Full Show: MCRI Update on Car T Cell Update by Dr. Michael Hudecek, MD, University of Würzburg, Germany
Dr. Michael Hudecek, MD University of Würzburg, Germany Interview Date: August 24, 2016 Summary The Myeloma Crowd began funding two research projects in 2016 specifically for high-risk multiple myeloma for patients who don't respond well to today's treatments. Today's show is an update by researcher Dr. Michael Hudecek on the CAR T cell work by he and Dr. Hermann Einsele of the University of Würzburg in Germany. In this show Dr. Hudecek tells us that there is intense activity in the CAR T cell space in the international community because it has the promise to lead to long-term remissions and potentially a cure. He shared that in order to minimize the impact of potential toxicity in the "cytokine release syndrome" that occurs when the myeloma cells die when the treatment is given, they are finding that the higher the level of myeloma, the lower CAR T cell dose is given. Conversely, the lower the level of myeloma, the higher the dose is given. He shares four key advantages and differences in their work vs. work by others in the CAR T cell field. 1) CS1 is a better target than BCMA but by combining the two, it can lead to even greater impact. He notes that people can have different levels of BCMA but always have CS1. 2) They are working on non-viral ways to manufacture the CAR T cell (using viruses is a biohazard in the lab) 3) They are working on how the CAR T cell is manufactured, so it appears as "human" as possible to the immune system and 4) They are engineering both killer T cells AND helper T cells to target the myeloma. Learn more about their progress with the funds received by the Myeloma Crowd Research Initiative (MCRI) in this important show and please donate to this key research: Donate to the MCRI Today Dr. Michael Hudecek on Myeloma Crowd RadioFull Transcript Jenny: Welcome to todays episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. Im your host Jenny Ahlstrom and Im joined today by some of our Myeloma Crowd Research Initiative Patient Advisory board members. Our show today is one of the most important we will hold all year. One year ago, we selected two projects to fund. We call it the Myeloma Crowd Research Initiative or MCRI because we believe that patients can help to find and fund curative research for multiple myeloma. At the beginning of 2015, we created an expert Scientific Advisory Board, Dr. Robert Orlowski of MD Anderson, Dr. Rafael Fonseca of the Mayo clinic, Dr. Guido Tricot of the University of Iowa, Dr. Noopur Raje of Mass General, Dr. Irene Ghobrial of Dana-Farber and Dr. Ola Landgren of Memorial Sloan Kettering Cancer Center. Then we invited 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 had been made in the disease. We also believe that by addressing high-risk, that 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 scored those proposals and selected the top ten. We did a radio show on each of the ten and then both with our patient and Scientific Advisory Board. The boards chose two projects and this is one of the two chosen. Then in 2016 and 2015 with your help, we began raising funds. We are thrilled to announce that with your support, we have raised over $330,000 towards our $500,000 goal so far for these projects. In 2016, we donated 100,000 to each project and todays show is an important status update to see where the project is now and where its headed. Additional funding will be given to both projects based on progress and need. Our ultimate goal is to raise $500,000 for the projects and weve targeted September being Blood Cancer Awareness Month to raise an additional $50,000. You can create a fund raising page at http//give.crowdcare.org/mcri and join us in September. So today we have with us Dr. Michael Hudecek from the University of Wurzburg in Germany. Dr. Hudecek works hand in hand with Dr. Hermann Einsele and they each have over a decade of experience in Immunotherapy. So Dr. Hudecek, welcome to the show. Dr. Hudecek: Hello. Thank you for having me on the show. Its a pleasure to be here. Jenny: Well, thank you so much for joining us. Let me just give a quick introduction for you and then we'll get started with our questions. Dr. Hudecek is a clinical fellow and research group leader for the CAR T-cell lab work at the University of Wurzburg. 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 or The Hutch. Dr. Hudecek joined the University of Wurzburg 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 Dr. Hudecek, youve been working on this CAR T-cell project for -- and weve been able to provide some funding in different stages. So maybe you want to give us an overview of CAR T-cell progress in general around the world because we heard at ASH last year that CAR T-cells were one of the hot topics and now over the course of 2016, weve seen different facilities who say, Were launching a CAR t-cell program." And companies who are launching programs. Theyre all ramping up. So maybe you can give us a broad overview of this activity and whats learned generally in the last year. Dr. Hudecek: Absolutely. So still, the CAR T-cell field is certainly one of the hottest topics in Hematology and Oncology. The CAR T-cell being basically a white blood cell that weve engineered to express the synthetic receptor that we call a chimeric antigen receptor and this is what CAR stands for. And this CAR is able to recognize surface molecules that are expressed on tumor cells and thereby the white blood cell T-cell learns to recognize tumor cells and starts to destroy them. The first clinical trials that were really successful in the clinical setting were reported in 2011 in patients with leukemia and lymphoma and since then theres been just a tremendous development around the world both in the clinic that is also then accelerated of course to preclinical development. And still, most of the applications for CAR T-cells are in leukemia and lymphoma against the CD19 molecule that is expressed in these entities. And this has also been the focus over the past year, that a lot of these studies have now reported longer follow-up, really demonstrating that in some patients this CAR T-cell therapy can lead to long-term complete remissions, potentially cure, of their leukemia and lymphoma. Whats also been learned over the last year is that, since investigators are performing larger clinical trials not only involving lets say a handful of patients but larger numbers of patients, is how these CAR T-cells work when they go into the patient, how physicians can start to predict the efficacies, whether the treatment will work or not. And also physicians start to learn of how some of the toxicities of it associated with the treatment can be predicted and potentially then prevented. The toxicities are