Hello, and good morning from New York City to all of our viewers. My name is Sara Jane Demy, on behalf of Demy-Colton and our sponsor for this virtual salon, WBB Securities and Research, it is my pleasure to welcome you to the 40th installment of the Demy-Colton Virtual Salon Series. As always, we welcome our past participants back and welcome all of you who are joining us for the very first time. As many of you know, who have been with us in the past, Demy-Colton's mission is to convene healthcare industry leaders to catalyze change, and we do this through our virtual and in-person industry events, including BioFuture, which is taking place this October in New York City. Biotech Showcase, which will be held next January in San Francisco. Our CEO Summits, which we just concluded, one took place in Barcelona, and the other one just concluded in Torrey Pines, as well as our Virtual Salon Series, which this is one of. Before we move on to the formal part of the program, I do want to thank our sponsor again, WBB Securities and Research. Please note that today's salon is a bit different than the ones that we've done in the past. The formal discussion will take place in two segments, and we will begin with a short video introduction prepared by Dr. Helen Heslop on CAR T, and then the first segment will discuss CAR T cells, an overview of the treatment landscape. Sorry, guys, I'm having a little trouble with my, my own laptop. The second part will focus on beyond CAR T cell therapy. The entire discussion will last around 55 minutes, and it will be followed by a Q&A session. Please note that the salon is being recorded, and that it will be available for on-demand viewing a little bit later today. Now I'm pleased to introduce our sponsor and one of the moderators for this event, Dr. Steve Brozak. Steve is Managing Partner and President of WBB Securities, and he will introduce our opening video. Steve? Hi, I'm Steve Brozak, WBB Research Institute's founder. Since our inception, our mission has been to examine critical, real-world issues at the intersection of healthcare and the life sciences industry. In keeping with that mission, we are pleased to offer this video synopsis of the current status and recent advances in CAR T-cell therapy, narrated by Dr. Helen Heslop. The presenter, Dr. Heslop, is a physician, scientist, and a leader in translational research centering on adoptive immunotherapy with gene-modified effector cells. A professor in the Departments of Medicine and Pediatrics at Baylor College of Medicine, she has authored more than 700 research pieces, and among her honors, Dr. Heslop has been elected to both the Association of American Physicians and the National Academy of Medicine. Now, the video. Therapy of cancer with immune cells should have many potential advantages. These immune cells should be able to have good biodistribution and, unlike monoclonal antibodies or small molecules, should be able to traffic through multiple tissue planes. Immune cells also have multiple effector mechanisms and are self-amplifying and can also recruit other immune effectors. T cells, in particular, also have specific receptors that give high targeting ability. This slide shows the receptors that native T cells have that recognize proteins from inside a cell that are presented as peptides by HLA molecules on the surface of the cell. This is the native T cell receptor, which allows T cells to recognize infected or malignant cells. Recently, there's been a lot of interest in an artificial receptor known as a chimeric antigen receptor. This differs from the native T cell receptor in that it can recognize intact molecules, including non-proteins, on the cell surface. A chimeric antigen receptor is generated by juxtaposing the antigen recognition domain of a monoclonal antibody with signaling components of the T cell receptor. This resulting artificial receptor can be transferred to a T cell and will give it the ability to recognize tumor antigens on the surface of a tumor cell. Upon recognition, there should be appropriate signaling, resulting in activation and the T cell killing the tumor cell. The initial first-generation CARs have been improved by adding additional co-stimulation moieties, most commonly CD28 and 4-1 BB, resulting in improved T cell activation and proliferation. Over the last decade, CAR T cells have moved from being a boutique therapy, evaluated in phase I studies in a small number of centers, to being a licensed product. This is because of very impressive response rates observed in acute lymphoblastic leukemia and CD19 positive lymphoma, as well as myeloma. One of these such responses is shown here in a patient who had very extensive involvement with a CD19 lymphoma and after receiving CD19 CAR T cells, has a very impressive response. These are the currently approved therapies as of August 2023. There are four therapies targeting CD19 in a variety of CD19 positive malignancies and two therapies targeting BCMA in myeloma. The current commercial CAR T products are living drugs, which have significant side effects. A certain infrastructure is required to access this therapy. The patients have to be able to be apheresed at an apheresis center at a tertiary hospital. That requires a local cell processing facility to assist with handling. The centers that administer these cells need contracts with pharma companies, agreement with insurers, and expertise in handling complications, such that most companies require such centers to be FACT accredited for immune effector cell therapy. While these CAR T cells can have very beneficial therapeutic responses, as I showed in the previous slide, not all patients respond, and even patients who do respond can eventually progress. There are three major causes of failure. The first is tumor-specific and includes loss of the target antigen in many cases. The tumor microenvironment can also impede the activity of the infused CAR T cells, and sometimes the infused cell product may not be optimal because of the patient's previous therapies. Future directions are aimed at improving activity, and there are several ways to do this. One is to use CAR T cells earlier in the course of the disease, and while initial approvals were for relapsed or refractory disease, two of the products are now approved as second-line therapy. Another approach is to target multiple antigens, so as to reduce the risk of tumor evasion due to downregulation of one antigen. Another area of interest is in simplifying the logistics of manufacture for an autologous product. Several academic centers and companies have now developed CAR T cell products, where the manufacturing time has been reduced to two to three days, and these products are now being tested in clinical trials. Another strategy is point-of-care manufacturing, which is being explored in several European centers, where the products are manufactured locally, as we do for standard of care bone marrow transplants. Another option is to try and overcome some of the limitations of an autologous product by using banked allogeneic CAR T cells. The limitations of an autologous product are that it's patient-specific, and it may have variable quality if the patient has been heavily pre-treated. As I've discussed previously, it's time-consuming and expensive. Another option is to make banked cells from a healthy donor, where you'll have an allogeneic off-the-shelf, or more accurately, out-of-the-freezer product, that will have predictable functionality and be readily available and hopefully eventually also have a lower cost of goods. As shown here, instead of having a manufacturing process which involves ex vivo expansion and quality testing and may take 28 days from an autologous donor, you can have a product immediately available that has been manufactured from an allogeneic donor. Another area of current research is trying to extend the success that we've seen in CD19 and BCMA positive cancers to other hematologic malignancies. CD30 CARs have shown activity in Hodgkin lymphoma, and there are multiple targets that groups are exploring for AML and T-cell lymphomas, but the challenge with these tumors is the same antigens are also expressed on normal cells. While it's acceptable to deplete your normal B cells with a CD19 CAR, depleting normal myeloid or T cells has more serious consequences. At present, using CAR T cells for these two malignancies is a transplant-enabling