Atara Biotherapeutics, Inc. (ATRA)

Investor Update

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Nov 29, 2018

Welcome everyone and thank you for joining us this morning. My name is John Craighead. I'm the Head of Investor Relations and Communications for Atara Biotherapeutics. Welcome to Atara CAR T Breakfast Teach In. We're so excited to share this story with you this morning. And joining us also, I'd like to welcome everyone on the webcast this morning, joining us early in from the West Coast as well. Before we kick it off this morning, I want to make sure to mention our forward looking statements and the risks and uncertainties described in more detail in the SEC filings that you can find posted on our website. Now just a few brief details about the agenda for today. Doctor. Isaac Ciechanover will lead off the session to talk about the strategy of our CAR T immunotherapy pipeline. Next, we're very delighted to have with us Doctor. Michelle Sedelin from MSK as well as Doctor. Marco Davila from Moffitt Cancer Center. And then to wrap up the whole session, Doctor. Dietmar Berger, the Global Head of Research and Development at Atara, to talk about our allogeneic CAR T platform and CD19 program. We'll end the whole session with Q and A. So if you could save all your questions to the end, we'll wrap up with everyone here on stage. So with that, I'm delighted to introduce Doctor. Isaac Cihanover to introduce the event. Thank you. Good morning, everyone. Thanks so much for making the time. I'm really excited to share with you some wonderful programs that we've been working on internally. This has really been a bit of a stealth set of activities, but there have been ones that were from inception of Atara thought about, focused on and making sure that we can get all the right pieces together. So Atara is building the next generation CAR Ts that are both allogeneic and it's important to separate those 2. These are not simply allo programs. These are the next generation better technologies because the revolution started with the 1st generation CAR Ts have a great deal of promise and save multiple people's lives and people like Michel Sedolene have really been in the forefront. But that is just the crust of the way. It's growing and we believe that through partnerships and through additional technologies we can really deliver on the promise of the next generation. And that's the mission of what Atara is. Atara was started almost 6 years ago to transform the lives of patients with serious medical diseases. And we've done that already with our tab cel program, which is in Phase 3. We're not going to spend much time on that program, but it really is the cornerstone by which everything else follows. Tab cel is in Phase 3 studies, both in the U. S, now in Europe for PTLD post transplant lithoproliferative disease. These are lymphoma that happens secondary to transplant. It's an allogeneic therapy. It will be the first, we believe, first to market and it will be able to give the promise of delivering therapy within days of need for patients. But that technology then transformed itself and allowed us to develop a next generation program for multiple sclerosis, which again is meant to transform lives to actually not just slow down progression of disease in patients with progressive disease, but also potentially actually improve and have symptoms return, and that's in Phase 1 study. But the focus of today is about our next generation CAR T programs. In January last year, we made an open statement that 2018 was going to be the year in which we start to unveil the investments that we've done as well as set up timing in regards to the programs that we're developing further. And that's what this breakfast is about. But all three programs, all three value drivers will be delivering data next year, and they all have in common the same platform technology. So I'm not going to spend a lot of time on the CAR T business. Again, this is a growing opportunity. It's really revolutionized medicine, but it's really in its nascent stage. There's a great deal of value people have ascribed to it and that's in an autologous setting focused specifically on hematologic indications. But with the promise of solid tumors and next generation work really spearheaded by some of the folks here, Doctor. Sedolime and Doctor. Davila, will really deliver on the promise of these therapies. They're not going away, right? CAR Ts are not a single entity product. They are a new category that will play a larger and larger role. And we believe that Atara will be able to be at the forefront of this. So where is Cartiste today? It's important to focus on what I mean by 1st generation and next generation. Well, 1st generation has really done some incredible things, high response rates in advanced hematologic conditions, disease unfortunately patients who've had relapses can come back to this therapy and these relapses can be stopped in some cases. Unfortunately, there's been limited efficacy in solid tumors, but that's something that's going to be addressed. Autologous manufacturing has really been the main early delivery mechanism. It makes sense for a lot of cases because if you could take cells from a patient and if you can transform and manufacture, you could reduce risks for any rejection. The problem with it is unfortunately it's logistically burdensome with improvements and has ultimately a constrained capacity because this is really a one to one delivery system. There's narrow eligibility for patients, there's some pretreatment that needs to be done as well as safety issues that again are being dealt with. But it's created a cornerstone to build a promise of wonderful new technologies. We can now talk earnestly about curative intent for next generation CAR Ts. We can talk about solid tumors and moving earlier in therapeutic intervention lines. We can go from not just speaking about oncology, but going into autoimmune and infectious diseases with these programs. And there are strategies today to address resistance. Off the shelf has clearly become a much larger focus of where this industry is going with lots of companies focusing in this area, rapid delivery as well as streamlining the treatment in these patients and improving safety and efficacy. There are many technologies addressing each and every one of those. But Atara is the company who is addressing all of them and they're addressing all of them today. Our strategy at the start was very clear. Right from inception of the company, we knew we wanted to go into CAR T. I mean anecdotally, I'll tell you a funny story in which I literally chased Doctor. Sedaline at JP Morgan, and he only agreed to meet with me if I drove him to the airport. I believe that what he was doing was going change the practice of medicine, and I wanted somehow for us to figure out a way to work together. But there had to be a strategy behind it. So this is Atara's strategy. This is what we set forth years ago. We said we're going to assemble a portfolio of novel technologies. We're not going to develop AlloCAR T's, we're going to develop next generation AlloCAR T's, which had to leverage new technologies. We were going to leverage our world class manufacturing. And first of all, we had to have our own manufacturing. We weren't going to rely on the 3rd party. As well as using the knowledge base that we're gaining from our tab cell programs on the regulatory side to quickly accelerate the development of AlloCAR T. We then entered into collaborations with academic leaders. We didn't believe that we had to be in house the best of everything. We needed to make sure that we could collaborate with the best, and we've done that. And rapidly then established CAR T programs using established targets, but most importantly, ones that already had data. We wanted to reduce the risk. So Atara today has assembled these core technologies and that's what this morning is about. You're going to learn about what we brought together, not everything, but a good sense and you'll understand that this isn't a nascent set of programs. This is something that we've been investing on for many years. You'll hear about match me systems, you'll hear about our manufacturing, you'll hear about our from our collaborators, you'll hear about our own internal CD19 programs. But as I said, there are certain shortcomings and there's a bridge that gets us from where we are today in the CAR T business to where we go in the future. We've taken our strategy and tried to address each and every one of those issues, and we'll talk about those technologies. That's not to say that there aren't other technologies and other ways of doing it, but I will tell you that from an Atara perspective, we didn't focus on one specific area. We didn't focus on resistance. We didn't focus simply on allogeneic. We didn't focus specifically on gene editing. We took an approach that went holistically from beginning, from target discovery, all the way to delivery. And that's what makes Atara unique. So with that, I'm going to switch over because really what you want to hear is from the experts. But hopefully you can see that the investments we've made have been very profound and probably most important is the manufacturing. This summer we opened up the Adams site. This is a unique industry specific manufacturing facility that was built from the ground up to both develop viral targeted T cells as well as CAR Ts. It's already in its licensing stage. I will tell you that within 2 months of our opening the site, we were already transforming CAR T cells as well as B cells for our TAV cell program, and it houses nearly half of our staff. It is a world class facility and will be an area which continue to produce value for us and it's what enables us to go from concept to clinic so quickly. So with that, let me turn over to Chris Hack, who will introduce our first speaker, and I look forward to answering your questions at the end of the Great. It's a real honor and pleasure for me to introduce Doctor. Michele Sadelain. Michel is the founding director of the Center For Cell Engineering and Gene Transfer and the Gene Expression Laboratory at Memorial Sloan Kettering, where he's also the Stephen and Barbara Friedman Chair. Michel received his MD from the University of Paris and his PhD from the University of Alberta and trained in Paris at the Centre Hospitalier Universitaire San Antoine and at the Massachusetts Institute of Technology with Richard Mulligan. Michelle is well known as the pioneer in the CAR T field, who championed the targeting of CD19 malignancies and was the founder of Geno Therapeutics. He's recently in 2018 received 2 honors that are worth mentioning to you the Pesano Award as well as the Pasteur Weizmann International Prize. He will speak to us today to put the CAR T field in perspective and will highlight a couple of key technologies for co stimulation and cell autonomous checkpoint inhibition that are part of the collaboration that we are enjoying. So please welcome, Michel. Thank you. It gives me a great pleasure here to speak on behalf of the network of academic collaborators that Atara has put together and also to introduce this session on CAR T cells. As Isaac just said, we are at the beginning of what he called a revolution, some use also the term of tsunami. I don't know if these big words really be fit, but what is certain is that we are living through a new form of medicine entering the clinic, first in oncology and perhaps soon spreading to other diseases beyond cancer. The premise for this therapy is really to utilize cells rather than chemicals or proteins to treat disease, especially with the goal of achieving curative outcomes. CD19 CAR therapy, which is really the poster child for this of treatment is a hybrid discipline. It draws a lot of course on immunology which teaches us the principles of T cell biology, what T cells are, how they recognize their targets, which are called antigens. And in the case of cancer, also teaches us how cancer protects itself from an immune attack. But it is also predicated