mainly related to the CAR T-cells being a very potent immunotherapy drug. So theres something called cytokine release syndrome when all these T-cells are suddenly releasing the cytokines, these are little molecules that they use to communicate with each other. And people have learned that one can start to measure these cytokines very, very early after the transfer in the serum of patients and does predict how big this release will be and whether it will lead to this cytokine storm and to start to take counter measures very early on so the patients dont feel sick anymore. So these are the, probably some of the lessons that have been learned mainly clinically, experienced in larger clinical trials, longer follow-up, starting to predict efficacy and toxicities of the treatment. And then generally then whats also being initiated in the clinical trials not only in leukemia and lymphoma targeting the CD19 molecule but then theres also more experience with other molecules. Also in multiple myeloma, theres been a clinical trial targeting the B-cell maturation antigen and this clinical trial is just being reported and also shows proof of principle that the CAR T-cell therapy can work in myeloma. So this is excellent news. It also shows, however, that it is not as effective as in leukemia and lymphoma yet and that further refinements of this CAR T-cell therapy needs to be done to really become highly effective and eventually a curative treatment in multiple myeloma. Jenny: Well, we'll come back to that point. Now, in CAR T-cell research, theres a difference between a drug that somebody takes versus a therapy or a treatment and so when you see companies jumping in, can you describe some of the process about how it works and then are facilities going to develop their own program and creation of the CAR T-cell, do they send that out to a company to do or whats the difference there because I think sometimes people think, Well, this is a treatment. This is like a personalized treatment that Im receiving with my own T-cells. So how does a company join in and would you use a company or would you just do it at your facility or how does that work? Dr. Hudecek: And so the first question or the first part of the question relates to the CAR T-cell therapy being a very personalized treatment and that is indeed the case. I mean, its usually the patients own T-cells that are taken out of the blood, then gene modified or engineered as we say to express this CAR receptor. They are then usually amplified and then reinfused into the patient. So it is a very personalized treatment because its the patients own T-cells. Some investigators are also trying to create universal CAR T-cells. So they make the CAR T-cells from lets say a healthy donor and trying to use the cell product for multiple patients. One of the challenges, of course, being that typically it is not possible to just administer T-cells from lets say a third party individual to a patient because usually they will get rejected. So these are the barriers they have to overcome but most of the activity is focused on using the patients own T-cells. Now your question is how are the facilities or biotech companies that are starting to engage in the CAR T-cell field, how are they manufacturing this cell product. Something that is needed is what's called a clean room or good manufacturing, GMP, laboratory. So this is very tightly controlled laboratory environment that is, as the name says, very clean and sterile so that it allows you to manufacture the cell product for clinical use, so that its possible to infuse this cell product into a patient. And these GMP facilities usually exist at academic centers and very specialized cancer centers but now theres, since the CAR T-cells can be so effective, theres more interest also from biotech and pharmaceutical industries and theyre also building these GMP or cell production facilities now. So the capacity in the United States but also globally is dramatically increasing at the moment. Still, a lot of the CAR clinical trials are initiated by academic investigators. Also I have to say that obviously also the pharmaceutical and biotech industry is now very interested in, is investing a lot, and is also launching their own CAR T-cell programs. Does that answer your question, Jenny? Jenny: Yes, it does. Thank you. And lets talk about the target. So you mentioned earlier about the CD19 target, which has been used in leukemia and other blood cancers and I know UPenn ran a study on that. They were surprised to have one patient respond really, really well even though CD19 isnt on the surface of myeloma cells. And your project was going after BCMA and CS1, so everyone seems to be looking for the right target. So what have you found in your latest research about the target? Whats the most appropriate target? And we liked your project so much because you were going after two targets versus one. In the United States, they began with one. UPenn ran a CD19 trial, NIH ran a BCMA trial, and now UPenn is running a BCMA trial. But two versus one might clean up more. So could you talk to the dual strategy and finding the right target? Dr. Hudecek: Well thats an excellent and very critical question, defining the right target. And of course the first critical question is when you select the target for the CAR is it expressed uniformly and highly on the tumor, in this case multiple myeloma? And is it at the same time not at all or at very, very low levels expressed on normal tissues in the body, so that you dont induce toxicity when you target this molecule? And there are in fact a number of very good candidate targets in multiple myeloma. You mentioned the CD19 molecule. CD19 is expressed on a normal B-cell. So when you target this molecule with the CAR, patients will lose the normal B-cells but this can be compensated by infusing just immunoglobulins, antibodies. The problem is -- the question, as you mentioned, is CD19 expressed also on the multiple myeloma cells? And theres no definitive answer to that because what we know so far is that CD19 may be expressed but maybe only at very low levels. So its hard to detect it with the methods that we currently have in the lab. And so also the clinical trial that you mentioned from UPenn was surprising in that it showed efficacy of the treatment in some of the patients even though it was hard to really conclusively demonstrate that the target molecule CD19 is really on the myeloma. So thats something that we and others are investing further work on. Weve actually -- this is another project thats going on here in Wurzburg. Weve teamed up with biophysicists that develop high-end microscopes. These are microscopes that are so strong that you can detect even a single molecule on the cell and this is a power that so far not many investigators