Everyone, thank you so much for joining us. Really pleased to have Lyell with us today. With us, we have Lynn Seely, President and CEO, Gary Lee, Chief Scientific Officer, and Charlie Newton, CFO. To level set here, maybe I'll start with you, Lynn. Can you provide a brief overview of the technologies, the programs, and how you're leveraging each across Lyell's assets and development?
Sure, sure. So for those who aren't as familiar with Lyell, we are an oncology company focused on developing novel cell therapies for patients with solid tumor malignancies. And Lyell has a focus on getting T cell function right. So we have a number of very specific reprogramming technologies that are proprietary to Lyell. They're wholly owned, and they're designed very specifically to help our T cell therapies resist exhaustion so that they can kill cancer cells, even in the very hostile tumor microenvironment, and also to have durable stemness or this ability to persist over time. And so right now, we have four different technologies that we are incorporating across our portfolio. Lyell is unique in that we have both a CAR T cell program as well as a Tumor-Infiltrating Lymphocyte or TIL program.
Right now, in the clinic, we have a ROR1-targeted CAR T cell program, clinical trial, phase 1 clinical trial, that has two of our technologies, c-Jun overexpression, which is designed to help the T cells resist exhaustion and manufactured with our Epi-R technology, which is an epigenetic modifying technology to give the cells durable stemness. We also use that same technology in our tumor-infiltrating lymphocyte program, which is also in phase 1, and we're going to have data for both of those programs this year. And then we have a third program entering the clinic in the second half of this year that incorporates all four technologies.
These include both the c-Jun overexpression to help the T cells resist exhaustion, as well as a new technique where we are knocking out NR4A3, which is another regulator to help the cells overcome exhaustion. It's a negative regulator of T cell exhaustion. And then finally, the fourth technology, which is incorporated in our manufacturing in a very efficient, timely way, is a novel way to activate and stimulate T cells during expansion. It's a much more physiological way than has been used over the decades. Collectively, these cell technologies are all geared towards bringing products that have the right T cell function, that can have the cell killing, the persistency to work in the solid tumor environment.
Maybe starting with your lead program here, we're going to see first-in-human data from LYL797, which will include data from at least 20 patients. Per your prior commentary, the company's aiming for about a 25%-30% overall response rate, with durability in the 4-5 month range. Can you contextualize this clinical bar for us, as well as talking about how meaningful this is to patients?
Yes, and let me back up just a little bit. So, when I talk about cell therapy for solid tumors, right? We're looking about developing products for patients. So I like to think about what is the minimal bar for approval at the recommended phase 2 dose. So when we're finished with this phase 1 study, we've run what we hope to be a single-arm pivotal trial for accelerated approval. What is going to be able to be the bar that the FDA is going to need to see? And we think the minimum bar that we'd have to achieve in this late line, for example, triple-negative breast cancer, which is where we'll be, our first dataset will be this 25%-30% overall response rate with a minimum duration of 4-5 months.
This is cell therapy. This is our first initial dataset. It's going to be, the data are going to be maturing on time, but we are working very hard to bring to investors the ability to really understand our product. We'll have clinical data, we'll have safety data, and we have a very robust translational program, built in, so that, A, you can see if we're doing what we set out to do, which was to help T cells overcome exhaustion and have persistence. And then, can we give you the vision that we can get to this bar that we want, which is, product approval?
Great. And the dataset's still on track for end of the quarter, just to check?
End of this month. Sometime between now and the end of June. Yes, we're on track and intend to present the data.
Can you expand upon whether this data will de-risk the c-Jun overexpression and Epi-R technologies? Maybe help... Let's start there, and we can delve into it a bit further.
Yeah. Gary, do you want to take that?
Yeah, absolutely. I think, as Lynn mentioned, this is really the first in-human evaluation of these technologies, specifically the c-Jun overexpression, to see what impact it can have on the T cells when it's infused into a patient with solid tumor. And second, the Epi-R, to see whether the durable stemness quality that we introduce the cells actually makes substantial difference to the cell therapy or not. So to some extent, we have done an exhaustive amount of preclinical data to show the impact that this technology can have in preclinical model. It will be, really, in this data disclosure with the translational study, give us a chance to get a first look at seeing whether similar outcomes can be observed in human.
