Marker Therapeutics, Inc. (MRKR) Earnings Call Transcript & Summary

Hello, and good morning to all of you from New York City. I welcome all of our viewers. I'm Sara Demy, Founder and CEO of Demy-Colton. And on behalf of Demy-Colton and our team, I'm excited to welcome you to the 50th installment of the Demy-Colton virtual salon series. As you welcome all of our past viewers, and we welcome you all back and we welcome everybody who was new and joining us for the first time. Demy-Colton's mission is to convene health care industry leaders to catalyze change. We do this through our events, including BioFuture, coming up in New York City in October, Biotech Showcase, which takes place during the JPMorgan health care conference out in San Francisco, our virtual salon such as this one and our Global Biotech CEO Summit. The upcoming one will take place in Napa in July. And if you are a CEO interested in joining us, please reach out to us to request an invitation. Before we start today's salon, I'd like to introduce Steve Brozak. Steve is the President and Co-Founder of WBB Securities, who would like to say a few words before we begin this salon. Steve?

Thank you, Sara. We present this Demy-Colton Salon as part of WBB Research Institute, WBBRI's mission. Founded in March of 2022, WBBRI is an independent non-audiological health care Public Policy Research Center. It was conceived to analyze health care issues with the ultimate purpose of fostering change in medicine. Our goal is to advance innovation by publishing articles, studies and presentations like this salon on matters of science that will be used by leaders from government, health care, the media and social movements to both inform the public and to improve the health care and quality of life. As such, we believe viewers of this discussion on CAR-T therapy will benefit from this discourse. Thank you again, Sara, and back to you.

Thank you very much, Steve. Before we begin, our salon today is CAR-T therapies: After Seven Years, the Results are In, and the Debate Isn't Over. I'd like to go over some of our housekeeping issues, just so you understand the layout of the panel. We will start with a few short presentations by our distinguished guests this morning. This will be followed by a roundtable discussion, and then we will go into an audience Q&A session. This salon is being recorded and will be available for on-demand viewing later today on the Demy-Colton YouTube channel. So now to today's salon. It is my pleasure to introduce our starting panelists. Our first panelist is Dr. Helen Heslop, who is a professor in the Department of Medicine and Pediatrics as well as the Director of the Center for Cell and Gene Therapy at Baylor College of Medicine. Dr. Heslop will discuss understanding the shortcomings of CAR-T therapy. She will be followed by Dr. Malcolm Brenner, who was the Founding Director and Professor in the Center for Gene and Cell Therapy at Baylor College of Medicine. Dr. Brenner will discuss improving the outcome of T cell therapy for cancer. And finally, we will hear from Dr. Juan Vera, who is President and CEO of Marker Therapeutics. He will briefly highlight MAR-T cells as a novel approach to address unmet needs. These presentations will be followed by a roundtable discussion moderated by Dr. Richard Marfuggi of WBB Research Institute. And our presenters will be joined by Dr. Manali Kamdar, Associate Professor of Medicine and Clinical Director of Lymphoma Services at the University of Colorado; and Dr. Geoffrey Shouse, Hematologist-Oncologist and Researcher at the City of Hope. So Dr. Heslop, the virtual mic is yours.

