the CS1 protein found on myeloma cells, grown up and expanded and then given back to the patient. This is a non-transplant option that stays active in patients for years. Because some testing in leukemia has shown "immune escape" or a loss of the targeted protein in 5-10% of patients, Drs. Einsele and Hudecek have identified a companion target, BCMA, to give the immune system a second targeting option. Because CAR T cells are potentially curative but extremely powerful, they have also developed an emergency brake in case of any possible negative reaction in patients using a specific antibody. And because all CAR T cells are not the same (as they are engineered), they are using what has been already proven with the safety studies done in elotuzumab; the HuLuc63 targeting domain . The work shows a very thorough approach with much contingency planning, based on many years of immunotherapy research.  The Myeloma Crowd Radio Show with Dr. Hermann Einsele and Dr. Michael Hudecek. 

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 Petersen, Jack Aiello, and Cynthia Chmielewski as co-hosts. We would like to thank today's episode sponsor, Takeda Oncology, for their support of Myeloma Crowd Radio and myeloma patients. This is the ninth in a very important series featuring the Myeloma Crowd Research Initiative. This is proof that patients can help to find and fund curative research for myeloma. This has been an amazing journey so far. We have created an expert scientific advisory board and invited active patient-advocates to join together for the project. Together, we decided to go after solutions for high-risk myeloma because these patients have dismal outcomes even with the great advances that have been made in the disease. We also believe that by addressing high-risk, new discoveries will ultimately help all patients because we all become high-risk at some point in our journey. We called for letters of intent and received back 36 high-quality proposals from top investigators around the world. Our scientific advisory board then scored these proposals and selected the top ten. This show is #9 in the 10 that we will complete. After the shows are finished and full proposals have been submitted, both the scientific advisory board and the patient advisory board will vote to select a small number of proposals to fund. Now to all of our listeners and readers, today is the day that you can join with us to find a cure for this disease that threatens our lives. As Gary said in a video that we prepared, this is our chance to save ourselves. So today, you can now help by creating your own fundraising page. In a web browser, you can go to https://mcri.myelomacrowd.org/ (notice that there's no www) and click on “Build a Team”. You can upload your own photo and write your own text to customize your page. We won't have you share that page with friends and family just yet because we want to first know which projects will be selected but this is an easy first step you can take and we are going to need your help. Now today we are very privileged to have with us Dr. Hermann Einsele and Dr. Michael Hudecek from the University of Würzburg in Germany. Welcome, Doctors.

Dr. Einsele: Hello! Welcome.

Dr. Hudecek: Hello! It's nice to be on the show.

Jenny: Thank you so much for joining us today. Let me introduce you both. Dr. Hermann Einsele is Professor of Internal Medicine and Director of the Department of Internal Medicine at the University of Würzburg. Following his medical training at the Universities of Tubingen, Manchester, London and Seattle, he became a research fellow in the Department of Hematology/Oncology/Rheumatology/Immunology at the University of Tubingen, Germany. He's a member of the American Society of Hematology, the European Group for Blood and Marrow Transplantation, and the EBMT working parties for Infectious Disease and Immunobiology. He is currently a member of the board of the German Society of Blood and Marrow Stem Cell Transplantation. In 1999, he became Chairman of the German Study Group in Multiple Myeloma. In 2003, he received the van Bekkum-Award of the European Society of Blood and Marrow Transplantation. He has published more than 350 articles in peer-reviewed journals. His research interests include multiple myeloma, stem cell transplantation and adoptive immunotherapy. He's a member of the board of the German Lymphoma Group. In April 2011 he was elected Honorary Fellowship of the Royal College of Pathologists in the UK. Dr. Michael Hudecek is a clinical fellow and research group leader for the CAR T cell lab work at the University of Würzburg. Dr. Hudecek obtained his medical degree with summa cum laude from the University of Leipzig, Germany, and performed his post-doctoral research fellowship at the Fred Hutchinson Cancer Research Center in Seattle. Dr. Hudecek joined the University of Würzburg in 2012 as a clinical fellow and research group leader. His awards include an LLS Fellowship Award, German Cancer Health Award for the Max Eder Excellence Program for his T-cell engineering work, and the Young Scholar Award for the Bavarian Academy of Science. So again, thank you so much for joining us today. Maybe you can give us just an overview of your history in immunotherapy, how this all came about and specifically how it relates to your work in CAR T cells.

Dr. Einsele: First of all, thanks very much for letting us present our proposal here to explain our strategy to deal with myeloma including especially immunotherapeutic strategies. Now, apart from multiple myeloma and we really have a large number of programs here in Würzburg, we see about more than 500 patients with myeloma per year and we have different clinical trials open. We have quite a bit of research ongoing in the field of myeloma. So my second interest is really immunotherapy and I was one of the first that really used T cells to treat infections in patients with hematological malignancies and we later on developed strategies to redirect T cells. So we took T cells that were, for example, specific for influenza virus or cytomegalovirus and by using a new antibody constructs, we forced these T cells to actually attack tumor cells. That was the strategy which is kind of a precursor of the CAR T cell program and we started this already in the early 2000s. And because we actually developed this strategy, I think we are very well prepared to use CAR T cells in the clinic because this strategy of biospecific antibodies has a similar approach to redirect T cells to attack the tumor cell and also to learn about the side effects of the strategy. So we have seen the typical side effects of CAR T cell therapy already when we use the biospecifics and develop strategies to really get around this. So this is my kind of history of immunotherapy and I will hand it over to Michael Hudecek who really is the expert -- at least in our clinic -- for CAR T cell therapy.

