Good morning, everyone, and thank you for joining the H.C. Wainwright 26th Annual Global Investment Conference 2024. My name is Daniel Smith, and I'm an H.C. Wainwright Equity Research Associate in Biotechnology. With that said, let me introduce our presenter for the session. I'd like to welcome Dr. Lynn Seely, President and CEO of Lyell Immunopharma, who are developing modified CAR T for solid tumor treatments. Lyell is traded on the Nasdaq under the ticker LYEL. The floor is yours.
Thank you, Dan, and thanks to H.C. Wainwright for inviting us here today to tell you a little bit about Lyell Immunopharma, an oncology company focused on developing novel T cell therapies for patients suffering from cancer. I will be making forward-looking statements this morning, so please consult our website and SEC filings for additional disclosures. Let's begin. Lyell is advancing multiple T cell therapies into the clinic. These are wholly owned product candidates addressing large patient populations and supported by strong intellectual property. Our lead program is a chimeric antigen receptor T cell project, or a CAR project. It's ROR1 targeted, so that's the target on the cancer that we're going after. But we use, very specifically, technologies to help these T cells function well when they hit their target.
We have recently reported phase I clinical trial data from this program, the initial data which I'll be telling you about today, where we were able to show dose-dependent clinical activity and a 40% objective response rate, as well as a 60% clinical benefit rate at the 150 million cell dose. We're currently expanding this phase I program from two into six total tumor types. In addition to our CAR program, we also have a tumor-infiltrating lymphocyte, or TIL program, LYL845, which we are enrolling patients with advanced melanoma, and we'll be presenting the first data from this program this year, so coming very soon.
And then we have LYL119, our next-generation ROR1-targeted CAR T cell program, which incorporates four of our proprietary technologies, which we're proud to say has recently cleared the IND, and we're actively engaged in getting sites up and activated to initiate that clinical program. Lyell is well known for our scientific expertise, and we have multiple proprietary technologies, which we're incorporating into our T cell therapies to help them better kill tumor cells and to have this durable stemness so that they can persist over time. And I look forward to telling you about these stackable and complementary technologies, which are designed to be usable in any CAR, TIL, or TCR program. Additionally, Lyell is distinguished by the fact that we have our own manufacturing center.
Our Lyell manufacturing center has a capacity up to 500 doses per year, enough to really replenish, provide all the materials we need for both our preclinical and our clinical programs. And then finally, we have a very strong balance sheet with $490 million in cash as of our last filing, which gives us the opportunity for runway into 2027 through multiple clinical milestones on our key programs, which I'm going to tell you about. First and foremost, we are focused on getting T cell function right. The target in CAR T cells is important until. But more importantly, once the T cells get to the cancer, they have to work. And so we have multiple proprietary technologies, which we're deploying across our clinical programs, to help the T cells function correctly.
We have two genetic reprogramming technologies and two epigenetic reprogramming technologies. So let me walk through these with you. The genetic reprogramming technologies, we use CRISPR-Cas9 either to overexpress or to knock out proteins. The first technology we have is c-Jun overexpression. It was discovered in Dr. Crystal Mackall's lab, Stanford, one of our founders, that one of the reasons T cells become exhausted when trying to kill solid tumors is because of a lack of AP-1 transcription factor pathway signaling, and that if you overexpress c-Jun, you can enhance this and help the T cells to resist exhaustion. As the science progressed, we also learned that this pathway was negatively regulated or restrained by a family of proteins known as the NR4A proteins.
And what happens is, if we're able to knock these proteins out, specifically NR4A3, we can open up more AP-1 transcription factor binding sites and really enhance this anti-exhaustion pathways signaling. And so using these two technologies in combination gives us really powerful anti-exhaustion technology. On the epigenetic side, we have two manufacturing protocols. We hired some very expert scientists from the NCI to help us develop this, which allows us to develop more stem-like cells as we expand the T cells during the manufacturing process. So this is our Epi-R technology to develop stem-like cells that can persist and self-renew over time.