have received and we are currently doing studies. The CD19 target, where the expression of the molecule is so low in myeloma that its getting hard to detect, is then also making it difficult to decide if thats a treatment for an individual patient or not. The other targets I was mentioning are the BCMA molecule, B-cell maturation antigen, and that has been known for a long time to be expressed on multiple myeloma. Its also uniformly expressed on -- it is a very good target in the sense that its not expressed on any normal tissues in the patients body. Theres also the first clinical experience with targeting BCMA both with CAR T-cells and theres also a whole wave of development with antibodies, by specific antibodies. So the next year or so will also teach us more about how suitable BCMA is as a target molecule in multiple myeloma. A concern with BCMA is that also the BCMA protein is being shed from the myeloma cells and is floating in the blood stream and that is a concern because essentially this, what we call soluble BCMA protein, may just block antibodies, CAR T-cells, and other agents that target this molecule. So they kind of neutralize the antibody or CAR T-cell before it even reaches the multiple myeloma cell. And that is part of the reason why weve been focusing a lot on the CS1 or SLAMF7 molecule. These two names refer to the same molecule. I will just call it CS1 for the rest of the radio show to make it easier to follow. And CS1 we know is expressed uniformly on myeloma cells. We never had a patient here in our program that was negative for CS1. So its a very highly expressed target molecule. And we had and continue to have very good success with targeting this molecule here in our preclinical experiments in the lab, targeting CS1 with CAR T-cells on myeloma cell lines and primary myeloma cell lines. So these are the targets that are out there. There are a couple more that also exist but these are probably the most interesting ones. Now, our rationale for targeting not only one molecule but get to a point where we target two molecules is that what can happen is a phenomenon that has been described when a tumor comes under pressure from a treatment is that the tumor can start to lose the molecule. Its called antigen escape and one strategy to be smarter than the tumor is to target two molecules at a time because the likelihood that the tumor learns to lose two antigens rather than one is very low. So thats one part for the rationale and the second part is that we know that in multiple myeloma, often there are multiple clones of myeloma cells that are coexistent and what we want to prevent is that one of these myeloma clones learns to lose the molecule and then starts to grow out and grow over and we think that with the dual targeting strategy, targeting both CS1 and BCMA we may be therefore more successful. Jenny: So what percent of patients have the BCMA? And youre saying most -- that all youve seen, youve never seen a patient without the CS1 and by the way, thats the same target that Elotuzumab is targeting, SLAMF7 or CS1, so patients might understand that thats a similar target but what percent of patients have the BCMA when youre going after two? Dr. Hudecek: I think if you look at patients at the primary diagnosis, what we know from our program here and from the literature is that also close to 100% of the patients do have it. Also there may be kind of more variability in what the expression level is. So how many BCMA molecules are there per myeloma cell. So there may be patients that have a lot of BCMA and others have rather low levels. What I was referring to is this phenomenon of antigen loss or antigen escape and I think the first studies with BCMA CARs that are coming out now illustrate exactly that problem that there can be kind of relapse or disease progression again with BCMA negative multiple myeloma cells. And thats a situation that we would like to prevent and therefore come to a point where we target two molecules simultaneously to make sure that the myeloma cells are being eradicated and that we dont give myeloma time to adapt to the treatment and lose the antigen. Jenny: Okay and then a question on dosing. So it sounds like initial clinical trials, the dosing was a single dose without any other type of treatments. Well, I know that with T-cell, the CD19 trial at Upenn, for one patient they give stem cell transplant and then they gave her the CAR T-cells afterwards. But in dosing, how do you administer that - as a treatment like kind of booster shots later or additional doses down the line? Have you added information from your research on how that should be given? Dr. Hudecek: So one important thing to consider upfront is that the CAR T-cells are like a living drug. So once they are infused into the patients, they do what we call engraft. So they kind of form to the bone marrow and then these also start to proliferate once they see their antigen, the target molecule. And this is different from a conventional drug like a pill of Aspirin or something where that has a defined dose and that is carried from the body with a defined time and rate. So the CAR T-cells because they are living drugs and because they can proliferate, they can persist in the patient for many days, many months, potentially years and even a very low dose of these CAR T-cells can, because the T-cells amplify in the patient, have a very significant anti-tumor effect. So thats a new principle when we talk about treatment with these new immunotherapy drugs. Doses that are typically being given to patients in clinical trials right now range between 100,000 and 1,000,000 per kilogram body weight and even if only 100,000 CAR T-cells per kilogram bodyweight are given, it is possible to see clinical response and this is the experience from some of the clinical trials with CD19 CAR T-cells. This is a very low dose compared to the number of T-cells that is present in the body of the patient. And still, people have observed that these CAR T-cells can proliferate in the patient to a point where they make up, after a few days after the infusion, double digit percentage of the patients T-cell compartment, right? So thats one important thing to consider. The other important thing to consider is, because I mentioned earlier that investigators in the CAR T-cell field are trying to start to predict efficacy and starting to predict toxicity, and something that has been learned is that the patient who has a high tumor burden should actually receive a lower CAR T-cell dose because then the likelihood for toxicity to occur and this cytokine storm to occur is much lower. The opposite is that the patient who has actually low tumor burden may receive rather a higher CAR T-cell dose because here, the stimulus for the CAR T-cell dose may not be so strong and