What types-- Go ahead.
I was just gonna say, before you jump to that, and also what's really important to know here is we're sort of benchmarking against the clinical trial that was done at the Fred Hutch Cancer Center, where they took a ROR1 targeted therapy, very similar to ours, without any enhancements, none of these technologies that I just spoke to you about, and were not able to show benefit. And in fact, in solid tumors, their cells didn't expand well, and they weren't able to see any responses. And so it gives us this nice benchmark to see if our technologies are, in fact, doing something to benefit patients.
Maybe just to step back here, can we talk about that study and the preclinical work and how you think, I guess, the confidence in that translation to this upcoming data set?
Yeah. And, and, you know, I'll start, and Gary can talk about. I think what Lyell does, I think in two ways, which are very special. So in, in both of our programs, we've started with clinical data to set our hypothesis. And so in the CAR program, we started with this data set at the Fred Hutch Cancer Center, where they really ran this clinical experiment to see why we've seen success with cell therapy in hematologic malignancies, but not in solid tumors. And so they took a ROR1 construct, they took it into patients with chronic lymphocytic leukemia, who have a very high ROR1 positivity rate, and saw exactly what they expected to see. The cells expanded nicely, the patients responded.
They took the exact same ROR1 construct and put it into patients with ROR1-positive triple-negative breast cancer and non-small cell lung cancer, but saw something very different. The cells didn't expand well in most patients, and they didn't see the responses. What they did observe is those cells rapidly developed markers of exhaustion. And so that really was, for the first time in the clinic, we understood what one of the key barriers was that was gonna have to be overcome. And so we took that data, and we brought it back into our deep research team to start to figure out how we might change that and augment the T cells so that they could fight exhaustion. And this comes into the validation. And, Gary, you might speak a little bit about the significant research we did to show that we could in fact do this.
Yeah, I think as Lynn mentioned, they clearly show that CAR T cells in the solid tumor setting quickly develop markers of exhaustion. And what are these markers? They are things that many are familiar with, including TIGIT, LAG-3, and PD-1, for example. And so what we did in the lab is to see, does our anti-exhaustion technology reduce the expression of these markers in the face of repeated killing of cancer cells, either in the in vitro setting as well as in an in vivo setting? And what we do see is that c-Jun overexpression definitely reduces exhaustion levels of the cells. It prolongs T cell functions, and associated with that, we see reduction of the expression of these markers, including things like TIGIT, which is the most prominent among them all.
So it will be really critical for us to see, when we were able to take on study evaluable sample from the patients, do we see a different outcome relative to the first generation of product? We have preclinical study, where we directly compare, CAR T cells with or without our technology and see a functional difference even in mice. So it'll be really important for us to see whether, again, the associations of these translational marker, like reduction of exhaustion marker, improves them, like quality, lead to the outcome that we see in preclinical study that can be translated into patients.
So today, right, there hasn't been a lot of success in solid tumors, so our preclinical models are validated, but now we sort of have an opportunity, don't we? Because we know that they... We've studied the Fred Hutch ROR1 non-enhanced CAR in our preclinical models, as well as our 797 CAR that has the enhancements. And so now we can see with clinical data, do our preclinical models, are they predictive? So it'll be interesting.
So, is there, with regard to seven nine seven, what other type of translational data maybe would you present where we could try to understand what you just mentioned outside of the responses and-?
Sure. So we have a rich translational program built in, and in our CAR construct, our CAR T cells actually have a tag on them, and so we can track what we call CAR PK. We can actually see what they're circulating in the peripheral blood. And so that's one thing that we'll be able to do. Now, it's interesting, isn't it? Because we definitely want to see CAR T cell expansion, but do we want the CAR T cells to be in the blood, or do we actually want them to be in the tumor, fighting the tumor? And so we're gonna be learning, you know, people say, "Well, what's good look like?" We're gonna be learning that, right, over time.