Dr. Hudecek: So how did I get into the CAR T cell work? This journey for me started when I was in medical school and this is eight years ago. When I was a medical student, I got interested in hematology and I learned through medical training how bone marrow transplantation was successfully used to treat patients with advanced leukemias and lymphomas. And I understood that essentially the curative mechanism of how bone marrow transplantation works is driven by T cells that are derived from the marrow donor and that they learned to recognize antigents - So molecules expressed on leukemia or lymphoma cells. And that this graft versus leukemia effect driven by T cells is so strong that it could cure a very aggressive leukemias and lymphomas. And that was so impressive to me that I decided to pursue this scientifically in the lab. And I got the chance to go to Seattle to the Fred Hutchinson Cancer Research Center, the center that developed bone marrow transplantation, and to advance my knowledge in science and how to deal with science as a medical doctor. So I tried to isolate leukemia-reactive T cells, T cells that can recognize leukemic cells and destroy them from panels of patients that had undergone bone marrow transplantation. And what I saw is that in each of these patients, the molecules that these T cells recognized on the leukemia were different. So it was hard to develop out of that novel therapies that would be consistent and unique or consistently share results between larger cohorts of patients. And this is how we got into this CAR work because the CAR receptor, this is like a sensor that you then introduce into your T cell. And of course you can determine the specificity of this receptor, of this sensor, and say, okay, if we have a molecule that is expressed uniformly between all leukemic cells or myeloma cells and ideally, a molecule that is shared between myeloma cells derived from different patients. And this would be a very elegant way of treating myeloma or leukemia with T cells. And so I started to get interested in these CAR receptors and actually started work in the lab in Seattle that is Doctors Stan Riddell and Philip Greenberg. They are also pioneers in this immunotherapy field. And I started constructing and then playing around with these CAR receptors. And we've learned many things about how to design these receptors because they are essentially synthetic molecules. These CAR receptors do not exist in nature so they are assembled of amino acids and it's an entirely synthetic modular receptor. So you take a targeting domain, put it in a spacer or in transmembrane, a domain that's how we call it, a membrane to put on a surface of a T cell and then you add to it a little signaling module that can activate the T cell once it sees an antigen. And there's a lot of freedom how to engineer these receptors and we learned some of the rules that are important so that this receptor works well and I had the privilege to design some of these receptors that are now actually in clinical application and clinical use. So one of these receptors targeting the CD19 molecule, that's the molecule expressed on leukemias and lymphomas and that is in a clinical trial where more than 40 patients have been treated as of to date and more than 90% of these patients are in a complete remission. So this is how I also saw firsthand how powerful this immune strategy can be. And now we've extended this work to target other molecules. One of them is called ROR1, that's a molecule expressed also in solid tumors. And when I then joined the team here of Professor Einsele in Würzburg, I also of course got interested in can we make a CAR receptor that can work for multiple myeloma. And we've written about some of this work in our proposal. The CS1 molecule is in our view one of the hottest or best-suited target molecules and we've constructed CS1-specific CARs that work really, really well in our preclinical models. So this is how I got into this CAR work. And it's really a pleasure to be in this field because it has so much potential in treating very advanced malignant diseases so it's very exciting to be part of that.

Jenny: Well, perfect. Thank you for giving us that background. We have done one show on CAR T cells so we have learned a little bit about that. But for those who have not listened to that before, could you give us a short overview of how CAR T cells work in general?

Dr. Hudecek: Of course, absolutely. So as I said, the CAR receptor, that stands for Chimeric Antigen Receptor, it's a synthetic receptor. It works like a sensor so it allows a cell that expresses the sensor to recognize a target molecule, we call it an antigen, on target cells. And if that antigen is being recognized, then the T cells get to work. T cells have several ways of how they work. They can lyse and destroy the target cells, it's called cytotoxicity. They have other effective functions so they produce cytokines – so molecules that T cells use to communicate with each other and kind of say, "Look, there's something going on here and we have to work together on eradicating whatever that target is." And the T cells proliferate and they proliferate until they reach sufficient numbers so they can very efficiently combat in our case, the tumor. And all this is triggered by the CAR receptor. Now the question is why do we need a CAR receptor to do that? The answer to that is that is a fundamental principle in immunology and this is that the immune system has learned to distinguish self from non-self. So the immune system will not attack the normal body so it is what we call tolerant to self. But as soon as it sees an intruder, a pathogen, typically a virus, it will start to get to work and eliminate it. The problem with tumors like myeloma is that the immune system is kind of torn. It doesn't really know "Shall we attack this or shall we not" because the tumor or the malignant cells are deriving from normal cells in the body. Still we clearly think these myeloma cells, these malignant cells do not belong there and they should be attacked. So with the CAR receptor, we help the immune system out a little bit. So we introduce this receptor and say, "Look, the myeloma has to be attacked and this is what the CAR does." Just a few words on what the CAR receptor then looks like. It's a chimera because it binds to a surface molecule like an antibody. But then it is coupled of course to the killing machinery of the T cells so the immune response is a lot stronger. The T cells can divide and amplify in the body so it's like a living drug that we generate and they can also form memory. Then it's a very particular feature about these T cells. So it's not only that we give these T cells to a patient and they get to work against the myeloma or the tumor, they can also form memory and protect the patient from a relapse. And this is why we're so excited about this strategy because it might be possible that with a single infusion of these CAR T cells, you can not only eradicate the tumor but you can also protect the patient from a relapse. And that's why the CAR is needed because it mediates that recognition of malignant cells and in our case, myeloma cells.

Jenny: That's a great explanation for a very basic question and you gave a great answer so thank you. So we were asking in the other show why the CS1 target, maybe you want to address that just a little bit?

Dr. Hudecek: As I said, using immune-based therapies, these are very potent therapies so selecting the right target molecule is an essential part in this process. So you want to choose a target molecule that is ideally only expressed on the malignant cells, on myeloma, but not on any healthy tissues because otherwise you would see a lot of side effects, which we don't want. In every cancer and also here in myeloma, we've been looking for target molecules that fulfill that in the best possible way and this is how we got interested in the CS1 molecule. Because the CS1 and there's work from other groups who've shown that and we've confirmed it in our own work, the CS1 molecule is very highly and almost uniformly expressed on myeloma cells. So every myeloma cell has the CS1 molecule on it. And this is true for patients who come for the first time to the doctor who have a new diagnosis. This is also true for patients who've undergone some treatment and this is also true for patients who have undergone a lot of treatment, intensive therapy, and have relapsed with the disease multiple times. So the CS1 molecule is really in our view a good target because it's very uniformly expressed, independent from the treatment history of the patient and the disease stage of the myeloma.