therefore a higher dose of CAR T-cells is applied in order to make sure that all the tumors are actually being cured. So this is actually the opposite of what has been done conventionally with conventional chemotherapy and other drugs, right? The dose of a treatment is adapted through the burden of a tumor in the patient and a patient with a higher tumor burden may rather receive a lower CAR T-cell dose. And the last part of the question relates to how often are the CAR T-cells given. We still think that administering a single dose of these CAR T-cells is adequate and sufficient because these CAR T-cells persist. They amplify themselves. Some investigators have given multiple doses of these CAR T-cells and one issue that you then start to run into is that the CAR is a synthetic molecule, its a designer molecule, and it can happen that because it is a synthetic molecule, that the immune system of the patient is starting to recognize this CAR molecule as something foreign and is starting to eliminate these CAR T-cells and thats something we dont want. We want these T-cells ideally to persist for a long time to make sure the patient doesnt incur a relapse. And the likelihood that the patients immune system is starting to recognize the CAR as foreign is getting higher if you give many, many doses or multiple doses of these CAR T-cells because then its like a vaccination or a booster. So with the current CAR constructs, we only give one dose and at the same time people are -- and also our lab, we're working hard on making these CARs, even though theyre synthetic molecules, make them look as natural as possible so that this immunorecognition phenomenon does not occur anymore and in fact, most of these CARs are now fully humanized. So theyre indeed not immunogenic anymore. Jenny: And maybe you can explain what that means when you say fully humanized. Dr. Hudecek: Fully humanized, make sure we look at the molecule and we really make sure that theres nothing that the immune system of the patient can recognize and that could potentially lead to recognition of these CAR T-cells. Jenny: Great. Now, I shouldve verified this before but I heard that the second NIH BCMA trial was actually going to only accept patients that had 50% or less myeloma plasma cells because of that cytokine release syndrome that you mentioned. So I think what youve learned is fascinating that a higher tumor burden equals a lower CAR T-cell dose. So lets talk about reducing the tumor burden before you get to the CAR T-cell because it would make sense. In my mind, I would want a higher CAR T-cell dose and start with lower tumor burden to get a better impact but maybe that doesnt translate. What have you seen in terms of other treatments being used to knock down a tumor burden before you can get this CAR T-cell? Have you tried different things like that or are you testing in people who just have higher load tumor burdens to see the dosage? Dr. Hudecek: That is a very valid strategy to try to reduce the tumor burden before the CAR T-cells are being infused and the problem is of course that patients that are enrolled in the clinical trials of CAR T-cell therapy right now are patients who are refractory - they do not respond anymore to the conventional treatment. So of course, the first challenge is to actually find a treatment that can reduce the tumor burden. The next aspect is that typically if there is a response, typically this response to let say pre-treatment or debulking treatment will only be of transient nature. So it's then also a matter of timing but thats something that can certainly be attempted to reduce the tumor burden in patients where physicians are concerned that the tumor burden would be too high. But other than that, I think reducing the CAR T-cell dose is a very valid strategy to make sure that there is no toxicity from cytokine release syndrome or tumor lysis syndrome, right? One thing also to say is that here in Germany, we are not performing clinical trials yet. Thats part of the work program that we have in our project with Myeloma Crowd Research Initiative. So were currently preparing clinical trials here but were not yet doing them but were hopeful to initiate these trials soon with the CAR T-cells targeting disease, one molecule, and potentially then with CAR T-cells targeting both CS1 and BCMA. Jenny: Well, lets talk about just a little bit -- so we have funded your project in 2016 up to $100,000 and it wasnt done all at once because we were raising the funds and then distributing them to you. So maybe you can explain how you've used the funding, how your research has progressed, and what the key lessons are that youve learned. Dr. Hudecek: Absolutely. So first of all, we were very excited about the support from Myeloma Crowd Research Initiative and very grateful for the support and funding weve received. With this support that weve received, weve been able to hire a very talented post-doc, also a researcher in the lab. So weve increased our manpower and this researcher is just fully dedicated on work on this project in addition to the people that we already had in the lab. Some of the key lessons weve learned are weve made a lot of progress on targeting this CS1 molecule on multiple myeloma and weve really refined this approach now and come to a point where we can quite reliably in a preclinical (that is a mouse model) can cure the multiple myeloma. This is a significant step forward. Weve also made a lot of progress with the BCMA CARs and trying to now engineer T-cells targeting both the CS1 and the BCMA molecule. The first step here was to compare the efficacy of T-cells targeting CS1 or BCMA alone. A very important lesson that weve learned here is that targeting CS1 seems to be more effective than targeting BCMA. Weve seen a greater reactivity against multiple myeloma with CS1 specific CAR T-cells compared to BCMA specific CAR T-cells. The next step that we now want to tackle is to ask the question, is targeting these two molecules in tandem more effective than targeting the CS1 molecule alone? And that will be the big research question for the next coming year. These are the next milestones we want to accomplish in this aim. Another aim that weve defined in our research program is the question, what are the T-cells that we're equipping with the CS1 CAR? A very distinction in the T-cell field is to distinguish killer cells and helper T-cells and typically investigators focus on the killer cells because they are the ones who are doing the job in killing the multiple myeloma. Weve been interested in the question, what are the helper cells doing and how can they support the killer cells in their work? And we have shown an earlier work that CD4+ which are helper CAR T-cells are very important. And we've shown this also an example of the CD19 CAR