And then we also have on study tumor biopsies, which is gonna be very important because that's where we want the CAR T cells to be. And, Gary, you might talk about some of the other translational things.
Yeah, absolutely. So obviously from the on study tumor biopsy, one of the most important for us to look at is whether we see CAR T-cell infiltration. What we have seen, again, drawing back from what we've learned in preclinical to what we may or may not see in the patient sample, is that when we actually endow the T-cell with the ability to resist exhaustion, not only these T-cell can traffic into the tumor, they can get stimulated and potentially proliferate in the tumor as well. So we do see in preclinical study, improved infiltration or presence of CAR T-cells in the tumor, and we'll definitely look at whether we see CAR T-cell presence in the tumor biopsy samples.
So far, there's very few studies, in fact, none that I can see that's published, on definitive demonstration of CAR T cell infiltration in solid tumor. So it'll be very interesting to see what we observe from these samples that we're collecting so far. Beyond that, I think, as we mentioned, we'll be very interested to look at exhaustion marker expression on the peripheral blood CAR T cells because there are some benchmarks we can compare to against the previous study. But I think technologies have certainly developed over time that we can look beyond just a single or two markers on the cell surface.
We can also do bioinformatic analysis, look at transcriptomic analysis, to see whether our CAR T-cells benchmark against T-cells that are in the profile that is not exhausted versus definitive exhaustions, to see again, whether our c-Jun overexpression does endow the T-cell with the ability to resist exhaustions and how much of what we see in the preclinical setting translate into the clinical setting.
What number of cells are needed to be efficacious? Do you have an understanding?
... Yeah. Oh, sorry.
Go ahead.
Yeah. And I think this is something that we'll have to learn. You know, there are a limited number of understanding on how much CAR T-cell is needed in the solid tumor setting. I think there are growing evidence that, you know, for TIL, tens of billions is the standard dose. For TCR T-cell is in the north of a billion, and for CAR T-cells, the emerging data to suggest somewhere in the hundreds of millions, potentially. But obviously, there is some variability from target to target and indication to indication.
You felt comfortable with the dose work that you did and the dose escalation aspect?
Yes, and, and I think, there's so much that we need to learn, and so you say: How many cells are necessary? Well, there's the number of cells that we infuse, right? And that could be different than, for example, in heme malignancies, where they use, you know, lower doses to what we may need on solid tumors, and I think Gary gave great examples of that. There's what cell expansion do you need, and does cell expansion even correlate with benefit that you're seeing in the patients? Because you may imagine that, you know, the tumors are trafficking to the-- the cells are trafficking to the tumor. So we've got a lot to learn in the difference between heme malignancies and solid tumors. But I think in general, we believe at least that you need to see cell expansion.
We don't know to what number, to what degree. That's something that will be learned over time. Clearly, we want to see cells infiltrating into the tumor because that's the one thing we know about the biology, that that's where they need to be active. So, we do have a nice dose range, and we'll be looking forward to presenting that to everybody very soon.
It's gonna be exciting. Can you measure the ability to maintain durable stemness?
Oh, so...
Yeah, no. I think the ability to measure expressions of certain genes and markers that allow us to classify whether this cell is a stem-like cells or terminal differentiated cells on the other extreme has been well understood in T-cells. So we do have the capability to assess where we are in that spectrum, what fraction of cells we see can be on the memory and stem-like side versus what fraction that are in the terminal differentiated side. I think as we will be one of the first few companies to look definitively into those outcomes. Now, I think to your point, to what level is sufficient, I think the data will have to emerge and benchmark against other studies, but I think it's really important for the field to advance on that side as well.
And so what we hope to provide is this nice way of looking at the data, clinical outcomes, safety, of course, and then this deep translational work so that we can really understand where we're going with our technologies.
You've set a cutoff about 10% ROR1 positivity. Is that sufficient for targeting the tumor cells, or could that be played with a little bit as well?
