Hi, everyone. My name is Mitchell Kapoor. I'm a Senior Biotech Analyst of H.C. Wainwright, and I'd like to welcome you to the annual H.C. Wainwright Cell Therapy Investor Conference. Today, I have Lyell Immunopharma joining me, and from the company, I'm pleased to welcome Lynn Seely, the President and CEO of Lyell. Lynn, thank you for joining us.
Well, thanks for having me, Mitchell. I appreciate it.
So, it's an exciting year for Lyell. Maybe you could just, you know, for those who are not familiar with the story, just give us an introduction to Lyell and, and what you have in store for this year.
Absolutely. Well, let me begin by saying I will be making forward-looking statements, so consult our disclosures and our securities filings and on our website. But yes, this is a big year for Lyell. Lyell, for those of you who don't know us as well, is an oncology company, clinical stage, focused on developing T-cell therapies for patients suffering from solid tumors. And we have two programs in the clinic, diverse programs. We have a CAR T-cell program, as well as a tumor-infiltrating lymphocyte, or TIL program. And each of our programs incorporates genetic and epigenetic technologies, which we have developed. They're novel, and they're geared with a very specific focus on getting T-cell function right. So at Lyell, we believe that the T-cell function is absolutely critical.
The target of these T-cells is important, but if the T-cells don't function with great potency, and continued cell killing over time, when they get to the target, they're not gonna be effective in solid tumors, so that's really our focus. And our platform technologies, it's important to know, can be used once they're proven effective in any TIL, TCR, or CAR program, so, quite, quite powerful. As I said, we have two programs, in the clinic, a ROR1-targeted CAR T-cell program, that's enrolling patients with triple-negative breast cancer and non-small cell lung cancer. We'll be having data, from that program in the first half. That will be our initial, data disclosure. And then we have a third program, which we expect to enter the clinic this year. We'll be filing the IND in the first half, so a lot going on at Lyell.
And if I were gonna tell you a couple of other important facts that you should know about us, we have our own manufacturing center in Bothell, Washington, where we can really have control over our manufacturing. We can make vector, we can make CAR T-cells, we can make tumor-infiltrating lymphocytes, so very important. And then finally, we're well-capitalized. We have over $560 million in cash, giving us a runway into 2027, which is important because it gets us through multiple clinical readouts, which I'm sure we'll be discussing.
Absolutely. We, we think that's an important thing as well, allowing you to show the fullness of the Lyell story from multiple different angles. So starting with the CAR T, what we've been focused on, I think is the lead, the ROR1 CAR T program, if you could talk about just the clinical data we can expect in the first half, and give us a sense of where we are in the dose escalation process so far.
Yeah. Well, maybe I'll backtrack a little bit, if it's okay, just to let people understand a tiny bit about the program. So this is a ROR1-targeted CAR T-cell program. It's a phase I program, which consists of dose escalation and dose expansion. We initiated the trial with women with triple-negative breast cancer, relapsed refractory disease, and are also recruiting patients with non-small cell lung cancer. In this program, we have a ROR1-targeted CAR T, but we also have enhancements for our T-cell, which is really designed to help the T-cell resist exhaustion, and so we have c-Jun overexpression as the genetic engineering in this program.
And then we also manufacture these CAR T-cells with our Epi-R technology, which gives them these durable stem-like features, and so you'll consistently hear me talking about resisting T-cell exhaustion and durable stemness, and that's what this program is really designed to test. So as I said, we do have dose escalation in this program, multiple doses, as you might imagine. We haven't been specific about what those doses are, where we are in dose escalation, other than to say we'll be presenting data in the first half, and at that point, we intend to give meaningful data for investors to really understand exactly where we are with the program, what doses we're evaluating, and really to give them an idea about the potential of the product.
Great. That's a great overview. Could you talk a little bit about the target, ROR1, and what we've seen so far pre-clinically, and what else from the field de-risks ROR1 as a target?