Jenny: Let me ask a follow up question. Is that also regardless of genetic feature, it just doesn't matter, all myeloma patients are expressing this protein?

Dr. Hudecek: As far we can tell, yes. We have analyzed about 100 patients here in our institution and we have seen the CS1 molecule to be expressed in all of these patients. The expression levels of the number of molecules that is expressed on myeloma cells, that may vary between patients but still we would call all of these patients to be CS1-positive and that includes patients with various cytogenetics. So we would say that this is one expression can be found independent from what the cytogenetics status of this myeloma is. And to just comment on the other part of the story of course, CS1 is not expressed on any essential normal tissue in the body. So we think that when we target the molecule, we will see very little or even no side effects, that there is no solid organ that is CS1-positive. And that is of course of great interest and of great importance for us because if the target was to be expressed on a normal tissue, then we would also cause damage to it. With the CS1, we don't think that would be the case. We think the CS1 will be very a tolerable and very safe target.

Jenny: That's what we understood. So in leukemia they're targeting the CD19, is that correct, but sometimes the CD19 can be on normal cells as well. So is that what's happening in the world of leukemia?

Dr. Hudecek: Absolutely. This is what's happening in the world of leukemia and lymphoma. Most of leukemias and lymphomas are derived from B cells, the B cell lineage, and all of these B cells express this molecule that is called CD19. So when it treats in our patients with the CD19 CAR, what happens is that of course the leukemia and lymphoma is very well recognized and in a lot of these patients, also eradicated. What also happens is that the normal B cells that are still present in the patient or that are starting to redevelop once the leukemia is gone, these normal B cells are also being eliminated. So it is an anticipated but still undesired outcome. However, it is quite tolerable to not have these B cells around. It's unpleasant but typically these patients live a very good quality of life and it is tolerable. You can do infusions to these patients to replace the antibodies that these B cells normally produce.

Jenny: But you are looking for something better for myeloma which makes us happy, right?

Dr. Hudecek: Yes, but to be honest with you, the CD19 is a very good target for immunotherapy because it is very hard to find target molecules that are only expressed on the tumor and not anywhere else because where would that come from. So the CD19 is actually a very good example and it's an example how even though the target molecule may be expressed on a small subset of normal cells, it is still tolerable to not have these cells around. So when we look at different cancer entities, we would be quite happy to take anything similar, anything that is at least as good as CD19.

Jenny: That makes sense. So in your proposal, I was reading also about BCMA antigens, can you explain the addition or the relationship to CS1?

Dr. Hudecek: So the BCMA, that's the abbreviation for B cell maturation antigen and that is an alternative candidate antigen that we and others are investigating as a CAR target for myeloma. We're in a lucky position that in myeloma there is not only CS1 but there are also other candidate antigens. And of course for us, a research question is "Which of these should we select for the first clinical application?" And we think that also BCMA is a strong antigen however, in our hands, we see that the CS1 expression on myeloma is typically a little higher and a little more uniform compared to the BCMA. So we would I think favor the CS1 antigen over BCMA. However, one aspect that we want to address in our research proposal is the following. One thing that can happen with tumors, when we treat tumors with immunotherapy: the tumor, because the tumor now get under pressure, can try to lose the antigen so that it is not visible anymore to the immune system. That's a phenomenon that call immune escape. That can occur. We don't know if that will occur with multiple myeloma but we think it's always a good idea to be prepared. And in order to be prepared, we are investigating multiple antigens or an antigen that we can then select in the event that CS1 expression is getting lost. And then we think BCMA would be a strong target. Also we think that from our experience in our immunotherapy work and in our preclinical models that it can be a very strong strategy to do what we call combinatorial antigen targeting. So we're not only hitting the tumor targeting one antigen but we're hitting it targeting two antigens at the same time. So we think that targeting both CS1 and BCMA in combination is actually a very strong strategy and doesn’t give the myeloma time to adapt and start losing one antigen because it's under pressure from two sides. And that's one thing that we want to address. And also here we can probably say that BCMA we would consider as potentially very safe antigen. It's from the name, you may guess it already, it's called B cell maturation antigen so it's something that is also on this B cell lineage. So we would not expect toxicity to any normal organs and that would be a good thing. Does that answer your question?

Jenny: Oh, yes, it did. Great explanation. So it sounds as if you are anticipating the immune escape potential. So basically a CS1 cell might actually be CS1-negative but still might be a myeloma cell, that's what you were saying, correct?

Dr. Hudecek: Yes.

Jenny: So how frequently might that happen? Have you seen that already in some preliminary data or some pre-lab work that you're doing?

Dr. Hudecek: That's an important question. And the thing is we have not seen it in our lab work and probably we would not see it or not know until we've treated patients with it. I think it would be quite hard to predict it in the lab. But it's something that we want to be prepared for if it occurs in a clinical setting. I think we've learned a little bit from these CD19 CAR clinical trials. CD19 is a very strong antigen on these leukemias and lymphomas and it is very, very rare that one of these leukemias is actually CD19-negative. But we've seen also in the clinical trials with CD19 CARs that a very small fraction of patients -- and this is about 5%, maybe 10% -- the leukemia learns to adapt and it learns to lose the antigen to hide from the immune system. So here we've learned that this can occur in the clinical setting and that's why we want to be prepared for it. We've not observed it so far in our preclinical work in the lab and that is very encouraging. But it's something that we know can happen so we need to be prepared.