on the use of genetic engineering, which is critical to retarget, to repurpose, to reprogram T cells to enable them to become the drugs that we want them to be. As you know, chimeric antigen receptors are actually not physiological normal receptors. They are scientists, man made scientists made molecules, synthetic receptors that differ from the natural receptors for antigen. And what they recognize is also different from what a T cell normally recognizes on a target cell. They recognize cell surface structures. So anything at the surface of a tumor cell, for example, can potentially become a target. And CD19 was the one that we identified many years ago and that indeed broke the ice and I'll come back to this in a minute. As we develop this CAR therapy, we realize that new manufacturing modalities are going to have to be developed. Perhaps what we did is what Isaac called the 1st generation. That's where obviously there's going to be room for much, much improvement. And all of this has to fit within a regulatory framework that actually we at Memorial have worked on very closely with the FDA to advance. To the left here is the normal receptor that a T cell uses to recognize what's called HLA peptide complexes. When this binds to an antigen that's on a tumor cell not depicted here on the upper part here, this triggers the T cell to initiate a response which is called T cell activation. T cell activation starts the response but alone is not sufficient to produce an effective immune response. For that the T cell needs to engage several other molecules that are known as co stimulatory receptors. I'm sure you've often heard the word co stimulation in recent years. There are many receptors that perform this function of co stimulation. One of them is called CD28. It's the primary costimulatory molecule of T cells. It belongs to a family of genes called immunoglobulin genes. And that second family of these costimulatory receptors includes again many more than the 2 that are depicted here, one of them being 4 1BB. It's the concerted action of all of these cosimatory receptors that really shapes an immune response and tells the T cell what to do and defines ultimately how good the response will be. Some of these molecules are target of current immunotherapies. But from the perspective of T cell engineering and creating powerful drugs in a single cell, there was a need some years ago create something new, something different, something that in a single molecule as you see here, which we called a 2nd generation CAR from years ago, a single molecule that could be coded for by a single gene that would instruct the T cell to achieve multiple tasks. So the outside part of the molecule here, for example, binds to the antigen. That could be CD19 or some of the other antigens that we will pursue with ATARA. And then inside the cell is this what's called the signaling domain. And I'm going to discuss this in greater detail in the next few slides. That is really what dictates what kind of a response the T cell is going to produce. So some years ago, many years ago, 15 years ago really, we identified CD19 as a molecule that we thought would be a good molecule to target in our program at some Kettering a few blocks or 20 blocks from here. We chose CD19 because it's on the surface of some cancer cells. Therefore, it can be recognized by a CAR molecule and it is found on the vast majority of lymphomas and leukemias for which there was and actually still is to some extent an unmet medical need. We knew it was fairly abundant, fairly consistently expressed and for those and other criteria we decided to make this the focus of our program. And we provided the 1st demonstration that you could take human T cells, instruct those T cells to recognize CD19 by inserting the gene coding for the CAR into those T cells, infuse T cells in mice that bore these different B cell malignancies, leukemias or lymphomas. This is what this PET scan shows you. This is a control here, but this is all the cancer in the hematopoietic areas in the calvarian in this mouse. But a single infusion of these T cells could lead to these long term remissions. They're actually cures documented in the mouse. We don't use this word lightly and a higher dose of these T cells could even cure all of these animals. So with that, we decided to establish a manufacturing paradigm that we thought we could show to the FDA and initiate trials. And this is what we accomplished again at Sloan Kettering. We start by collecting the patient cells. We use beads that are coated with antibodies that can purify the cells, the T cells that is expand them and introduce the gene into those T cells while in culture. The gene is carried by a vector which we produce also at Sonkeren. And after a short term expansion of these cells, you can test them, make sure that they're safe to release and freeze them down or infuse them in delayed fashion to the patient. This is what we want to change. This is called an autologous process. It works well. It has to be done though for every patient. The question is, can we make one batch of cells and now infuse multiple recipients as opposed to this 1 to 1 relationship, which is the staple of today's therapies? So we spend this is old news now. In 2013, we showed that this could induce dramatic remissions in adults with relapsed leukemia. Our colleagues at the University of Pennsylvania showed that they could do that in children with leukemia. Also other colleagues at the National Cancer Institute who had also read our work and to whom we had even given some of our molecules tested this in lymphoma and they too came up with dramatic results in lymphoma. All of this resulting in science, proclaiming immunotherapy to be the break through, the scientific breakthrough of the year. There were 2 forms of immunotherapy recognized at the time. 1 was checkpoint blockade, which I'll be coming back to in a few slides, And the other one was this emerging nascent discipline, if you like, based on the use of engineered cells. And by today, several centers have now reproduced these data. I guess you cannot really read this, but what's also led to the rapid embrace of this therapy is that different centers are developing the same idea, our ideas, came up with very similar results. So right away, if you like, believe it when several centers confirm these very remarkable results. So these are the 2 CARs that were approved by FDA last year. Both of them target CD19. Both of them are what we call 2nd generation CARs. They differ in this portion of the molecule. The one that codes for this costimulatory domain that I mentioned earlier. Some of them use CD28 and some of them use 4 1BB. I just want to illustrate quickly what we can achieve at our center with current trials. This is in adults with relapsed refractory acute lymphoblastic leukemia, ALL. When they are refractory and relapsed, they have a few weeks to perhaps a few months to live. And there was and there still is today no alternative treatment before the CAR T cells became available. So earlier this year, we published in the New England Journal of Medicine an update on the first 53 patients that we have treated at Sonkeren, manufacturing cells in autologous fashion in our laboratory at Sonkeren, you can see that the rate of complete remissions seen in the smaller series was confirmed, 83% of those. And if you look at these different parameters here, how much cancer the patient had, whether they had previously received a bone marrow transplant or not, whether they had received 2, 3, 4, sometimes 5 different kinds of chemotherapies, the genetic status of their disease, there's different types of mutations that you could find in relapsed ALL. Whether you look at their age or whether you looked at what's called the conditioning that's given prior to T cell infusion, none of that made a difference. In every subset of patients, the probability of obtaining what's called a complete remission was the same. That shows you how robust a cell based approach is because you might be 65 years old and have p53 mutations and have gone through 3 prior chemotherapies and you can still anticipate this high rate of complete remission. Now, complete remission is not a cure and this is going to show you why this is a baseline, as Isaac said, but there's definitely room for improvement. The 17% or so of adults who did not go into the complete remission will eventually and soon progress from the disease. This is an absolutely lethal condition, relapsedrefractory ALL. But also those that did go into a remission, a complete remission, in the case of ALL, a little over half of them will still relapse. And so it's wonderful that we can save all of these lives here, but there's clearly room for improvement. How do we make it 100% response now, not 83% and how do we prevent these relapses? Well, this is now where we get into the new molecules that we want to bring to this collaboration. And so we're talking about new designs of new cars. And this slide is just put together by a member of my lab here. It just shows you over the last decade the growth, if you like, in the design of these cars. So the first two here are the ones that I showed you in a previous slide, which are approved by FDA today using either CD28 or 401BB as their co stimulatory domain. Various groups, mostly academic groups, have proposed other designs, but it's noteworthy that extremely few of those have made it to the clinic because it wasn't clear at the end that they're really better than the ones that already exist. And so I would like to tell you about another one today that we're very excited about that we intend to bring to the clinic very soon in partnership with Atara. To do that, I'm going to go into a little more hardcore biology. I hope I can make it fairly understandable. This is a study that compares 3 different cars, not the new one that I'll show you in a minute, but those that exist currently. This one does not have a costimulatory domain. It's just an activating type of CAR. It's called the 1st generation. And here are the 2 kinds of CARs that are in the clinic in the U. S. And around the world today and those that are FDA approved that again use either the CD28 co stimulatory domain or the 4 1BB. And I'm going to show you some data in mouse experiments and the reason I show you these mice data is to explain to you how we can improve the design of these cars. And also because what I'll show you in a second in these data mirrors very, very, very well what we know from the clinic. So it's not just a mouse experiment. It's a synthesis, if you like, of clinical experience. So these mice have leukemia. We infuse T cells once and then we look at what happens to the T cells in the cancer over time. So we look here at 3 time points, 7, 14 21 days after the infusion of the T cell. And all of these mice get the same dose in different groups of course of either one of these 3 CARs. So the 1st generation CAR, there's very few of those T cells that make it to the bone marrow where there's the leukemia. And both these 20A and BV CARs are much more abundant. On this scale, it means there's 30 or 40 more times T cells. That's quite a big difference. At that same time point, 7 days after the infusion, the 28th CAR has already eliminated the tumor and the 4 1BB did not. This is a 10 fold difference, right? Same number of T cells, but 10 fold difference. That tells you that this CD28 CAR is far more active, has a lot of punch, if you like. However, over time, this CD28 car starts dwindling down in numbers. It's very powerful, but it doesn't last so long. The 401BB CAR is a weaker killer as this shows and this fits a lot of other data, clinical or not clinical that we know of. But you see it's still the T cell is still abundant here at day 14 and even at day 21. And it ultimately eliminates the tumor. What this says is that looking at these 2 CARs, we have a very powerful version that's short lived and we have a less powerful version, but that's very good too, but because it lasts longer. So how can we improve the design