Thank you, Sara. Could I have the first slide, please? And I think we could move to the second and then the third slide and the next one. These are just my disclosures. In the next slide, I'd like to emphasize, first of all, that CD19 CAR-T cell therapies have been transformative for patients with -- no, back to the previous one. Sorry, back to -- no, back another one. They've been transformative for patients with relapsed disease where we've seen very impressive response rates in patients who didn't have other therapeutic options. And over the 7 years since they've been approved, they've even moved to second-line therapy, the diffuse large B-cell lymphoma. Next slide. This shows the current approved products. There are 5 approved products targeting CD19, and they have a variety of different indications. Next slide. Now that we have 5-year follow-up, it's clear that some patients who receive these cells have prolonged disease response. And this is shown in this 5-year follow-up of the pivotal trial in Yescarta where the estimated 5-year overall survival rate is over 40% and the disease-specific survival rate over 30%. The next slide shows the trial led by one of the other panelists, Dr. Kamdar. This was comparing Breyzani to standard therapy with chemotherapy and autologous transplant in patients with relapsed diffuse large B-cell lymphoma. And you can see here an advantage in outcomes for the CAR-T cells. The next slide shows that these are a complex therapy. It's a living drug with significant side effects and the infrastructure to access therapy is complex and that you need an apheresis center and a tertiary hospital. The local processing facility sends the cells for central manufacturing, unique contracts and agreements with insurers, expertise and handling complications, and this means that there is some degree of limited access to these therapies. Next slide. And this is partly because, although it's a very potent therapy, it also has unique toxicities. The most well-known toxicity is the cytokine release syndrome, which presents as high fevers, hypotension and multi-organ damage and immune effector cell-associated neurotoxicity or ICANS that can present with aphasia, encephalopathy and seizures. But the next slide shows that really the side effects of CAR-T cells could involve almost every organ system. And while with experience, I think physicians who care for these patients can treat ICANS and CRS more effectively by either earlier intervention and therapies and patient selection. The next slide shows there's been an increasing recognition of other toxicities of CAR-T cell therapies, such as cytopenias, caused by a combination of the lymphodepletion therapy prior to infusion and inflammatory reactions. And there's also been appreciation of immune effector cell-associated HLH, and there has been the issue raised of secondary malignancies, although with lymphoma, that doesn't seem to be a major issue. The next slide shows that the major cause of failure though is still relapse. So while up to 50% of patients can have sustained responses, over half the patients saw relapse after receiving CD19 CAR-T. And this is due to a number of reasons. Some of the cause of failure is tumor specific factors, such as loss of target antigen or inhibitory factors in the tumor micro environment, and some is due to the quality of the infused cell product obtained from patients who have often been heavily pretreated. So there's a number of strategies to improve functions, such as genetic modifications and to enhance signaling auto block inhibitory factors. And an example of this is the recent publication from the University of Pennsylvania Group and the New England Journal of Medicine, which showed that adding IL-18 to a CD19 CAR produced very impressive response rates in patients who failed their initial conventional CD19 CAR therapy. So the next slide just shows my summary of the current state-of-the-art in 2025. This is a transformative therapy with up to 50% of patients with refractory B-cell malignancies, showing durable complete responses, but it's also an expensive complex therapy with limited access, so there's a need to simplify production and increase access. There are very specific toxicities that requires specialized management and over half the patients still relapse, so there's a need for overcoming tumor evasion mechanisms, targeting multiple antigens and treating earlier in the disease process. And I'm going to hand over to Dr. Brenner to expand on improving outcomes.

Thank you, Helen. So as you've just said, CAR-T cells for CD19 malignancies have been transformative, but highly imperfect. And if you go beyond CAR-T cells for B-cell malignancies to other hematologic malignancies or go to solid tumors in particular, then it's true to say that the misses greatly exceed the hit. Next slide, please. So I thought what I'd do here is just briefly explain the reasons for failure, taking of where Helen finished and explain some ways in which we can maybe overcome those deficiencies. T cell mediated cancer therapy is intrinsically attractive because it recognizes processed internal tumor antigens with very targeting ability. And the fact that it's polyclonal means that you have a lot of different receptors that can recognize a range of antigen expressions and have different affinities. There's multiple effective mechanisms, very good biodistribution, which is active. And in principle, one cell, one time could cure a patient. Next slide, please. A few substitute a chimeric antigen receptor for the native T-cell receptor, then you retain most of the desired properties of the T cells, but you now have MHC independence so you can use one receptor for everybody, essentially. And you can target carbohydrates, glycolipids or non-processed surface proteins in a way that the conventional receptor can't. But with those gains come losses of function, and they turn out to be very important. You can no longer recognize process internal tumor actions or at least not simply and the monoclonality of a CAR versus the polyclonality of a standard T cell response means that you don't have the range of affinities you need to really deal with certainly solid tumors. Next slide, please. And this is important because in solid tumors and also on many hematologic malignancies, lineage-restricted target antigens are just not usable, that they're unsafe. They destroy vital organs. And most of the real safe, effective targets are neoantigens that are internal and need to be processed and presented and recognized by T cell receptors. And what's worse in many ways is that antigen expression is no state static, it's heterogeneous, and it's plastic. So you need the T cell product that you have infused to be capable of matching that's change in antigenicity that heterogeneity. In other words, you need something called hepato or antigen spreading, which for reasons I won't go into is much more easy to obtain with a native T cell receptor manages with a CAR. Next slide, please. In addition, and again, as you heard from Helen, the tumor microenvironment is very hostile. And it's hostile in many different ways, like in inhibitory ligands, inhibitory metabolism, soluble factors that turn off the immune response cells that were recruited in the turn off the immune response. And next slide, please. Just like antigen expression, the tumor inhibitory environment is not stable. It's dynamic and it's reactive. It responds to how it's being attacked with counter measures. Next slide, please. What people have been trying to do, as you heard, is improve upon this by adding in stimulatory factors armoring the T cells by making the resistant to other immune inhibitory environments to adding an additional targeting MAR-Ts. But all of these are very individual and don't really keep up with the dynamism of the events. So what we've been trying is a more holistic solution, combining CAR-T cells with the binary oncolytic virus and the helper dependent virus so that we get a tumor that now looks like an ongoing virus infection. We got oncolytic factor damaging the tumor in the inhibitory environment, the helper dependent expresses immunomodulatory genes and the simultaneous CAR effective function and TCR, residual TCR stimulation produces antigens spreading and stimulation. So you get an evolving response that matches the tumor. And certainly, in preliminary studies, these and related approaches have produced some interesting clinical -- long-term clinical responses. And next slide, please. So I'd summarize really by saying that what we're going to need for success in the next 10 years, is to combine modalities so that they can evolve to match the changes in the tumor. And as you heard also have an economic solution that will overcome the obstructive costs and regulations that are causing far too many biotechs at the moment to fail because they're running out of other people's money. I'll hand over now.

