Cell and gene therapy company primarily focused on oncology indications. Tim?
Thanks so much, and it's great to be here and have the opportunity to share with you what we're doing at Senti, which is engineering the future of cell and gene therapies. For a start, I wanted to share our standard disclaimer regarding the information to be presented in this presentation. So Senti is a clinical stage company focused on developing next generation cell therapies for important unmet clinical needs. We are very much focused this year on generating valued, accretive clinical catalysts, including our product, SENTI-202, which is purposely designed to tackle the key outstanding issues in the treatment of cancers, in this particular case, Acute Myeloid Leukemia. We look forward to be able to share initial clinical data before year-end 2024 , as well as future data in 2025 regarding durability of this product.
We're also very excited to have a second program called SENTI-301A, which is designed for liver cancer, which is targeted at first patient dosing for this year. SENTI-202 is tackling one of the central challenges in oncology, which is that current treatments do not precisely distinguish between cancer cells and healthy cells. The vast majority of products that are being developed today rely on a single target that has to be really well expressed on cancer cells, but not expressed on healthy cells in order for the drug to find a suitable therapeutic window. However, for most cancers, that perfect target doesn't exist, and this lack of specificity leads to limited efficacy, relapse, and safety issues, so SENTI-202 is designed with our proprietary Logic Gate technology to overcome these key challenges.
We attack AML disease heterogeneity through our Logic Gate technology, going after targets like CD33 and FLT3, which are well-validated in the AML space. And in addition to that, we've built in our Logic Gate technology to protect healthy cells from being killed. We believe this has a tremendous opportunity for patients who unfortunately are suffering with AML, but also, if successful, the ability to broaden this approach out to a wide range of solid tumors that have this similar issue. So Senti's core platform technology that has driven the development of our exciting platform programs are shown here.
What I'll focus on today, with regards to our SENTI-202 product, is our Logic Gating platform, which allows us to sense disease cells as well as healthy cells, and depending on the presence or absence of disease targets or healthy targets, we can program the cell therapy to decide whether to kill or whether not to kill, and that gives you a great amount of control over specificity and efficacy. In addition to that, though, we have developed what we call multi-arming gene circuits, enabling cells to produce multiple therapeutic payloads to maximize the therapeutic response. We have a technology called the Regulator Dial, which allows us to use FDA-approved small molecule drugs to control the activity of the cell or gene therapy product.
And we have a variety of ways of engineering cell and gene therapies to be smart through our Smart Sensor technology, allowing these products to detect when and where they should actually be active in the body. So our Gene Circuit platform is being used to advance a variety of really exciting programs. I'll focus most of our discussion today on SENTI-202, which is a CAR-NK program designed to go after CD33, as well as FLT3 in AML, MDS, and other blood cancers. We are in the clinical stage of development for this particular program. I'll briefly touch upon SENTI-301A, which is our GPC3-targeted CAR-NK product for liver cancer. We also have two collaborations, one with Roche/Spark around AAV gene therapy, where Senti has designed very, very specific and strong promoters that allow us to achieve very targeted and specific gene therapy opportunities.
We also have a collaboration with Bayer/BlueRock, engineering our gene circuits into iPSC-derived cells. We're very excited to have a great roster of team members at Senti. We're based out in South San Francisco. I'm joined by Yvonne Li, our CFO, and Kanya Rajangam, who's our President, Head of R&D and CMO, and has a wealth of experience at cell and gene therapy and cancer development companies. So let me tell you a little bit more about SENTI-202, which is the product we're very excited about. SENTI-202 is designed to go after relapse refractory AML, which unfortunately is a very severe disease with a high unmet need, with a median survival of about five months.
AML is difficult to treat for a variety of key reasons shown here on the left, including disease heterogeneity, which leads to poor durability of response, toxicity of treatments against healthy cells, as well as that leads to essentially treatment tolerability challenges. For these patients that are in this category, there's not many great opportunities for them currently a llogeneic hematopoietic stem cell transplant is the curative option, but is limited generally to younger or fit patients. And as I'll show you the next slide, one of the key challenges that we aim to overcome in AML is this disease heterogeneity, largely caused by the presence of residual leukemic stem cells, or LSCs, that exist in the patients post-treatment that are not killed and that can regrow and repopulate the tumor. So here's the general concept here.