of the cars? Well, one would be to take a 28 car, which is so good, but make it act for a longer period of time. And that's what I'm going to show you in a minute. You can also do the reverse, which I will not show you today, which is to take this kind of poor killer and make it a stronger killer. So how do we do that? And these by the way are unpublished work that I'm showing you today. So this is this CD28 CAR, again, drawn in a different way. It has the CD28 and CD3 Zeta chains together. And it turns out this zeta chain has 3 regions that immunologists have known very well for a long time that contributes to the activation of T cells. And here we started mutating them. So for example, 1XX here has this these regions are called ITAM. This one is preserved in its natural form. These 2 are inactivated. In this one here, we keep the third one, Om Shao Cao ITAM3 active and we mutated these 2. So now we go to these very strict comparisons that we perform in animal models. And we compare and this is very stringent in the way we generate T cells from human peripheral blood, introduce these different CARs and make sure that when we treat these mice, when we're comparing these CARs that they all get same dose expressed in the same way. So take my word for it that these comparisons are done very stringently. And so this is the CAR that's in the clinic today. This 28V car by the way is what Gilead is using. It's what Juno was using. It's what several academic centers are using. So it's the same one here. And it's given at a dose here. This is 100 days where you can see a few mice are cured, but most of them fail. So we like to be at that dose. We don't want to we could cure everybody, all the mice here with more T cells. That's not what we're trying to do. It's at a point where it's really a transition point. You can see that XX3, which is this molecule here, doesn't work well. There's a bit of a response and boom, everybody relapses. All the mice eventually die with the leukemia. But then when you go to 1XX, you can see there's progression of the tumor. Why? Because we give a very low T cell dose and they have to grow, grow, grow before they catch up to the tumor and then they eliminate it. So only one item in 1XX, I'm sorry, which is here rather than 3. But it's not just reducing to 1 item, it makes a difference which item it is. If you go with XX3, there's a very poor response. If you go with XX3, there's a very poor response. If you go with 1XX, there's this very dramatic response. Because I've been speaking a bit This shows you now when we do the most stringent test of all, where we introduce these so the classic, if you like, here 28 Z car and then our favorite here 1XX. We engineer them using genome editing and what's called the TRAC locus. So sorry for I'm sure most of you are not expected to know about this, but it's a very powerful tool to introduce genes into T cells. And from a scientific standpoint, is really the most stringent comparison. You can see in these mice, a very big difference between 1XX and 28Z. Those treated with 28Z all die in 30 days and the other one survive. In fact, if we give back leukemia on purpose to these mice, it's called a challenge. Many times, those that were initially treated with a 28Z car can't handle this 3 challenge, whereas the TRAC1XX6 does so very well. We're feeding it back tumor over and over again. Thank you. And these mice to which we gave the TRYC1XX T cells only once, they're fine. They can keep rejecting this leukemia that we're giving them. And why is that? Because they keep making cells more and more. And what I don't have time to show you here is that these cells are memory cells. And this is backed up by, thank you again, all of these genetic studies looking at the profile of these T cells. What kind of T cells do they look like? Well, these are genes that are involved in either T cell activation or memory. And you can see that the genes that are expressed in the classic CAR, red means the genes are on. It's all the activity genes. And indeed, they're very good killers. But the memory genes, which allow the T cell to survive for a long time, and that's the key to our long living drug, right? We wanted to act for a long time, are turned off. That fits perfectly the clinical experience and mouse models that I showed you. The XX3 cell that I showed you before, remember, wasn't effective. And I didn't show you that these cells are abundant in the mice, but they were not eliminating the tumor. Oh, they have their memory genes on, but the effector functions were not turned on. No tumor elimination. And the 1XX is here in the middle and it has turned on these vector genes, but it keeps the membrane program. And that's the key to your long acting drug that's powerful enough to turn on effector functions, but in such a way that it doesn't compromise its ability to renew and be acting for a long period of time. The other tool that we're bringing to this collaboration serves a different purpose. I'm over time I'll try to finish this in 30 seconds. It is about checkpoint blockade. Now I think all of you know that the other immunotherapy, your evolution, that's the word for today, targets these molecules that put the brakes on T cells. And the most effective one really is PD-one. Our antibodies have blocked the PD-one, PD L1 access. So if a tumor cell has a molecule called PD L1 and because T cells when they are activated produce the receptor called PD-one, when PD-one engages PD L1, it turns off the T cell. And as you know, there are antibodies to say, I don't need to tell you about that, about KEYTRUDA and Nivo and many others that interrupt this access. But we can do that in the T cell without using an antibody. We can just engineer the T cell so that it no longer is controlled by PD L1. And we do so by introducing what's called a dominant negative receptor PD-one here, which will bind to PD L1 and prevent it from acting on the T cell. So I've spoken a bit too slowly. I will not show you the data that we have, some published and much more unpublished that shows that T cells that express the dominant negative receptor to PD-one are both better killers than those that don't have this molecule, but they extend the efficacy of the therapy. And that even a year later, after having given these T cells to mice, although there are very few T cells almost undetectable, those T cells are still functional and protect mice to a rechallenge. So we're very excited to have this dominant negative receptor to protect the T cells from PD L1 without requiring the co administration of antibody because it's all engineered into the same T cells from the very beginning. And I'll stop here. And it's my pleasure now to introduce briefly the next speaker because he's not only an authority in the field of cars, but he's also one who trained with me many years ago. And I look forward to seeing all of our students doing better than us. It's also my pleasure to who is an associate attending physician in the Department of Blood and Marrow Transplant and Medical Director of Cellular Immunotherapy at the Moffett Cancer Center in Tampa, Florida. Marco is also the Director Medical Director of the Cell Therapy Cancer Center in Tampa, Florida. Mark was also the Director Medical Director of the Cell Therapy Manufacturing Facility at Moffett And he received his MD and PhD training at Duke University, followed by training in medicine here in New York at New York Presbyterian Weill Cornell. And he was a celebrated research and clinical fellow at Memorial Sloan Kettering. He served as the principal investigator for some of the first CAR T therapies and working with his mentors, Ranir Brentchens and Michelle Sadelain at MSK, he was among the first people to clinically administer CAR Ts to patients and develop the algorithms used for treatment and management of toxicity of CAR Ts. He'll speak to us today about his innovations in the development of CAR Ts that are intended to serve patients with AML as well as B cell malignancies. And he'll also highlight some of the pioneering work that his lab and team will be presenting at the upcoming ASH meeting this weekend. Welcome, Marco. Thank you. Good morning, everyone. Almost feel like this is an impromptu satellite and lab meeting. Just going to wait for my first slide. I will say this is a really exciting time for me when I started my fellowship at Sloan Kettering. The standards of care for patients with acute leukemia, acute lymphoblastic leukemia and lymphoma, was basically either chemotherapy or kind of clinical trial. Now being able to offer these patients curative therapy and as a medical oncologist to not talk about necessarily kind of just extending survival, but talking about offering definitive curative therapies is a major kind of transformational shift that has occurred just within the last, 5 to 10 years. So I'm going to be speaking about, the research that we have developed over the last few years on terms of targeting AML as well as B cell malignancies. And when I transitioned from Memorial a few years ago, I had kind of a great opportunity to be able to see how the technology was being developed from soup to nuts in terms of from the lab, GMP production of CAR T cells as well as clinical application. And I really kind of developed my research program, start focused on what I felt were going to be obstacles in terms of efficacy for B cell malignancies as well as trying to adapt this technology. The first malignancies that I wanted to so I'm a tried and true leukemia physician to help a CAR T cell therapy before with AML. I've been treating patients with AML for nearly a decade and the standard of care for about 30 years hasn't changed. There's been a lot of recent approvals in the last few years, but it's not really changed in the natural history of relapsedrefractory acute leukemia. Most patients are still going to die of their disease. So I really wanted to bring a cell therapy to these patients. And again, from our experience with B cell malignancies, one of the things I kind of anticipated from the very bat was that a monoantigen CAR is not going to be a technology that will work very well for acute myeloid leukemia. Multi antigen CARs are going to be the way to go. Seeing the CD19 negative antigen relapse rate in patients with B cell ALL as well as even some patients anecdotally with non Hodgkin lymphoma was very kind of clear to me with the heterogeneity AML that developing multi antigen CARs can be really the primary our primary preference. And looking at the expression of multiple targets on patients that included both healthy donors as well as patients with acute myeloid leukemia, what you're seeing here is basically the flow cytometry, 25 patients kind of compressed and we're looking at here stem cell markers CD34 and here a couple of different targets. And what this is really highlighting is showing that some of these targets are not enriched within the stem cell compartment and that they are coexpressed. So when we started developing these CARs for AML, this was really based on what's been well described in the literature in terms of good self-service targets for AML. So we started looking at how these things are co expressed and which ones we could readily develop antibodies in CARs for. So again, from the prior experience, we kind of understood how CARs had been made, go to the paper, go to ATCC, find a hybridoma, sequence the IG heavy chain and light chain and then make this into CAR. But this, of course, relies on what was that initial antibody developed for. Was it as an IHC antibody? Was it a flow cytometry antibody? Was it therapeutic antibody? Some of it doesn't necessarily correlate to that antibody making it into a great car. So we wanted to start from the very beginning immunizing mice and then screening these antibodies for what we felt would result into a good CAR. So this means that we developed systems for rapidly screening a large number of antibodies and then sequencing the heavy chain and light chains together and putting them with different co stimulatory and