Dr. Einsele: Maybe I can add in something. There is some indirect evidence that CS1 is rarely lost on the surface of myeloma cells because you all know that there is an antibody that is directing the CS1 molecule in the clinic, elotuzumab. And this antibody has been given to patients for more than two years and it still seemed to be able to work, indicating that the target for this antibody which is CS1 is still present on the myeloma cells after long term exposure to an antibody that is directed against this antigen. And therefore, we are fairly optimistic that the same will hold true also for CAR T cells that are directing the CS1 molecule. But I think the strategy that we kind of generate a CAR T cell that is addressing two antigens on the myeloma cell's surface will allow us also in the rare event of a down regulation or loss of this antigen on the surface of the myeloma cells to still be able to recognize and to kill the myeloma cells.

Jenny: And has elotuzumab helped you determine that the CS1 would be a good target or you are already hitting in that direction anyway? It just gives greater validation maybe?

Dr. Einsele: Yes. And therefore we actually chose the target that is also addressed with elotuzumab with our CAR T cell to be really on the safe side that we can use the efficacy and the safety data that are available from the elotuzumab administration to patients also for our CAR T cell approach.

Jenny: And a follow up question on that. I know that we just had a show where Dr. Morgan was saying that on average, the typical myeloma patient has five different types of myeloma clones in their cells and it sounds like you're saying that doesn't really matter because they all express, all these different clones no matter what they are have CS1 present on them. But when you think about using one therapy, I know many people in myeloma say you need to attack myeloma with multiple therapies. So is there a possibility that this could potentially just wipe everything out? Could there still be residual that you need to handle in some other combination type approach? Would you like to speak to that for a minute?

Dr. Einsele: Happily. I think if we take the example of the CD19 CAR T cells, what we know with the CAR 19 T cell that is specifically targeting B cell malignancies especially acute lymphoblastic leukemia and the CD19 CAR T cell can work in patients that are completely refractory to any other treatment and it has been shown now in not a lot of patients but in a significant number of patients that these CAR T cells are able to completely wipe out all, even resistant tumor cells. And therefore we are quite confident that the CAR T cell approach targeting an antigen that is so broadly expressed like CS1 that is actually a strategy to really control for long term multiple myeloma, maybe even to eradicate all myeloma cell clones. I think these different cell clones, they have different genetic backgrounds so treatments like chemotherapy, like targeted strategies like for example, proteasome inhibitors or IMiDs, probably there'll be resistance mechanisms. But I think for this kind of approach that we are choosing, the CAR T cell approach, resistance is very unlikely. And even if there is, we have this kind of second strategy by using the BCMA CAR in addition to the CS1 CAR. So I think this is a combined strategy that will really help us to really get around the problem of resistance and get around the problem of different tumor cell clones that are present in a patient. Was it kind of helpful?

Jenny: No, that's perfect. So this BCMA is like an extra backup strategy to make sure that you're hitting it from all sides, it sounds like.

Dr. Hudecek: I think so, yes. One additional comment just briefly. When we look at current myeloma therapies, it's very rare that a single drug is curing the disease. We acknowledge that and we also envision that the CAR T cell therapy may be used in combination with other already established myeloma therapies. And we are addressing this in our proposal in saying we want to see how do commonly used myeloma drugs interact with the CAR T cells. We've selected drugs that we think could be synergistic. So we're looking at the IMiDs, lenalidomide, pomalidomide for example, we're looking at the proteasome inhibitors and these checkpoint inhibitors because we think that all of these drugs have the potential to work synergistically with our CAR T cells. So it is also quite possible that if we can demonstrate the CAR T cells are safe that then in future clinical trials we may use them in combination with existing myeloma drugs and then find the dose of each of the components to accomplish optimum efficacy into myeloma function but also optimum safety and the best safety profile also in terms of side effects so we can accomplish the best possible quality of life for the patients.

Jenny: Well, let's talk about safety but before we talk about safety, maybe you can just walk us through an example of how you would use this. You pull the T cells out of the patient and then you engineer them to target the CS1 and then could you just kind of walk us through the steps? And then after that let's talk about how you are mitigating safety.

Dr. Hudecek: Yes. So Hermann explain the manufacturing quite well. So we would draw blood from the patient and we have done this in the lab a couple of times. So we can draw as little as one syringe of peripheral bloods from the patient and that allows us to isolate enough T cells to do the trick. And then we take the T cells, we start to activate them and that's happening then in the lab so we can do the gene transfer. So we insert the gene that encoats our CS1 CAR and then we amplify these T cells until we have sufficient numbers to treat the patient. And we have been thinking very hard about how to best design this what you call manufacturing process so we're using very advanced reagents that we can use to select the cells but we can also detach these reagents. So these T cells look like they've never been manipulated. And then we've been thinking about how to best get this gene for the CAR receptor in. A lot of groups are using viruses, they are called retroviruses or lentiviruses that infect the cells and then they integrate the gene. We're pursuing a non-viral approach so it's like we're using a process called electroporation. So we're shooting a lot of tiny holes in the cell wall of these T cells and that is enough to allow them to take up the gene for the CAR and integrate it. And that's a very gentle method. It's also quite easy with this method to disseminate this procedure to other institutions because the requirements to do this are quite easily met. And this process should not take us more than two weeks and we're actually working very hard on cutting the time down that we need to manufacture such a cell product. Some of my PC students in the lab, they have it down to five days. The patient comes in on a Monday, we have the sub product ready on the Friday. And we run a work on this proposal on optimizing the short manufacturing process so we can allow patients everywhere to get access to these kinds of therapies. And that brings a link to safety, what do we think about safety. Shall we go through a couple of thoughts about that?

Jenny: Oh, sure.

