Hematologic malignancies, specifically aggressive large B-cell lymphoma, which we think is going to be a true next-generation disruptive CAR T-cell program, and also are continuing to work on the next wave of cell therapy innovation for solid tumors. Here, I want to tell you in a nutshell really the most important things to know about Lyell. We are a late-stage clinical company entering pivotal trials with a strong balance sheet. Our lead program, IMPT-314, is a dual-targeting CD19/CD20 autologous CAR T-cell product candidate with the potential to be a disruptive innovation for the treatment of second and third-line aggressive large B-cell lymphoma. This program is expected to enter pivotal development by mid this year.
In addition, we're developing next-generation solid tumors, CAR T-cell programs, CAR T-cells that are fully armed with a suite of proprietary technologies, including our clinically validated anti-exhaustion and durable stemness technologies, as well as new enhancements designed to overcome the hostile tumor microenvironment. This program is expected to end the clinic next year. Lyell has scalable manufacturing strategy. Very specifically, at full capacity, we have the ability to launch out of our Lyell Manufacturing Center with a capacity of over 1,000 doses per year. This really gives us control over our manufacturing, a very important advantage for us.
We have a strong balance sheet as of our last 10-Q filing, $460 million in cash, but we finished the year with $384 million in cash, which will be reflected in our upcoming 10-K filing, which does reflect an upfront payment we used for the acquisition of ImmPACT Bio at the end of last year and the acquisition of IMPT-314. With disciplined expenses, we have a cash runway into 2027 through multiple clinical readouts, which I'll be telling you about, including new pivotal programs. Finally, Lyell has a team of cell therapy pioneers on our board, on our management team, and really seasoned drug developers. We have the ability to bring to patients these next-generation products that they so desire. Our lead program, 314, is a dual-targeting CD19/20 CAR that we presented recent data at the American Society of Hematology at the end of last year.
Based on these data, we expect the program to enter pivotal trial in mid-2025. At ASH, what we were able to show is a 94% overall response rate and a 71% complete response rate with 314, all with a manageable safety profile, including no high-grade cytokine release syndrome and low rates of grade 3 ICANS or neurotoxicity. The key differentiators of our dual CAR T-cell therapy, what we really believe sets us apart, is that it was designed to achieve more complete responses as well as bringing longer duration of responses because it is a true CD19/CD20 or logic-gated CAR. What that means is it has full potency at CD19 or at CD20, giving it a broader ability to kill malignant B cells. Our CAR T-cell products are also enriched for CD62L expressing cells.
These are naive T-cells and memory cells that persist longer and have longer duration of action, therefore prolonging the duration of those complete responses. All of this is aimed towards giving patients what they most want: a one-time treatment that has potential to provide them with longer disease-free, treatment-free intervals, and of course, bringing the hope of cure. Based upon these very exciting data, the way that they're continuing to emerge, we have committed to doing both a pivotal trial in the third and later lines of aggressive large B-cell lymphoma and also in the second line. You'll see this reflected on this pipeline slide. First, you see the third line program where we have fast-track designation. We showed the initial data at ASH, but we're going to be presenting more mature data mid this year, as well as initiating the pivotal trial.
In the second line, we are actively accruing those patients and will be submitting or showing the initial data mid this year with more mature data later in the year. Based upon the way the data are emerging, we stated that we intend to initiate a pivotal trial late this year or early 2026. Of course, we are continuing to pursue solid tumors. I am using our anti-exhaustion, stemness, and new technology to help fight against the hostile tumor microenvironment. Here, the target is as yet undisclosed, but we expect this program to be in the clinic in 2026. Let us dive deeper into these program 314 for aggressive large B-cell lymphoma. Many people say, "Why do you need another CAR T-cell for a lymphoma?
I thought the field was already crowded. It is a true statement that CD19 CAR T-cell therapies have made transformative benefit for patients with lymphoma above and beyond chemotherapy. The factor remains that there is a great need for higher complete response rates for these patients with longer duration of response. Because despite the benefits seen with the CD19 CARs, there is tremendous room for better therapies. In fact, when you look in the third line setting, approximately 50% of patients treated with an approved CD19 CAR T-cell therapy do not achieve a complete response or remission. 30% do not respond at all. In fact, if you look at the graph on the right, this is progression-free survival from Yescarta, the market leader in the third line setting. What you see is by six months, 50% of the patients have either died or progressed on this therapy.