procedure, where the patient is subsequently rescued with an allogeneic transplant. Another challenge is extending this therapeutic modality to solid tumors. Solid tumors present much more of a challenge because they have a number of other infiltrating cells and a tumor microenvironment that's hostile to adoptively transferred T cells. There's a number of strategies that can be explored to try and overcome these tumor evasion mechanisms, and these include modifying the CAR T-cell with additional moieties, so you also inhibit agents such as TGF-beta produced by the tumor. You can also try and optimize trafficking to the tumor site. There's a number of genetic modifications that are being tested in the clinic to enhance signal three so that T-cells have better long-term persistence. The current state-of-the-art for CAR T-cell therapy is that up to 50% of patients with refractory B-cell malignancies, who had very few available previous therapy, are now showing durable, complete responses to CD19 CAR T-cell therapy. In addition, over 50% of myeloma patients who receive CAR T-cells respond. The major research focuses are trying to extend this success to other malignancies, to overcome tumor evasion mechanisms, and to simplify production and increase accessibility of this therapy. Thank you, Dr. Heslop, for that very informative video. Now it's my pleasure to introduce the moderator of our first segment, Querida Anderson. Querida is editorial director and biopharma expert. Querida is joined by two renowned panelists, both professors at Baylor College of Medicine, Dr. Helen Heslop, as she prepared the video, which was wonderful, and Dr. Malcolm Brenner. Without further, further ado, Querida, the stage is yours. Thanks, Sara. Yes, thanks, Dr. Heslop. That was just an excellent primer on the CAR T space and where things stand today as well. Welcome to both you and Dr. Brenner. Let's dive right in. I have quite a few questions to try to get through in a relatively short period of time. I wanted to start, Dr. Brenner, your last couple of slides hit upon this a little bit, but I wanted to start with getting an update on what the clinical experience has been with CAR, with the CAR T therapy so far. Our first CAR was approved about six years ago. We have five more now. All of them posted some eye-popping efficacy data. How has that translated to the clinic? I think it's been very encouraging that the real-world data with the commercial CAR Ts has really reflected the data from the registration studies. There's been a lot of real-world consortia, the Center for International Blood and Marrow Transplant Research have obtained data on patients treated since the licensure. Really, I think the response rates have been very similar, and that's particularly encouraging because some of the patients treated would not have been eligible for the registration trials because of comorbidities or age. Yeah. I think despite a slightly higher risk patient population, the initial good response rates have been attained. That is incredibly encouraging because it's not often that you see that happen when you get from phase III to the clinic. Just to dive in a little bit more into that topic, Dr. Heslop, I'm gonna stick with you for the next question as well. You know, of the six CAR T therapies that are approved, five of them. Or rather, of the five indications that they're approved for, four of them have multiple CAR Ts approved. Those four also have more recently approved monoclonal antibodies, bispecifics, in fact. I'm just wondering, how are clinicians weighing the pros and cons of these various options that they now have? In particular, how much does the price point and the access hurdle that comes with CARs play into that decision as well? Well, I think that's a very big question in the field at present. Should you use a CAR or a BiTE if you have a patient who would be eligible for each? I think what's obviously going to be important in the long term is which has the best long-term disease-free survival for patients, we don't have that comparative data as yet. I think there are some access factors that may influence the decision. For example, if doctors and community hospitals may have access to BiTEs, but not to CARs, so that may influence the decision for some patients. I think we really need more data to know which is the best option for the patient. Understandable. Let's talk about side effect profiles. You know, obviously, cytokine release syndrome and neural damage are the most significant of the adverse events that are experienced with CAR T therapies. Dr. Brenner, I would love to get your thoughts on the spectrum of dealing with side effects. What I mean by that is, for the products that we have now that do trigger these side effects, how can we better assess or predict patients who are at greater risk for developing these side effects? How do we monitor all patients? How do we mitigate the severity? What approaches or drug combinations might there be? Then I'd also love for you to blue sky it for me and talk, just, you know, talk about whether you think we can develop CAR Ts that totally eliminate these two adverse events. Yes, well, I think, I think that a lot of separate questions in there, obviously. I think cytokine release syndrome is probably the best understood of, of all those adverse effects. I think that the introduction of preemptive or prompt therapies to prevent and treat them will reduce the morbidity and mortality. Those, some of those will be antibodies, some of those will be inhibitors of T-cell function or even a monocyte function if they're producing the cytokines. I, I, I'm sure that the monitoring will improve as, as time goes by. It's interesting that that whole Cytokine release syndrome was first discovered with CD28 monoclonal antibodies, of course, when they were given agonist antibodies in a hospital I used to work at in the U.K. It took a long while, surprisingly, for people to appreciate that that same thing was going on with CAR T cells. With the availability of the monoclonal antibodies, I think that's improved. The neurological abnormalities, those are a lot harder to understand, and I still don't think we've really got to the bottom of those. Until we have a clearer idea of exactly what's affecting what and how, it's going to be a bit empiric in terms of how we predict it, prevent it, and treat it. I think I'll take a hard pass on that one. In terms of, of future, future o-options, then clearly what we need is a much more regulated CAR T target interaction. We need something that can be turned on and off, not just in a binary fashion, but in a sort of rheostat fashion. Killing, if necessary, or inhibiting a proportion of the cells, damping them down. That may be achieved by introducing regulatory genes that can be triggered by small molecules. There has to be very fast on/off times for that, and a high level of rapidity of response. We do have molecules that will do that now and, and have been used clinically. Also probably in improving CAR T, the, the chimeric antigen receptor itself, so that it engages more with the normal machinery of the cell, instead of being a standalone component that goes its own sweet way as and when it's stimulated. If it can engage with the other intrinsic regulatory mechanisms that a T cell has, for example, by engaging partly with the T cell receptor signaling, then I think we'll see an improvement as well. That's the future of it. Yeah. No, you gave us a s much as you said you were gonna take a hard pass, you did give us a wide range of possibilities there. I appreciate that. Let's move on to solid tumors. Again, Dr. Brenner, I'll, I'll give this to you, and again, it's gonna be a two-part and a big question. In terms of the side effect side of things, do we expect to see a similar sort of side effect profile? Might we be anticipating other types of side effects to whatever degree of severity? Then also touch upon the efficacy. You know. Obviously, solid tumors have had very specific hurdles in, in development with developing CAR Ts that can recognize the solid tumors. Can we get to a place where we can develop strong, potent CAR T therapies for solid tumors that also have a relatively clean side effect profile? Yeah, I, I think ultimately, but there's a lot of steps that are in the way, unfortunately. There, there will certainly be some solid tumors that will be