Thank you, Malcolm. Can we go to the next slide, please. Thank you. Very excited to be here today. Next slide, please. Very excited to be here today to talk about Marker Therapeutics and our technology MAR-T cells. This technology was developed at Baylor College of Medicine with the purpose of addressing many of the limitations currently observed with CAR-T cells, but particularly the negative antigen selection that is observed by the restricted target recognition profile as Dr. Heslop and Dr. Brenner explained just a moment ago. And this cartoon illustrates how we generate this product in the laboratory. We extract tumor reactive T cells present in the patient peripheral blood and stimulate this with synthetic peptides that represent target antigens. And in this manner, create a final drug product that is capable of recognizing multiple different targets present within the tumor across different tumor-associated antigens. And I believe this -- particularly this target profile, one of the things that is going to be key in order to be able to provide long-term and durable responses. Go to the next slide, please. Here, we go into more detail in terms of how the product is generated. This is an autologous therapy, where we isolate PBMCs from the -- from a patient. These are stimulated with peptides, expanded in the laboratory. This expansion result in selection and amplification of tumor reactive T cells. After this the cells that cryopreserved and then distributed to the clinical sites in a cryopreserved manner. Next slide, please. And we have advanced this technology across multiple different indications. And without a doubt, our lead asset is MT-601. It's a product that recognize 6 different tumor-associated antigens and multiple epitopes across those particular antigens. And we're advancing this in lymphoma into our APOLLO study. And even though this is a Phase I clinical study, this study is now advanced with the purpose of becoming a future pivotal study, and I will present some of that data in just a moment. Next slide, please. But let me share with you first some preclinical data that dive a little bit deeper in terms of the mechanism of action. Next slide, please. This is probably something that many of us have observed in the laboratory and that recapitulate very clearly what we have observed in the clinic. Here in the left-hand side, you see a tumor that express CD19 as a target. And in Panel B, you can see that after administration of CAR-T cells, you see a robust control of tumor growth. However, if you monitor these cells long enough, you basically see the subsequent relapse of these tumor cells. And upon further examination if you take these tumor cells that expand, if you go to the next slide, please. You now observe a tumor that looks very different. And I think that Dr. Brenner explained that, right, is basically how dynamic tumors are and the ability that they have to adopt this mechanism of attack that are provided in the clinic. And what you see here is a tumor that looks different that does not longer express CD19. And if you were to treat this tumor again with CAR-T cells, you basically see that this become no longer effective. Now if you take this tumor and now treat our drug, MT-601, you see a very different picture resulted in tumor elimination. Next slide, please. And now we have clinical data that support some of those statements and are able to recapitulate this observation. And I think that this is actually really transformative data, right? So we released this when we have seen now close to 80% overall response rate and close to 40% CR rate in patients that are heavily pre-treated and patient that have failed in multiple lines of treatment. If you go to the next slide, please. Here you can basically appreciate that we have seen responses across multiple different histologies. Patients that have failed multiple lines of treatment and patients that have failed only CAR-T cells but also bispecific antibodies. And despite that, we have been able to put these patients in complete responses and responses that are durable. In addition to that, we also have seen that this treatment has been very well tolerated in the clinic. And I think that, that is also another of the elements that make this technology very different when we compare with CAR-T cells. Next slide, please. Finally, we also have reported and we released this data just last week. In our most recent efforts, we are now able to monitor these T-cells in -- after administration to patients, and we see the positive influence of lymphodepletion, promoting the expansion of the persistence of these T-cell clones. And now we are moving forward in enrolling additional patients into the clinical studies. And we have seen a significant uptick in patients coming into this study throughout 2025. And I think that, that can be explained in part to the change in clinical landscape as well as the positive responses that we have observed in this part of the study. Next slide, please. So I think that the data is definitely very exciting and what we have seen today in patients that I will consider with a high unmet medical need, and we still have work ahead, but I do believe we're going to be able to advance these products with the purpose of getting the MT-601 approved in patients that have failed CAR-T cells based on the efficacy data that we have seen today as well as the favorable safety profile. And with that, thank you very much to the organizer for an invitation. I hand over back to you. Thank you.

Hello, everyone. I'm Dr. Richard Marfuggi, the Medical Director of WBB Research Institute. And we have been receiving wonderful questions from our participants and from those who are listening to this webinar. So I'm going to go in not -- with no particular order. But Dr. Shouse, what are the major limitations as you see of CAR-T cell therapy for lymphoma?