Dr. Hudecek: We already covered that these CAR T cells are very powerful, they're very potent and one thing that we've learned with the clinical studies with our colleagues in Seattle and also through our preclinical work is we don't need a lot of T cells to cure even a large tumor. So one very important safety issue is to recognize that we don't have to give a lot of T cells. So basically, what we're giving is in the order of 100,000 maybe 200,000 T cells per kilogram body weight. If you have these cells in a lab tube and you put them into a centrifuge, you can pallet them down, that's a pallet that is much, much smaller than my fingernail for example, if you look at it. So that's a very, very tiny amount of cells and using a low number of cells in our view, that's the first and very important thing we can do to make sure that we have a safe treatment. Then what we do is we're looking back at nature and say, how does the immune system typically fight when it goes against influenza virus, for example. And what we see is that there are so called killer cells and there are helper cells and they're both part of doing the job. So one thing that we do is we give equal proportions of these killer and helper cells so that in every patient that we treat, there's an equal amount of both. And that's different from the current protocols in the clinic. The current clinical protocols are that you draw the blood, you do this cell manufacturing but you don't control for the proportion of killer cells and helper cells. So that literally in each patient, the cell product is a little different and that is a variable that is being introduced both for the work against the myeloma but also for the safety. So what we do, we use equal proportions of killer cells and helper cells so that we have a uniform sub product for all patients and then it is much, much easier to make sure that the treatment is safe and if side effects occur, that we can almost predict whether side effects will occur, how strong they will be and when they occur. And last but not least, we have included in our CAR a safety feature, we call it an EGFR tech. So we've taken a little molecule and we put this into the T cells as part of our engineering process. This little molecule is called EGFR, it's called the epidermal growth factor receptor, and we've taken that from the naturally occurring molecule but we've modified this molecule such that we can use it for all purposes. And the purpose is this receptor sits on the surface of the T cell and we can target it with an antibody. And this antibody is clinically approved so we can give it to a patient and we can use it to deplete the T cells if we are worried about the safety or if we see toxicity. So you would call it in scientific terms like a depletion marker or a suicide gene. So we can, if we are worried, give this drug, this antibody to our patient and it will eliminate the CAR T cell. So that's a very unique feature. There are only the clinical trials coming up from the Seattle lab where I worked before that have this feature and we think that's a very important component of our safety strategy.

Jenny: So it's like an emergency stop button basically?

Dr. Hudecek: Exactly, that's how it is.

Jenny: So it would stop everything though? If you were starting to have a major reaction that was life threatening for the patient, you would give them that and you would just say, Okay, we have to redo our strategy with how these T cells were taken up by that particular patient?

Dr. Einsele: Yes. By just giving this antibody which is kind of attacking these gene-modified T cells, we can eliminate these T cells very rapidly and thereby stop any side effects that are occurring in the patient. Of course we are also losing then the efficacy of the strategy in this patient. Maybe one additional point. In the CAR 19 T cell, there was a specific side effect that was neurotoxicity. So patients experienced kind of fits or they had speech disturbancies and we have very good data that are indicating that this phenomenon is CD19-specific and we are not anticipating these kinds of side-effects in the CAR T cell therapy addressing CS1 or BCMA.

Dr. Hudecek: We understand of course that safety is the first and utmost concern also for us so we're thinking about this a lot. A lot of what is being viewed as a safety issue with these CAR T cells is actually related to how well they work and it is when they start to see the antigen and when they start to see the myeloma, it's a very strong immune reaction that takes place. It's like when you have a very strong flu for example and the patient recognized it and it can be very unpleasant to experience that. We call it a cytokine storm when all these cytokines and this is what the T cells produce are being released into the blood. But I think with more and more patients getting treated with CAR T cells, we are also getting better at how to deal with it and seeing the cytokine storm come very early and I think this is what's happening in the field right now. When you just do a routine blood draw, there are some parameters that can indicate to you even before the patient is experiencing the side effects that these side effects may come and then you can take preventive measures with treatments that are readily available in the clinic. But again, we have thought hard about how to provide patients with safe treatment. The cell composition we discussed is important as the suicide or depletion markers are important. And of course one thing we want to emphasize again is our CS1 CAR is unique in that it uses the same targeting domain as the elotuzumab antibody called the HuLuc63 targeting domain. And elotuzumab has been given to many, many patients and we think it's a safe drug so we think that also our CAR will be safe because it's targeting the identical epitope and our CAR is the only CS1 CAR in the field that is using this particular targeting domain. So we're quite hopeful that the treatment will be very safe.

Jenny: So you're saying not all CAR T cells are the same and not all CAR CS1 T cell therapies are the same?

Dr. Hudecek: Exactly. As I said, the CAR is a synthetic molecule so all these receptors of different research groups are called CAR but if you look at how they are designed, there are a lot of differences because there's some essential portions that each of these receptors has. But because it's a synthetic molecule, all of these can vary slightly or even quite significantly in how they are built. And the other thing is the CS1 molecule on the myeloma cells, there is a very large molecule. Of course it is folded in a three-dimensional way and there are different locations of where antibodies directed against CS1 can target. That is what we call an epitope. And there are several antibodies that people have generated to target CS1, the Luc90 antibody that some groups are using and there is for example the HuLuc63 antibody. The HuLuc63 antibody binds to an epitope, a specific site on the CS1 molecule that is in a particular location and the design of the CAR needs to be in a specific way so that the CAR can bind to that epitope. When I did my training in Seattle, we did a lot of work on how to best design these CARs and we found that what we call the spacer domain is very important. We can make this spacer and this is what anchors the sensor on the T cell surface can be long or short. And we found that a particular spacer length is desired to bind this epitope, HuLuc63, very effectively. And that's the trick that we included that's why we can use the same targeting domain like elotuzumab.

Jenny: That's a lot of detail about trying to create this target. It's amazing what you are doing. So can we talk about duration a little bit? I know one of the objectives was to give this single therapy that could perpetuate itself for a long period of time and ultimately maybe avoid the toxicity that chemotherapy brings. But would you like to speak to that?