amenable to CAR T's, as we have them now, a little bit beefed up, a little bit more resistant to tumor inhibitory mechanisms. Longer term, for the broader application to the great majority of solid tumors, is it is gonna be difficult because solid tumors aren't just malignant cells. They're all the support mechanisms that those malignant cells require. Such a good point. Yep, such as the blood vessels and the fibroblasts, all the rest of it, the inhibitory macrophages and so on. We need things that will deal with them. The problem with having a multiplicity of cell types is that you have a multiplicity of defense mechanisms. The target antigens present. I think what we'll move to more is a recognition that the tumor, solid tumors, human solid tumors are dynamic, that if you just go from one target, it's gonna be whack-a-mole. You're gonna knock that target down. Then all sorts of other things will pop up because it's reactive. I think what, what we're going to need is an approach that deals with the tumor holistically, with all the different components. One of the ways it might be possible to do that is by focusing not so much on the proteins that those tumors express, which is primarily what CARs are recognizing, but also on the whole tumor glycan, not just the tumor cells, but the support cells of the tumor. Those could also be targets for, for CAR T cells and modified CAR T cells. You could expand the range in that way and deal with a whole lot of different tumors by using the same sustained target cell expression patterns. I believe that as we expand the range of antigens that CARs recognize, we'll be able to deal better with tumors. I think also that by getting rid of the support mechanisms, we'll have less of a worry about tumor immunoevasion strategies. A lot of those will have been deleted. Yeah. Yeah. Dr. Heslop, I would love your thoughts on that same point, but let me give you another add-on to that, and Dr. Malcolm Brenner hinted at that as well, in terms of resistance mechanisms. You pointed to the, to this as well in your video. One of the critical things in improving the efficacy of CAR Ts is obviously bringing it, bringing it earlier in the line of treatment. As we start to do that, and we are beginning already to do that, also, how do we think about the potential to develop resistance? First of all, yes, I think there are a number of strategies that you can use, either by combining CARs with other agents, such as checkpoint inhibitors, or, as I mentioned, adding other moieties to the construct that allows them to be resistant to inhibitory factors or to secrete cytokines. Obviously, if you do that, though, you may increase your risk of getting deleterious effects, such as CRS, and you may also need to include suicide gene strategies there. In terms of resistance, I think that's always a risk when you target just one antigen. A couple of ways to potentially overcome that are to target multiple antigens. Another, as I said, is to treat patients earlier in the course of the disease, where there may be a smaller amount of disease where the tumor may not have acquired so many resistance mechanisms. I think, those are all potential strategies to address that issue. Yeah, wonderful. So, you know, we're trying to cover a lot of ground right now. I'm gonna try to use the last few minutes that we have to talk about manufacturing, because, of course, manufacturing is such a critical, you know, part of any CAR-T product success, right? It hits on efficacy, it hits on the side effect profile, it hits on the turnaround time for treatment and, of course, critically, the cost and access as well. Right now, we have autologous products. Let's just start with the allogeneic option, because that's been simmering for a long time, but we've yet to see one hit the market. The obvious benefit, obviously, is on the manufacturing side, Dr. Heslop, like you pointed out, but besides that, and, you know, definitely feel free to weigh in on that, but besides the manufacturing benefit, can allogeneic options improve on the risk-benefit profile that we're seeing with autologous options, and/or can they expand the number of cancers that can be treated? I think first, the first task is to show the same activity in terms of initial responses and sustained responses as the autologous products do. Obviously, the issue with an allogeneic product is that it can be rejected by the recipient immune system. If you do, do need long-term persistence, you need to develop strategies to ensure that the allogeneic cells can persist, or you can administer multiple doses. I, I think that's a task for the allogeneic cells. A potential advantage is you can make them from a defined donor who has very fit T cells, whereas with an autologous product, you're always going to have a range of T cell fitness in your initial starting cells, which may impact your final product. I think for allo products, the... There are certainly some reports where they've seen similar initial response rates, but I think the challenge is going to be having the same sustained response rates. What, what do you feel about that challenge? Because we've been developing allogeneic products and trying to get them to market for so long. It's not actually that long. I would, I would say it's about five years. I think if you think of normal drug development, it's still relatively early in the course. I, I think there are potential solutions, and there are a number of strategies being tested in the clinic. I, I certainly think it's possible. Yeah. Then, of course, the other strategy is to make the autologous product simpler by shortening t he manufacturing time or eventually having it as a point-of-care, product, like a, like a transplant. Yeah. Perfect. Let's talk more about that, focusing on the autologous options, because that's obviously what we have now, that's gonna, that's gonna continue to be part of our options. What are the different approaches that are being considered in the clinic, in other countries to shorten that so-called vein to vein period? Well, I think there's a lot of process development going on there. There is some sort of shortening it down to about 7-10 days. That's being done in some countries, such as Spain, where they're making the cells in an academic facility and then administering them to patients. I know a lot of centers in the U.S., such as the University of Pennsylvania, even some companies, have various protocols, particularly with lentiviral vectors which get the manufacturing time down to two to three days. The initial results of those that have been presented have been very encouraging, and I think those are entering later phase trials to determine if they're equivalent to the previous or better than the previous products. Yeah. Personally, I'm definitely excited by the point-of-care possibility. I think that could be a game changer on multiple fronts. You know, in the last couple of minutes that we have, Dr. Brenner, I'll give you the last question. It's a little bit of a crystal ball type of thing as well. I wanna think beyond cancer, so not just into solid tumors, but beyond cancer itself. What other indications, Dr. Brenner, do you think are right for CAR-T to target? Yeah, well, there's a lot of interest, obviously, in, autoimmune disease, particularly those caused primarily by antibodies, since we do have a very good B-cell depleting CAR T cells already. That's, that's one obvious low-hanging fruit. I think if we can safely extend CAR T cells to deal with T cell directed targets, then I think we can obviously even further broaden the range of autoimmunity that will be treatable. I'm not sure that destruction is gonna be the only way of bringing that about. I think there's gonna be much more availability of regulatory T cells that are targeted to specific antigens and to specific clones of T cells, so that they can regulate them rather than broadly destroying the entire immune system. I think that, that would be the sort of second generation of products for autoimmunity. Beyond autoimmunity, really, there's the whole chronic inflammation issue that is certainly associated with increasing age and degenerative diseases as well, and I think if we can find ways of controlling that using CAR T cells, regulatory CAR T cells, that will make a huge impact on a whole range of different disorders. That is exciting. I had not thought about, that expanse