battling against leukemia and lymphoma. Weve now extended this work also to the multiple myeloma setting and therefore extracted these helper T-cells from myeloma patients, equipped them with the CS1 CAR and have shown that also from the myeloma patients, these helper cells are very efficient in doing their job and really support the killer cells in eradicating the multiple myeloma cells. This has a number of important implications also for clinical translation. The first implication is that when we treat patients with CAR T-cells, we want to make sure that the cell product contains both the killer cells and the helper cells and thats why the approach we take is that we actually manufacture them separately. Killer cells, equip them with the CS1 CAR, then we isolate helper cells, equip them with the CS1 CAR. And in the end, formulate a cell product that contains both cell populations at a defined one to one ratio. The other implication is to the efficacy and also safety of this treatment then in the clinical setting, because weve shown that when you add these helper cells to your cell product, you can reduce your total dose of the CAR T-cell product that you give to a patient. That is coming back to your question, Jenny, about safety of the cell product. And in the end, if we could use a lower total dose of the CAR T-cells, it will also make it easier for us to manufacture the T-cell product. That is getting back to your earlier question about facilities and who is able to produce this CAR T-cell product in the clean room. So this aim that weve been working on, weve made a lot of progress therein and I think this has a lot of implications for the efficacy and the safety of the treatment later on. Jenny: And Ive never heard that. Thats a fascinating point that you just made. That youre manufacturing both CS1 killer T-cells and CS1 helper T-cells and combine them one to one. Dr. Hudecek: And actually theres a concept that I developed when I was still in Seattle and actually the group in Seattle has done the first clinical trials using this concept in Leukemia and Lymphoma patients with the CD19 CAR. And these are studies that were just published a couple months ago. And were now taking this concept also to the CAR T-cell therapy in multiple myeloma. And the first question of course was for us, how effective are these helper cells in myeloma patients? Because we know that the immune system is affected by multiple myeloma, by the disease. And the good news is that the helper cells from myeloma patients after we modified them with the CAR are just very functional and still retain their intrinsic capacity to provide help to the killer cells. So this is very good news. Jenny: Great news. And going back a little bit, so youre looking at the CS1 and BCMA, how does someone test for BCMA expression or CS1 expression have a blood test or some other type of test? I mean, is there something patients can ask their doctor because I would be kind of curious to have BCMA expression, how would my doctor test me for that? Dr. Hudecek: Thats an important question and a lot of patients they come to our clinic and say, Can you test our myeloma cells for expression of these two molecules? and its in fact quite simple blood tests or blood is drawn or just a very small amount of blood where the myeloma cells are contained. So it would typically be bone marrow actually that we use for the analysis and then we clean up the myeloma cells from the bone marrow and use an antibody to stain the molecule. And this antibody usually has a little tag on it and this tag emits light of a certain wavelength that can then be detected in a lab instrument that we call a Flow Cytometer and this Flow Cytometer is then showing us where the light is emitted and this indicates that the antibody specific for BCMA or CS1 has bound to the myeloma cells and this indicates that the molecule is present or not. So in the end, its a routine test thats done in the lab and it can be done from a very small amount of blood or bone marrow. Jenny: Oh okay, either one. So you said that it may show more effectiveness in leukemia or lymphoma versus myeloma, what are the issues that are surrounding that? And also one of the doctors mentioned that immunotherapy as a whole, not necessarily CAR T-cells, that sometimes the status of a patients immune system shows that it either works really well or it doesnt work very well and you mentioned this very briefly at the very beginning. Is there a way of identifying who will and wont respond before the treatment is given based on that immune status because as I understand that this is not related to genetic features per se of multiple myeloma but maybe you can address that? Dr. Hudecek: Thats an important point and of course it would be desirable to predict the outcome of the treatments before you even do the treatment. I have to say though that at present there is no established test that can be done to kind of predict whether the treatment will work or not. Something that some investigators do is they draw blood from the patient and count the killer and helper cells just to make sure that they can obtain enough T-cells from the patient to do the CAR modification. So they kind of predict whether they can produce the CAR T-cell product. We dont do this because we have refined our methods for producing the cell product so far that we basically are not concerned about getting enough blood cells. We can manufacture a CAR T-cell product from so little amount of blood and this would be just a syringe of 50 milliliters of blood, contains enough white blood cells that we can extract and modify with the CAR that we dont do any testing in advance to make sure that we can manufacture the cell product. Thats one thing. The other thing is predicting the efficacy. So predicting whether the treatment will work or not and the truth here is that theres no reliable marker that people have identified yet that predicts the outcome. Jenny: So more testing. Youll have to just do more study it sounds like. Dr. Hudecek: I think when more patients have been treated and when longer follow-up has been obtained, then patterns will start to emerge where people can say, Look, these are the patients whove responded the best and these are patients who had a less favorable outcome. And then people can start to draw conclusions. Jenny: And kind of surrounding that, what we were talking also about lowering the tumor burden and its probably way too early to ask this question because youre trying to determine do we use two over one and whats more effective just with CAR T-cell treatment alone. But when you look at immunotherapy as a whole or existing drugs that are available for myeloma patients, do you foresee any kind of combination approaches like with monoclonal antibodies or vaccines or