Dr. Hudecek: Yes. You mean how long these CAR T cells will be effective? We think that a single infusion of these CAR T cells may be sufficient. It's like a living drug. These T cells will go into the bloodstream, they will look for and probably find the myeloma cells and as soon as they see the myeloma cells, they will get activated and they'll say "look, here's our target." And then they start to divide and to amplify hopefully until all or most of the myeloma cells are being cleared. Then what typically happens is when the target cells are gone, the number of these CAR T cells will start to decrease again and hopefully what will happen is that the T cells start to form memory cells that can persist in the blood stream and the bone marrow for potentially many years, maybe decades. In the event that somewhere in the body myeloma cells come back. Then the T cells are ready to attack again. So they can, from this memory state, go back into activation mode and destroy the myeloma cells. And that's why we're so excited because it's a one-time application of a drug, of living cell product, and it can potentially be active for many, many years. Of course this is what works very well in the lab and in the preclinical models and the best evidence or experience we have is from the CD19 CAR trials and here some of the patients are out three years now from their treatment. And indeed, in some of these patients, we can still detect the CAR T cells that were infused three years ago. So that is very encouraging and kind of makes us hopeful that what we think will happen is indeed happening. Of course we can only tell that definitively if we've treated patients with it and then have done the follow up. But we think this treatment can, with one-time administration, be a very effective treatment and be effective for many, many years for the patients.

Jenny: Well it sounds amazing.

Dr. Einsele: Maybe just an illustration. When we first used this redirection of T cell strategy, we used it in patients with ALL. And one of our patients was a patient who was 35 years old, she had two young children, had undergone allogeneic stem cell transplantation and had a full blown relapse 60 days after the allo and everybody was really afraid this was the end of the story. And then we gave her one application of this redirection of T cells and she came into molecular remission of her ALL without any chemotherapy and remained in this molecular remission now for more than three years. So just to illustrate the capacity and the opportunity this kind of redirection of T cell strategy has in the clinic.

Jenny: Well, that's truly stunning.

Dr. Hudecek: We're hopeful that with immunotherapy we may enter into a new era in myeloma treatment where the treatment is essentially chemotherapy-free because we realize that a lot of patients are kind of worried or afraid of the chemotherapy and rightfully so with a lot of the side effects that occur. So we know with the immunotherapy like CAR T cells either alone, maybe in combination with other drugs or antibodies, but more like conventional drugs that can modulate the immune system like the IMiDs or like the checkpoint inhibitors. We may indeed come into a new era of treatment that is essentially chemotherapy-free and with that, free from the typical side effects of chemotherapy. And that's why we're working very hard every day in the lab but also in the clinic to make that happen and transform therapy into that direction. And we're happy to take any questions that you still have so please do.

Pat: I just have two short questions and I'm late for a Kyprolis infusion my second day. So to review, you can do this infusion and it's not necessarily tied to either an auto or allo stem cell transplant. It's independent, correct?

Dr. Einsele: It's completely independent, yes. So you don't need either auto or allo transplantation, you don’t need an intensive chemotherapy before you do the transplant. This is not necessary for doing the CAR T cell treatment. You do this without chemotherapy. 

Pat: That's wonderful, that's great. And the second question I had was have you looked at this in amyloidosis?

Dr. Einsele: No, we haven't. I think the first step will be to go into myeloma. If it works in myeloma patients, it could well work also in amyloidosis patients. But I think the first step will be the patients with myeloma and if successful, amyloidosis might also be a target. The issue in amyloidosis is as you probably also know very well is that in patients with amyloidosis, often these patients have cardiac or renal problems and this could interfere with CAR T cell therapy. So therefore we would like to start in myeloma and then see whether we have any problems and if not, then it might actually be transferred also to amyloidosis patients.

Pat: So I hear from a lot of patients that are both myeloma and amyloidosis and so does that mean, at least initially they would probably be excluded from a trial, right, because you wouldn't want to confuse the mix and the match?

Dr. Einsele: Yes, I completely agree. In the first trial we probably wouldn't include them.

Pat: Great. And then my final question which is a personal plea is as I've now relapsed four times and as this thing's progressed over eight years, I've become a non-secretor. Any chance that non-secretors would be eligible for clinical trial work?

Dr. Einsele: Absolutely. Because what happens in non-secretors is that the biology of the myeloma cells is changing so that these cells are stopping to secrete paraproteins or light chains. But they don't change the surface molecules so in spite of the myeloma cells becoming non-secretory cells, they are still targets for the CS1 CAR T cell. So being non-secretory is definitely still a target or a patient that is eligible for a CAR T cell therapy directing the CS1 molecule.

Pat: Oh! Hey, Doctor, that's wonderful. Jenny, sounds like we got a winner here. Sorry, I got to run. Really appreciate all you do.

Jenny: Okay, thank you so much. Jack, I know you have some questions. 

Jack: I do. Just to finish up on Pat's question though, I think his question being a non-secretor, could he still be included in the clinical trial? Because usually has a measurement to a clinical trial.

Dr. Einsele: Yes. I can understand what you are aiming for. The problem to assess the response in a non-secreting myeloma patient but you still can do bone marrow punctures, you can still do assessment of circulating myeloma cells so there are tools to measure the efficacy also in patients that are non-secretory. So we would definitely like to include non-secretory patients in our first clinical trials.

Jack: I'm sure that will be great. I'm interested in the CD19 approach that Dr. June and UPenn have taken. But I heard him say that in January when they tried this on a few myeloma patients, that they've shown some response and that they're going to announce something regarding that at ASCO. And yet, as you noted and he noted, CD19 is not expressed very much in myeloma. So I'm wondering why has it worked a little bit maybe.