Yeah, it's a great question. So we are. Some people will just take all comers in a phase I study because they wanna go as quickly as possible. We wanted to enrich for patients more likely to respond, so we did pre-screen. Every patient had to have a biopsy that was ROR1 positive, and so we did set a pragmatic cutoff, and we'll call it arbitrary. It was pragmatic at 10%, which was meant to exclude those with the lowest ROR1 expression, the least likely to respond, but not limit our patient population too much, right? So that those who had higher expression would be included. Now, the job of phase I is actually to determine the optimal cutoff, and so is it gonna be 10%? Is it gonna be a little bit higher? You know, we'll see over time.
I think 10% is a reasonable place to begin, and in our hands right now, our immunohistochemistry assay is working exactly as we would expect it to, with about 50% of triple-negative breast cancer patients positive for ROR1, and about a third of non-small cell lung cancer patients. So that may get fine-tuned before we go to phase II, but in general, that's where we're looking.
Just from a platform, you know, side, I guess just from that aspect, you leverage both c-Jun overexpression and Lyell's Epi-R technology. Can you talk about the synergistic aspect here and whether you'd be able to read through to that? Because I would assume, as you look to the TIL program and then to the future program you commented on, that would be really important if you could start to see that play out.
Yeah.
Yeah, I think the choice between those two technology is really in part to be complementary. They solve, quote, unquote, "different problems" that the T-cells has to deal with in the setting of solid tumor. And so the question is whether we can tease out exactly which one is most important in the demonstration of the outcome in 797. It will be difficult to say in this initial analysis. So I don't know. I don't think we can assign whether, you know, certain aspect of improvement is based on one or the other, at least initially. But I do think it demonstrates the ability to be able to execute on the expression of... overexpression of c-Jun, as well as our ability to manufacture cells using the Epi-R technology protocol.
Could you provide us with an update on the datasets from the ROR1 class and where it stands today?
Sure. So there are a number of programs who have looked at and are using ROR1 as a target, and we and others believe ROR1 is a very good target. And number one, because we haven't seen on-target off-tumor toxicity, and that is extremely important with the target. And I've described to you already the Fred Hutch data, where they were able to see great cell expansion, for example, in CLL patients... and didn't see on-target off-tumor toxicity. There are a number of companies who are pursuing ROR1 antibody drug conjugates, and the same thing is true there.
On the efficacy side, I think we've got a ways to go, and I think one of the reasons in the CAR T world we're moving towards enhancements is because we know that a very good target, ROR1 in solid tumors, was not sufficient by itself, and so that's why we have moved to the enhancements. In the antibody drug conjugate world, they've absolutely seen responses in hematologic malignancies and more recently in solid tumors, but still, these companies are in very early or in dose escalation.
Are there any learnings or experiences when you look at Oncternal's program that read out that get applied to your program?
Yeah. So Oncternal is a company that has a ROR1 CAR T cell program that put out data, a very small number of patients, with B-cell malignancy, hematologic malignancy, and they did see some responses. They did report one death, which was presumed to be due to CRS and ICANS, and are sort of now moving forward at a lower dose. I think we don't perceive read-through to our program from that, largely because, first of all, we're not in heme malignancies, where they have a tendency to see more ICANS, for example, and we also have a very different binder, and so it's not apples to apples.
Let me just the last question on this program. You do have a preclinical program, LYL119. Maybe you could compare and contrast how they're differentiated.
Sure. So maybe I'll start, and Gary, you can augment here. But we're very excited. We're gonna be introducing a new program into the clinic in the second half. It's another ROR1-targeted CAR T cell program, which again, just tells you that we're doubling down on on ROR1, and here we have four technologies. And when we started this, we really were agnostic. We wanted sort of our scientists are continuing to innovate, kinda keep up and lead the field, and so we're looking for ways to further enhance our product candidate and have really come up with something that is a step change and that has two genetic reprogramming technologies and then two technologies which can really enhance in the manufacturing process.
And so we think we've considered a large number of things and believe this is a real step change. And so you might describe some of the data that tell us that we're in the next step forward.