activation domains into a final CAR. And the other kind of research that I'll be talking about is in adding in co stimulatory domain. So for a very long time, really the research has been focused on co stimulation CAR T cells was really kind of qualitative. We know it makes it better. We know that it helps proliferation. We know it helps some cytokine production. But there was really lacking a mechanistic understanding of what co stimulation was doing to CAR T cells. We have a lot more research published these last few years that has helped kind of, I think, improve this understanding. We've, I think, contributed to this as well, and I'll speaking about that in just a bit. So this is an example of basically what we did, screening 100 and 100 of 96 well plates of hybridomas and identifying first those antibodies that would bind. And here you see things that bind with really high intensity and those are the darker kind of black circles, those that bind less efficaciously the darker purple and those that bind kind of poorly the slider purple. And part of the reason that this is exactly what we want to see, because this was probably going to end up correlating with affinity. And this meant that we could potentially pick these at a very, very early stage to antibodies that had different affinities and that we kind of predicted that these different affinity devices correlate with slightly different functions within the CAR product. And there's this idea of affinity tuning that the affinity of the CAR can potentially lead to recognition of a tumor target which is higher expressed, but also ignorance of the same target expressed on lower levels in a wild tissue target. So this is the screening that we've done and this is just showing kind of an example of a plate where we selected many of these things and just confirming that they bind either very strongly or very, very poorly. So, we selected several candidates from each one of these targets and started developing these into CARs. And this is just an example of 3 different ones for an AML target that we have. This is just showing the gene transfer when we've made this into an SEV. We've made this or we sequenced the antibody into an SEV, made into CAR, shows the robust gene transfer, shows that the CD4, CD8 ratio of these CAR products are relatively similar when you put them in the human T cells. And we also see that there is a slight kind of disparate population of memory cells in some of these antibodies. And again, as Michelle was mentioning, that's one of the important characteristics of these products is how much memory do they have, because memory is what gives you persistence. It's one of the major things we've learned in terms of the clinical application of CAR T cells is that persistence is one of the kind of major obstacles to long term good outcomes for these patients. And the idea at least is that when you have products that have this greater central memory compartment, which here is listed in red, that you'll have better persisting CAR T cells. So it just shows you here in the screening of these three products alone that this one CAR for no difference other than the SCV itself has a greater population of central memory cells. Also, there's a slightly difference with cytotoxicity as well. This is kind of a new standard. When I was in Michelle's lab, we all did chromium release assays, but this is now a real time cell analysis assay where you're basically looking how well targets bind to a microchip. And when these cells are killed and sloughed off, the impedance of an electrical current across that chip is removed and you end up seeing that measured in this kind of assay here. So cells that aren't killed run up high and then cells that are killed are lower on this graph. So you're seeing here, for example, that these 2 CAR products kill much better than our negative controls. And screening again dozens of these different targets, we have a vast diversity of cytotoxic CARs, anti AML CARs as well as B cell CARs where some that kill very, very low, some that kill medium and some that kill poorly. So this kind of gives us that diversity of CAR selection where we are able to start combining these things in different ways. So our idea at least is going to vary based on the target. For AML, we're focusing on the and gating because we know that the concern for off tumor on target toxicity is very great with AML. One of the really, I think one of the important features of targeting CD19 on a B cell malignancy is that it's not expressed out of the B cell lineage. So there's basically no risk for or very kind of minimal clinical risk for off tumor on target toxicity with a B cell. However, that's not the same with AML. These things are commonly expressed on hematopoietic stem cells, on later stage blood cells as well as even non hematopoic requirements. So the concern for that is that you can have some significant toxicity. That's why we're combining these things in an AND gate where you have one where it's present on CD3 zeta CAR and the other where you lack zeta. And as Michel demonstrated, you need Zeta for basically T cell activation. But you need co stimulation for full activation of the CAR T cell. So only when these T cells when the T cells are ligated by one of these targets, you don't get sufficient activation. But when you, ligate the T cell through both of those CARs as well as the chimeric costimulatory receptor, you get full activation cytokine production, proliferation and persistence in vivo. So that's the AND gating. So what we're doing now is we're combining these multiple AML targets into a single human CAR T product in an AND gated system For CD19, CD20, CD22 for B cells, we're not using AND gating, we're using OR gating. Again, the main reason the rationale behind that is the concern for off target or on target off tumor toxicity is much less because of the very tight tissue expression CD19. So I'm going to talk briefly about some of the work that we're going to be presenting, at ASH, which, is the source of at least this partnership with at least some of it is a partnership with Atara. So, one of the things that we kind of really appreciated early on, even when the laboratory data wasn't there, is that these costimulatory products do drive different clinical functions. And one of the best examples that I have of this is the different kinetics of persistence in these patients. So up on the bottom, this part right here is the 4 MBB based CAR T cell product that now is known as Kymriah. On the right here is a CD28 CAR T cell product. Again, all these are targeting CD19. And what you can see here, if you look at, this is the Kymriah data published by Shannon Maude in New England Journal of Medicine is that these R stand for relapsed. And what happens before every one of these R's is the CAR T cell product ends up getting lost. It no longer persists. In this kind of striking case here, it's literally almost 9 months out. This patient is maintaining a remission, maintaining remission. 9 months out, they lose the CAR T cell product and the patient relapses. So you would say that for 4BB, persistence is absolutely critical for its function. This compare this to CD28 CAR T cell product where these things are nearly gone by 1 month after adoptive transfer and this is by QPCR, not necessarily showing function, just so when you're able to detect that genetic imprint. Likely, functionally, they're gone even earlier than that. So but the remission rates and the durability of the responses are somewhat similar to the Kymriah product. So I'd say that at least long term persistence for some of these initial outcomes are not absolutely critical for a CD20 based CAR. So it's kind of showing clinically that there are some clear biological differences between these costimulatory domains. And that's why we when I again transitioned from New York, I really wanted to focus on comparing and contrasting how these things worked different mechanistically. And I was able to at least have some early data from Michelle as well as other really prominent CAR T cell investigators that started publishing in this field. Number 1, 4 1BB just seems to drive a metabolic phenotype that resembles central memory cells. Metabolism with CD28 co stimulation is more similar to an effector memory cells. 41BB can reverse or prevent an exhaustion phenotype. And lastly, CAR expression impacts tonic signaling of CD28 co stimulatory domains. So those are some of the things that were kind of published in the last few years that helped guide our research. So what we decided to do is start doing targeted mutations of the CD28 costimulatory domain, starting to define are any of these costimulatory domains absolutely required for enhancement of CAR T cell function? And there's 3 subdomains, Ymin, NPRP, PYP, that bind different signal or that can activate different signaling pathways downstream of CD28, the PI3 kinase pathway, the ITK pathway and the LIK pathway. And partly this is based on just classical T cell biology where a great T cell immunologist basically does this very similar work to try to identify which of these sub domains is absolutely required for CAR T or for just T cell persistence. So these are the different constructs where we basically made single mutations, so knocking out the other 2 sub domains and keeping one of these sub domains present. And so the first thing that we saw is in terms of cytokine production, this is 28 zeta here in red, is that when you leave only a single subdomain, you reduce cytokine production, but it's still greater than a 1st generation 19 zeta construct. So you're still having enhanced cytokine production, but not nearly as great as when you have the 1920 Z CAR. And also, when we put this into the cytotoxicity assay, the real time cell analysis assay, you can still see very robust cytotoxicity. Again, some of this is probably going to be driven by mostly through the zeta Itam domains. But we can actually see enhanced cytotoxicity when we drop down the T cell to target ratios to one that really favors the tumor target, we see 1, this MEAT6 construct which has only the pyedu domain actually kills better than all the other constructs. And then we're I'm kind of skipping some animal kind of modeling data. So let me kind of tell you what we've done here is that we put these things into these different CAR T cell products with the mutations into mice. These things were really kind of developed to look at persistence and exhaustion in mice long term because certainly these things will impact the immediate signaling of the CAR T cell product, but we were more interested in terms of what happens after a month in the mouth. So we really focused on looking at the potential for exhaustion in this model. So these are immune competent mice that have been given conditioning chemotherapy followed by the CAR T cell infusion and then 1 month later we've challenged them with antigen, sacked the mice and isolated the CAR T cells and stimulated them again with antigen, but this time the antigens also express PD L1. So we're really trying to see if we can induce significant exhaustion or evaluate for exhaustion in these products. And you can see here, this is a standard 1920 Z product that there's really no significant secretion of cytokine better than a negative control, similar for bbzeta for a 19 bbzeta product. But this MUT6 CAR, again, the one that contains PYIP in the lysiclibulin domain, actually has enhanced cytokine production. So it appears that this is resistant to exhaustion in long term into these incompetent mice. And this relates to the fact that you see very prominent B cell killing that's occurring in these mice as good as 28. You actually this was something I was very surprised to see is it actually has enhanced leukemia killing in immune competent mice. So here's the 1928 Zeta product. Here is the product with the MEET-six CAR that virtually all of the mice are cured by this construct. I was very surprised to see this, but I think it's very kind of consistent with the earlier data that we've