I think some of these key limitations have been kind of touched on by the great lectures we just heard. One of the biggest ones, I would say is that although the response rates are quite promising and compared to the prior standard treatments, these therapies are really revolutionized treatment of lymphoma in general, especially large cell lymphoma. The majority of patients still relapse. I'd say that's the number 1, probably biggest limitation, which means we still need therapy for these patients when they do relapse. Other limitations would be toxicity to include cytokine release syndrome, neurologic toxicity. And those toxicities can be debilitating for patients. I mean, severe ICANS is treated with high-dose steroids, anakinra, Solu-Medrol, sometimes doses of 1,000 milligrams at a time, patients end up bedbound for weeks, severely debilitated. And so having something available that doesn't have that same toxicity would be game changing. In addition to that, there's been recent studies that suggest non-relapsed mortality associated with CAR-T is as high as 15% to 20%. And a lot of that has to do with delayed infections. CD19 is present on normal B cells and those get targeted by persistent CAR-T that are present leading to hypogammaglobulinemia and recurring infections. And that seems to be a significant driver for this non-relapsed mortality. In addition to that, the fact that we're using a genetically altered product has the potential to lead to new novel T-cell malignancies. And we haven't seen that in lymphoma, but there's concern for that in other diseases like myeloma.

Now will turn, if I may, to Dr. Kamdar. What do you see as the most significant unmet need for patients with relapsing or refractory diffused large B-cell lymphoma?

Yes. Thank you for the question. Dr. Shouse has rightly pointed out, CAR-T has certainly been able to salvage 1/3 of patients who would have otherwise succumbed to their disease with large B-cell lymphoma, but majority of these patients will relapse or initially respond to relapse later or not respond at all. So refractory and relapsed diffuse large B-cell lymphoma continues to be an unmet need in the field. But I do believe some new molecules may have made a small but significant impact such as CD20 bispecific T-cell engagers, immunomodulators. But unfortunately, majority of these patients who relapse after CD19 CARs, they really don't respond to these other FDA-approved treatments. So in my opinion, the most important and the unmet need is for patients who have been dual exposed, which is patients who have relapsed after CD19 CARs as well as CD20 bispecific T-cell engagers. This population of patients continues to be a significant unmet need. And I believe in my anecdotal experience, it constitutes about 60% of my patients with relapsed/refractory large B-cell lympho.

Here is a question from The Great State of Florida, perhaps best answered by Dr. Heslop. Citations indicate that only 4% to 5% of CAR-T-eligible patients actually receive therapy. What can be done to improve access?

So I think that's a multifaceted question. I think some of it may be that they don't get referred when they should be referred. So that's a measure of education of primary physicians caring for these patients. But I think some of it is that some people are not located close to one of the centers that currently administers CAR-T cells. Because of the complications when these products were first rolled out, they were set up in centers that are experienced with transplant and have that accreditation for an administration of immune effectors. This does mean that patients have to move for about a month to one of these major centers, which may not be located close to where they live. So I think there's a lot of interest now in trying to make CAR-T cells broadly available in other community hospitals located or closely to where the patients live. And in fact, the foundation for accreditation of cell therapy has just announced an initiative to accredit such centers to safely get the product. There are other models that people are looking at, such as maybe have the patient come into the primary center for the initial therapy, then set up collaborations with peripheral hospitals close to the patient's home to do the later part of the care. And I think there's a lot of advances such as connecting with patients by Zoom or by other means to allow such care and then other devices such as wearables for monitoring.

Dr. Vera, you mentioned in your presentation that Marker Therapeutics is advancing a novel T cell therapy for patients with hematologic malignancies and solid tumors. Based on what we heard from Dr. Heslop and Brenner, how do you think MAR-T cells differ from CAR-T cell therapies? And how do you think that they can overcome current obstacles observed with CAR-Ts?

Yes. Thank you. That's a great question. And from a mechanism of action, there are very, very big differences, right? And I think that the similarities are basically that you're talking about an autologous T cell transfer, right? But the differences are probably larger than the similarities, right? When you think about CAR-T cells, and I think that Dr. Brenner and Heslop talk about this, you're basically talking about molecules that recognize surface target in an MHC unrestricted manner. But that creates a lot of limitations and recognizing only one epitope of one antigen, right? In contrast with MAR-T cell, you recognize multiple targets simultaneously in a natural manner. And from a technology perspective, instead of a genetic engineering, our technology relies on millions of years of natural evolution to develop the perfect killer T cells, right? And in that manner, generating a product that is very diverse and address the diversity that is also present within the patient on tumor, right? So it's a natural treatment, right? It doesn't require genetic engineering as we are also facilitators of basically the patient-own immunity to participate in the killing process. And I think that the results that we see so far speak for themselves, right? And the ability to actually have some objective responses that so far are durable in patients that otherwise have no other therapeutic alternatives. So I would say, big difference is perhaps more than the similarities in short.