of chronic, inflammatory phase. Thank you very much, and that provides a really good segue into the next segment of this panel discussion. Before I hand this back over to Sara, thanks again, Dr. Heslop and Dr. Brenner, for the time and your insights. Thank you. Yes, thank you. Thank you both very much. Bye. Bye-bye now. Bye. Okay, wonderful. That was really great and informative. Querida, I do want to thank you as well. I know you can hear me, even though you're not on screen, for moderating this discussion with Helen and Malcolm. Now, Steve Brozak is back. Steve is our sponsor, as everybody knows. Give me just one second, and we are going to begin the second segment with Dr. Mark Frohlich, who is the CEO of Indapta Therapeutics, and Dr. Juan Vera, who is the CEO of Marker Therapeutics. Steve, the virtual podium is yours. Great. Thank you so much, Sara. In starting right away, 'cause, candidly, I wanna make sure we use this opportunity to start asking questions and start the discussion. Juan, let me jump in right now. Based on your current understanding of limitations, Dr. Heslop described with CAR T cells, how do you think Marker's approach can overcome these issues? Yeah, sure. That's a very good question, Steve. I think that without a doubt, CAR T cell therapies have validated and advanced the field dramatically, right? I think that now we have therapies that actually work, and there's a big appreciation for the therapeutic benefit that these therapies can bring to patients. However, as Helen mentioned in her presentation, I think that as we collect more and more clinical evidence, it's also clear that there are certain limitations, particularly related to the longevity of those responses. In many cases, that actually is related to the single target pattern that some of these therapies actually have. One of the elements that we're developing at Marker Therapeutics, Marker Therapeutics is a clinical stage immuno-oncology company that is developing a multi-targeted T cell approach that address particularly that limitation. We actually have tested that concept in the laboratory, and we presented that data recently, where we actually evaluated in the laboratory the response of lymphoma tumor cells to CAR T-cell treatment. What we observe is, as expected, about a 98% elimination of those tumor cells upon treatment with CAR T19. The problem is really this remaining 2%, that over time, basically result in the growth of clonal tumor cells that lack the expression of the target antigen, in this case, CD19. As you would expect, the retreatment with CAR T19, at that point, results in a failure, recapitulating very well what we actually have seen now in the clinic. The important thing is that if you take those resistant tumor cells and challenge them with Marker MT-601 product, which is the one that we're advancing in lymphoma, you can now see that these T cells are able of eradicating the tumor cells, right? I think that definitely being able to develop a multi-targeted approach will be key to address the limitation of... that we currently have seen. Thank you, Juan. Mark, what approach are you taking at Indapta that addresses some of these challenges? Sure. In Indapta, one, we're very focused on developing an allogeneic product as Dr. Helen Heslop had kind of outlined. Principally, taking cells from a healthy donor that we can then administer to the patient, kind of in an off-the-shelf manner, which I think really addresses some of the challenges of accessibility of these products for a much broader range of patients. The other important aspect is that we're focused on a different type of cell. The, the field in general, myself, personally, as well, we've been very focused on T cells as a major effector arm of the immune system with clinically validated benefits. There's increasing enthusiasm in pursuing other cell types. In Indapta specifically, we're very engaged in developing a natural killer cell or NK cell platform. NK cells are, are very different from T cells, so they don't have a T cell receptor. The benefits of T cell receptors for having anti-tumor effect also can mediate some of the side effects, like graft versus host disease, when you use another person's T cells in a patient. NK cells have been tested in the clinic for the last past several years, hundreds of patients treated, and importantly, they have a very favorable safety profile. None of that cytokine release syndrome, none of that neurologic toxicity has been observed, and in the allogeneic setting, no graft versus host disease, which is a challenge using allogeneic T cells. Very encouraging data have emerged, particularly in treating lymphoma in combination with a monoclonal antibody rituximab. Other NK cell companies have seen response rates in kind of the 60%-75% range, and many of those are quite durable. So that's the approach that we're taking. In particular, NK cells have an ability to target cancer cells by some of the innate inhibitory stimulatory receptors they have. They can differentiate normal tumor from tumor, but then they also bind to antibodies, which either can be, arise in the patients themselves to, identify abnormal virally infected or cancer cells or, administered monoclonal antibodies, of which there are many approved. Okay, Mark, thank you. Juan, with Marker's therapy, it's got a broad target spectrum. How do you decide? How do you determine which clinical indications that you really want to follow? Yeah, that's, that's a good point. I think that one of the things that I would like to highlight of Markers is that it's truly a, a platform technology, right? What I mean by that is that at the moment, we have two programs currently in the clinic, one in AML and one in lymphoma. We use exactly the same manufacturing process, and the only thing that changes is the composition of antigens that we target. That is a wonderful thing, right? That allows basically to extend this therapy to multiple indications. Clearly, it pose that question, right? Which indications to pursue? I think that the strategy that we have followed in order to identify that is basically to, first, you need to identify which are the tumors or clinical conditions that express or overexpress those particular target antigens, to identify unmet medical needs. I think that the third condition is something that is perhaps. We're very lucky to have, and it's basically the ability to refer back to experience and clinical data, right? In, in this particular case, we actually have tested this therapy in the past in some of the earlier academic studies, where we identified clinical signal, both in lymphoma and AML, of efficacy and safety. That when you combine all those different things, basically create a, a pattern that would allow us now to extend this therapies to those particular indications. Got it. Mark, I've always been amazed by how the initial registration trials for oncology products have always tended to be in the sickest patients, the most advanced relapse refractory patients. Aren't those patients less likely to respond to immunotherapy, you know, particularly if their immune systems are compromised by prior chemotherapy? What are your thoughts there? The, the reason that most companies pursue the most advanced patients is that the, the route to approval is much quicker because if you take patients who have no other options, you can often get approval with a single-arm trial, whereas if you're going earlier in the course of disease, often a, a randomized trial is required to compare the standard of care. I, I agree with you that I think there's some real attraction. I think that there's a potential for immunotherapy to be more effective earlier in the course of disease. On that said, I think it is worth pointing out that, you know, the approved cell therapies to date, Provenge, the therapeutic prostate cancer vaccine, the CAR-Ts, were approved in late-stage settings and were able to show efficacy there, and now are starting to move earlier. I think that'll probably be the prominent, you know, still route of approval. Then, you know, I think if we can develop these allogeneic products from healthy donors, where you don't really have the issue that you're, you're relying on the patient's own, own immune cells that may be beaten up by prior chemotherapy, you can potentially circumvent one of the major challenges of going in these advanced patients. Got it. Juan, in