Shown on the left-hand side, imagine having any cancer, in this case AML, be a mix of leukemic stem cells, which are rare cells in the population that are not well attacked by the current therapies. So even if you're able to wipe out the majority of the AML blasts, if these leukemic stem cells survive, they can repopulate and cause relapses. This has now been seen in a variety of clinical studies associated with diseases like AML, where, for example, Dana-Farber illustrates that increased presence of these leukemic stem cells does lead to an increased risk of relapse, even post-transplantation in these patients. No available therapies today specifically target LSCs, primarily because leukemic stem cells look very, very similar to hematopoietic stem cells, and so it's hard to tell them apart using conventional approaches. So how does Senti solve this issue?
As I mentioned, SENTI-202 is a first-in-class, off-the-shelf product based off of the use of adult peripheral blood-derived NK cells. These natural killer cells have baseline anti-AML activity, which is great. On top of that, we transduce the NK cells with a virus that carries three important genes. The first gene is shown here on the upper left, which is a bivalent activating CAR that goes after two different targets in AML, CD33 and FLT3. Both these targets are well known and well validated to be good targets in AML and allow us to attack AML blasts and leukemic stem cells with great efficiency. Now, it seems obvious that you would go after these targets since they're pretty well known, and putting them together should give you greater efficacy. So why hasn't this been done to a greater extent by other approaches?
It turns out that both CD33 and FLT3 do have off-target, off-tumor expression, that leads to the limited therapeutic window. So, for example, FLT3, if you simply go in and try to attack cells that have that, you not only will kill the leukemic stem cells, but you run a risk of killing the healthy hematopoietic stem cells. And that's unfortunately a limitation to single target approaches such as bispecific T-cell engagers, ADCs, or conventional cell therapies. So we get around that through the use of our gene circuit platform. What we've designed here is what we call an inhibitory CAR, which is shown here in the middle gene. It basically recognizes healthy hematopoietic stem cells through a target called endomucin.
Endomucin was identified by Senti to be highly expressed on the healthy cells, but not on the cancer cells, and that basically shuts down the activity of the NK cell and protects these healthy cells from being killed. Lastly, we have our Calibrated Release IL-15 technology, which is an IL-15 that is on the cell surface, but also secreted and has this dual activity of both autocrine and paracrine signaling. As I mentioned earlier, SENTI-202 is designed to address the key challenge of AML heterogeneity, and the way we do that is, again, through three key killing mechanisms. The first is the use of NK cells that innately kill cancer cells. Two is the CD33 targeting element allows us to very efficiently go after AML blasts, since CD33 is well expressed in that population.
FLT3 is also expressed on leukemic stem cells, and that element of the CAR allows us to really target those cells for a substantial killing activity. Now, NK cells, we believe, are a great choice for this particular application. It is very difficult to derive autologous T-cells in AML, whereas NK cells have this innate activity and can be made off the shelf, especially for patients that may not have time to tolerate the extraction and development of an auto CAR T, which has not been very successful in the past. So we have run a variety of preclinical studies as we develop this program, showing that SENTI-202 CAR NK cells, shown in blue here, have significantly elevated killing compared to non-engineered NK cells, and this is across a wide range of diverse AML subtypes, of which there's a lot of diversity out there.
This basically lends itself to the idea that we are essentially bolstering the overall anti-tumor killing activity by using our SENTI-202 gene circuit. We have presented this data, as well as others, in a variety of scientific conferences. This is just a snapshot of our in vivo data showing that with our SENTI-202 treatment in mice, we're able to achieve significant long-term survival of a significant poor population of mice over 230 days. And this includes models such as MV4-11, as well as venetoclax-resistant AML, which is very exciting to be able to demonstrate. Now, as I mentioned earlier, why hasn't this been done in the past?
