Everyone, for taking the time to join today. My name is Kevin Kong with TD Cowen, and today I have the pleasure of introducing Lyell Immunopharma, a company that we're really excited about here at TD Cowen. We're joined here by Lynn Seely, the CEO of the company, and with that, I'll let you take over.
Thank you, Kevin, and thank you to TD Cowen for inviting us here today. For those of you who may not be as familiar with Lyell Immunopharma, we are a clinical-stage oncology company developing extraordinary T-cell therapies for patients suffering from solid tumors. I will be making forward-looking statements during this presentation, so please consult our regulatory filings and website for further information. We'll simply put: people with cancer need better therapies. While it is true that cell therapies have been approved for and are benefiting patients with hematologic malignancies, success in solid tumors has not come so rapidly. Solid tumors, in fact, account for 90% of cancer deaths. These cancers progress rapidly, and in fact, most patients die within three years of having metastatic disease. This is where the real unmet medical need lies, and this is where Lyell is focused to develop novel therapies for these patients.
So what are we doing? This is a big year for Lyell. We're going to have clinical data coming from two clinical programs. We have both clinical programs in CAR T-cell therapy and in tumor-infiltrating lymphocyte. These are wholly-owned products supported by strong intellectual property and addressing large patient populations. First, we have LYL797, which is our ROR1-targeted CAR T-cell therapy, which we're developing for patients with triple-negative breast cancer and non-small cell lung cancer. And we're going to be presenting phase I clinical and translational data from 20 patients in the first half of this year, coming soon. We also have a tumor-infiltrating lymphocyte program, or TIL program, where we're enrolling patients with advanced melanoma and will then be expanding to patients with non-small cell lung cancer and colorectal cancer.
Here we have guided that we'll be presenting phase I clinical data in the second half of this year. Our third clinical program is a ROR1-targeted CAR T-cell, next-generation product with even more potency and cytotoxic capabilities of our cells in preclinical studies. Here we have an IND filing in the first half of this year. At Lyell, we're very proud of our scientific expertise, and our scientists have developed four technologies which are very important. They're epigenetic and genetic reprogramming technologies that we use to get T-cell function right. Because we believe that if you can get the cells to function when they hit the target, these are platform technologies that can be used across T-cell programs, whether it be TIL, TCR, or CAR T programs.
We're also have our own Lyell manufacturing center where we're currently manufacturing all of our clinical supply, and we are working aggressively to increase our manufacturing speed with our shortened TIL manufacturing process that we are introducing this year. And then also we have a collaboration with Cellares to use fully automated robotic CAR T-cell manufacturing. That's a tech transfer pilot project. And I'd be remiss if I didn't tell you that we have a strong cash balance with $563 million as of our last securities filing, which gives us runway into 2027 through multiple clinical readouts. Well, at Lyell, it's all about the cells, and I talked to you about getting T-cell function right.
Lyell, since its founding, has really been focused on doing two things: helping T-cells resist exhaustion and to have durable stemness, because that's where we believe we're going to have major inroads into cell therapy. This slide really illustrates that factor. One of the reasons that T-cells have been effective in hematologic malignancies, but not so much in solid tumors, is because in the hostile solid tumor microenvironment, the T-cells undergo repeated antigen stimulation and they undergo exhaustion. You see this depicted on the bottom of this illustration. But up above, the other problem is that the T-cells need to be able to proliferate and self-renew, have durable stemness so that they can persist over time. These are the two key features that we're focused on bringing to our T-cell product candidates. They're illustrated here in this slide.
What you see is that we have four technologies that are currently being deployed in our pipeline. Two are genetic reprogramming technologies where we use lentiviral vectors, or CRISPR-Cas9, to genetic reprogramming. Then two involve epigenetic reprogramming, which really are ways in which we, in our manufacturing protocols, influence gene expression not by altering the underlying DNA, but by influencing the transcriptome. And we'll talk more about those. Let's start at the top, with c-Jun overexpression. This work comes out of Stanford, Crystal Mackall's lab, where she really began to understand the mechanism of T-cell exhaustion and came to learn that if you overexpress c-Jun, you can get more activation of the AP-1 transcription factor pathway, which is, in fact, largely responsible for T-cell exhaustion. And this work was published in Nature by first author Dr. Rachel Lynn, who's currently a scientific director at Lyell.