going back to something you said a few minutes ago, On Monday, you just had a press release on proof of concept. Can you give us any kind of update on how these studies are progressing? Sure, yes, I think that that actually alludes to a point highlighted by Helen and Mark, and it basically relates to the complexity of the individualized manufacturing process. What we released on Monday is precisely, our advancement in our off-the-shelf program, right. This is a strategy that so far has been approved by the FDA, and we now release news into our updates and our access to a clinical inventory that will be ready to use in patients in, in the near future. This strategy is actually something that has been tested extensively in the context of virus-specific T cells, where a product can be manufactured in advance from healthy individuals that can be characterized appropriately and then provided to patients very quickly by performing partially HLA match testing. Here we're basically planning to do exactly just that. I think that if successful, right, we need to test that in clinic, but if successful, this basically will remove a significant bottleneck, as outlined by Helen and Mark, by passing the complexity of individualized manufacturing products. When you combine that with the broad spectrum target of our technology, it will allow us to extend this platform to multiple clinical conditions. Got it. Mark, you basically, on the NK side, you just raised a question, and I, I want to follow it. Indapta has identified a subset of NK cells that you're calling g-NK cells. How do these cells arise, and how do they differ from conventional NK cells? Indapta identified this subset of NK cells, as you noted, what we call g-NK cells, in individuals who've been exposed to the virus cytomegalovirus, which is a virus that most people have been exposed to and remains kind of dormant and held in check by the immune system. About a quarter of patients or individuals who've been exposed to CMV develop this subset of cells, presumably to help keep the CMV infection in check. This subset of cells undergo a number of epigenetic imprinting or changes that lead to a number of genes being either up or down modulated, which gives them very potent properties. In particular, when we look experimentally, these cells are able to secrete much higher levels of cytokines than conventional NK cells. They have more cytolytic enzymes like granzyme B. They upregulate Bcl-2, so they can persist longer. In particular, when they're combined with antibodies, they're just way more potent at mediating what we call antibody, dependent cytotoxicity or ADCC. Got it. Both Juan and Mark, these questions are for both of you. I'll start with you, Mark. In contrast to the development we've seen with small or large molecules, cell therapies require substantial investments to get to clinical proof of concept. This must be really challenging in this current environment for raising funds. How do you support your early-stage companies, and how have you navigated this? Mark, do you wanna start on the answer there? Yeah, I think it's, it's definitely a substantial challenge, and I think we're seeing a lot of companies that perhaps over-invested in process development and manufacturing now really struggling to remain in business. We've taken an approach of, of running a very capital-efficient model. We have a very lean team. We're, you know, less than 12 people, including myself, leveraging, you know, very qualified consultants to help with that. We've also taken the approach to delay the investments in building, manufacturing, or process development dedicated facilities until after we get to clinical proof of concept. Actually one of the other hats that Juan wears as, as CEO of CellReady, we've partnered with them. Juan and his team have tremendous experience in growing cells, in particular with the G-Rex flasks that we use for our current process, and have really added a lot both to our understanding of the biology and manufacturing these cells in a very efficient manner. You know, one of the challenges for NK cells is they appear to require higher doses than autologous T-cell products, so I think, you know, the whole field hasn't really addressed this yet because there hasn't been a need, but ultimately we'll need to be able to grow many more cells at much higher density than has traditionally been done with T-cells. We think we have a path to that with our current manufacturing process, and ultimately may even be ways to improve on that further with things like, you know, stirred-tank bioreactors. Got it. Thank you, Mark. Juan. Yes. Your answer? The, I think that that's a very, very hot topic at the moment, and I think Mark summarized it very well. I think that the current climate, you have to be creative, resourceful, and responsible, right? It really requires a combination of all those different things to, to make it through. I think that raising capital now is definitely much challenging than 5, 10 years ago, and advancing clinical trials is definitely expensive, right? Now, I think that in this particular case, we're dealing with complex manufacturing process and biologicals that add to the expense of basically running clinical trials. I think if, if you are creative, you can basically find ways to, to advance your mission. Mark alluded to that, in, in his response. I mean, we, Marker, had basically manufacturing facility and internal capabilities that although were great to have, they basically resulted in a huge burn, burn rate. Recently, we actually had to adapt to the economic situation, and we basically separated the companies into two, right? Marker, our current Marker company, that basically is dedicated in advancing the clinical program, and then a different company that basically then is a technical company called CellReady, that basically have access to the GMP, physician development, quality, and regulatory. In that way, we basically were able to drop significantly the burn rate from about $5 million to a significant number less per quarter. What that basically resulted is in our current ability to basically move our cash, cash position to basically the end of 2025, right? I think that if companies are creative and resourceful and basically do things like basically Indapta is doing, for example, being very cash responsible, I think you can basically navigate this difficult economic climate. Got it. Speaking of difficulties, Mark, you encountered substantial challenges in the reimbursement and commercialization of Provenge. Not to bring back any bad memories, but how has that informed you? How has that crafted your perspective on the development of cell therapies? Yeah, you know, the approval of Provenge was a major milestone for the field, being the first cellular immunotherapy approved by the FDA. But as you noted, encountered real commercialization challenges. Principally among those was that it was a fresh product. Because antigen-presenting cells don't cryopreserve well, we had a fresh product on both the front and the back end, so that gave us an 18-hour shelf life. When you're thinking about fully loading a manufacturing facility, you know, you'd like to be able to, like, have a day zero, start on a certain day, plan your resources and your personnel for that. When you have a fresh product, basically, you have to have your staff on call 24/7. That led to really overbuilding the manufacturing facilities. Dendreon had three different manufacturing facilities to really try to service the whole U.S. In addition, I'd say we, we, we knew what we thought the mechanism of action was, but we really hadn't documented that particularly well. It wasn't until after the drug was approved that we had a number of publications that really, you know, pointed to the mechanism of action. That's problematic both from a getting physicians to understand and understand the story about how the product works, both for them to be convinced and to share it with their patients, but also when you think about moving to things like automation, the FDA really wants to know what the key quality attributes are to show comparability of your old process to your new process, and unless that's really well-defined, that becomes very challenging. Provenge also was saddled by the, the challenge that it didn't really cause, you know, the tumor marker PSA to drop or tumors to shrink. It was