Then we also have a very novel way of activating T cells in the manufacturing process, known as Stim-R, which are basically very tiny mesoporous silica micro rods, which can present antigens and antibodies, c ytokines to the T cells to activate them in a much more physiological way, giving us really great cell killing and better persistence. Here is our robust pipeline, and I want to walk through these with you in some details because it helps you understand how we're deploying these stackable technologies. Our lead ROR1 CAR T cell program, LYL797, we've just presented phase I data, has c-Jun overexpression and Epi-R. You can see we're developing this in triple-negative breast cancer and non-small cell lung cancer, and more recently, we've begun enrolling patients with ovarian and endometrial cancer. We've presented initial data already, which I'll walk through with you today.
Then, because it's becoming increasingly appreciated that T cell exhaustion plays a role in hematological malignancies, we have also initiated, and about to file an IND in hematological malignancies, multiple myeloma and chronic lymphocytic leukemia, in the back half of this year. Our next generation CAR T cell program, LYL119, incorporates all four of the technologies I described to you, and this recently has cleared its IND and will begin entering the clinic very soon, focused initially on the GYN malignancies of ovarian and endometrial cell cancer, or endometrial cancer. Then LYL845 is our TIL program, which will be having data in the back half of this year. This is manufactured with our Epi-R protocol, and we'll be presenting data in advanced melanoma. Of course, we have other programs coming up, pre-clinically.
So let's dive into our ROR1 CAR T cell programs, first LYL797, and then our next generation program. We obviously believe ROR1 is an excellent target, so let me spend a minute focusing on that. ROR1 is highly expressed in many different malignancies, both solid tumor and hematologic malignancies. Its expression is typically associated with a poor prognosis, and this is a protein which is expressed primarily in fetal life, but is not highly expressed in normal tissues. And in fact, despite programs in the clinic, ADCs and others, as well as in non-human primate toxicity studies, on- target, off-tumor toxicity has not been reported with this target.
So we really like this target, and as you can see here, in our own hands, with our own data from our own clinical trial, ROR1 expression occurs in 51% of triple-negative breast cancers and 35% of the very large indication of non-small cell lung cancer. From the literature, about 50% of patients with endometrial cancer and about 50% of patients with ovarian cancer also express ROR1. We're currently screening patients, and we're finding about the same numbers in our hands with our assay. On the hematologic malignancy side, there are many cancers which express ROR1. Multiple myeloma, ROR1 is expressed in about 60% of patients, and this is a novel target in multiple myeloma. And then in chronic lymphocytic leukemia, the vast majority, 95% or more, have ROR1.
So it's a good target, and we're really looking forward to exploring it fully. And the reason we've expanded this is because recently we have been able to show dose-dependent clinical activity in our initial data set, which we presented in June. This showed a 40% objective response rate, including two confirmed partial responses in patients with triple-negative breast cancer at the 150 million cell dose. We're continuing to dose escalate, but that was the highest dose achieved at June. And we have a clinical benefit rate at 60% at that dose, as well as 38% across all dose levels. Importantly, for the very first time, we were able to show that we could get our ROR1 CAR T cells with our enhancements, our anti-exhaustion technology, to expand, infiltrate solid tumors, and kill cancer cells.
This is the first demonstration I'm gonna show you today of CAR T cells infiltrated into solid tumors, as far as we're aware. On the safety side, we did not see any dose-limiting toxicities in patients without lung involvement or lung metastatic disease. However, we did observe some pneumonitis in patients with lung involvement, and we're now using dexamethasone prophylaxis in the attempt to mitigate that pneumonitis. It is treatable and manageable with steroids. Let's dive into the data. What you can see here is we've explored several doses across this study. We started the study in patients with relapsed refractory triple-negative breast cancer, and then more recently, have included non-small cell lung cancer.
You can see from the data that about 80% of the patients I'm presenting here today had triple-negative breast cancer, with just a 20% with non-small cell lung cancer. These were relapsed refractory patients, and as you can see, on average, had failed six lines of prior therapy. And here's some data. You can see here that, we were able to show two partial responses at the 150 million cell dose, that had duration through 90 days. The clinical benefit rate down at the bottom line really shows you this, emerging dose-dependent clinical activity, with 60% clinical benefit rate, at the 150 million cell dose level. And this, this is a slide demonstrating the two confirmed partial responses. What you can see here is in gray, these tumors were rapidly growing between screening and baseline.