Our scientists have continued to innovate and learn that not only is the AP-1 transcription factor pathway positively regulated by c-Jun, it is negatively regulated by the NR4A family of proteins. And in fact, if you knock out NR4A3, you can open up the AP-1 transcription factor gene to make it more accessible to c-Jun stimulation and so on in binding. And so when you use c-Jun overexpression and NR4A3 knockout together, we get complementary, if not synergistic, activation of this pathway. So that's on the genetic reprogramming side. On the epigenetic reprogramming side, each of our product candidates has Epi-R, which is a novel manufacturing protocol that we use to develop stem-like cells during the expansion process using novel proprietary media and cytokines. And then finally, we have a new Stim-R technology, which is something we've licensed from Harvard.
These are lipid-coated silica micro rods, which really represent a breakthrough technology in T-cell activation. You'll see this, being introduced into our new LYL119 program. So these technologies are all underpinned by strong intellectual property. They've been published in major journals Science, Nature, and Nature Biotechnology. And the technologies have come with scientists that now work from Lyell that are working to prosecute these programs. And so this slide shows you how these are deployed across our pipeline. LYL797 is a ROR1-targeted CAR T-cell program that we talked about. It has c-Jun overexpression and Epi-R technologies. We're enrolling patients with triple-negative breast cancer and non-small cell lung cancer. And we will have data coming in the first half of this year in at least 20 patients.
Behind that, we have LYL119, which is a next-generation ROR1-targeted CAR T-cell, which has all four of the technologies that I just described to you and we believe represents a major step change in terms of, cell potency and cell killing. And here we will be filing the IND in the first half of this year. LYL845 is our TIL program. This has our Epi-R technology, and we're currently enrolling a phase I trial in patients with advanced melanoma to be expanded into colorectal and non-small cell lung cancer. And we do have orphan drug designation for this program and will be presenting initial data in the second half of this year. And we do have a follow-on TIL program in development, which is a second-generation TIL which has both genetic and epigenetic reprogramming.
I would be remiss if I didn't tell you that we are targeting large cancer populations. There's huge unmet need in these tumor types. With the programs we've just described to you, there are about 180,000 deaths annually in these patients. There are other indications that we can expand to as we prove out our technologies in these patients. Well, let's zero in specifically on our ROR1-targeted program. Let's begin with the target. ROR1 is expressed highly in multiple tumor types, including triple-negative breast cancer and non-small cell lung cancer. It does portend a poor prognosis in these tumors. We and others believe that this is a great target, not only because, others this target has already been in the clinic. Others are developing antibody-drug conjugates to this. And to date, both in non-human primate toxicity studies and others, we haven't seen on-tumor off-target toxicity.
You can see this is with our immunohistochemistry assay, with our cutoff about half of women with triple-negative breast cancer are ROR1 positive and a third of patients with non-small cell lung cancer, exactly what we had hoped to see when we started this program. So our clinical program, LYL797, has c-Jun overexpression and uses our Epi-R technology. And what you're going to see here, I'm going to walk through some preclinical data that show you in a very aggressive syngeneic non-small cell lung cancer model that we can see the type of intratumoral killing, cytokine production, and tumor reduction that we're hoping to see. And that we can generate the cells with the right stem-like features, durability, and cytotoxicity with our Epi-R technology, finally all coming together in a xenograft non-small cell lung cancer model. So let's start with this syngeneic KP mouse model.
This is a very aggressive non-small cell mouse model. It's a model where you activate KRAS and p53 knockout that recapitulates the human non-small cell lung cancer. It's in an immune-competent hostile microenvironment that looks under the microscope very similar to what you would see with non-small cell lung cancer. It's important to note that chemotherapy PD-1 checkpoints don't work well in this model. Yet, let's look what you see when we treat these mice with our c-Jun overexpressing ROR1 CAR T cell in purple. What you can see in the first panel is enhanced intratumoral function, as shown by high levels of interferon gamma as compared to the wild-type ROR1 CAR T, and importantly, enhanced tumor infiltration.
It's important to know that if T cells can overcome exhaustion, they're better going to infiltrate into these solid tumors, which is going to be a critical success factor for seeing success in the clinic. So in the purple, you can see the much better, enhanced tumor infiltration. And then finally, this results in 50% of animals getting tumor control in this very aggressive model. This is an experiment that shows you what our Epi-R technology can do. It's a transcriptomic data set where you can see the distinct gene expression profile of cells that are expanded in the setting of Epi-R versus standard preparation in gold. And so this purple, you can see the gene sets are very different, the gene expression profiles are very different. And this translates into better serial cell killing in this assay that's shown on the right-hand panel.