presented here that these cells or this construct is very resistant to exhaustion. So this is data in part that's going to be presented in much more detail Monday afternoon in the adoptive immunotherapy session at ASH. And that's about CD28, but also we've done some stuff with 4 1BB, which we recently published. So I'll kind of give a quick highlight to that. So one of the things that we kind of I think certainly agrees with what Michelle has discussed is that 4 MBB is a very, very crummy killer. And we were able to kind of look at this in mouse modeling. And again, I think as Greece with when Michelle has published that this is compensated by the fact that these things persist better, that they proliferate better at least in mice. And what we were able to demonstrate is that, it looks like the NF kappa B signaling pathway is contributing to this functional difference. So you compare everyone knows that CD20 also activates in its kappaB signaling pathway. But what we're surprised to find is that it's activated at much higher levels when you have a 4BB co stimulatory domain. And we're able to also start identify which Traft, which stands for TNF receptor associated factors, are modulating this pathway. So this is an example of a 19 BBZ CAR that we have put in combination with different troughs. So trough 1, trough 2 and trough 3. When we add an excess of trough 2, we see NF kappa B skyrockets through this reporting kind of cell line. So what happens in a natural CAR T cell product when you have 19 BBZ with Traft2? We see enhanced proliferation. We have to see enhanced viability. We have to see advanced tumor killing in vivo as well. So for us, I think we've kind of identified and this was published recently by, Gangavoli in my lab and JCI Incyte where we feel that we've kind of identified really the critical signaling pathway that accounts for this enhanced persistence and proliferation in these CAR T cell products. So what we're excited about now with the SITAR collaboration is developing these multi antigen CAR products for AML as well as B cells. And I think one of the things that we're also offering is the ability to be able to do these clinical trials at Moffett where Fred Lach and Claudia Anasetti, my collaborators in the cell immunotherapy program, has developed this ICE T program, where it's a collaboration of both immunotherapy working group, where basically where we collaborate to develop preclinical as well as clinical evaluation of these CAR T cell products, the IST research program and the IST service itself. And this to me is really kind of one of the crown jewels of Moffett. In some ways, it's been modeled on was done at Sloan Kettering. So now when I kind of again started my clinical training, was really focusing on chemotherapy. When I transitioned to Moffett and when I left Memorial, I started to transition to bone marrow transplantation and cell therapy because that of course makes sense in terms of that's the clinical service where this is often given. So when I rotate, when I leave ASH and do another IT rotation at Moffett, I'm going to be using TCR gene therapy, CAR gene therapy, TIL therapy for patients with leukemias, lymphomas, sarcoma, lung cancer as well. So this is to me is created now of just a really vast clinical expertise at Moffett that's going to allow us to be able to translate this quickly to patients in Phase I trials. And I'm going to have dozens of clinical collaborators that are very familiar with adopted T cell therapies that will be able to administer this technology and report it relatively rapidly. And with that, I think is so as final conclusion slide, so we're working on this and or gating for AML and B cell malignancies. And our idea is that since we've identified NF kappa B, which can be upregulated by Traft 2 as the main mediator of the enhanced proliferation persistence of 4 1b based CARs. What we're doing then is combining this with the mutant CD28 to try to finally create this 3rd generation construct that works that brings the qualities of CD20 cytotoxicity with persistence proliferation of 4BB. With that, I will say thank you. Good morning. My name is Dietmar Berg. I'm heading R and D at Atara. And it's my pleasure to try and bring these different aspects that you've heard during the last 40 minutes really together from an Atara perspective. And I want to start doing that by going back to the strategic vision that you've heard from Isaac before, how are we approaching allogeneic CAR T cell development from a strategy perspective. We have assembled a deep portfolio of what I would call building blocks that we will utilize in order to put together our CAR T cell approach. We already have an allogeneic T cell therapy approach in our EBV specific off the shelf CAR T cells, we have established, as you've heard from Isaac, manufacturing with that, so we can also build on a state of the art manufacturing capability. We are looking at, as you've heard, novel targets and very specific SCFVs in our development. And again, as you've heard, we're utilizing multi targeting CAR T cell technology together with MARCO and next gen co stimulatory domains that have been discussed as well. In addition, we have the built in checkpoint inhibition, the PD-one dominant negative receptor technology to unlock the solid tumor microenvironment. Collaborating with academic partners is key of our strategies, and we feel very privileged to work with people like Marco and Michel. And these collaborations at this point in time focus on hematologic malignancies. I'll talk more about that on acute myeloid leukemia and B cell targets and in the MSK collaboration to develop novel CARs also against a broad set of diseases, not only in oncology, but also focusing on autoimmune and infectious disease. And finally, we're working to rapidly establish those CAR T cell programs. With all the programs that you're going to hear about, we are trying to bring at least one IND into the clinic during the course of 2019. The EBV specific T cell immunotherapy platform is really our starting point. And when you look at that in more detail, it has specific advantages versus other approaches that are out there versus some of the competitor approaches. For example, we are starting with a T cell population that is sourced from established healthy donors. So we're moving away from that one to one manufacturing. Really, one of the healthy donors provides material for a multitude of patients. And furthermore, in the production process, we can also store intermediates and we can go back to them adding more manufacturing efficiency to our process. On the basis of the partial HLA matching that we're doing, no gene editing or HLA edits are required. So we're maintaining the healthy donor T cell proliferation and persistence advantages. The T cell platform that we have developed, the EBV specific T cell immunotherapy platform has been tested in the clinic. So we have data. We know that in both immunodeficient and immunocompetent situations, we have a low risk of graft versus host disease and a low risk of cytokine release syndrome, which again is a clear advantage here versus other approaches that you've seen. And then finally, these T cells, these EBV specific T cells expand in immunocompetent patients out any need for lymphodepleting chemotherapy or any type of pretreatment, which further indicates that this T cell population may actually be immunologically privileged, which is a forms a very strong basis also for the development of a CAR T cell approach. This slide summarizes really the core of our approach. We're starting with a clinically validated EBV specific off the shelf T cell platform. We are adding these next generation CAR T technologies to then come to off the shelf CAR T cell applications with broad usage across oncology, hematology, potentially autoimmune disease and also infectious disease. What this slide also indicates is for the left part, for the EBV specific off the shelf T cell platform, we have fully established manufacturing. So we're just adding one more process step here, which is after we've arrived at the EBV specific T cells, we're adding those next generation CAR T technologies. That's an in process step that we're doing in our manufacturing technology, and that already gets us to the off the shelf next generation CAR Ts. We can freeze those cells down. We generate multiple T cell lines, and we can target basically a broad population of patients with those T cells that have been pre manufactured moving away from the old autologous paradigm. ATA-three thousand two hundred and nineteen is an off the shelf allogeneic next generation CAR T cell approach targeting CD19. It is based as you've seen, it is based on the EBV virus specific T cell technology, but now we're adding a CD19 specific CAR to those cells. So using a CD19 targeting FCFV and we will also use novel co stimulatory domains. You've heard a lot about these from both Michel and Marco. And these may enhance the CAR T cytotoxicity, obviously, also proliferation and persistence. This work is currently ongoing in our research labs at the Adam facility. I will show you in the next few slides a few proof of concept data that we've obtained with an ATARA allogeneic T cell that is again based on the EBV platform and has been transduced with CD19 and CD28 data. And the first slide here demonstrates that we can actually very efficiently transduce our EBV specific T cells to make these specific CAR T cells. On the left side, you see the untransduced cells. What you want to see is as many cells as possible inside the box. So here you see about 1%, less than 1%, that's background noise. On the right side, you see that roughly 80% of the cells have been efficiently transduced with the transgene and express the CD19, CD28 characteristic. So here we have more than 80% transduction efficiency, which is very comparable to what you get with state of the art autologous CAR T cell transduction. Furthermore, the T cell platform that you use, despite the transduction that we do, still maintains the original T cell receptor. So on the left side, you see untransduced T cells. On the right, you see the EBV CD1928 data CAR Ts. And you see the frequency of T cell receptor positive cells, again, inside the box. On the left side, you see 99% of the cells carry the EBV specific TCR that is unchanged for those cells where we introduce the transgene and the CD19, CD28 characteristic. This is important because we believe that the EBV specific TCR actually contributes to the persistence and to the viability of the cells over time. And you've heard a lot about why proliferation of the cells, why persistence of these cells is important and influences efficacy. You've also heard a lot, and you've made my job here really easy, you've heard a lot about Central memory phenotype is the desirable phenotype for generation of CAR Ts, and it's depicted here in green. What this really is, it's a specific subtype of T cells. And what you see below is the T cell proliferation paradigm where you go from a naive or stem memory cell to a central memory and then out to these effector cells. The early cells have a high proliferative capacity, but less of an activating status. You want the cells in the central memory field, in the central memory box, basically to balance the proliferation capacity and the activation. And what we get is more than 50%, and we get that reliably more than 50% of cells with that central memory phenotype, which compares very favorably versus peripheral blood mononuclear cells on the left or standard autologous CD19, CD28 CAR Ts, where you roughly have about 30% to 40% of those cells. Now we're looking at some of the function of the T cells that we get with our ATARA allogeneic CAR T cell approach. And here, what we compare is activity against CD19 expressing targets. On the left, you see our classic EBV specific T cells. They do not carry the CAR and they show low activity against CD19 positive target cells. What you have here is 2 different lines that are CD19 positive, NAM6 and Raji. And then