The overall survival at one year after approved CD19 CAR T-cell therapy is only 50%-60%. There really is a tremendous need for better therapies. IMPT-314 was designed to bring exactly that to this multi-billion dollar marketplace, a disruptive therapy with better responses. Here you see that the worldwide sales are already $3 billion and expected to grow by $6 billion, largely based upon more uptake in the second line setting and greater availability as more community hospitals are adopting cell therapy. We think this will advance even further, grow even further with better therapies with acceptable safety. This slide really shows the state of the field as it is now and why there is room for a new therapy with higher response rates and longer duration of response. It's a lot of data on this slide, but let me walk you through it.
On the top, what you can see, the top white panel shows the approved therapies. The very top line is Yescarta, the market leader, and these are data from the third line approval trials in the third line. What you see in the first column is overall response rate, 72%. Right below that, you see Breyanzi and their third line setting registration trials, a response rate of 73%. Next to that, complete response rate of 51% or 54%. That's clearly better than what chemotherapy could provide. Let's look down below now. This is data from UCLA where the CD19/CD20 construct that we're using today was invented. In a single center study conducted there, this construct, these CAR T-cells delivered a 92% overall response rate, comparing very favorably to what you see above at 70%. The complete response rate was 77%.
Now, this was a single center trial in multiple histologies, but this was outlicensed and is now being developed as IMPT-314. You can see data that were presented at ASH last year in a multi-center study with all relapsed refractory large B-cell lymphoma, 94% overall response rate and 71% complete response rate. Now, these data are in a relatively small number of patients compared to what you see above. If this data set continues to mature in the way that it looks, this is a meaningful, has the potential to bring a meaningful advantage to patients. If you look at the safety, you see something that looks very much more Breyanzi-like with an ICANS rate of about 13% compared to the 31% you see with Yescarta. Again, an opportunity to bring benefit to patients both with better efficacy as well as a manageable safety profile.
Sometimes people say, "Well, why are you developing both in the second and the third line? Isn't CAR T-cell therapy the standard of care for the second line?" That, of course, is true. The reality is that many of these patients are treated out in the community. They get their first-line therapy with R-CHOP. As they progress, very often in the community, they're started on second-line bridging therapy before referral to a CAR T treatment center. This gives us an opportunity by developing both in the second and the third line to treat the largest number of patients. The third line, of course, pathway to approval is faster with hopefully a single-arm trial being what's required for registration. This slide depicts the construct that we're using.
It's a true CD19/CD20 or logic-gated CAR, which is designed very specifically to bind to either CD19 or CD20 with high potency. You can see it as a 41BB CAR. We are the only company that we're aware of that is enriching our CAR T-cell product for naive and central memory T-cells. These cells, we believe, give better engraftment and have the opportunity for improved persistence and better duration and outcome for patients. You can see some of the data that support that concept in this next slide. This is data from the Zuma7 clinical trial of Yescarta, where they looked very specifically at patients who'd received cell products with higher naive T-cell phenotypes versus those who received lower, in gold, naive T-cell phenotypes.
What you can see is that those with more naive T-cells in their cell product had better overall survival than those who did not. Finally, on the right-hand side, why are we including CD19 as well as CD20? It's because CD20 tends to have greater stability and retention of expression when you're exposed to other CAR T-cell therapies. You can see in this panel that CD19 and CD22 antigens tend to be lost as exposed to other CAR T-cell, single CAR T-cell therapies. We believe by giving the doublet of CD19 and CD20, we'll be able to retain and have less antigen loss. Here, data from the UCLA phase single center trial. This was patients with mixed histologies, all relapsed refractory B-cell non-Hodgkin's lymphoma. The overall response rate was 92% with a 77% complete response rate.