even the proteasome inhibitors and the drugs that exist right now, like the IMIDs that exist right now as a combination? Or would you like to just avoid all of that and just say, Lets just do the CAR T-cell and we think thats going to be effective. Dr. Hudecek: No. Thats very important to define. What is the most effective way to use these CAR T-cells, is this as a single treatment or a combination? Of course, when we do clinical trials with CAR T-cells, this would be the first time that this method is used in multiple myeloma and usually in the setting where something is done the first time, this novel treatment has to be done alone to determine the safety and also the efficacy of the treatment alone. And, of course, when then the safety is demonstrated, then very quickly we start to think about what other combinations to potentially enhance the efficacy. So the answer is first, new therapies have to be done kind of as a standalone treatment, mainly to look at the safety in the clinical setting. And then with subsequent studies of combinations are being done. An example of the CD19 CARs that are certainly the most advanced application, clinical application of the CAR T-cell field, there are now clinical trials in lymphoma so lymph node cancer, where combination therapies are being started, combinations with other agents that activate the immune system, these are check point inhibitors. So with multiple myeloma it would be quite similar. The first studies would be done with the CAR T-cells alone and then once we show targeting CS1 with the CAR is a safe treatment, we can then look what is the efficacy. To be honest, there has never been a single agent in multiple myeloma that has cured multiple myeloma, right? Of course, the CAR T-cells can potentially be very effective and we think they will be effective also in the clinical setting but its also rational to assume and predict that at least in some patients, a combination therapy will be needed. And here, therere a lot of interesting substances that are already in clinical use that could be used in combination with CAR T-cells and this includes the IMIDs that you just mentioned and they are known to modulate the immune system and are known to modulate certainly also the function of the CAR T-cells. So they are more reactive. And we have too a very interesting aspect of work that I can share with you now because they are one of the aims that were working on in the project that youre supporting. One interesting finding is also in relation to these checkpoint inhibitors, the most known checkpoint inhibitors is an antibody called Nivolumab. Its targeting the PD-1 molecule. And weve tested the CS1 CAR T-cells in combination with such a checkpoint inhibitor and then this in fact enhancing the reactivity against myeloma cells. So this is the first demonstration that a combination therapy of a CS1 CAR and an antibody treatment and the checkpoint inhibitor can even enhance the reactivity. Now, the second good news is that weve done another trick to make the treatment easier for the patients. If such a combination therapy would be done, it would mean that were infusing the CAR T-cells into the patient, then we also have to concomitantly give the antibody treatment of this checkpoint inhibitor. So this would mean that the patient would then have to come back to the clinic at regular intervals to receive this checkpoint antibody and also these checkpoint inhibitor antibodies are not without side effects, at least in some patients. So weve done a trick and weve tried to include this checkpoint inhibition into the CAR T-cells. So were kind of knocking out the gene that encodes this PD1 molecule and weve been successful now in doing this. We've engineered a CS1 CAR T-cell that has already a built-in checkpoint blockade to increase its reactivity. So for the patient again, this would mean that there's only a single treatment, a single infusion of this CAR T-cell but with the added benefit that this checkpoint blockade is also administered And the good thing here is that only these CAR T-cells that are targeting the myeloma cells are actually affected by this PD-1 blockade because weve knocked out the gene and the rest of the immune system is not altered. So many of the side effects that comes with the checkpoint blockade treatment will not happen in the myeloma patient. So this is something weve accomplished through support from Myeloma Crowd and its something that we want to continue on and really show also in our preclinical models so this treatment is now even more effective. Jenny: Wow, thats fabulous news, fantastic. So I want to just ask two more questions and I know we have some questions from our Patient Advisory Board members and well also open it up for a caller question if you have any. But how close is your research to opening up into a clinical trial? Dr. Hudecek: So preparing a clinical trial is part of the aims for this project. Weve defined an aim where we say that we want to establish the clinical-grade manufacturing of CS1 CAR T-cells. In here, were also making a lot of progress, something that were really proud of, I can say that is that weve defined or weve developed a novel method of manufacturing the CAR T-cells and something that is typically being done to introduce the genetic information for this CAR receptor is that people use viruses that infect the T-cells and thereby deliver the cargo, which is the genetic information for the CAR. And we for the first time now developed a non-viral way to manufacture CAR T-cells. Non-viral meaning we dont need any lab virus anymore. So we basically take a small molecule that has the genetic information for the CAR receptor. We do something that is called electroporation. So we give a little electric shock to the T-cells, that helps us to introduce this genetic information into them and these T-cells then take up the information express receptor and this worked beautifully in our models. This is something that investigators have been trying for quite a while now and weve played some tricks in how we design this little DNA molecule and how we apply the electric shock that really has allowed us for the first time to come to a point for this method is working very effectively, very rapidly and where we can use it to prepare a clinical-grade cell product. This will help patients around the globe, patients in the United States but also patients elsewhere where the initiation of clinical trials of CAR T-cells has been more difficult. One of the -- for exactly these reasons that you use viruses to introduce the genetic information, is challenging -- something that the regulatory authorities look at very closely. So weve now been able to simplify the way that the CAR T-cells can be produced. And this will be part of our concept for clinical