really. Its benefit was really only seen in a randomized trial with overall survival. Then finally, there was a perception, you know, that it was highly priced, which in retrospect, actually, the other small molecules that followed in prostate cancer were equally priced despite the cost of goods being way less than it was for Dendreon. To answer your question, I think the implications for me when I think about drug development in the cell therapy space are, one, the product needs to be cryopreserved. So the final product has to be cryopreserved, and ideally, the starting material should be also be able to some either the apheresis or an early intermediate cryopreserve so that, you know, you can build a bank of cells by which to expand at will and at need. The second, I think it's really important for companies to invest in understanding their mechanism of action early and documenting that in the early phase clinical trials. Really investing in that translational research that furthers that. I think the bar for efficacy has to be higher than for small or large molecules. I think the requirement, particularly given the current reimbursement environment, you need to see meaningful responses that are durable for at least six months. Otherwise, I think it's a non-starter for a cell therapy. Then finally, I think it's important to educate payers before the drug is actually approved so that they understand the merits of your, your product and what it provides to patients. Okay. Thank you. Thank you. Juan and Mark, I wanna... We're, we're closing in on probably the last question, so I wanna see if you can both wax and wane on this. For both of you, and I'll start with you, Juan, where do you think the field of, of cellular therapy will be in the next 5 to 10 years? Well, I mean, I think that it is, is perhaps hopeful, right? I think that in... hopefully, in the next 5-10 years, we'll be able to overcome some of these challenges that we've been discussing for the past hour, right? The limit target recognition that hopefully will improve the efficacy of some of these therapies, especially the durability of the responses. Understanding better the mechanism of action and, and the safety profile and how to manage those events when they occur. Finally, improving elements that are technical in nature related to the manufacturing process. I think that that is gonna be huge, right? I think that one of the important bottlenecks at the moment is the cost of goods of making these complex biologicals. Those can be addressed in multiple different ways. One, without a doubt, is you need to have a very simple and robust manufacturing process. The other one basically is be to bypassing all those together by developing an off-the-shelf approach. I think that that is something that, that definitely would enable the technology to be broadly applicable. What I would like to see in the future is a therapy that is safer, that has better durability, and that hopefully will have a lower price points, and it will be more broadly applicable and better access for patients. Mark, that leaves you, with the last word. Yeah, I would agree with all those points. I think that we will see the evolution and of new cell types, as I mentioned, so NK cells, gamma delta T cells. I think we'll understand better the role of off-the-shelf allogeneic products to complement, potentially replace some areas currently where autologous cells are used. I think all these developments will lead to improved, you know, efficacy and safety for patients. I think we'll see multiplexing of targets and agents, so combining adoptive cell therapy with, you know, other molecules that can modulate the tumor environment, engineering more factors, particularly for solid tumors, into the cells themselves. You can have a single product that is able to, you know, provide multiple different mechanisms of action. We'll see, you know, more payloads being introduced into cells. Finally, I think we'll see increased tailoring of therapies to specific patients. You know, now it's much more common for everybody's tumor to really be sequenced, to really understand what the drivers are of that, what the targets that might be expressed on that tumor are, what some of the tumor microenvironment factors may be that are driving that particular patient's cancer, so that maybe we can actually tailor the specific cell therapy and/or the combination with other agents to optimally benefit individual patients. Again, gentlemen, I want to thank both of you, and now Sara is going to come on to pile on some more questions from the audience. Well- Thank you. I think, Steve, you covered a lot of them, during the, the whole discussion. Let me run through some things and just, if we're too repetitive, let me know. The first question that we have, and I think these, again, coming in from the audience, are a little bit repetitive of everything that we've covered: Can you comment on the newer efforts of creating CAR T in vivo? Mark, do you want to- Not too competitive. Sure. Yeah. I mean, I think the concept is that you might be able to take a virus, for example, that encodes a CAR T and infuse it into the patient, get those viruses to persist long enough and come in contact with the T cells, for example, and actually engineer a CAR T on the surface of that cell in vivo. The idea is that if you can do that, even in a relatively small number of patient cells that they come in contact with, those cells could then, with a stimulus from recognizing their target, proliferate in vivo to kind of create a similar effect. I think it's a very exciting area for exploration. There are a number of different companies pursuing that. We don't have clinical data yet, so I think it really remains to be seen. One of the key things is, you know, is the virus going to persist long enough? Will the immune system reject it? Can we get the high enough levels and get to the right numbers of cells? It's been demonstrated in, you know, animal models. Whether it will turn out to work in patients, I think remains to be seen. Right. Thank you. Juan, do you want to add anything to that? No, I agree with Mark. I mean, I think that it has huge potential, but it's still very early, right? I think that if something like that could work, it basically will address some of the shortcomings related to the complexity associated with the manufacture of this product. Okay. For both of you, or, and Steve and Querida as well, what do you estimate the percentage of allogeneic versus autologous treatment are in clinical trials for CAR T? Any idea? I mean, I would venture to say currently, it maybe is 50/50. That there's quite a number of allogeneic therapies out there. I think a lot of these trials are all focused kind of in CD19 lymphoma, because people, you know, that's what's been validated, and people really want to show proof of concept there, or in myeloma, where BCMA is a validated target. You know, I think, you know, there it still remains to be seen whether we can get the durable responses with allogeneic therapies that have been seen with autologous, because you have the issue of the graft being rejected by the immune response, and that requires some manipulation of a host to get the cells to persist long enough or potentially immune cloaking these cells. A number of strategies are in process to do that. I think if we can, you know, companies can start to show that proof of concept that we can, and there's some early Caribou data that they just shared, I think was quite encouraging about the durability of responses they were seeing in lymphoma. I think we'll start to see, you know, a shift towards more, allogeneic therapies. Okay, great. Thank you. Thank you very much. Juan, anything? No, I mean, I think that the- He agrees with you all the time, Mark. It's difficult to top that up. Okay, another comment question is: failures with current cellular therapies may be attributed to the loss of target antigen with [audio distortion] and immunosuppressive TME and suboptimal cellular product. Can these be addressed, and how? Yeah. So, I mean, I think that definitely as... And again, this, this probably have multiple dimensions, right? I mean, I think that today the field recognize the limitation of targets, especially when going after liquid tumors, right? I think the CTLA-4 is actually quite, the exception of the rule, right? I mean, I think that it's actually