Here's a question for the entire panel. Our CD19 CAR-T therapy is durable in autoimmune disease?

Do they need -- how durable do they need to be in order to eliminate the autoreactive clones?

Okay. Does the panel think that decentralized manufacturing will improve accessibility to CAR-T therapies and perhaps reduce cost?

Yes. I think that would be another model to do it as a standard of care like hemopoetic cell transplant. I think there's a network of GMP facilities throughout the country that could potentially do manufacturing. But you'd have to develop a model to do that perhaps using a vector that a company provided and then having a standard operating procedure. It would depend a little bit on the product and the complexity of the manufacturing, but there is certainly a lot of facilities in the U.S. that have that capability.

Yes. I don't know from the -- like the point-of-care perspective, I don't know Dr. Kamdar and Shouse, do you guys feel that would address your problems? Or is that some frequent request?

I think it would address some of the problems, but not the majority because CD19 CARS come with the plan to have a caregiver, a caregiver that must be with the patient, 24/7 for at least 2 weeks. And for the areas that we cater to, we have patients coming from 500 kilometers away. It may or may not always be possible. So yes, we may be able to help some patients, but there are many others that kind of get stuck with having to relocate with the caregiver that may not always be possible. So to develop treatments that are predominantly outpatient that do not have the risk or the unique toxicities that CAR-T carries would be really a game changer.

Yes, I would agree. I think we have a large catchment area that goes from the West Coast of California up to the border of Nevada and even further. And there are some areas where, I mean, there aren't centers around, period. And those patients, this model wouldn't help them either. I mean, getting the word out there so that the physicians that are serving these patients understand the importance of getting patients in to be seen at the center that's able to offer these types of treatments is important, but at the same time, there'll still be a majority of patients who have barriers that stand in the way of receiving a therapy like this.

So this seems to go back to Dr. Heslop that administration may not necessarily require a tertiary center.

I think that depends on the product and it's side effect profile. I think if we were giving a patient with extensive disease, one of the products that has a higher risk of causing CRS ICANS, we would want the patient to be in a center that had experience dealing with those complications. But I think as we get newer products that have different side effect profiles, then we might not need the same level of care and it could be done in smaller hospitals closer to where patient resides. It's going to be very product dependent, I think.

Here's another general question. Given the success of CAR-T, how will it be impacted by nonviral gene editing, such as messenger RNA? And what challenges would you anticipate?

You're talking about CAR-Ts...

In vivo, I think.

Yes, in vivo mRNA, is that what you're saying?

Yes.

That's difficult. I think that's -- you could do the gene editing, but the success rate, the frequency and the targeting will be major obstacles. It's doable, I'm sure, but not immediately. I think before then, what's going to happen is that CAR-T therapies as Helen says, it will probably be dependent on the side effect profile. But I think it will follow the same pattern when it is kind of cardiac catheterization and stroke treatment. It'll start off in a few specialized centers. And gradually, as it becomes more commonplace and more widely used, it will spread out into local and point-of-care places that are not tertiary referral. I think we're just being -- I know it's been so many years, 10 years.

[indiscernible].

I know it's been a slow process, but medical care is horribly slow and expensive.

Dr. Marfuggi, if you don't mind I'd like to ask a question to Dr. Brenner. Dr. Brenner, I'm familiar with NCATS, which is NIH subsidiary where they go out there and they actually spend money for approved therapies so that clinicians can actually implement it because their opinion has always been that medicine is practiced the way it's learned in its residency and while you're actually apprenticing. How do you advocate going out there and increasing the speed of health care science? What would be -- having seen how breakthroughs take place? What would be your #1, 2 and 3 solution to that?

I think picking winner is very important. You don't want to spread something that has such fearsome toxicities that it actually has a negative impact on the field. And I'm not sure that that's not true for current CD19 CAR-T cell therapies. I think they maybe should be done in specialist centers or as Helen's factor credited individuals rather than being further spread. But I'm sure that it will follow the same model as bone marrow transplant, but it will start off in a very few centers of cardiac catheterization, very few centers and then gradually spread out. Bone marrow transplant never got beyond more than the minority of centers nor should it because it's extremely complex. Cardiac cath got a little simpler and has spread wider. And I think CAR-Ts will be somewhere in the middle. We'll change where they're made, how they're made and how they're given and how patients respond to them, but that's going to be a process that can be encouraged by training people. See one, do one, teach one was the old sort of axiom, but I think it is a little bit more than that. But that's basically, I think, what will happen. But it's happening really slowly.

Yes. That reminds me of the dictum. If I've done one, it's my experience. If it's done -- if I've done two, it's in case after case. And if I've done three, I am an expert. Anyway, Dr. Vera, you presented us with data from your Phase I APOLLO study, which investigated MT-601 in patients with CAR relapsed lymphoma. What makes you most excited about the research and clinical data you've observed so far?