trial that were preparing right now. We think that within one or two years well be able to initiate a clinical trial with CS1 CAR T-cells at our institution and partner institutions also in the US. And this I think is very much what Myeloma Crowd is striving for. Jenny: Sounds like you wouldnt partner necessarily with a corporation because you have your own kind of competitive advantage in creating your own program. So last question would be, what else needs to be done, how much more is necessary and how will the funds be used? Dr. Hudecek: Just following up on the last aspect of the previous question is whether we would partner with any corporation, and, of course, that is something that is also on the horizon. Of course, we are well aware that as an academic center, were not able to treat patients on a global scale. Our job is to develop novel technologies to provide new concepts and principles of how treatments can be improved and then show on a small scale in clinical trials that what we've developed is working and that what we've developed is safe. And once weve demonstrated that and I think there will be significant interest also from biotech or pharmaceutical industry to pick these technologies up and just make them available on a global scale. So thats something that were, of course, also pursuing and I think with the support from Myeloma Crowd, that is exactly what were trying to do. Were trying to refine these new technologies, targeting two molecules at the same time, using helper cells to improve the effect, bringing in checkpoint blockades built-in into these CAR T-cells, or using non-viral gene transfer. These are all novel technologies that were developing, that were defining, and for this, the support of Myeloma Crowd is essential. And once we make it to a clinical trial and show the CAR T-cells that weve developed are working and theyre safe, then it is time for big companies to take these technologies and make them available on a global scale to all patients. Jenny: It sounds like youre doing something just very unique. What you just mentioned is just extremely unique. What youre saying is all CAR T-cell work is not the same. Thats really important for patients to understand that it's not all the same. People are doing it in different ways and youre including at least four different unique aspects of how youre going about this. Dr. Hudecek: Thank you. And you asked what is the support that we need. I mean, so far, the support from Myeloma Crowd Research Initiative has been wonderful. It has allowed us to really accelerate this work and do the experiment that we need to do and demonstrate that the concepts that were developing are working. And what we need is to really refine these concepts and show in our preclinical models that this is working against myeloma, this is getting even better in treating myeloma and for this we need and appreciate the continuous support of Myeloma Crowd Initiative. I think we had to find a work program and also the means that we would request from you is to make this work program happen. And I think what you mentioned in terms of the fundraising youve done, were just very excited and very appreciative of all the funds that youve raised. And we hope that also with the progress that we talked about now, you can be certain that this is in good hands. Jenny: We are sure that it is in good hands but I think whats unique about how we went about selecting these projects is very important because we took experts that were in the myeloma world and we invited investigators to contribute their ideas and then it was a very extremely well vetted process and so we feel very confident in what youre working on and are just very thrilled to be supporting it. So what Id like to do is open it up for some questions from our Patient Advisory Board members and also for the callers. So if you are on the line with your question, press 1 on your keypad and if you are listening by computer, you can call 347-637-2631 and press 1 on your keypad. So we will start I believe with Gary. Go ahead and ask your question. Dr. Hudecek: Hi, Gary Caller: Hello. Can you hear me? Dr. Hudecek: I can hear you well. Hi, Gary. Jenny: We can hear you, Gary. Caller: Okay, great, fantastic. You know, I am so impressed, Dr. Hudecek on all the things that youre doing and how you kept yourself invisible to the world up until recently is really amazing to me. And I say that out of just sheer joy at what youre doing but one of the things that I wanted to ask is how does somebody like you guys compete against the likes of Juno who has a billion dollars that has been invested by Celgene and has also got a $250 million war chest from a private or from going after becoming a public company? Do you need to start a company? Lets call it Julyo, which will go public and get some kind of a war chest for you guys. From my perspective, as cancer patients, you cant go fast enough and if its money, we dont really care. We want to see the -- its kind of like we dont want to talk about the nine-month pregnancy. We want to see the baby. Dr. Hudecek: Yeah. Well, thank you, Gary, for that. I really appreciate your comments. I think one thing to keep in mind is that even though there is so much interest in CAR T-cell technology now, also in big pharma and biotech, I think this is also a development that really came from academic investigators and scientists, right? And clinicians, that said, What is a new technology that we can develop? And how can we compete? We have to be smarter, faster and then just do our job. That is as you say is difficult when you have competition from companies with so many resources and so many employees. Also at some point, certainly its also not just quantity but also quality and I think the team that I have here in my lab is just very thrilled, very enthusiastic and I keep challenging them and say, Look, we have to think outside the box and think harder because we have a formidable adversary and this is Cancer and this here is multiple myeloma. So were doing our job. Were trying to think of new concepts and just try to develop them as quickly as we can in the lab. But also then being able to bring them to a larger audience and make them communicate this data to a larger audience and bring these new technologies to larger groups of patients is another challenge and here, of course, a liaison with pharmaceutical industry and biotech is also coming into place. And also here we have concepts and also well make sure that we partner with companies and create liaisons that will allow us to make these therapies accessible by a larger quote of patients. So I hope that answers your question at least in part. Were trying to work harder and be smarter and were also aware that we have to and will partner with companies that have then the