in the purple, you've got a CD19 negative lines. And then you see low activity against that without the CAR. Once we introduce the CAR, you see specific and potent killing of CD19 positive target cells in vitro. Again, here that's NAM6 in blue and Raji in green. Our original allogeneic EBV specific T cells require HLA matching. And our whole technology, our whole platform is based on partial HLA matching. That's why we can give an allogeneic T cell therapy without doing anything to the HLA without further engineering those cells and maintaining a really low rate of GvHD and cytokine release syndrome. Here, what you see on the left is allogeneic targets, right? This is describing alloreactivity. You don't want to see killing in that area because that would be unspecific killing that clinically you would see primarily as side effects. You would see that as cytokine release, you see that as unspecific inflammation. So we do not want aller activity. We do not want killing on the left side. What we do want is specific killing on the right side. And you see we get that with our original T cell platform where EBV positive cells are killed when the HLA is matched because the EBV characteristics are presented by the HLA, and you need that in order to get specific killing by the T cells. You do not get killing in an HLA mismatched fashion, which again helps us to prevent GvHD and other types of side effects. The target cells here are also CD19 positive, but the EBV specific cells are not CD19 targeting yet, right? So the CD19 does not play a role for these cells. It does though here. Now we have again our EBV specific platform. We have introduced the CAR. And on the left side, you see we're still not getting alloreactivity. That is because we have a highly specific T cell population. That's also because during our manufacturing process, we are engineering the alloreactivity out. Alloreactive T cells are actually dying off during the manufacturing process. What you do get in an EBV positive and CD19 positive T cell population, you do get strong and potent cytotoxicity specifically targeting CD19. So here you have activity both in the HLA matched. This is the EBV activity plus CD19 and in the HLA mismatch, which is the CD19 activity only. Finally, with our production we show strong antigen specific proliferation and persistence. And what you see here is robust multi day proliferation of the cells following stimulation with CD19 and EBV targets. For those cells, and that's the red line where you see no target, for those cells that were not exposed to targets, you did not see expansion, you did not see specific proliferation. So in conclusion, we are building a next generation CAR T cell capability. We believe with the building blocks that we have, we are building better CAR Ts and we're leveraging innovative licensed technology as well as our own EBV specific T cell expertise. We have the ability to rapidly accelerate and advance those CAR T programs, integrating our research and process sciences as well as manufacturing, which is all under one roof in our ADAM facility in Southern California. The EBV CD19, CD28 CAR Ts have demonstrated high transduction efficiency, a really high frequency of central memory phenotype T cells, potent and specific killing, potent and specific CD19 activity and low levels of allergy activity, which is important from a side effect profile from a GvHD and cytokine release syndrome perspective and also strong antigen specific proliferation and persistence in vitro. As discussed, we are developing an off the shelf allogeneic CAR T targeting CD19, that's ATA3219, and we're hoping to bring that to an IND with similar timelines. This is how the overall oncology CAR T pipeline is coming together at Atara at this point. Besides the programs that you have here in this table, we are working on earlier programs, again in oncology, autoimmune disease and infectious disease. But for today, I want to focus on these 4 programs. The first two are in collaboration with MAPFRETA, in collaboration with Marco Davila. We are focusing here, as discussed, on acute myeloid leukemia, where you have dual targeted CAR T, the targets are at this point undisclosed. We're still working on them. The dual targeted characteristic really being that in order to distinguish between normal hematopoietic stem cells and the cells we want to target, which are the acute myeloid leukemia cells. This approach is also utilizing a novel postimulation domain. The second CAR T cell approach coming out of that collaboration is in B cell malignancies. Now we have a multi targeted, actually triple CAR T. We have disclosed the target CD20, CD19 and CD22. We're using an OR gate in this fashion. This is really in order to address what you see as a mechanism of resistance, which is antigen loss. And again, we are using a novel co stimulation domain. Then we've spoken about ATA3219, which is also against B cell malignancies. This is our allogeneic CD19 targeting approach that we are developing in house. And again, we're using a novel co stimulation domain. And finally, we're working together with Memorial Sloan Kettering Cancer Center on an undisclosed program. This is a solid tumor program. It's a clinical stage program. We are looking forward to disclosing details around this program very soon, and we're utilizing a PD-one dominant receptor here and a novel co stimulation domain. I find this is a very exciting program, and I'm very sure you will find this really exciting as well. We are rapidly advancing all 4 of these programs with the objective to have at least one IND towards the end of 2019, early 2020, with the other 3 following rapidly thereafter. With that, I want to thank you for your attention, And I want to bring Isaac back up to lead us through the Q and A. Thank you very much. Maybe I can invite Michelle and Marco to come sit on the stool. So a great deal of information was passed on in the sense of an opening salvo for what Atara is doing in the CAR T space. There is a lot more information, there's stuff here because this is all novel. You'll be finding the additional information in publications as well as as we file our patents. But this is truly on the cutting edge. But hopefully what you can come see here is, there was a very clear strategic plan to go all the way from target discovery through development and into clinic and be able to bring all the pieces together. If you step back, one of the key things about what I call the revolution or the tsunami as Michelle likes to call it, is it is very difficult for any company to think that it can develop a single agent all on its own and bring in all of the expertise. The field is moving too quickly to be able to do it. And if you do it, then you're harnessing an older technology. We've taken the approach that we're going to take the best of breed from all from the community outside. Where our expertise lies is on the manufacturing, putting the facility together. For example, Moffitt, Adam, was something that took nearly 3.5 years to develop and get licensing. It's not something that you can accelerate if you decide today. But we did it with a foreknowledge that we are going to be doing CAR Ts. At the same point, we are looking at really the leaders here to bring the technologies together to be able to say we have a horse race of 4 different CAR T programs with novel approaches all heading into the clinic in call it the 12 to 18 month timeframe. So with that, let me open up for questions and my panel will be happy to answer. Great. Thank you all for that. And I do like to focus on these co stimulatory domains, really trying to dive down. So first question, I just have 2 because I'll try to keep it quick. But have you tried the CD3 data mutation and the CD28 mutation together? Are they overlapping pathways? Is there maybe you're then not getting enough stimulation? Or is this something where you might have different indications for each kind of co stim subunit? It does feel like lab meeting, Marco. Coming up next, we have to see where the synergies lie. It's all about signaling signals and signals, I'm sorry, and how they integrate when you create these fusion molecules. And but you're spot on. That is on the list on the to do list, but we don't know yet. And then, Isaac, what's the clinical development pathway for some of these? It looked like you're going to start maybe get proof of concept with an autologous product. I think there was an asterisk there. And is this something where you would try to do an intent to treat head to head because they'll have manufacturing failures if you actually do intend to treat analysis with autologous? Or do you see this as more of a bridge to transplant or multiple dosing? So the short answer to your question is we're going to move as fast as possible because patients can't wait. So our expertise is on the allo side. The autologous focus here is really at the center. So as long as these programs move in parallel and that's exactly what we're doing, We will get this proof of concept on the autologous side while simultaneously then be able to bring forward the allo approaches first. That has multiple benefits. It allows us to open INDs at the FDA while with these programs develop the clinical data and then quickly thereafter bring in the allo approach. In regards to the patient population, like in the CD19 patient population, there's clearly a need where patients simply either can't make cells because the other thing that we haven't really talked about is even if you had all the time in the world, you can't harvest cells from every patient and be able to manufacture cells. And then there's the fact that some of these patients simply can't wait by the process. That is absolutely improving, but it's never going to get to the point of an off the shelf approach. So a fast to market indication would be go out to the population that you can't wait that you can't treat. And that's really the promise. But that opens up obviously a whole new field in regards to patients. Now if you talk about the novel approaches, obviously an allo approach would be ideal in any case, right, because you want to be able to hit as many patients as possible. But we are now feeling very confident about our moves into these B cell diseases and AML, but also into solid tumors. And we again, we'll be happy to talk to you when that information comes through. There you're talking about a novel approach into patients who have no options available to them. Whether it's allo or auto, the ability to be able to offer something to physicians and to patients for those diseases will be very well received. But the intention very clearly is to move all these programs into the allo approaches and that's the power of what Atara does. This platform technologies, these donors, Adam, the assays, all the aspects that we have put together allow you to then expand multiple many different programs. And that's where you have the multiplication effect here versus, for example, some of the other companies that have taken different approaches. Hi, Maury Raycroft from Jefferies. Thank you very much for the presentation. It's very helpful. I'm interested in dosing strategies within allo approach and if that could if you could potentially overcome persistence issues with multiple dosing and if that central memory compartment would build up over time with multiple doses, any thoughts on that? I think it's one of the things that we've learned in terms of the clinical application is that some conditioning regimens can minimize anti CAR immunity. So there is that potential to be able to do multiple doses. And I think from an advantage, unfortunately, one of the things that we experienced very early on is that when patients relapse after a CAR T cell product that oftentimes they wouldn't have another response. And I think we appreciate that's partly due from the anti CAR immunity. But with an off the shelf approach with good condition regimen, I think that there is that potential. And I'd like to kind of echo what Isaac had said in terms of the off the