You can see here the majority of patients were treated with 50 million cells, and you can see complete response rates lasting over four years in some patients. One patient in particular, you can see had relapsed after four years, was retreated with the same CAR construct and went back into complete response. Overall, these responses were durable, and the median progression-free survival was 50.1 months. This compares very favorably to what has been observed, and I showed you previously with the CAR T-cell CD19s that are approved. Here you see an example of one patient who at screening was CD20 positive, but CD19 dim/ negative. This is a patient, you might imagine, may not respond well to a CD19 CAR T-cell therapy. This patient went into complete response for 18 months, then did recur with a mixed population of cells, some which were CD19 negative.
The patient was retreated with cells originally manufactured at the beginning of his treatment and went back into CR. Based on these very promising clinical data out of UCLA, the multi-center IMPT-314 trial was launched. This is a phase one two trial. The recommended phase two dose moving forward is 100 million cells. There are multiple cohorts being enrolled, focusing now on the third line CAR T-naïve , where I'm going to show you some data, and also actively enrolling the second line CAR T-naïve patients as well. Here are the data that were presented recently at the ASH meeting in December. What you can see here is this was a very standard patient population of large B-cell lymphoma with a median age of 65. Most patients had diffuse large B-cell lymphoma.
On the characteristics on the right, what you can see is a relatively significant patient population with significant disease. The median lines of therapy were three, ranging up to six. About half the patients had a high LDH, which represents a significant tumor burden. Here is the safety profile. What you can see was there was no high-grade CRS seen, no grade three or greater CRS, and that there was about a 13% rate of grade three ICANS, which is again very much in line with the type seen with Breyanzi. Overall, a very manageable safety profile. If you look now at the best overall response, you can see that the overall response rate consisting of both partial responses and complete responses was 94%, and that with a 71% complete response rate. This slide represents the swim lane plots.
Here you can see each patient is represented by a single line. Green represents complete responses. Blue is partial responses. You can see in some patients, a deepening response over time. Again, very nice overall response rates and complete response rates. While we're extremely excited about the promise of 314, we're also continuing to pursue and develop our next generation CAR T-cell therapies for solid tumors. To do this, we're using multiple approaches and very novel technologies to enhance the function of our CAR T-cells to really address the need in solid tumors. We have very proprietary anti-exhaustion technologies where we edit the CAR T-cells to be able to fight against exhaustion. In the first place, we overexpress c-Jun, which is a positive regulator of the AP-1 transcription factor pathway, which controls T-cell function.
We knock out NR4A3 expression, which is basically a negative regulator of that same pathway. These two taken together, cJun overexpression and NR4A3 knockout, are very potent anti-exhaustion technologies. We couple that with EPR, which is a manufacturing process we use to develop or to have our CAR T-cells have durable stemness to be much more likely, more stem-like, and able to persist and self-renew over time. In addition, we are using some new technologies to enhance our CAR T-cells, to enhance cytokine signaling to help overcome the hostile tumor microenvironment. By developing fully armed CARs, we hope to be able to approach in next year, bringing into a clinic a new program with an undisclosed target for solid tumors.
Just by way of summarizing, we're excited, incredibly excited about IMPT-314, our dual-targeting CAR T-cell product, which we think has a tremendous advantage in the lymphoma space. We bring together the scientific expertise, the capabilities, and the manufacturing to be able to develop at scale. We have a strong balance sheet, which enables us to get through multiple clinical milestones, which I've listed here, so that you'll be able to see the data, more mature data in the third line setting, as well as initial clinical data in the second line setting mid this year, with more mature data coming in the second line setting later on in the year. We'll be beginning pivotal trials both in the third line setting as well as in the second line setting. I think I'll stop and take any questions you have.
Thanks so much, Lynn. I can say that we're really excited for that data release mid-year. To kick it off, sort of in that mindset, IMPT-314's initial third line plus phase one two data was presented at ASH of last year. Now you're expecting to report the second line and third line data, more mature data later this year. What are the differences in efficacy and safety expected between the second and third lines?
That's a great question. I think in general, what has been seen with the CD19 CARs is that as you move earlier in the disease from third line to second line, typically response rates and complete response rates go up higher and also duration of response lasts even longer. What we're really looking forward to is being able to show more mature data over time.