Yeah, absolutely. As Lynn said, we, for example, decide to pick a gene knockout target. We did benchmark against various targets. Some of them has been literature that claim they may have benefit, but in our hand, the combination of c-Jun overexpression and NR4A3 knockout really outperform all the other combinations that we've looked at. So we really believe in this data. And in preclinical studies, in vitro, we recently showed some data at AACR, where, when we ask these T cells, LYL119 T cells, to keep on killing tumor cells, and basically in this assay that we call serial killing assays, we can now extend the killing out to months, depends on the cell line that we looked at.
I think even more importantly, when we look at one of the best benchmark we have against the potency of the CAR T cells, which is a xenograft tumor model and dialing down the number of cells. I think going back to what we talked about before with LYL797, we have the preclinical model that shows the inclusion of two technology significantly outperforms the T cells that are not reprogrammed. So that's essentially what the Fred Hutch study looks like. In the same model, now, we can now test comparing LYL797 against LYL119, and we can control the tumor at more than tenfold lower cell doses. So this is not simply a small incremental change. In our view, it's a step change in ability to make more potent T cells to fight solid tumor.
And some people must say, "Well, you're bringing forward the second generation 'cause you don't believe in LYL797," and that is just absolutely not the case. We absolutely believe in LYL797, and the preclinical data to support this clinical program is very strong, but the science has continued to evolve, and so we are continuing to evolve. And what a lot of people don't appreciate is that there are large number of ROR1-positive tumor types, and these are. The expression of this protein correlates with a poor prognosis. And so we're studying triple-negative breast cancer and non-small cell lung cancer, but there's ovarian cancer and endometrial cancer and pancreatic cancer and colorectal cancer and hematologic malignancies. So there's a broad swath. We can do these, and we are going to be moving them forward in parallel.
At some point, if we make a data-driven decision, one is far superior, we can move in that direction, or we can take them into different tumor types. So this is tremendous optionality for us. But remember, our goal is to get T-cell function right. These four technologies can be used with any CAR target, with any TCR target, and, and with TIL even. And so this proving out of our technologies and getting our T-cell function right then allows us to go in innumerable different direction.
You commented on the TIL program that you have earlier.
Mm.
How do you think it's differentiated from a standard, I guess, from a recently approved- ... TIL program like Iovance's drug, or Obsidian's asset?
Yeah, so the TIL field is moving forward, and kudos to Iovance for getting the first cell therapy approved in solid tumors with great perseverance and resilience, and I think in many ways, they've paved the road for us. And in some ways, sometimes it's better to be second than first, not often, but in this case, there's so much work that had to be done for the regulators to figure out how to provide oversight for this very complex therapy. And not everybody understands patients have to undergo a surgery to get a biopsy, for which you harvest the tumor-infiltrating lymphocytes, then you have to expand them from millions to billions of cells, and then reinfuse them in the patient. And so it's a very complex process.
Took the regulators a little while to figure out how to provide oversight, work with the company to get approval, and also the sites to get set up. And so in many ways, we're reaping the benefit of that. And so we're differentiated because we consider ourselves a second-generation TIL product, where we learned from the National Cancer Institute, they went back, and they did a retrospective study of their clinical patients who responded to their cell product with advanced melanoma and identified the characteristics that they wanted in that cell product to bring about responses. And so we've developed our manufacturing process to do that in sort of a novel way with our Epi-R technology, and we can talk more about that.
Basically, it epigenetically changes the cells to maintain their stem-like features, so they don't become so differentiated and short-lived. So we believe that really is an opportunity to set the processes apart, not only in advanced melanoma, but more importantly, in tumor types like non-small cell lung cancer and colorectal cancer.
What will we see from the in terms of data in the second half, and will we be able to compare it with the Iovance asset?
Well, it's, of course, always very difficult to do cross-trial comparisons. They have an approved product. We're gonna have an initial data set, but we are starting in advanced melanoma just because that's where people know TIL work, and so it will give us some idea if we are differentiated in terms of response rates. Durability, of course, takes more time.
Can you describe the Stim-R technology and how it's applied here?
Yeah. So, Stim-R is something that we're using in our CAR product to date, in the 119 it will be in that product. But Gary, it's a very novel product. Do you want to describe it?