Yeah, and the story behind ROR1 and Lyell is very intertwined because really it's the basis of the founding of Lyell. There was a wonderful experiment, a clinical experiment conducted at the Fred Hutch Cancer Center by Stan Riddell and his colleagues. Stan, Dr. Riddell, is one of our founders. And what they did was they took ROR1 CAR T-cells, manufactured them and gave them to patients with chronic lymphocytic leukemia, a hematologic malignancy, and just as you would expect, the T-cells expanded, and they saw partial responses. When they used the exact same ROR1 CAR T-cell construct, and they made CAR T-cells for patients with ROR1-positive triple-negative breast cancer or non-small cell lung cancer, and they gave those cells to the patients, something very different happened. The cells didn't expand, and they rapidly developed markers of exhaustion.
And this clinical experiment was so important because it was really the first time that there was clinical data to help us understand why CAR T-cell therapy could be so beneficial in heme malignancies. We know blood cancers are very well-treated in many cases by CAR T-cells, but these CAR T-cells haven't been as effective in solid tumors. So for the first time, we knew these CAR T-cells were gonna have to overcome exhaustion if they were gonna be successful. Well, right at that same time, Dr. Crystal Mackall, who's the founding director of the Stanford Cancer Center for Cell Therapy, and a postdoc in her lab, Dr. Rachel Lynn, who's now a research director at Lyell, discovered a key to helping the T-cells overcome exhaustion.
And that is, that if you could overexpress c-Jun, that the T-cells were much better at overcoming exhaustion, and this was data that they published in multiple different animal tumor models in vivo with CAR T-cells, and showing that overexpression of c-Jun really led to much better anti-tumor efficacy. So coming together, Lyell decided that we were really gonna focus on this c-Jun overexpression, helping the T-cells overcome exhaustion, and we took ROR1 as a target. Why? Because it had been used successfully in this Fred Hutch trial, without any evidence of on-tumor, off-target, on-target, off-tumor toxicity. And also, there's a non-human primate study showing very much the same thing, where we knew it was a good target.
Others have used this target, for example, with antibody drug conjugates, as well as other CAR T-cell therapies, and really, there hasn't been any evidence of on-target, off-tumor toxicity, which is always of concern in when you're selecting a target for CAR. So we had a target. We had a great hypothesis to test. We then went about getting all the preclinical data we needed to engineer these cells to take them into the clinic. And one of the things we're very proud about at Lyell is we have a very rich scientific history, tremendous scientists at our company, and they prosecuted this preclinically to the greatest degree possible. You know, at some point, you can only answer this question in the clinic.
But we ran multiple in vivo xenograft models, where we could show a marked advantage with c-Jun overexpression over non-c-Jun expressing CAR T-cells. And in particular, we ran a very important study, which used the most difficult non-small cell lung cancer animal model that at least we've ever heard of. It's known as the KP mouse model, and it's a syngeneic mouse model. So when you look at the tumors in these mice under the microscope, they look just like non-small cell lung cancer in humans, and the whole hostile tumor microenvironment is intact. And this model is very aggressive because it's driven by tumor driving mutations, p53, KRAS. And chemotherapy doesn't work well in this model. PD-1 checkpoint inhibitors don't work well in this model, and so it was a really aggressive test for us.
But what we were able to find is, when you gave ROR1 CAR T-cells without c-Jun overexpression, they didn't work well. But we saw a marked advantage when we used the c-Jun overexpression, and in fact, could control tumors in 50% of the animals. So if we were able to see a similar response in people, that would be really important. So this gave us the confidence to initiate the phase I clinical program. So we're the only ones, we in-licensed this technology from Stanford. We're the only ones really developing this hypothesis and with this technology, so we're very excited about it.
Great. And ROR1 has relevance, as you mentioned, to triple-negative breast cancer, non-small cell lung cancer, and a variety of other tumor types. Circling back to the clinical data that we'll have this year, could you give us a sense of how many patients we might be able to see with the data, and roughly how many of those patients could come from one tumor type versus the other? Obviously, the prevalence is much higher in certain of these tumor types, so would expect to have more, but could you just give us a sense of what you're seeing on your side?