shelf approach. In terms of the clinical application, that's really one of my major difficulties as a clinician is going, okay, you have relapsed refractory acute leukemia, relapsed refractory aggressive B cell lymphoma, you need a CAR T cell product, come back and see me in 6 weeks when I have something ready. And that's just of course, we don't necessarily say that. These patients have to get bridging therapy, whether it happens locally or center. It just is a major obstacle to it. And so when I had was looking for partners, one of the industry partners I was focusing on someone that had a clinical stage company for an off the shelf product, I feel that that is the direction of this field in the next 5 to 10 years that the focus has to be on developing products that can get into patients very rapidly. The CAR technology is going to be the same, whether it's auto off, autologous versus off the shelf, But that to me is where the power of this field is headed. And maybe just to add that, I think one of the strengths of our platform is that in our current applications, we're not using any lymphodepleting therapy or anything, and we can use multiple doses, right? And we're hoping to really translate that also to the allogeneic CAR T cell field with based on the off the shelf characteristic, but also seeing, right, whether we need lymphodepleting therapy. We're going to test yes and no, right, and looking at potentially multiple doses, which I think will be very beneficial. Jean, do you have thoughts? Sorry. No, I agree with every word that was said before. I'll just add that our focus is on making the best possible T cell, hence this focus on co stimulation activation and affinity of SCFVs selecting the right epitopes. And the idea behind making a better and better T cell is to not have to give repeated dosing. Having said that, we think that the 2 are absolutely complementary. I mean, the better the T cell, the less multi dosing will be needed. But you have both approaches are complementary, if you like. Thanks. Yes, Maury, the one other thing I would just add is have to also remember the patient here. Time matters. You may have the ability to redose, but you're redosing because either you're trying to maintain a response, but in some cases, you're trying to salvage a patient. And over time, these are patients who failed multiple therapies. You may not even have the opportunity to do so. So as Michelle says, you want to hit hard right upfront. And this is where sometimes that links I have a discussion with the experts and I say, technology can do a lot of things, but it's still the slowest, the weakest link of the patient. And so you can try to do these things, but by that time the limitations of the patients may preclude your ability to do it. Got it. And the other question is just on creating allogeneic T cell and, just the necessary components that are required and how you think of the haplotype matching strategy compared to some of the other strategies that are out there for an allo approach? I'm going to quickly grab it and you have access we're involved. There are obviously multiple approaches to Gopalan. I think they're all very exciting to have their benefit. You have stem cell approaches, I know Michelle is working on them, have the ability to create a master cell bank and deliver them. You have approaches in which you combine both gene editing to make a cell allo and then transfect with a virus to bring in our car, a 2 step approach. We've taken our approach because what we believe very strongly is every time you do something to the cell it comes at a cost. These cells are not meant there's a reason why CD19 is not something that you find in that it could CD19 CAR naturally in any one of us. It's a Frankenstein and the reality of it is when you ask the cell to be transformed with something and then to proliferate for the hopes of efficacy, it comes at a cost. It comes at the cost of the cell's ability to proliferate, to maintain, to freeze, to be viable, all of them. So our approach simply is, can we take advantage of something that's already naturally, innately produces responses, allows expansion beyond in the face of Treg cells. That's why we believe our technology matters and we have all the pieces today because it's not the hypothetical. We can do it from beginning to end. That's not to say this is better or worse than others. Ultimately, the best molecule will win because we're all working, all these companies are doing the same thing. These are patients who have no choices and if something is better for them, I'll be the first one to applaud another technology. We just think that there's a thoughtful approach because we all are working on the same basic laws of biology and there's certain constraints around it. And so we're just trying to figure out what's the best way to be able to take advantage of them. Okay. Thank you. Hi, good morning. Excuse me. John Newman from Canaccord Genuity. I think I've got the same cough as you, Doctor. Sadelain. Yes, we're working on the common cold. Sorry. And first, I'd like to thank Doctor. Sadelain and Doctor. Davila for joining us this morning. Thank you very much. My question is, regarding the work that you've done with the costimulatory domains, whether it's trying new domains or modifying existing domains, Do you believe that the efficacy effects that you're seeing in your models are more independent of the rate of T cell proliferation than what we've seen in the past? Or are they still more closely tied? Thank you. Well, I guess I'll start. I think, I think Michel stated kind of really clearly with that slide where he put all these different kind of the standard second generation and next generation CARs together. There's a reason that there's a lot of folks that are focused on mutating CD28 and optimizing 4 1BB because we have hundreds of patients now of clinical data in terms of how those work and how they fail patients. So I think that's probably the reason that multiple investigators are really trying to be able to focus on how to make these things better. So my research has been directed to understanding why I know how CD28 fails, how can I enhance that function? So everything has been really geared towards trying to limit the ability of CD28 co stimulated CAR T cells to be exhausted. So my expectation is that I'll have a different clinical activity than a standard second generation 1920 Z CAR. I'm not sure whether Michel has that. That's a great question and I completely agree with Marco's reply. I think you were also asking how this will change the expansion characteristics of the cells. And that's a very good question. We know that most of the toxicities occur when T cells reach very high levels and whether they are 4 1b CARs or CD28 CARs or perhaps any other, it is when those patients, typically those with a high tumor burden, but also those in whom for reasons that we don't understand the T cells have expanded tremendously that we see the toxicities. So this goes back to this the same theme of making a better cell that then requires administration at a lower dose and that indeed would not undergo a massive expansion because then we may get back into these toxicity zones. So I can tell you that for the 1XX type of mutations that I mentioned this morning, we've characterized that extensively in the mouse model. And it doesn't relative to the current 28z, it doesn't increase the proliferation. It increases the persistence definitely, but the more dramatic effect is maintaining the function of the cells. Because you can have persisting cells and at first physicians are happy if they detect persisting cells and that's the kind of data that's been reported for several years. But it wasn't known if they were persisting and functional. And it turns out that we appreciate more and more that not always, but often they are persisting, but exhausted, meaning not very useful. And that's why sometimes there's a relapse even though you can still detect T cells. I mean the T cell the CAR T cells are there relapsing. Either the antigen is gone and that requires Merkel's strategy of multiple targeting or the target is still there, which means the T cells are there, the tumor is there, the target is on the tumor, something's wrong. What is it? The T cells are exhausted. And so the strategies that we're developing really combat that exhaustion. But I'm pleased to say that the 1XX design in particular does not give you this raging proliferation because we wouldn't want to see that actually. Tom Brakolier, a question for Doctor. Sutherland de Fila. So I assume that you probably believe that we can create allo CARs with gene editing approaches quite nicely eventually. And so if that is true, what do you think the advantages are and the disadvantages would be over using a virus specific T cell as a starting point? Well, I guess, for me, I think there's a very kind of recent appreciation that one of the roles of the immune system is to sense and eradicate cancer. But even more important to that is to sense and eradicate viruses because 1000 of years ago viral infections would kill people. So if you look at the function of a viral T cell, these things are very sensitive to antigen. They are designed to activate and kill to low levels of virus to expand to persist. And I think that's somewhat reflected in the data they show when you see that for no reason other than the fact that they're creating this viral specific T cell product that you have in expansive central memory compartments. So I think that to me is one of the big advantages by utilizing vial specific T cells is that these are T cells that already have those characteristics that Michel was talking about in terms of being having those great optimal characteristics and what we're doing or what Atara plans to do is putting cars into these things that already have a lot of those characteristics. So I think to me that's probably one of the biggest advantages. And I'll answer as Isaac said, there are 3 approaches to these allogeneic strategies. One where you start from peripheral blood T cells from a healthy donor. And now to prevent graft versus the T cells from attacking the recipient, you have to remove their T cell receptor, which is what recognizes the recipient and triggers the attack. And as we all know, gene editing strategies allow us to do that today to delete inside the T cell its own receptor so that it now only has the CAR. That's one approach. Another approach, which Isaac mentioned, is to create T cells in vitro starting from reservoirs of pluripotent stem cells. The attractiveness of that is that in that pool of stem cells, you could do all the genetic modifications that you want. But then from those stem cells, you have to derive in vitro the T cells, which otherwise you can easily collect from a donor who's already made them in their own body. The third approach is the one we're discussing today, which is the use of EBV reactive T cells. And the advantage of those is that these banks of cells, these GMP banks already exist. They've already been vetted in the clinic. We already know that they don't cause graft versus host disease without, as Didmar said, having to go and remove the T cell receptor because it's a vetted safe receptor. So you don't need the genome editing. So there are 3 main approaches and we could go through a list of pros and cons for each one in a detailed technical fashion. I don't think we have the time for that. I'll just say that I think that all of them have pros and cons. And we'll have to see which one is more effective, which one is safer and which one is most cost effective and the most competitive in the market down the road. And that certainly I could not predict. Tom, I'd just say one other addition. When we use the word gene editing, it almost assumes it's a one event where you use it. From our perspective, gene editing to make something autologous, we don't think has it's not the approach that we've taken because from our perspective, the cost versus benefit don't hold. Gene editing, for example, as