And then you can see in purple the decrease in tumor volume and the target lesions after LYL797 was infused. So really aggressive tumors, nice benefit seen here. And this gives you some idea of the dose response, with the best response at the target lesions. And you can see even those places where you see stable disease, that's a benefit because those tumors were rapidly progressing. And then in dark purple, you can see the 150 million cell dose. This dose-dependent activity, which is really so important in a phase I study to show you have an active therapy, you can see here in the clinical benefit rate, which is stable disease, partial response, or complete response. And in addition, these patients had evidence of clinical benefit, including weight gain, they were sleeping better, feeling better. Some had improved liver function test.
On the safety side, what you can see here is in patients without lung involvement, we saw no dose-limiting toxicities, very minor CRS across the study, Grade One or Two, easily treated with tocilizumab. There were no reported events of ICANS in this clinical study. We did see dose-limiting toxicity of pneumonitis, as I alluded to, but after the index case, these patients were readily treatable with steroids. The index case did have a Grade Five event, but this was not treated in the way it was expected, and so it was diagnosed a little bit late. At this point, with investigator awareness, these patients have been well treated with steroids, so just a moment about pneumonitis. When you think about this, this is in the safety event that we believe is manageable and predictable.
We don't think it relates to on-target, off-tumor toxicity because we only see it in patients who have lung involvement. In fact, we think that it is related to local cytokine release, and it's predictable. It happens very consistently between days four and day 10, which makes it much easier for the physicians to manage. And one thing that's important to note is that pneumonitis is something that's seen very commonly in oncology clinical practice these days, whether from checkpoint inhibitors, antibody drug conjugates, and so, physicians are very comfortable in how to manage it. And based on the CD19 CAR data, which have shown that dexamethasone suppression can be very helpful in reducing the intensity and the severity of CRS, we're incorporating this now in our dose escalation as we move forward.
And now, this is some translational data from the same program that has shown we've been effectively able to have CAR T cell expansion in these patients, and this is quite distinct from what was seen in a naked ROR1 CAR T cell program done in the Fred Hutch, where they didn't use any anti-exhaustion technologies. And here we can see at both 50 and 150 million cell doses, this nice cell expansion, and this is about five times higher than what was seen without our anti-exhaustion technology. So we're very pleased to see this. And then, for the first time, we're able to show you in on-study tumor biopsies, CAR T cell infiltration into the tumor.
This is exactly what we would expect and what we showed in preclinical models, that if you're able to help the T cells overcome exhaustion, you get much better T cell infiltration. And so here, using an mRNA in situ hybridization assay, when you see this coupling of green cells, which indicate T cell receptors, blue staining, which is the nucleus, and then red, which is very specific to our CAR T, you can see that that represents undeniably a CAR T cell. And even a lot of these red dots, which are hard to see, all represent CAR T cells. So we're really proud to see this. We also saw in a tumor biopsy that was taken four months after infusion, evidence of tumor necrosis and T cells infused in...
Present, infiltrated into the tumor, as well as a lymph node that had no evidence of cancer, so at four months, we've been able to show these CAR T cells persisting, so in summary, after this brief presentation of the data, I hope I've convinced you that our ROR1 CAR T cells have dose-dependent clinical activity. They've expanded, they've infiltrated and persisted and killed tumors in patients with triple-negative breast cancer, so we believe we're on the right track. We have a 40% objective response rate at the 150 million cell dose. We are continuing to dose escalate to get better durability, as well as in potentially an increase in the objective response rate.
We haven't seen any significant safety in patients without lung metastasis, and that we're using steroid prophylaxis to mitigate pneumonitis we saw in patients with lung involvement. The translational and early clinical data have validated our hypothesis that if you can counter exhaustion in T cells, you can get better clinical benefit. I'd be remiss not to note that we've had a 100% manufacturing success rate, which makes us pleased that we've invested in our own manufacturing center. Just to say a few words about our next-generation ROR1 program, LYL119, which will be entering the clinic soon, as we've just cleared our IND. This has four anti-exhaustion technologies. The same two that I just showed you in LYL797, with c-Jun overexpression and manufactured with our Epi-R technology.