It turns out that many and almost all of the antigens that people have identified as AML targets are not just expressed on AML cells, but they're also expressed on healthy cells, including the healthy stem cell population. And so it's been challenging to rely on a single target to give you both efficacy and safety, therapeutic window at the same time. Again, we do that by our inhibitory CAR element that recognizes endomucin. Endomucin has been shown in our studies to be expressed on up to 76% of hematopoietic stem cells and not on the leukemic stem cells or blasts. So this is the only CAR NK program that we know of utilizing this inhibitory CAR or NOT Logic Gate technology to protect healthy cells, and we're very excited about this approach.
We have shown now through a variety of studies on the left and the middle here. This is in vitro studies, showing that we're able to achieve around 75% or more hematopoietic stem cell protection. These hematopoietic stem cells in the middle here are so active in that they continue to form the colony-forming units that lead to downstream lineage differentiated cells. This does translate in vivo, which is shown here on the right, where after treatment, we're able to see an increase in the overall healthy cell population in a mixed model. Finally, as I mentioned, our third gene in this product is Calibrated Release IL-15. We have shown on the left-hand side here that this IL-15 is indeed active.
It can stimulate the NK cells themselves, as well as transactivate surrounding immune cells, including other T cells in the body. So this dual activity of keeping the NK cells that we're infusing alive, but also stimulating other immune cells in the body that may play an important anti-tumor role, is a key feature of this Calibrated Release IL-15 technology. On the right-hand side, we do show that this program, this component does allow us to achieve greater in vitro which is up on the right-hand side, and on the bottom right, in vivo persistence and NK cell levels. So we're very excited about this being able to generate good NK PK in mice. As I mentioned, SENTI-202 is in the clinical phase currently.
Our clinical study is designed with two different dose levels, one billion CAR NK-positive cells for the first dose level, escalating to one point five billion. This is a great starting dose, and we believe that this will lend itself well to potential results in patients that we hope to disclose this year. We do have the ability to dose expand into specific AML populations, as well as MDS, and by doing so, be able to access and demonstrate the utility of this program potentially in these diverse patient populations. The SENTI-202 phase 1 trial design is shown as follows, essentially involves a lymphodepletion step, which uses Flu/Ara- C, which is AML-specific lymphodepletion. This is followed up with three doses of SENTI-202 at Day zero, Day seven, and Day fourteen.
Efficacy can be assessed at 28 days, and the patients do have the ability to go into downstream additional cycles, if desired. We believe this protocol is very well suited for NK cells being generally quite safe in patients based on previous studies, the allogeneic off-the-shelf nature of the product, and the ability to repeatedly dose patients, whether upfront or later on, as necessary to treat the disease. Just briefly mentioning why the use of Ara-C. It turns out Ara-C has a nice potential synergy with the SENTI-202 product. This is showing a particular cell line called KG1A, which is a low expressor for CD33 and FLT3, which are the two targets the SENTI-202 is going after. After treatment with Ara-C, you actually see increased expression of CD33 and FLT3, and this does translate to enhanced cytotoxicity.
So there's also potential synergy for using this particular type of lymphodepletion in patients with AML. So as I mentioned, we're really excited about SENTI-202. We do anticipate clinical efficacy data release in before year end. This product has been purposefully designed to go after well-validated AML targets, CD33 and FLT3. We have shown in a variety of studies the ability to achieve highly efficient killing of both leukemic stem cell and blast across heterogeneous AML population. One of the key differentiators of this product is the addition of the endomucin inhibitory CAR that is shown to protect healthy hematopoietic stem cells, and we think this will potentially lend itself well to a good therapeutic window in vivo and hopefully drive efficacy.
More data on this can be found in our recent publication in a Cell Press paper, as shown below, and this will be-- is available through our website. So please feel free to check that out and also reach out to Senti in case you're interested in finding more information. So let me tell you a bit more about Senti's additional clinical programs, including SENTI-301A. SENTI-301A is a CAR NK cell targeting GPC3, which is a well-validated target in liver cancer. It also contains our Calibrated Release IL-15 technology as well to drive potentially stronger solid tumor responses. We're very excited about this program. GPC3 has had some really interesting data emerge over the last year in the CAR T setting.