We were enormously pleased with the data released at ASH, particularly that it confirmed so nicely what had been seen out of UCLA. Their single center data was then seen in a population of patients that were all relapsed refractory large B-cell lymphoma. The data were still relatively, were not as mature as we might have liked. We would love to see more patients with longer duration of follow-up. That is what you can expect to see in the third line setting mid this year. In the second line setting, that is a larger marketplace and one we are very interested in. Hoping to bring out very promising data in that setting as well.
Awesome. Kind of staying in sort of the mindset of the second line, it is a considerably larger addressable market. Are there any limitations?
I know that you talked about the manufacturing capacity of about 1,000 CAR Ts. Are there any limitations to the scalability of autologous CAR T-cell therapies? What are some distinct challenges there? How is Lyell tackling them?
Yeah. I think certainly we believe that given the ability to have more than 1,000 doses at scale in our current manufacturing center, that allows us to get off to a great start with commercial launch. Ultimately, we'll need more capacity. I think we're constantly looking for ways to be able to do that in as efficient a way as possible. As we all know, the technology with manufacturing is improving by leaps and bounds. Step one is to be able to get into commercial launch with what we have at full capacity and then to think beyond that.
I do think capacity is, of course, important. This is a marketplace which is addressable, I think, with autologous cell therapy, which really has limited it a little bit as the ability to get out into the larger community centers. I think with better efficacy and a manageable safety profile, that will give us an advantage as we move out into the community.
Awesome. Thinking about those data releases, are you targeting any medical conferences for the releases here? Yeah, are you targeting any medical conferences?
We haven't given guidance at this point on where we will be presenting the data, but I think, yes, medical conferences are always preferred when possible.
Okay. With those releases, would you be able to disclose approximately what length of time on drug the second line patients will have been on?
What is the enrollment status of that part of the trial? Is it fully enrolled?
Yeah. What you will be seeing mid the year will be relatively early data, not dissimilar to what we showed at ASH for the third line last year, but you will see that data continue to mature over the course of the year. This trial has been enrolling for a while, and it continues to enroll in the second line at a nice rate. I think that just speaks to the enthusiasm of the investigators and that they are putting their patients in the second line into this investigation, recruiting into this clinical trial, even though there are approved second line therapies on the market. I think that gives you a good idea that there remains need in this space.
Got it.
Thinking back on the third line CAR T-naïve patient population, 94% ORR, 71% complete response rate, what's the confidence that those numbers, that ORR and that CR will translate to durability of response?
Yeah. I think that's left for us to prove. I think based upon the mechanism of action and the UCLA data, I think we feel confident that that will be the case. I think there has been other data that have been published coming out of China with a similar dual-targeting CAR construct that have also been able to show nice duration of response. I think taken together, we feel quite confident. Our data, of course, will need to mature and will need to demonstrate that.
I think you can see our enthusiasm based upon the fact that we're moving forward into pivotal trials both in the second and the third line setting.
Got it. Makes sense. Switching gears a little bit to the solid tumor programs, what are the differences and challenges between treating liquid and solid tumors with CAR T?
Yeah. I think the operation and the logistical challenges are very similar. The cell therapy centers that treat these patients are the same. Everything we have learned in solid tumors applies to hematologic malignancies and vice versa. I would say hematologic malignancies are easier in some ways. Obviously, that's where the approved CAR T-cell therapies have made the most headway. We have to think of that as sort of the lower hanging fruit.
Solid tumors tend to be challenging, which is why we are approaching them now with what we call our fully armed CAR T-cell product candidates, where they have both very potent anti-exhaustion technology because the CAR T-cells have to kill in this sort of they get repeated antigen stimulation in these solid tumors. They have to really be able to stand up over time. This anti-exhaustion technology really helps them do that. Also, enhancing their cytokine signaling also we believe is going to be an opportunity to add additional cytotoxicity and killing power to our CAR T-cell therapy. I think solid tumors is something that has held great promise for CAR T-cells, but continues to need more work. We are very excited about this combination of sort of coupling our anti-exhaustion technology with some cytokine signaling.
Awesome. Makes sense.
Lynn, Charlie, thank you so much. This has been incredibly helpful to us. Thank you to all of our investors who've dialed in as well. We really appreciate your time.
Thank you for having us.