But in addition, we're now incorporating NR4A3 knockout to get even better anti-exhaustion, as well as our novel method of activating T cell Stim-R. And I can tell you that this is a dramatic step change in what we've seen, at least preclinically. And I'll now tell you, our preclinical models are validated because we've shown clinical activity. This is a non-small cell lung cancer xenograft model, and what you can see in the top panel is, in purple, LYL797, and in gold, LYL119. Now they look the same. This is at a million-cell dose. So when you give these animals one million CAR T cells, both LYL797 and LYL119 work very well. But look what happens down below when you give only 100,000 CAR T cells.
This is a very low dose in these animal models. You can see that LYL119 is able to control these tumors even at that very low dose. So this is a real step change and something that makes us very excited to, to get this into the clinic. And you can see that the comparable benefit, prolonging overall survival in these animals. And so now, in my last few minutes, I wanna turn to our tumor-infiltrating lymphocyte program, LYL845. We will be presenting data, in this program in the back half of this year. We have initiated this clinical trial in patients with relapsed, refractory advanced melanoma. We know this is where TIL therapy has worked, and so we're starting our program there to really demonstrate the benefit of our Epi-R technology.
We'll be presenting data, as I said, on about twenty patients before the end of the year. What is differentiated about our program? We're manufacturing with our Epi-R technology, and this is very specific technology, which was designed to help the manufacturing process. When you take these tumor biopsies from patients into your manufacturing center, you have to harvest the tumor-infiltrating lymphocytes. You get millions, but you have to turn them into billions of cells, expand them to such a degree, and you don't want them fully differentiated in these late-stage effector cells because they won't persist and have the durability of effect in enough patients that we're looking for.
And so we have a very proprietary media way of activating these cells and expanding these cells that gives us this nice mix of stem-like cells, which you see depicted here in this illustration in purple, as well as the effector cells that are ready to kill now. And we've designed this manufacturing process very specifically to give us the phenotype of the TIL that we're looking for. How do we know what that is? It turns out that TIL have been developed at the National Cancer Institute. They've treated lots of patients with advanced melanoma, and then retrospectively, they went back and looked: What are the phenotype of the cells in the cell products that were given to patients who responded? And this was published in Science.
What they found is those patients who are more likely to respond had cell product that were skewed towards CD8-positive effector T cells. If we take tumor biopsies and we split them, and we manufacture the TIL, either with a standard NCI-based manufacturing protocol or our LYL845 protocol at Lyell, you can see that we have nice skewing CD8 effector cells. The other thing that was learned from this retrospective study is that we want stem-like cells, and those patients most likely to respond had CD27-positive T cells, as well as the CD39-CD69 double negative T cells. You can see here in our hands, with the LYL845 manufacturing protocol, we get a substantial improvement in these phenotypic cells that are known to be correlated or associated with responses.
So we are able to make the cell numbers in a variety of tumor types, and we have the phenotype that we're looking for. Uh-oh, not advancing. Can you advance the next slide for me? Okay, and so lastly, this is an in vivo TIL model that we developed to be able to show the benefit of our TIL in an advanced melanoma model. What we do here is we take tumor samples, we divide them in two. Again, we manufacture them either with our LYL845 process or a standard TIL process, and then put them into this engineered melanoma model. And what you can see here is that at the top, no TIL, the melanoma grows very rapidly. If we use the standard TIL preparation, you can see that some benefit, but the cells are- the tumor is still growing.
Then with our LYL845 matched for cell numbers or TIL number, you can see that we're able to control the tumor given, so showing the potency of the cells that we're able to manufacture. With that, I will close and tell you that we have multiple potential milestones that we're able to get through. We have a strong cash balance of $491 million, which allows us to get through multiple clinical milestones. On the LYL797 program that I've told you about, enrollment of patients with ovarian and endometrial cancer has already begun. We're gonna submit the IND for multiple myeloma and CLL this half, and then we'll be giving a clinical data update in the end of this year, early next year, about how things are going with further dose escalation and our dexamethasone prophylaxis.
For LYL119, as I've told you, we've already cleared our IND. We're busy getting in the clinic. We'll be giving a progress update about that next year, and then data later in the second half. And then, of course, very importantly, our TIL data will be coming out before the end of the year. So thank you, and I'll be happy to take any questions you might have.