Yes. That's an excellent question. I mean, I'm very excited for the study, first because we're able now to recapitulate observations from a proof-of-concept clinical study that we conducted at Baylor, right? So we actually conducted that study many years ago and have similar observations in terms of the clinical benefit and safety profile. And I think that now under the company umbrella across -- and performing in collaboration with multiple investigators across the U.S., we are performing a multicenter clinical study using MT-601 and we are now able to recapitulate these observations, right? So I think that I'm excited to be able to repeat these responses in a larger study across multiple collaborators. I think that, that is very reinsuring. And I think that is despite the best efforts I do recognize that this is a group of patients with high unmet medical need. And I think that it does take a village to make a difference. I think that with this drug, we have the opportunity to make a difference to many patients that need the help, right? So we definitely have a lot of work ahead of us. But I think with the data that we have in our hands, I think that we have a very clear path in order to develop this and make this available for as many patients as we can.

There seem to be a lot of questions from participants audience -- from the audience here on malignant melanoma. How well is CAR-T working in a malignant melanoma?

I think we are all hematologic malignancies physicians. So there are some potential targets in melanoma, such as GD2. But I think there's a lot of interest in using -- I mean there's an approved tumor-infiltrating lymphocyte product for the melanoma that I think is being widely used. And there's a lot of other therapies with checkpoint inhibitors. So I'm not aware of many CAR-T cell studies. I don't know whether my colleagues know of any of their institutions.

I would concur with Dr. Heslop. We have some TIL studies going on in malignant melanoma that are really in patients with very refractory and showing responses, but I'm not quite aware of CAR-Ts in malignant melanoma.

Okay. Mal, this, I guess, is going again back to you. There's concern about the respiratory syndrome and neurotoxicity associated with this therapy. What, if anything, are your thoughts on approaching these problems?

Well, we've been working for a long time on control switches, safety switches. And there are several that are effective, one in particular that we and other people have used called inducible Caspase-9, which is good because it's not a one-off. It's a very highly titratable drugs and very rapidly acting. So about 1,000 fold dose range difference between getting 50% control and 99% control of the T cells, so you can retain activity without having the toxicity. And because it acts within an hour or 2 hours of administration, you can titrate the dose very nicely. It's in its infancy for various reasons. But certainly, there have been a number of reports in published papers of benefit without loss of activity. And we hope that would expand substantially.

This is probably way in the future, but maybe not. Could in vivo CAR-T produce the same efficacy and safety profile, enabling a replacement of ex vivo?

Yes. I think that kind of came up when we're talking about the gene editing, the mRNA and the issue is targeting the T cells that you want and getting efficiency and avoiding the off-target effects that you might get if you start transducing a lot of cells in the liver, for example. Certainly, some people are very advanced in early-stage studies for that, but I don't think it's going to take over within the next few years.

The first trial is in the clinic, but I haven't seen any reports yet.

Okay. Here is a question about medical tourism. Does the panel consider all CAR-T therapies to be the same? If so, why not travel to India and receive CAR-T therapy treatment for about $40,000?

I guess I'll take that.

I didn't ask you directly.

In my opinion, the efficacy of all 3 constructs in third line is very similar, although the toxicity profile is slightly higher for one construct versus the other. In second line between the 4-1BB and CD28, there is absolutely a curative impact that CD19 CARs have made, but the toxicity profile, again, is quite dissimilar. With that said, I am very aware of the initial efficacy toxicity rates that CD19 CARs are showing in India, that are homegrown in India. And I do understand that they are very, very inexpensive compared to what is available in the United States. I think at this point in time, exactly like what Dr. Brenner said, it's all going to follow an approach, which is like cardiac cath. It's eventually going to be generalized. Medical tourism is going to take its way, and maybe CD19 CARs are going to follow suit. But I do want to also pause here and say that long-term follow-up matters. I think the durability of the responses matter. The complication rates long term matter, nonrelapse mortality, secondary malignancies, all of these things matter to my patients and to all of us in general. So I think with long-term follow-up data that probably would become much more clearer if this would be the route to go, not just to India, but also maybe to other developing countries where these are very inexpensive.

I think I would add just a little bit to that. I think in the U.S., CAR-T is highly regulated, and there's specific cutoff criteria for viability of cell product. And we've been able to give patients, products that don't meet those criteria, but in my experience depending on how far they are away from that criteria, the efficacy and the safety profile changes within the same product, maybe more toxic, it may be less efficacious, the durability may be off. And so ensuring that it's not just a different product, but also that within that same product, you're getting the same product each time it's made would be an important question to answer before that -- the question about medical tourism could be safely answered.

How many locations are there around the world for medical tourism for CAR-T therapies?

I don't think so much medical tourism as centers that are manufacturing their own point-of-care cells because of cost issues. Certainly, in Spain, they're doing that. The Barcelona Group has bought several parties into the clinic with the regulatory mechanism that they can use in Europe. And even in my home country of New Zealand, there's a locally growing CD19 CAR because they don't have the commercial CARs. So I think several countries are looking at various different models.