Of course. So you're, you're right. ROR1 is a great target because it is expressed in many different tumors, and in fact, many tumors, it is associated with a poor prognosis. So, for example, in triple-negative breast cancer, it's associated with a poor prognosis. We elected to initiate our dose escalation in women with triple-negative breast cancer. Obviously, they have tremendous unmet need, but also, they are younger, they're fitter, and so it's a great place to collect initial safety data. We're now also enrolling patients with non-small cell lung cancer, so those are the two indications currently in our clinical trial. But we've guided that for this initial data release, we're gonna be putting out about 20 patients, and that the majority will be with, excuse me, triple-negative breast cancer. So that's what you can expect to see.
But it is very important that a number of other tumor types express ROR1, so this is the beginning, not the end. And I think it gives us a great opportunity to begin to understand the potential of this product candidate. But, again, there are things like endometrial, ovarian, pancreatic, many, many other tumor types. And then the one thing I should also share is that, you know, whenever you start a trial like this, you have to make a decision of: Are you going to enrich for ROR1-positive patients or not? And, you know, when you do a screening for ROR1, obviously you have screen failures. So in our hands, with our assay, about 50% of women with triple-negative breast cancer are positive in our ROR1 assay, about a third of patients with non-small cell lung cancer.
And so we did enrich this patient population for ROR1 positivity.
Okay, that's very helpful. How much follow-up could we see on these patients? I know you said that you haven't really said much about the dose level, but is there anything on dose you can say that gives us kind of an idea in the cell therapy landscape of.
Mm-hmm
Dose levels or subtherapeutic dose level? Just anything what those could be.
Yeah. So we haven't at this point yet disclosed the precise dose levels. We are in dose escalation, and we expect to give investors a good idea of what the recommended phase II dose moving forward is at the time of our data disclosure. And so we're really aggressively collecting data and looking forward to getting out there. As you might expect, there'll be multiple sort of types of data from safety and tolerability, which is always number one, the response rates, of course, and then we'll wanna give investors an idea of the duration of responses that we're seeing. And of course, durability data matures over time, and so that's something that will continue to evolve as we continue to enroll and follow patients.
Okay, great. And what would you consider the bar for success in triple-negative breast cancer and non-small cell lung cancer?
Yeah. In both cases, we're studying very late-stage patients, so these are patients who failed most available therapies, as you might imagine. While the requirements for enrollment are for triple-negative breast cancer to fail two lines or for non-small cell lung cancer, one line, most of these patients recruited have failed many lines, and so the bar for approval is quite low. And when you ask me, what's the minimum bar we're looking for? It's the bar for approval, because we're in the job of developing products for patients. And what happens then as you get products approved or moving towards approval, then people become comfortable with the product candidate, and then they can start recruiting earlier patients.
Ultimately, if we get approval in a late line, maybe accelerated approval with a single-arm study, then we can move earlier, and that's when we should see even better responses. In a relapsed refractory patient population who failed most other lines of therapy, the minimal bar for approval is a response rate of about 25%-30%. It's low, and a duration of response of about four to five months, and I would say that's the bar. Anything above that is fantastic, and again, it's something that, in this relapsed refractory setting, the goal would be to see it improve over time as we got earlier line patients.
That is very helpful and something to definitely look forward to. And we agree, that's a low bar, and would be meaningful. From a kind of elucidating the mechanism, the target, you know, validation whenever we see the data, sometimes biomarker analysis can help with that. Is that something that Lyell plans to share, to help validate the c-Jun and our platforms?
Yeah, yes, and I think I mentioned before, Lyell is very proud of our science. We are a science-driven company. We started out with a clear hypothesis on what we're hoping to see. And so while we, like everybody, is most interested in actually the clinical data, the safety, tolerability, and the response rates, the story can best be understood by the translational data and really seeing what we have. And so we have a few things built into our trial, which I think are quite interesting. We do have a tag on our CAR T cells, so we can track them in the periphery. We can do basically CAR T- cell PK, if you will, and understand how they expand and their persistence. But obviously, we don't necessarily want the CAR T cells in the circulation.