a very good target, very well expressed and get it uniformly expressed on the tumor cells. If you go to other clinical settings, particularly solid tumors, it becomes more and more rare to identify those targets that are so expressed at a homogeneous levels, and becomes more and more difficult to identify them. I think that without a doubt, being able to identify therapies that are able to target multiple components within the tumor will be critical in order to have a long-term durability of these type of strategies. Again, there are multiple ways to get into that point. Without a doubt, for these therapies to be able to provide long-term durability, we'll be able to develop the strategies that take into account the complexity, heterogeneity present within the tumor. Okay, thank you. Thank you. We're, we have, really one more question to go through because I think, again, a lot of the topics have been covered. This is for both of you. Where do you think the field of cellular therapy will be in 5 to 10 years, 15 years? Then I'll bring both Steve and Querida back to ask you questions if they have a final one. Mark, you want to take that one? Yeah, I mean, I think, I think, Steve asked a similar question, you know, previously. You know, I'm very excited. I mean, if you think about when, when Juan and I trained, or maybe more when I trained a little older, you know, what we had in our armamentarium was really just mixing and matching chemotherapies. we think. You know, I think, you know. There were believers and non-believers in immune therapy when I trained. Everybody takes it for granted that, you know, immune therapy is part of the treatment armamentarium and really become part of the standard of care of most, if not, you know, almost all cancers. I, you know, I think it's incredibly encouraging if you think about the exponential increase in our scientific understanding. I think still within our careers and lifetimes, we're going to see that translate into meaningful benefits from patients. I see, as I noted, you know, different cell types, greater use of off-the-shelf types of therapies, multiplexing of agents, including more payloads into cells. I think, you know, really addressing this issue of the immunosuppressive tumor microenvironment as solid tumors, both from, you know, payloads and additional agents, I think is highly encouraging. You know, I think we will see not only more tumor types responding to cellular immunotherapy, but also more patients within a given tumor type getting greater benefit. We should ask, where, where will we be in 20, 25 years? Which I, you know, I, I think we'll be in a, in a really great position. Querida, Steve, do either one of you have final questions for Mark and Juan before we sign off? Actually, there, there is one that I just saw here that speaks to something that you had said, Mark, and I'd like both of you to answer it. Imagine adding co-therapy, such as macrophage modulation. How might it help to accelerate and improve the efficacy and minimize current contraindications seen in biologics? I'd be kind of curious to see if you have any insights. Mark, you opened up the idea. What do you think there? Juan, if you want to end it on that, that'd be great. Sure. I think there's a lot of targets in the tumor microenvironment, including, you know, myeloid cells, macrophages, that could be targeted by small molecules, large molecules, even engineering a, a CAR-like cell to target those cells and eliminate them. You know, one of the ways that we think maybe the lymphodepleting chemotherapy that we give before cellular therapies is actually to modulate the tumor microenvironment and reduce T-regulatory cells and, and other myeloid cells also. I, I think it's a highly promising strategy, and I think, you know, a number of different companies are pursuing those, and whether that's, you know, via cells, small molecules or large molecules, I think all of them are encouraging and need to be pursued. Yeah. I, I think I, I agree with you, Mark. I mean, I think that there are multiple ways to basically tackle this question of the complex tumor microenvironment. You can probably go on one way of basically thinking to further create an engineering of your product, or you basically couple with products that are already approved or drugs that are approved, right? I agree with Mark. I think that perhaps one element that the lymphodepletion actually helps, and that's probably one of the reasons we see enhanced antitumor activity when combined with cell therapies, is the effect that those have in the immunosuppressive tumor microenvironment. I think that what this basically highlights is the potential of combining T-cell therapies or NK cell therapies with the standard of care drugs that would act in a synergistic manner, right? There's not necessarily the need to go and reinvent the wheel. Potentially just using drugs that are currently available will allow these therapies to work much better in the clinic. Another question. Suddenly, we've gotten a few more questions coming in. What is your perspective on point of care manufacturing? Always a tough one. Well- I see you smiling. I saw Juan smile first, Mark. I, I like Mark going first. He does very well. Yeah, I mean, I think, you know, the, the paradigm that Dr. Heslop noted was, you know, that allogeneic stem cell transplants are really done point of care by individual academic centers. I think the challenge when you're talking about, you know, a more complex cellular therapy, particularly ones that require engineering, you know, the resources required to do the process development work to show that you have a very robust and reproducible process takes considerable resources that are really outside the scope of an academic medical center, really need to be done by a well-resourced, you know, either biotech or pharma company. So I think, you know, for the near term, I expect that these will continue to be done as products, you know, developed by companies. I think as this, you know, manufacturing gets better understood, as we understand the biology better, as we move, you know, I think it becomes more turnkey and straightforward, I think you might see academic medical centers beginning to take on more. Again, if we really realize this shift towards off-the-shelf, you know, allogeneic cells that can be manufactured in bulk, kind of the need for point of care becomes less because really it's just then the physician, you know, requesting shipment of the cellular product, much like they do for an antibody or small molecule that can be then delivered in their office. That's 20 years from now. Yeah, we're getting there. Juan. Yeah, I totally agree. I mean, I think that the point of care is definitely something that has been explored in Europe and is really trying to address bottleneck, which is basically the complex manufacturing and the cost and the access to those, right? For sure, it is an alternative to trying to bottleneck that element. There are multiple solutions to trying to overcome that, and one of those is basically, you know, to improve and simplify the manufacturing process for sure. I agree with Mark. I think that if, if the field evolves into an off-the-shelf platform, which again, many groups are exploring, this could basically bypass or release the pressure in terms of the requirements for some of these point of care access. I don't think that it. We're gonna be looking at one solution that fits all, all the buckets, right? I mean, I think that we, in the future, we might see a evolution of multiple solutions, right, including the development of off-the-shelf programs and point of cares, and improve and simplify manufacturing process for a shorter in vitro time, that ultimately, what I would like to see is these therapies moving, as Mark mentioned, you have to entry as a first-line therapy going to second. Really, I think what we all would want to see is these therapies being as a first-line therapy, right, and for patients to be able to benefit out of this. Right. Thank you. Thank you, Juan. Sara, can I ask a question if there is time? Sure. Yeah. Okay. Mark, you made a point of this earlier, but question for both of you, the importance of talking to payers early on to not repeat the problems that we saw with Provenge, but even the current slew of CAR-Ts. Could you say a little bit more about that? How early on, are you saying any