Israel, Greece, Australia.

Australia.

Australia has actually got several of the commercial CARs.

I think they do some...

They've got investigator trials. I don't think they've got a mechanism like the Barcelona Group has worked out for getting reimbursement.

And then Argentina and Colombia are starting.

Dr. Vera again. MT-601 targets 6 tumors, 6 tumor-specific antigens, sorry. Given the broad tumor recognition profile, do you think MT-601 could be used in other indications beyond lymphoma?

Yes. That's a great question. I mean, I show a brief illustration of our pipeline. Our lead asset is MT-601 in lymphoma, and we are concentrating our attention there for a multiple set of reasons. One is because I believe that given the fact that this is a patient population with an unmet medical need, we'll be able to advance this very rapidly to a point of approval. And from a corporate perspective, we are very focused on clinical execution on this particular indication. But from a technology perspective, yes, that is actually correct. The technology can be extended outside -- conceptually outside of the hematologic malignancies. In fact, we recently received funding from [indiscernible] from the state of Texas as well as from NIH to explore the same product MT-601 in patients with pancreatic cancer where we also have proof-of-concept clinical data from Baylor that is quite intriguing, right? So I think that in the future, we definitely will look forward to explore these into solid tumors, but at present, we remain focused in advancing this in patients with lymphoma, given the current situation and the current clinical data that we're observing.

This is maybe a follow-up to that. What role does the discovery of better solid tumor targets play in CAR-Ts growth?

That's a complex question. I mean, I think that tumor heterogeneity is a complex biology makes it very difficult to discover new targets, right? I mean, I think in the context of hematologic malignancies is perhaps a little bit easier, right? And then you have some antigens that are perhaps the exception to the rule, such as CD19, which is itself not a tumor target. When you go to solid tumors, however, I think that there's definitely a lot of endeavors to basically look into AI and look into multiple different things that would explore new potential targets. But in general, I think that those targets are far more restricted and the distribution is not as intense or homogeneous. But I mean, I would like to see what others think in terms of basically target selection in the space, I don't know.

Where do you see us going in 10 years?

Maybe I hand over that to Malcolm. Why don't you start with that one.

I think our target -- a known target is where you can start for a solid tumor. But I don't think it's where you're going to finish, so I think you have to have something that will progress as the tumor progresses and changes. Otherwise, you're going to get short-term benefits for high cost and no secure outcome.

Yes, I agree. I like how you describe it, how dynamic evolves that tumor, right? And I think because of that, you need to have a therapy that is equally dynamic, right, able to adapt the escape strategies utilized by the tumor cells. Yes, you're totally correct. But to Richard's question, what do you think that the field will be in 10 years, right? We have talked about technical things, distribution, how to make it more available, cheaper, right? And yes, I agree, I think that as I feel we're getting better. But in 10 years' time, what do you guys think and this will look like?

Richard, I just wanted to note that we've just gotten a slew of queues in from the audience. Do you want to do some rapid fire with them since our time is coming up?

Absolutely. Dr. Brozak, this might be one for you. What is the financial environment for the funding of future trials and therapies?

Wow, okay. I've been doing this for 40 years. And I would say this has got to be the most difficult environment that we have ever seen, both in the capital markets and obviously, with a lot that's taking place in Washington. And it's particularly problematic in that if you were to shut down a program, a trial or whatever, it's not like you can just restart it. The patients, the system and everything involved there is a very delicate balance. It's almost comparable to maintaining a nuclear reactor. You don't do enough and it can implode and not to be restarted again. So this is one of those times where people have to very, very carefully think about what they're going to put of their resources into both on the government, the VC and even the private equity side because these individuals that run them are not immune to unfortunate oncological issues. And the research, the therapy that's decided now, as everyone has stated, is going to be the practical solution 10 years from now. And if you don't do it now, you don't have anything when you need it. So that's a sober statement as I can make. If anyone wants to jump in and say things are different, I'd be thrilled to listen to their personal opinion.

We're waiting for them to join us, Steve. But we do have a number of questions that came in, and I just want to go through a few of them. What differentiates the approved CAR-T products beyond indication, i.e., are there differences in CRS and ICAN rates and efficacy? That's the first question that came in. Does anybody want to raise their hand and address that? I see everybody smiling. Okay, Geoff, it's you.

I think the limitations are that we don't have head-to-head trials, of course, but just looking at the numbers as they're reported, yes, there's differences. I think as an institution, we make decisions based on the data we have available. So if we have a patient we don't think can tolerate significant toxicity, we'll go with one specific product. If we have a patient who's younger and healthier and we think maybe there's a slight benefit in terms of response or durability, then we'll go with the different products. But it's something we discuss case by case with every -- with our entire group every time we have a patient going to CAR-T.