We want them in the tumor, right? Because that's where they need to go to, to fight. Very different than blood cancers, right, where you like to see them circulating here. You know, what matters is what's going on in the tumor, and so we do have on-study tumor biopsy, which also can be helpful. We will be looking, as much as we're able, at markers of exhaustion, because, as I said earlier, one of the key things we set out to do was to help T- cells resist exhaustion, so we're gonna learn if our product candidate can actually do that.
Great, and so the last thing I'll touch on this program is just the, you know, the form in which we could see the data, if you're able to share any information about that. Would this likely be at a medical conference or a press release type of a topic?
Well, we're very excited to get the data out there. We haven't specified which, whether it's gonna be a company announcement or at a medical meeting, but I think our goal with this announcement is really to give investors an idea of what this product candidate can do.
Great. Yeah. We're looking forward to it. Okay, moving to 845, LYL845, which is that your engineered TIL program. That's also exciting. The space is rapidly evolving, and then Amtagvi just got its approval, which I'm sure you've been receiving a lot of inbounds about and excitement around. Can you talk a little bit about what that means for Lyell, and does that influence the development and regulatory path for 845 at all?
Yeah, sure. So, first of all, fantastic that Amtagvi was approved, and for those who don't know, Iovance got the approval for the first cell therapy in solid tumor. So it's a huge breakthrough for the field. It's something wonderful for TIL. Iovance gets a lot of credit. They have been working on this for a very, very long time, and it takes a lot of work to set the precedent, and then, if you will, pave the road. And it makes life easier for those of us who are following along behind because we have a path to follow. And so for us, it's enormously helpful on multiple fronts. You know, the regulators have spent a lot of time figuring out what they need to provide adequate oversight for this very complex therapy.
I mean, tumor-infiltrating lymphocytes, for those in the audience who may not know, you have to take a biopsy from the patient, you send it to your manufacturing facility, you harvest the tumor-infiltrating lymphocytes. Let's say there are millions of them. Then you have to expand them to billions of cells that then get given back to the patient, and the idea is here that you need several things to make a cell product that's gonna work. You have to have enough cells, and within those cells, they have to be the right type of cells, cells that are actually able to potently fight the cancer, but also persist and renew over time. And then you need to have the right, what we call, polyclonal. The beauty of TIL is that they react to multiple different tumor antigens, and if you just grow up.
When you're growing up billions of cells, a few clones that select themselves out, you lose many of the other ones that could be very important. So you wanna really preserve that polyclonality as much as possible. And so I think Iovance has been working on TIL. They got the first TIL approved, but there's plenty of room left to improve upon that, and plenty of room left in the field. And so how this impacts us, I think makes our job a little bit easier, because we know what's expected from the regulatory standpoint. The sites have. This is a very complex therapy for the sites to manage, so we have to have a surgeon, you have to have a cell therapy expert, you have to have the solid tumor doctors to participate.
The sites are very much organized around that now, and I would say enthusiasm, we're, we're out at these sites talking to these investigators and physicians. They're quite excited about the promise of TIL, and are getting organized and are using it, and so that makes our job easier. But what I would tell you is they want more, and they want better. And so, for example, I've been asked, well, is the Iovance approval going to harm your ability to recruit your study? And the answer is no. There are lots of patients out there, and I think the investigators are very interested in continuing to explore this field and learn more about it. And so what Lyell is bringing is, you mentioned it, an epigenetically modified TIL product. What does that mean?
Means that we understood where the National Cancer Institute and Iovance have been developing TIL for decades, and what we did is we looked at their, they've published some data from patients, some clinical data, and retrospectively tried to understand, in those patients who responded, what did the TIL look like? What type of phenotype did they have? And so we've developed a manufacturing process to really improve upon that phenotype. So, for example, they showed that those patients most likely to respond to TIL with advanced melanoma had more stem-like features. So we've developed a manufacturing process that gives that sort of stem-like features, and very specifically, a CD39/CD69 double-negative phenotype, which has been shown to correlate very nicely with clinical outcomes.