You can see that the gold standard prep cells start to lose their function over time, whereas the purple cells, which represent, are manufactured with our Epi-R process, continue to have cell killing over time. This is now a xenograft model of non-small cell lung cancer using Lyell 797, combining both c-Jun overexpression and the Epi-R technology. What you can see is at the high dose of 5 million CAR T cells, you get beautiful tumor control there in purple as compared to the gold control ROR1 CAR T that does not overexpress c-Jun. You can see, again, the significant impact and benefit on overall survival in these mice. Very robust preclinical data that make us very excited to bring this into the clinic and bring out the initial data in the first half coming very soon.
This is the clinical trial design for LYL797. We're enrolling patients with triple-negative breast cancer. That's where the bulk of the data you'll be seeing in the first half will come from. These are relapsed refractory patients, also non-small cell lung cancer. And all patients are ROR1 positive. So we have enriched the study objectives are, of course, safety and tolerability, the overall response rate, recommended phase II dose. And then we will be looking at CAR T-cell pharmacokinetics and a rich translational program along with this data set. And so, from here, we're moving to LYL119, which is our next ROR1-targeted CAR T-cell program. This now incorporates all four of our technologies. So in addition to c-Jun overexpression and Epi-R, we also have NR4A3 knockout. And we're expanding and activating the cells in the setting of Stim-R.
I just wanted to dive in a bit more detail about Stim-R because we think this is a real breakthrough technology. T-cell activation has been done in the same way for decades, but this is really a new way of doing it that we've in-licensed from Harvard, from Dave Mooney's lab. With it, we brought the inventing scientists to Lyell who have continued to innovate. What Stim-R is, is a way of activating the T-cells in the manufacturing process that is much more physiologic and natural than the standard, commercially available cell activation protocols with the magnetic beads. They're lipid-coated mesoporous silica micro rods. They're cylindrical in nature. They're hydrolyzable, so they degrade over time. But they create this much more natural way of activating the T-cells and allow us to really fine-tune the signals that we give to the T-cells.
We see really substantially better results when we use this method of T-cell activation. So I'm just going to show you one slide of data from LYL119. Again, this really represents in our hands a step change over data that you've seen previously. This now looks at the same xenograft non-small cell lung cancer model that I showed you before. Here with 1 million CAR T cells, we see beautiful tumor control. Our scientists were so excited by those results, they wondered, how low can we go? You can see in the bottom panel, beautiful tumor control even with only 100,000 CAR T cells. So really potent cells that have exceptional T-cell expansion in the mice.
And then you can see with that purple dot at the end on the overall survival data, really beautiful overall survival benefit in this mouse model of non-small cell lung cancer. So again, we're very excited to get this in the clinic and are on track to file the IND, the first half of this year. And so with that, let me move now to our tumor-infiltrating lymphocyte program. I think people know that TIL are a little bit different. Here, we harvest the tumor-infiltrating lymphocytes from a tumor biopsy that the patient undergoes. We then send the tumor biopsy to our Lyell manufacturing center where we harvest the tumor-infiltrating lymphocytes and expand them from millions of cells into billions of cells. And so you might imagine that this expansion protocol is, very important.
We have a significant step in that protocol that we call our Epi-R manufacturing, which I'm going to show you some data on, which we think represents a real step change from what's been done before. I'm going to show you the data behind that that says not only can we manufacture the right number of TIL from both immunologically hot and cold tumors, but we also make TIL with the right phenotype, and a phenotype that we know has been associated with clinical responses from data in the literature. Then importantly, we also have the right polyclonality in our TIL, which is really the core feature that sets TIL apart, that these cells can react to multiple different tumor antigens. Finally, I'll bring it home with an in vivo cell model to show the improved cell killing.
And so at Lyell, we brought some very excellent scientists from the National Cancer Institute who'd worked on TIL there to help develop this Epi-R protocol for us, which really comprises proprietary media, optimized cytokine composition, and a well-defined cell activation protocol. And it was designed to bring about cells that have not only the right effector function ready to kill now, but also the cells with the right stem-like features. And this comes from data out of the literature when the NCI looked at their patients with advanced melanoma who had responded and said, what are the features of their clinical scale, their cells that they were infused with which helped them respond? And our product is designed to mirror that. And it's quite different from sort of the standard TIL prep where the cells become very well differentiated and short-lived.