insights from conversations you're having? There's, you know, obviously a battle, particularly with Medicare reimbursements or patient, inpatient hospitalization versus outpatient treatment and those rates and how they compare, and whether hospitals are actually making money from this whole process. Would love to hear your thoughts on that. I think the right time to begin those conversations is when you have sufficient clinical data to show what the safety and efficacy of your product is and are, you know, moving towards a registration trial or already embarked on a registration trial. Because you really need to understand that risk-benefit to be able to make an argument to payers about why this makes sense. I, and I think what payers are really focused on is, like, they, you know, they have capitated systems, and they... If, if you can provide evidence that even though there's, for example, a very large upfront cost, that if you've reduced the amount of side effects that require management or you reduce the number of subsequent therapies that are required, then it's actually a favorable value proposition. But that's not necessarily a given just from the pivotal trial, particularly if it's a single-arm, you know, 80-patient trial, the minimal amount required for accelerated approval, you may not have those data yet. That requires maybe additional theoretical modeling or as early as possible to actually generate those data that can substantiate your claim that there's substantial benefit. That comes, you know, there are a number of, you know, people with experience talking to payers that you can engage and get advice on what type of information to gather, how to position your product to ultimately get, get approval. I think, you know, I think since the time of Provenge, I think the bar has been raised, right? I think if, I think the requirements providing more benefit, you know, per cost is something that we're seeing in general, particularly for cell therapies where, you know, the cost, but also the inconvenience to patients if you need to collect cells from them, et cetera. You know, there needs to be more benefit than is seen, for example, with an off-the-shelf product. Yeah. Yeah, I mean, I agree. The, the things that to consider earlier on are all the associated complexities of manufacturing, right? I mean, I think, Mark, you mentioned earlier on that, you know, the complexities that were provided when they started with a fresh manufacturing product and the infusion also of a fresh material, right? I think that one thing that I have seen is that at, in early stage of development, of development, there is not enough thought put into the consequences that those decisions will have, commercial landscape, right? I think that thinking about elements that are fundamental in your manufacture and how you make the drug and how practical it will be to deploy will be critical in order to allow the cost of goods to be manageable. As Mark mentioned, I mean, Mark has far more experience than I in, in that regard, but basically having those conversations earlier on with the insurance companies, understanding the competitive landscape, understanding the, the benefits that are provided on a clinical level, are the things that will be critical in order to see how to best position this therapy. Okay, I have a few more questions that just keep rolling in, gentlemen, lady. One question, maybe we can do this rather quickly, in, how many markers do you need to target to get past tumor heterogeneity and immune escape? Is it 1-10? Is it 10-100? What's the scale? Juan, you're smiling. You smiled first. Yeah, that's, that's a complex question. It sounds simple, but it's a highly complex question and definitely something that we have considered for a long time. Because, again, it was very easy to criticize when it doesn't work, right? Perhaps harder to basically pinpoint what the endpoint should be. Without a doubt, I think you need to target more than just one antigen, more than one epitope, right? What is that secret number is difficult to define. Let me try my best to address the question. I think that I can speak of the Marker product, right? That's the one that I know the best. What our cell, they do, they basically recognize multiple antigens and multiple epitopes within those antigens. In one context, even if you're talking about one antigen and one antigen, and when you elicit the response to the natural T cell receptor, you're really talking about dozens of epitopes present within that antigen, right? That is an radiant amplification of an immune response itself, and that response is provided through thousands of individual alpha-beta TCRs. I think that in order to address your question, I probably will say that you want to have a very broad bandwidth, right? That broad bandwidth will depend on the clinical complexity of what, where you want to deploy that therapy. If you want to go something solid tumors, for sure, the bandwidth and broadness has to be something bigger than something in, in hematologic malignancies. It's a very complex question to address in probably the short period of time that we have. Mark, I don't know how you would tackle that question? Yeah, I mean, I'd say that obviously none of us know, right? There's just no clinical data yet. I would say that I think we are going to get some insights in the next couple of years. Like with CD19 CAR therapy, right, it's become clear that there is CD19 escape variants. Fortunately, in lymphoma, we have a couple other well-validated targets, CD20, the target for Rituximab, CD22, and there are a number of companies now pursuing bispecific approaches where they have 19 + either 20, 20 or 22, and even some going after all three3 targets simultaneously. So I think when we get data from that, we'll be able to determine is that enough, at least in the setting of lymphoma. In, in, in myeloma now, we have, you know, both BCMA and GPRC5D as validated targets. There's bispecifics going after both of those, as well as CARs going after both of those. I think we'll begin to get data over the next several years that will inform us whether that is sufficient. I'm, I'm hopeful. I mean, given how, at least in the setting of lymphoma, how much benefit we get from just a single target, I'm optimistic that a second or a third will provide substantially more benefit, you know, hopefully even curative benefit for a substantial portion of patients. Okay. Thank you. Thank you, Mark. Thank you, Juan. Another question: What is your opinion about combining oncolytic viruses to create an inflamed TME with CAR T cells in the solid tumor setting? I think it's interesting. Juan almost smiled. Well, I, it's very interesting, right? I mean, I think that we, there is a huge potential for combination, right? You're talking about oncolytic virus, but people could say the same thing about vaccination, right? I think there is a huge potential to combine multiple arms of the immune system, right? Where you can basically have the adoptive T cell transfer product that can be further enhanced by combination with oncolytic virus or vaccination that basically will further boost the immune system. I think that in some occasions, the clinical responses of those in isolation might be not as strong enough, but definitely when combined, it could provide patients and developers with the opportunity to increase the therapeutic potential. I think it's a very exciting area. We're contemplating some collaborations around that. There are people already pursuing it in the clinic with both T cells and NK cells. I think, yeah, it's worth exploring. Okay, I think that's. This is a wrap, gentlemen and Querida. Unless you either Steve or Querida, if you have any other quick questions? I'm good. That was very thorough. No, I think this is ending it on a high note, and I think that this has been a mini PhD for people in the CAR T space if they've listened to the entire program. Thank you again all for your participation. Yes, thank you, Steve, for bringing this to our attention and for sponsoring it. Querida, thank you for moderating the sessions and joining us. Of course, Mark and Juan, thank you very much for sharing your insights with us in a very important area. That is all that we have for today. Again, thank you, WBB Securities and Research, for being a sponsor of this event. Thank you to the audience. Thank you for joining us.