Dr. Hudecek: That's an interesting question that we're also trying to understand and I think also so is Dr. June who's an excellent colleague of ours and absolutely also a leader in the field. We're also looking at CD19 expression in our myeloma patients and we do not see it very often. Of course one hypothesis is -- and I really have to say that it is a hypothesis -- there are what we call cancer stem cells or myeloma stem cells that are at the very beginning of the disease and they may express maybe low levels of the CD19 and that's why you might see clinical effects when you target these stem cells. However, I think we should also note that the number of patients that he's treated is very, very small. Of course he's presented some of the data in oral communications at meetings but not in a manuscript with really all the details and are longer follow up is being presented. And one thing we also need to consider is typically before you administer the CAR T cells you give -- and I think I understand that's also the case in this particular clinical trial -- there is also some kind of we call it conditioning regimen so it's also a form of chemotherapy. So you would need to delineate very carefully if in this particular trial the efficacy you see against myeloma is really due to the CAR T cell, is it durable remission and a long-lasting response and/or well is some of the effect may also be driven by the conditioning regimen which contains some chemotherapy. We would still think in order to address really all myeloma patients, targeting a molecule like CS1 or BCMA would be preferable in our view just because it makes more sense because we can see the antigen, we know where it is and we know that it's on the myeloma. And we typically like to target something that we can see, that we can measure, rather than CD19 which is very hard to tell where it is and if it's maybe on some subset of myeloma cells.

Jack: Okay, makes sense to me. I have a question which is since you mentioned elotuzumab, the monoclonal antibody that targets the same CS1. It didn't have any single agent activity. Would it ever be used in conjunction with the CS1 CAR T cell or would they actually conflict with one another? Is there any reason to think the CS1 CAR T cell shouldn't have any single agent activity? Can you talk a little bit about that?

Dr. Hudecek: Absolutely. Well, we are well aware of the activity of elotuzumab and that as a single agent, it is not doing much. but that's why we think the CAR strategy is so appealing because now what we do is we put kind of to the elotuzumab a whole another set of functions because we couple the T cells to it. So not only can it amplify in the body but it also is much, much more potent because the T cells they are designed to kill and eliminate and that's why our CAR T cells in the lab are so strong. So we clearly think that the CS1 CAR T cells will be much, much stronger compared to the elotuzumab in treating myeloma. And we have very good evidence from our preclinical models. These are mouse models, these are mice who have myeloma and we've compared treatment with elotuzumab and with our CS1 CAR. And consistent with what you see in the clinic, the elotuzumab in the mouse model is not doing much but the CAR T cells, they have completely eradicated the myeloma in the mouse model. So we have mice that are now completely myeloma-free and that are long-term survivors of this disease and this is an activity that we've not seen with any other myeloma drug. If we use conventional drugs like melphalan for example, that's a common chemotherapy that you give. If we treat these mice with melphalan and we dose that high enough to eradicate the myeloma then these mice are really in trouble from the side effects. But with the CS1 CAR that we don't see the side effects and we can completely control the myeloma. So that is making us hopeful that also in the clinic the CS1 CAR will be much, much more powerful. Now you're asking about combinations, you always think of all that you would give the CS1 CAR T cells first and then after a while if you think it's helpful you can still add the elotuzumab as a backup and to reconsolidate a remission. That is thinkable but that's clearly also something for the future.

Jack: Thank you. I am really excited by all of this, and I love the -- not that I understand it -- but the equal proportion of the killer and the helper cells and the EGFR approach to minimize side effects. So this is very exciting, thank you very much.

Dr. Hudecek: Absolutely. Thank you for listening.

Jenny: So we have more questions from Gary and they are write-in questions. He said, "You're using the HuLuc63 versus the Luc90 monoclonal antibody to build a better CS1 CAR T cells. Are there others that you might want to consider or is this the best one that you found to date?"

Dr. Hudecek: That's a great question. I think I commented on some of our reasoning why choosing one over the other and I agree that there is really a lot of technical detail. I think there are other antibodies but for us the HuLuc63 is very appealing just as I said because it's the same targeting domain that elotuzumab uses and we have the safety data with elotuzumab so what could be better than having that on board. Essentially there are a couple of CAR receptors that are now entering clinical evaluation. There is the CD19, there are some CARs also on solid tumors. And we never had the situation that the antibody using the same targeting domain had been used in the clinic and had provided evidence for the safety. So for us, this is really a win-win situation because the elotuzumab has been used and it's a very safe drug and now we're using the CAR, using the same targeting domain so we're also thinking that our CAR T cells will be safe. So for us it's very strong rational to stick with the HuLuc63. Jenny: And sounds as if it might take you further than something else that you've already been able to prove things. So he also asked, "Do you envision CAR T cells to possibly be used as upfront myeloma therapy?"

Dr. Hudecek: Yes, that's an interesting question. In the way that clinical development of novel drugs work is you kind of have to work your way up to the front.

Jenny: Backwards.

Dr. Hudecek: Yes, you have to work your way backwards. So typically, you start in patients who had established standard treatments and where these treatments have failed and then the experimental treatments enter the stage. And this is also what has to be done here. Of course we will then see how effective the treatment is and if it is effective, what we hope. We of course then start to work our way backwards all the way to the front. If we will ever use it as a frontline therapy, we don't know and probably a lot of work is ahead of us to determine that. We also think that when patients come to see you, you probably will do some kind of stratification. It's not like all patients will be treated in the same way. For some patients, an upfront treatment with established chemotherapy or established regimens may be entirely appropriate whereas for other patients there are markers that let us think okay, the myeloma is high-risk, there's a higher risk of relapse and rapid disease progression. Maybe with such an entity even an upfront treatment with CAR T cells may be appropriate. But again, that is subject to a lot of clinical work that is ahead of us that we're happy to undertake and we hope for your support in starting this work because we have to start walking to start running and get this CAR ready for the clinic, get it into the clinic, see is it safe, is it as effective as we hope and then start working our way backwards, just as you said.

Jenny: And can you give us some idea of the timeline that you see ahead of you and the milestones for those and then an anticipated budget?