This gives sort of a picture worth 1,000 words. This is transcriptomic data of TIL from five different donor tissues that were then split processed and then combined. And what you can see is the gene expression on the left-hand side in teal, LYL-845-produced TIL. And on the right in gold, those from standard TIL process. And you can see that they're very different. In these UMAPs, the clustering is quite different. You see the clustering in the upper left-hand corner of LYL-845 as compared to the bottom right-hand corner in the TIL product. And that clustering is associated in LYL-845 with more stem-like features or a more stem-like phenotype. And you can see this as exemplified down below, TCF7, SELL, CD62L on the right, showing that clustering in the upper right-hand side.
And again, this is distinct from what you see with standard TIL where you see more exhaustion-like profile. Think TIGIT or PD-1, which you can see clustering down in the bottom right-hand corner. So this is a nice example of how you activate and manufacture and expand these T cells matters. And it matters not only there was a gene expression. This is a cellular phenotype. And this again was designed to match what we know from the literature correlates with responses. You see in teal, the LYL845 process versus the standard in gray. And you see this nice increase in cytotoxic T effector cells. You also see this increased percentage of stem-like cells with the CD8, CD27 positive cells. And then on the far right, the very important CD39, CD69 double negative, cells.
These are the cells that we believe are really important to get the benefit and the durability that we're looking for. So, number is important. Cell phenotype is important. But the right polyclonality is also important. You might imagine is that you expand out cells from millions to billions. Getting the right cells represented is critical. And so we did this very difficult experiment where we decided to look at the initial clones present in the tumor tissue and then the clones present at the end of the clinical scale manufacturing. And so what we did with the initial tumor tissue is we collected the TIL and we looked at those TIL that were present at high frequency and those that had markers of exhaustion.
We speculated and hypothesized based on very careful data done in the literature that the Venn diagram, those cells that are both exhausted and present at high frequency, those are the predicted tumor reactive clones. Then we looked to see what how many, what percentage of those tumor reactive clones were present at the end of the manufacturing process in the clinical scale material. I'm delighted to report that on average, 94% of the predicted tumor reactive clones were present in the clinical scale TIL products. A very great result across these nine specimens you see here, nine products you see here. Then finally, here's an in vivo TIL model where we looked at efficacy. These are melanoma tumor-bearing mice. We took samples from two different donors and manufactured them either with standard prep or with LYL845.
You can see the mice that got no TIL treatment at all growing rapidly, then with matched numbers of the standard TIL versus LYL845. And you can see the potency of the LYL845 cells with the nice tumor control when matched for cell number with the standard TIL. So again, an in vivo model preclinically showing the more potency of our cells. And so this is the clinical trial design. This is our phase I study that's currently enrolling. I will be bringing out data in the first half, excuse me, the second half of this year. We'll be starting with advanced melanoma. That's what you can expect to see. We'll also be expanding subsequently into non-small cell lung cancer and colorectal cancer. And we'll be looking, of course, at safety, tolerability, and overall response rate.
Just to finish off here, I want to turn to manufacturing. As we all know, it's a critical success factor. I'm proud to say that Lyell has our own manufacturing center in Bothell, Washington, where we're able to make CAR, TIL, and lentiviral vector, about an equivalent of 500 doses per year. We are constantly working to improve our manufacturing technology and are introducing a shortened TIL procedure this year, which will be down to about three weeks, which is an improvement. Then we're also doing a proof of concept tech transfer with Cellares, which is an automatic robotic way of manufacturing CAR T cells, our 797 in particular, which we think will give us a decreased cost of goods and again an opportunity to scale in a very nice way. So with that, I will close and take any questions you may have. Please.
Just to clarify, is the Epi-R an epigenetic modification or is it more of a selection process as you see it? Yeah. It sounded like a modification or started and then as you described it sounded more like selection? No, it's absolutely an epigenetic modification. And what we do is we give sort of a, we almost trick the cells into changing their metabolic pathway. We give them a functional caloric restriction with the media that we're using. And so they start using an oxidative phosphorylation metabolic pathway as opposed to a glycolytic metabolic pathway. And this is something which then persists with them over time, which we've shown in in vitro studies. So it truly is an in vitro, I mean, an epigenetic modification as opposed to a selection process. So it doesn't take additional time or steps. It's part of the manufacturing protocol, itself.
Thank you for that. Any other questions? All right. Thank you.