So I think we do this with a very special manufacturing protocol, a very special mix of media and cytokines, which, in a way, have the cells switch their metabolic pathway from a differentiated effector cell to one that's more stem-like. And so the cells come out in a wide range, but there's a nice mix of cells ready to kill today, and other cells that are ready to persist and self-renew over time, and we believe that that's a competitive advantage for us.
Great. And you have a data readout in the second half of the year for this program, so again, a very eventful year. How many patients worth of data might we see at this readout, and how much follow-up do we see in these patients? And there's a few different groups of patients you're enrolling here. Obviously, you're mentioning that Amtagvi may not sway, you know, dissuade, melanoma patients from enrolling, but could you comment a little bit more about where you're seeing the most excitement, and where you could have more patients worth of data in one particular tumor type versus another in the readout?
Yeah. So Amtagvi, as you said, is approved in advanced melanoma, and that's actually where we started our clinical trial. And so the bulk of the patients that you'll see in the second half, when we read out this data, will have advanced melanoma. But to your point, the beauty of TIL is it would be, and sort of the Holy Grail, is to not just have it treat these immunologically hot tumors, like advanced melanoma, but we're also evaluating patients in our protocol with non-small cell lung cancer, and ultimately, colorectal cancer is our objective. But the first data readout will be focused on advanced melanoma, because that's where we know TIL, TIL work.
Okay, and these patients wouldn't have received Amtagvi before, right?
No, no. And I should say, you know, you asked how is this gonna change our development pathway? We do have Orphan Drug Designation in advanced melanoma, and can continue in that vein. So I think it doesn't change our development path, but again, we have high hopes to do advanced melanoma and beyond.
Okay, great. And could you talk a little bit about the bars for success here? And I guess with particular relevance to melanoma, does Amtagvi now set the bar there, or is there some different way to look at this, and maybe the different populations you enroll with different baseline characteristics, could that influence how data could shape up?
Yeah, I think it's a fair comment. Again, when you sort of look at the overall response rate with the approved product, it's, you know, just a little bit above 30%. And so there's, again, pretty good room to be at or better than that. And I think for the other indications, again, these patients are relapsed refractory with very little treatment, so a similar bar that we talked about before. And so I think these are therapies which bring great promise, and unfortunately, we start developing them in very late stage relapse refractory patients. But where we really wanna develop them is earlier line, because we know in oncology development in general, but with immunotherapies in particular, cell therapies, that the earlier you go, the more likely you are to see even better benefits.
I think the bar will be held to, and the data release in the second half will almost certainly be cohort 4 of the Iovance data set.
Great. This is, this has all been incredibly helpful, and, wonderful, wonderful chatting with you. Just the last thing we'd love to touch on the year ahead for Lyell. Obviously, talked about two major catalysts, but there's a lot going on with the company, and there's a whole.
Mm-hmm
Pipeline of second generation assets. So if you could talk about what we could see from those particular assets, and anything else we didn't get to today that you feel is important to highlight in the last point.
Of course. Well, thank you. I would say, yes, data from our two clinical programs in the clinic today, but we also have an IND on track to be filed this half, which will be our third clinical program, which is LYL119, which incorporates four technologies. So even more potent T-cells, more able to resist exhaustion, and just absolutely spectacular preclinical data. So we're really excited about getting that into the clinic as well. So I think full steam ahead for Lyell. We're in a great position in that we have great science, strong clinical development. We're at these major cell therapy centers across the U.S., and I think also our own manufacturing. And I would say the one thing we haven't talked so much about is, but we're continuing to innovate for the future, because we're gonna have to scale this, right?
These are solid tumors. They're not small populations. They're significant populations, and you may have seen recently, we announced the manufacturing proof-of-principle collaboration with Cellares, which is a company developing these Cell Shuttles, which in a much more cost-effective way, in a robotic way, can manufacture CAR T-cells. And so lots of things going on at Lyell to lead today, and then lead well into the future.
Well, thank you so much, Lynn, and thank you to the Lyell team. And, thank you to all of the investors dialed in. We really appreciate all of your time, and look forward to following the updates this year. Thanks again.
All right. Thanks for having me. Bye.