Dr. Hudecek: Yes. So the timeline to enter clinical trial, we're working very hard on this. We have a very strong preclinical program and we would hope that within the next 2 or 3 years where we are in the clinic with this. It's not a trivial thing. The manufacturing process is technically challenging. To get our approval from the regulators and this is kind of the equivalent to the FDA before we can treat actual patients. And the typical experience is that this takes several years. We have started doing this also for CD19 CARs for example here in Germany and we're clear pioneers in Europe with this. And we're quite hopeful that in 2 or 3 years we can also do this with the CS1. For the project that we're proposing, this is of course some refinements of the strategy in the preclinical lab that includes the evaluation of CS1 and/or BCMA and the question whether using it in combination can make the treatment more effective and prevent this antigen escape and immune escape variants. We want to confirm that what we think is that the CD4 helper T cells are beneficial to have on the product and we want to look for the synergy established with myeloma drugs. These are three preclinical aims and of course one aim is to scale up the manufacturing of these CAR T cells such that we can do it in the clean room lab and then manufacture sub products for a clinical trial. That's the fourth aim, to do this what we call upscaling so we get transform the process from the preclinical research lab with the clean room lab and then the clean room lab, this is where the clinical grade sub products can be manufactured. So we think all this is feasible in a 2-3 year period. And you also asked for a rough estimate of budget?

Jenny: Yes, just ballpark.

Dr. Hudecek: We would think that a budget of $200,000 to $240,000 would be very appropriate to address these aims. And typically what is done with these kinds of proposals here in Germany is that also the host institution is making a contribution. So if the Myeloma Crowd Research Initiative would select our proposal for funding, then also the University here in Würzburg would make a contribution that will contribute to the successful conduct of the project and that would be in terms of staff, a research technician and the lab and some funding for consumer goods and reagents to make sure that all the timelines and milestones are being met and also to be appreciative of the support that we would receive from a philanthropic institution like you.

Jenny: Well, that would be fabulous. We would love that. Is it faster in Germany to get drugs approved than it is in the States with the FDA?

Dr. Einsele: Unfortunately not, I must say. Most of the novel agents are approved in the States before they are approved in Europe. So for example, Carfilzomib is already available in the States for quite some time and it's not officially approved in Europe. But at least in Germany we have access to Carfilzomib. And also Pomalidomide was approved I think one year before in the US when compared to Europe. So I think the American myeloma patients can be congratulated that they have access to more of the novel agents than probably the European patients.

Jenny: Well, outside of a clinical trial, right?

Dr. Hudecek: Yes. But we also see as part of our mission is we have a very dense network of national and also international collaborators in immunotherapy and also CAR and myeloma field. So we also clearly see this as a team effort in a sense that we're very willing and very happy and actually we'll be actively pursuing dissemination of the insights that we derive. So clearly the insights into how to treat myeloma with CS1 CAR we know would be disseminated to our European colleagues in France and Spain and the Czech Republic for example but also to our colleagues in the United States including Fred Hutch, this is where I was trained and still have very close ties to a friend at Fred Hutch. And then they’re very busy with running the CD19 CAR trial and they clearly indicated if we come up with a CAR solution for multiple myeloma, they would be very, very happy to adapt such a protocol and make sure that the protocol will also be opened in Seattle for example. And if in the end, Seattle would be first in opening a clinical trial because the US is always a little faster than Germany then okay, let it be. If it's for the good of patients then we're quite happy with it.

Jenny: Well, I think everyone would be delighted to see your results and would want to follow suit with those. One last question, to me this sounds potentially curative. Would you agree with that statement or what's your opinion about this new therapy because it sounds extremely exciting to me.

Dr. Hudecek: Well, I think both Dr. Einsele and I were kind of concluding comment on that. I think it's been the ambition and the dream of many investigators in the field for many decades to find a curative treatment for multiple myeloma. If we have such a treatment and the end can only be determined in clinical trials and very careful clinical evaluation. However, we see the efficacy of the treatment in the preclinical models and we see that it has a lot of potential, a very strong efficacy. And we've cured mice with myeloma so the next milestone and ambition is to cure patients. So if we can accomplish that with CAR T cells, that would be wonderful. If it's the CAR T cells alone or if we have to maybe play another trick adding in one other component, we will see. We're quite hopeful though and hope that we're close to that day.

Jenny: Well, we are just so immensely grateful. Dr. Einsele, did you have a comment?

Dr. Einsele: I just wanted to comment on the one patient I already mentioned before. I think if you have seen the power of this redirecting T cells strategy in patients with ALL where in different centers in the US or also European centers now, we've seen patients that are relapsing even after allogeneic stem cell transplantation. And after treatment with this strategy, without any chemotherapy, the chief molecular remissions and remain molecular emissions now for years clearly indicates that this is an extremely exciting approach and I think our strategy is trying to apply and to adapt this approach to myeloma. Therefore we are extremely optimistic about this and also very grateful that you gave us the opportunity today to present our ideas and to discuss our ideas with patients and colleagues.

Jenny: Well, this is amazing to learn about what you're doing and we think it's just incredible. So thank you for spending your lives and your work doing this for us as patients. We are really, really grateful.

Dr. Einsele: Thank you very much, indeed.

Jenny: Thank you for participating on this show and we look forward to learning more about your work in the future and hope we can support you. 

Dr. Einsele: Great. Thanks very much indeed again and hello to everybody.

Dr. Hudecek: It’s een an absolute pleasure to be on the show, it's a first for us, we've never been on a show like this. I think we would do it again. We think you're a lot of fun.

Jenny: Well, it is fun. You have to dumb it down for us a little bit but I think it's very helpful for patients to learn about what's being done in myeloma so they can start being involved. I think sometimes we sit back too much and I think that researchers are trying to work hard and do great things and we need to support that work.

Dr. Hudecek: Wonderful, excellent.

Jenny: Okay. Thank you so much. Thank you for listening to Myeloma Crowd Radio and the new MCRI series. We know that patients can help support the discovery of a cure and we encourage you to become involved.