Michelle talked about track locus about where you put a car is a different approach. So we have to be very specific about how we think about gene editing. The other problem is that if you start to mix them, then you sometimes have additive risk and potentially additive benefit. So I think the field will try to figure out where to maximize the gene editing, not just across the board for the reasons that Michelle brought up. And we've and to be clear, we keep ourselves open and have created optionality to take advantage of just not simply on the allo approach. We think naturally healthy HLA bank cells I'm not going to improve on Mother Nature. Hi, Phil Nader from Cowen. A question specifically on persistence. I think the panel made it pretty clear that persistence is important in the function and efficacy of the T cells. I'm curious what you think about the risk of the patient's immune system eliminating allogeneic T cells And what strategies you think are most promising for allowing an allogeneic preparation to evade the immune system of the patient? Sure. So the allogeneic tabyleclis cells, EBV targeted cells persist with the TCR betas sequence out to about 90 days. And in that time, patients with hematologic malignancies as we've seen with post transplant lymphomas have entered deep responses that are durable. And so we think that that type of longevity for hematologic malignancies is really perfectly suitable for many malignancies. In some of the solid tumor cases, we are also really attracted to the experience we've had with repeat dosing. I think in those settings, it may be a great clinical trial feature and we'll be evaluating that as we move these into the clinic to have that repeat dose or sort of a maintenance dose approach for these technologies. It's been striking that in both the immunocompetent as well as the immunosuppressed settings, we're seeing equal expansions of this EBV directed platform. And so the proliferation and persistence has not been affected by presence of the immune cells present in, for example, patients with nasopharyngeal cancer who we've treated with this cell therapy. So although I think you're raising a very important theoretical concern, I think the data that already we have from our validated platform that has a wealth of clinical data actually speak to the simplicity of the approach and the adequacy of the expanded cells in addressing even the solid tumor type of indications like nasopharyngeal cancers? It's a very good question. And it's a question that faces all allogeneic approaches no matter how you approach it. It's a big biological question that looms over all allogeneic strategies. So Atara is pretty unique and already having experience with one particular solid tumor. This is nasopharyngeal carcinoma, which can be targeted with EZBV T cells. So they're building up experience with this and that's why I'm so interested when I get to see a little bit of that data because that's really quite unique. Having said that, this question looms over the whole field. So the question of persistence and rejection of the allogeneic cell no matter what it is is very key, right? You want to infuse T cells, they have to work for a certain number of days or weeks, maybe sometimes months, but certainly several weeks before they are rejected, right, if they are going to be rejected. So if we we believe that we don't need to establish what's called immune tolerance, perfect immune tolerance as if you were being transplanted a kidney or a heart where you have to tolerate a foreign tissue for the rest of your life. And that's real tolerance, right? You got the cells from somebody else and you can't reject that heart. Here maybe you can reject them at some point as long as they've already done their job. So this question of potency of the cell product, persistence and duration of immune protection that you want to afford to lease T cells before they are rejected is really the key. And I think that nobody I think certainly I don't know, I don't think anybody in the field or in the world really knows exactly what those parameters will be. But that's why we think that the increasing the potency on the one hand and exploring different strategies to enhance or to delay their immune rejection is the way to go. And I think one key feature that distinguishes what Atara is doing from what others is doing is that several groups have said that they will eliminate all the HLA molecules. And I agree that's worth exploring. Of course, we don't know if that works yet. As Isaac said, when you change something, there are sometimes other problems that come up. So there's a chain reaction of events. But in any case, it's a logical idea and many groups are pursuing that. We don't know yet, of course, to what extent it works. And here the approach is different. It's based on HLA matching. So other than the fact that you don't need gene editing, biologically it's completely different. It's a completely different approach to it. So it requires a bank. But then Atara has already created a large bank. So the biology is different. And I think we need to learn as a field from all of these angles. Great. Just one follow-up question. On Slide 65, for your CD19 CAR T, you showed 2 different levels of killing in the HLA mismatched circumstance. And it wasn't clear to me what the difference between those two bars were, why one had a higher rate of killing than the other? I'm sorry if I missed it. These are individual experiments at this time. So you do expect some variation. That specific difference, I wouldn't read too much into it. The importance of that slide is that you get activity against CD19 carrying targets irrespective of the HLA status, which is really the CD19 activity of the car. Matt, if I can ask just two more quick questions. First, Marco, there's some other groups that are looking at taking a PI3 kinase inhibitor small molecule during culture to try to increase the stem cell like phenotype. Obviously, some of those mutations in the CD28 domain are getting rid of PI3 kinase signaling. Have you looked at the phenotype of those T cells when you do those slight mutations? I didn't see it in this slide deck, but Yes, actually no, that's a That's a great question. It's I think important work because it's something that can be done right now to products that are available for patients. The main disadvantage of that system is once you remove the drug and put it into the patients, then the PI3 kinase pathway gets kind of reactivated. So that's kind of I haven't published that data, but we've looked at multiple different inhibitors towards these pathways. They're not absolutely clean in terms of knocking out only one pathway. We haven't found the perfect drug that can kind of recapitulate what we're seeing with the mutation. Thanks. And then, Michelle, with JCAR-seventeen that was published show that they actually cultured those CAR T cells with an EBV infected lymphoblastic cell line to selectively kind of expand, I guess, some EBV positive CAR T cells. That's both in PDASH KLL and in the NHL in the two publications. Wondering if you have thought about that and maybe Marco too. I mean it's a kind of interesting technique to maybe expand the virus specific CD19 T cells a little bit to help with some of the persistence and other things? Yeah. Unfortunately, I'm not familiar with the exact details of that process, But that's eliciting the ZBB reactor cells in a donor specific fashion. And obviously, I know you know this, but Tara already has a bank already made and so which would therefore obviate the need for that. I think that generally speaking, EBV has been such a unique model in immunology because we're almost many of us are anyway infected with EBV. Many of us mount effective immune responses and generate these T cells that are yes, they're memory T cells, but they're particularly good. They protect us from EBV for the duration of our lives. So they are really a special case within the entire immune repertoire that we have. There may be other cases like it, but not many, if any. So that's why they are so unique. That's why they're so special. And what exactly leads to most of us producing real good T cells against EBV is not fully understood. Part of it is that the cell that presents these antigen is a B cell, which turns out to be a very good antigen presenting cell. And perhaps evolution has given us T cell receptors that are very well suited to generate just this kind of response that you want that has to be operational for your lifetime. Because once you got EBV, it's never leaving you. It's in your body till the day you die. And so you need a real good response. So I think that's why originally also Richard O'Reilly who had started focusing on these cells decades ago, noted these remarkable attributes. And that's why Atar and as you said, others too often come back to specifically this type of T cell. Great. Thanks. So I'm going to wrap. Yes. Yigal Nakhimovitz from Citi. I was just wondering if you've looked at some of the other costimulatory domains. I saw OX40 on one of the earlier slides. Is there a reason that, that one has been less favored in terms of some of these newer technologies? I haven't. I'm not sure if you have Michel. Yes. We looked a little bit, but not in-depth. CD28 and 401BB are pretty darn good. And so others have and we too at some point, as I said, we didn't push it so hard. But 15 years ago when we published the first, we had already looked at a whole bunch of them. Some was published, some was not. And it certainly wasn't done with the depth that you could do today because science makes progress. But we found that CD28 and 401BB really stood out. And in our comparisons, we found that others were no better. Some maybe came close, NOX40 is not bad, but we didn't see anything that suggested that it's better. Now we didn't do every experiment and maybe somebody tomorrow will report that OX40 or something else. We're not talking about OX40 in particular is better. But a lot of people have been working on this over 10 years. And yes, there's papers. But as you see, there's nothing yet that has unseated these two prototypes. So it seems like early on we hit on pretty good ones. Now maybe for IP reasons people then want to go to the 2nd best. That's a different rationale. But if you're looking for the best activities to this date and this is science, right, it's evolved, really nothing has surpassed these 2 pillars, if you like. You got one of the points. I tell you from a business development perspective we looked at all. And what we did find is you can't look at any one of these components independent of each other. This isn't the sense of best stimulation, best SCFE and then put them all together. They actually interact and they affect one another. So you can maximize in one way and have a negative effect on the others, for example, in regards to efficacy. And so to Michel's point, you have something that works very, very well and seems to cohabitate well. And I think that's why you're seeing the field go down the road. That's not to say that there isn't other approaches, but the question then becomes what's the cost. So I'm going to wrap up, but first of all, I will thank my panelists for taking the time right in front of ASH and the holidays to be here. I could tell you that I couldn't think, as I said in the beginning, I literally chased these my colleagues here to come join. But I think what you're hearing here is intrigued about what we're doing and making sure and feeling that this is a strong bet for being the best next generation programs. This is just one more step for us at Atara to share with you what we're doing. Stay tuned, more data is coming, more programs coming. As we said at JP Morgan beginning of the year, the car function as a third value proposition will become a larger and larger part of what Atara is doing. And hopefully this morning's presentation gave you some color towards that. With that, thank you so much and I hope you guys have a great day.

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