Yeah, absolutely. So Stim-R is a fully synthetic, degradable reagent that allow you to stimulate and expand T-cell outside the body. There are other technologies been in this space for decades, things like Dynabeads and TransAct beads. In fact, those are the standard reagents that almost all CAR T company uses to expand T-cells. One thing of note is that, of course, the bead size, the size of these beads are actually smaller than a cell. You can actually, in some cases, visually see it, and sometimes it's even smaller than that you cannot. But the idea is that you can basically anchor antibodies like CD3, CD28, and stimulate the T-cells. While it works, and certainly we can expand T-cell with these reagents and make that cell for more than 20 years.
But really, the few have not advanced beyond that and make any improvement in that space for a very long time. The inventor of the Stim-R technology originated at Harvard. In fact, we in-licensed the technology from Harvard and brought the inventors at Lyell to further develop this technology. And the vision really comes from the fact that when T-cells get stimulated in the body, they form a tight cell-to-cell junction with things like antigen-presenting cells. And antigen-presenting cells certainly are not smaller than T-cells, and the ligand that the T-cell sees certainly flow fluidly on a cell membrane that allow to form a tight cell-to-cell junction. Really essentially completely different than how these current reagents, bead-like material works.
So they have a hypothesis: Can we generate a fully synthetic degradable reagent that allow us to stimulate T-cells out of the body and expand them in a much more physiological manner? With the hypothesis that nature have evolved to stimulate T-cell this way, could we get better T-cells this way? At a CEC conference a couple of years ago, we first showed some data that actually indicate exactly that. When we stimulate the T-cell in this way, we have publication from the inventor that they do form this tight cell to cell junction from electron microscopy images, and that those cells that were generated in this way have more potency, have more durability and stem-like quality after they kill the tumor cells.
So this is really, I would say, a transformative improvement in the way we can potentially make T-cell products across both CAR T-cells and potentially others as well.
All right, Charlie, a two-part question for you. So one is, how are you thinking about cash runway and getting through these value inflection points? And the second would be, maybe you could touch base on the manufacturing capabilities or capacity and, and how you think about CapEx in that context.
Yeah. So our cash balance we have, as of the end of the last quarter, $526 million in cash on the balance sheet. And if you look at the actual cash burn off the balance sheet over the last four quarters or so, it's been about $35 million or so a quarter. So we feel very good about that, giving us a runway well into 2027, being able to see initial clinical data for not only 797 845, but also importantly 119, as well within that window. From a manufacturing perspective, we do all of our own manufacturing, as you know.
Up in our Bothell manufacturing facility, we produce CAR, TIL, our own Lenti as well, which provides us a lot of flexibility with Gary's research team, working with his process science and process development teams, along with the tech ops teams, to really be nimble and be able to test things like Stim-R. How do you get it to work on a clinical scale? And so that, that's something that we're very proud of, has provided us, I think, the ability to move more quickly than we would otherwise have been able to do if we were working with CDMOs, for instance. And that facility gives us capacity of about 500 doses per year when we're producing all of those things, if we're doing TIL, CAR, as well as Lenti.
If we were to specialize in one program, say, we used a CDMO for one of our programs and went exclusively CAR, say, in a facility on our own, we could probably take that up closer to 1,200, 1,300 doses per year. So you can see plenty for clinical, but even for early commercial stage as well. But as we think about how do we ramp for commercial, we entered into a proof of concept program with a company called Cellares, that does automated. They have an automated Cell Shuttle manufacturing system for cell therapy products. And we think that's really important as we think about not only how do you manufacture quickly but cost-effectively as we scale up.
As you can imagine, the capital intensity of one of their Cell Shuttles versus building another manufacturing facility, coupled with the fact that it requires fewer headcount than it would to staff a facility. So we think that's a way to really significantly reduce expenses going forward as we head towards larger, larger needs.
Got it.
Yeah.
A very big year for you.
Big year, yeah.
I have to imagine when we see this first data set, there is going to be platform read-through to your second program in the second half of the year, so.
Yeah.
Yeah. No, it's a very exciting time. It's exciting time for cell therapy in general, and we're thrilled to be a part of it.
Perfect. Well, thank you so much for joining us today. Really appreciate the discussion.