breadth and the potential and capacity to make these therapies available globally. Caller: I just dont see why companies arent throwing billions at your feet based on what Ive heard about your program and I guess thats -- and the reason Im a little bit concerned about that is that I know that Myeloma Crowd is providing some of the funding but I also just read that in order to provide clinical trials, it now costs $40,000 per person. So each person in a clinical trial and you probably need 10 or 20, right, in your clinical trial? That $40,000 for 20 people, thats $800,000 and thats just a lot of money. So thats why Im just hoping that somebody shows up to your party because I think your party is one of the best parties around. Dr. Hudecek: Well, thank you very much for that. Caller: One other question and that has to do with reducing the tumor burden prior to treatment and we on CureTalks, we have a program and you were on CureTalks, where we're talking about higher risk smoldering multiple myeloma and one of the points is that therere fewer clones in smoldering myeloma and also its naïve to any treatment and the tumor burden is low. So wouldnt that be -- would that be a great place to have a clinical trial for CAR T-cells, for your CAR T-cells, because of that low cancer burden? Dr. Hudecek: I think thats just reasonable. I think it would be an interesting and good setting. Having said that I think what the CAR T-cells once they are infused also need is, I mean, they need to see their antigen, right? They need stimulus, especially if we use rather low doses of these CAR T-cells having too low of a tumor burden may also come -- it may come to a point where the T-cells are not getting enough stimulation. So I think where Im getting at is that we dont depend on a situation where there is low tumor burden or even just minimal residual disease. I think the CAR T-cells can take on a significant amount of tumor and it may also be not bad for the efficacy if the T-cells are really seeing the antigen because then theyre getting activated, then they start to proliferate, and then they also go through this whole cycle where they eventually form memory and are able to persist for long term. Caller: Well, thank you very much, Doctor. I cant tell you how excited I am about the progress of your work and I just hope and pray that somehow you get all the resources that you need to bring this thing to fruition. Dr. Hudecek: Thank you very much. I appreciate it. Jenny: Okay. Thanks, Gary, for your question. Now, Eric, I think you had a question as well Caller: Yeah. Thank you very much, Jenny. Dr. Hudecek, this is just fantastic information this morning and I really cant tell you how exciting this is for us as patients, and as Gary mentioned, if we could be in one of your trials tomorrow, I think a lot of us would be there. But I do have a question thats probably way out in the future but based on your thinking outside the box and so on, with single-agent activity in a drug like daratumumab and youve got single agent as it were activity with your therapies of CAR T, do you see any potential or prohibitions to giving a patient the therapy of your CAR T product targeting CS1 and BCMA and then following that up say a month or two with a different CAR T therapy that targets CD19 for example, why use novel drugs? Would it be more efficacious to use two or three CAR T therapies? Dr. Hudecek: I mean, thats a very -- the question goes out into the future because, typically, what has to be done is to validate each target molecule alone, step by step. So I think the CAR T-cell field is quite a length away from targeting multiple and that includes three molecules at the same time or even sequentially. The question also is will that be necessary? I think if a CAR T-cell product targets two molecules and is potentially given in combination with other existing drugs, be that IMIDs or checkpoint blockade, for example, then the question is will that still be necessary to add a third molecule? So I think it is conceptually interesting and it goes along our line of ideas of saying, Okay, lets put as much pressure on the tumor as we can and lets target it from different angles. And targeting more molecules maybe along these lines. If a combination of CS1, BCMA and CD19 would provide an additional benefit, it can only be explored in preclinical models first and then we could decide whether it would make sense to do this clinically. But I think lets first look at what the CS1 CAR T-cells do by themselves, what they do when we target BCMA and CS1 and combination. And at present, CS1 and BCMA are probably the two front-runners in terms of immunotherapy targets in multiple myeloma and I would be quite confident that we'll achieve very good results when we target these molecules concomitantly. And if then CD19 is a necessary addition, that remains to be seen. Did that answer your question? Caller: Absolutely. Thank you very much, and again, I just am so pleased at what youre doing and so pleased and thankful for Myeloma Crowd for providing me an opportunity to help somehow. Dr. Hudecek: Thank you very much, I appreciate it.= Jenny: Thank you, Eric. Well, Dr. Hudecek, were out of time but we just want to thank you so much for all the effort that you are putting in to creating an effective treatment for multiple myeloma. What youre doing is really truly stunning. So thank you so much for your participation. Dr. Hudecek: Well, thank you very much. I appreciate it. Jenny: If our listeners would like to invite their friends and family to support Dr. Hudeceks work, you can find links to the Myeloma Crowd Research Initiative at the top of the Myeloma Crowd website with different buttons. Youll see a donate and create button. You can create your own page there or you can donate or invite those around you who love you and are trying to support you, thats a way that they can take action. And youve heard today in detail about the work thats being performed. So its truly incredible what youre doing and were so grateful. Dr. Hudecek: Well, thank you very much for the radio show. Its very exciting also for us to be on a show like this. It does not happen very often and we like to be in touch with you, Jenny. We like to be in touch with Myeloma Crowd and get the feedback from patients because that certainly is our strongest incentive and motivation to go 100% and beyond every day in the lab and in the clinic. Jenny: Well, thats wonderful and we will keep people updated on your work and do these periodic check-ins so we can hear more about your progress. Were thrilled to do that. So now we thank you for listening to Myeloma Crowd Radio and the Myeloma Crowd Research Initiative series. We know that patients can help support the discovery of a cure and we encourage you to become involved.