On a more practical level, what would the panel's recommendations be for a patient facing an oncologic problem in terms of navigating all of these therapies?

Stay away from Google.

I think that's an excellent question. I think the first pit stop would obviously be the primary oncologist who should be able to tie them to tertiary centers where newer treatments might be available besides just FDA-approved CD19 CARs or CD20 bispecs. But if a patient has a new diagnosis of cancer, it can be quite traumatic, initially very overwhelming considering Google doesn't really help us because everything is dismal if you Google cancer. So I think that's where some of the not-for-profit organizations definitely help in navigating these patients that are helpline set up online, where they can call them and they can basically say, "Hey, I have a diagnosis of this and this cancer, who should I see? I live here. Where is the next academic site I could go to?" and there are actually helplines are absolutely available made for them. And from a lymphoma standpoint, I do know that Lymphoma Research Foundation is one such stellar not-for-profit organization.

How are oncologists educated in the existence of these therapies?

Do you want to take that, Geoff?

I think if they're already in practice, I mean, we have CME requirements in order to show that we're keeping up with our CME. So it's basically on the physicians back how well and how up to date they want their practice to be. If somebody is going through training, of course, they're going to be exposed to it now that it's available and been available. But for people that have been practicing a long time, they really just have to be on the ball themselves.

But both Dr. Shouse and I do a lot of outreach. So we travel to community sites that are several, several hundred miles away and we actually educate those providers so that they are able to provide the up-and-coming treatments to their patients. So there's a lot of education that happens on the back end where academic oncologists like Dr. Shouse and I participate and provide education.

Are you facing any pushback from oncologists in terms of are they receptive to these instructions or outreach that you are giving?

They're very collaborative, at least where I live in Colorado. We have a huge catchment data across 4 neighboring states. I have never really had a community oncologist [indiscernible] at a recommendation. We're also very available. We're constantly on call for them. They can call us any time to get the patients in. So there's obviously this camaraderie that we have established over the last decade of practicing lymphomas that they don't feel like we are taking away their patients to not return them. But our goal is to really get them better and get them back home so that they can be continued to care for by the primary oncologist.

I think I have a -- we have a similar experience in our institution. I think the only comment I'll make is that it seems as though offering education and offering these opportunities to the community, you kind of select for the ones that are interested and you select for the ones who are collaborative and the ones that aren't, you never get to see. So I think that's a group that can be sometimes challenging to reach, but definitely the ones that I interact with are very collaborative.

I do have an anecdote to share on the MAR-T trial because I do have a patient who came from Wyoming to actually see me for a very different treatment and then got very interested in participating in the study because it was, obviously, we had some preclinical and then a handful of patients who have done well. And remarkably, this patient had, had prior 8 lines of treatment, did not respond to CAR-T, CD20 bispecs, and then got the entire MAR-T program outpatient. She did not experience neurotoxicity. It was just low-grade CRS that was managed with 1 day of hospitalization. So if you look through it and then towards the end, had a complete remission. So it was a win-win for everybody. And of course, cost utilization resources were very minimal because she only had 1 day of hospitalization. The health -- the recommendation from absolutely needing some sort of a caregiver was not that stringent on this clinical study. She would actually work remotely while she was getting treatment. So it was very remarkable to see how somebody who came from another state for a very different treatment believed in this trial, got the benefit of it and is continuing to enjoy it.

Wonderful. I guess, we're nearing the end here, but are CAR-Ts only used for lymphoma? Are they used in autoimmune disorders?

They're used in a lot of other applications. There's also approved CAR-Ts for leukemia and the myeloma. There's a lot of experimental studies in other cancers and they're extending to autoimmune diseases.

With so many patients who are eligible, why do you think there are so few studies going up, so few participants? It's not for want of a patient population.

You mean in clinical trials?

Yes.

Well, I think for autoimmune diseases, there's a lot of clinical trials out there. I think if somebody wants to access one, there are many available. There are probably not so many clinical trials for other CD19 products now because there's so many commercial products available. But there are some available, but I think if any patient is interested, there's a number of trials to access.

Wonderful. I think I'm going to turn it back over to Sara now.

Yes. I was just going to say we know who to contact now to find out about those trials. So thank you all. Thank you, Richard, for leading this discussion, and thank you, Steve, for organizing a great group of people. Juan, Geoff, Manali, Helen, Malcolm, thank you all for being a part of this. As I mentioned earlier, this has been recorded. It will be on the Demy-Colton website probably in about 4 or 5 hours. So you can listen to the whole session then. We'd also like to thank our audience for joining us and we hope you will join us at future Demy-Colton virtual salons. Our next salon is on the Science of Longevity. I have a problem with the word longevity just so you know featuring Tim Opler, and it will take place on June 11. All details can be found on the Demy-Colton website. So with that said, everyone, it's a wrap. Goodbye. Thank you.

Thank you.

Thank you.