However, we think the profile of CAR NK cells being able to have high degrees of safety, as well as the ability to be at, in the liver at high concentrations, lends itself well to this product profile. Due to the high prevalence of liver cancer in China, we have established a strategic collaboration with Celest Therapeutics that involves them developing the program through a dose-finding trial design in China to enroll about nine patients with advanced GPC3 expressed in liver cancer. And this study will allow us to take an early look at the efficacy and the safety of this product there, as well as then to potentially advance this program outside of China under the Senti rights.
GPC3 is expressed in multiple solid tumors, not just liver cancer, and so I think there's opportunity in liver cancer as well as with successful data expanding this into other solid tumors. We have published this data as well, but just a snapshot here on the left-hand side, we do see very robust serial killing over six to seven days of repeatedly adding cancer cells to the population. We see that SENTI-301A continues to robustly kill those tumor cells, whereas unengineered cells essentially peter out by the second and third cycles. This does translate to significant in vivo activity, as well as infiltration of the SENTI-301A cells into the solid tumor. This protocol is being designed in a similar fashion to AML, although we are using Flu/Cy lymphodepletion here instead of Flu/Ara- C.
Again, multiple doses can be given at Day zero, seven, and fourteen, as well as at multiple dose levels, and the ability to assess at the end of the treatment cycle and repeat dosing. Finally, I really want to emphasize that our platform here, although the first two programs are focused on NK cells, do have tremendous opportunity to be expanded into other cell and gene therapies. In particular, Senti has established what we call the Reveal Design Platform, which integrates bioinformatics on both public as well as our internal proprietary datasets, as well as integration with AI machine learning technologies that allows us to rapidly design and test hundreds of thousands of, and millions, up to millions of different gene constructs, whether it's through pooled library screens or robotic screens.
This allows us to rapidly iterate through our design, build, test, learn cycle and improve the development of cell and gene therapies across modalities. This includes NK cells, T cells, gene therapies, iPSC-derived cells, et cetera. I did wanna highlight that this Logic Gate technology, we're super excited about, because as we demonstrate the proof of concept in the clinic, we think the opportunity to expand this now into solid tumors is gonna be tremendous, so we've demonstrated the Logic Gate works well in both NK cells as well as T cells for solid tumor targets. I just wanna show you a highlight here of what this actually looks like in real life. Here we have a mixture of cancer cells and healthy cells. Cancer cells are in red, healthy cells are in green.
With no treatment, as you'd expect, both of these grow and overtake the culture over time. If we design a CAR NK cell in the middle here that only goes after the cancer target, CEA, but that cancer target is expressed on both the cancer cells and the healthy cells, what happens? What you can see here is that both the red cells and the green cells are being killed, and that's undesirable from the perspective of a therapeutic window. However, CEA is expressed on healthy cells, and so what we did is look at those healthy cells and identify a protective antigen, in this particular case, VSIG2. VSIG2 is highly expressed on those healthy cells and not on the cancer cells.
What you can see here is, when we treat those populations, sorry, with our Logic Gate technology, what you can see is we selectively kill the red cells, but we spare the green cells from being killed. This is super exciting, and we think there's a tremendous opportunity for this downstream. Let me wrap up. I really appreciate you taking the time today to learn about Senti. Our gene circuit technology platform has been well-validated and is in the clinic for the treatment of AML, with SENTI-202 as a potential first-in-class, best-in-class program in those patients. We do anticipate initial efficacy data soon, certainly this year, with follow-on additional durability data in 2025
Our SENTI-301A program leverages our multi-arming technology, for example, with our Calibrated Release IL-15, to improve the overall activity of NK cells for solid tumors, and we expect that patients to be enrolled this year as well. We do have an experienced, very experienced management team in terms of executing on these therapies, and as I mentioned, our gene circuit technology has now been validated across cell types, including NK cells, T cells, AAVs, iPSCs, and other. So with that, I'd really like to thank you again for taking the time. Appreciate the opportunity to share this. If you wanna reach out and chat more, we'd be happy to engage further. Thank you very much.
Thank you, Tim, for that fantastic presentation. I'd also just like to extend a thank you to all of our presenters this year, as well as everyone who took the time to watch this presentation. I hope you have a great rest of your conference.