Okay, thanks very much, Yao, and thank you to Jefferies for hosting us here. My name is Anish Suri. I'm the CSO and President for Cue. This is my disclaimer slide here. So moving on, I really want to touch upon a very central premise that we've been addressing through the platform that we've developed, which is selective modulation and perturbation of disease-relevant immune cells, with the, with the really is the main goal of trying to restore immune balance while preserving patient safety. So we've worked on this on both ends. We've made a tremendous amount of progress on the oncology side, where we focused on selective enhancement of tumor antigen-specific T cells while sparing broad immune activation. And we'll show you clinical data that validates this, essentially, the entire technology platform through this experience.
On the autoimmune side, we've got two very exciting programs that are progressing quite strongly. One, focused on selective induction and expansion of regulatory T cells. This is an alliance with Ono Pharmaceuticals on a very novel bispecific molecule. The second is a program where we've developed a novel biologic for selective depletion of pathogenic B cells for autoimmunity, which we believe offers CAR-T-like potential with the biologic, and I'll touch upon these as we go through. The entire platform sort of comes from this fundamental immunological node, which is how a T cell recognizes its antigen, which is essentially in context of a cell-cell interaction with the T cell interaction with an antigen-presenting cell. The two key signals there are the T cell receptor engaging the peptide HLA complex.
That sets the specificity and selectivity, along with the appropriate secondary signal, a costimulatory signal. And this is what the platform is built on. Instead of depending on any APC, we can make this on an antibody Fc scaffold. You bypass the whole need for antigen presentation and processing and essentially have a biologic that can directly engage the T cell receptor of disease-relevant T cells and selectively deliver signals to those very T cells, hence avoiding sort of the broad, immune activation that a lot of immune, modulation modalities face, okay? So with that as a background, we went and developed the CUE-100 series, which took advantage of interleukin-2. This is a validated molecule. It's a validated cytokine. The challenge has been all around safety, tolerability, and specificity.
As you can see here, targeting interleukin-2 via the T cell receptor generates a very unique proposition for creating a therapeutic index for this very important cytokine. So again, the 100 series in the middle there, it has bivalent peptide HLAs. The yellow circle is the tumor antigen epitope that guides it to those T cells that have the right T cell receptor, along with that, 2 molecules of interleukin-2, that are affinity attenuated on either end. The key being that you need both the TCR engagement and the IL-2 receptor engagement for proximal activated signaling, and that's what you see in the microscopy experiments on the right, done with Mike Dustin's lab at Oxford, where the right T cell engagement results in formation of an immune synapse and signaling components.
Whereas the irrelevant T cell, where the TCR is not engaged, the IL-2 by itself is relatively inert. And remember, the irrelevant T cells are essentially 99.99% of T cells in a patient's body. The tumor-specific T cells are a very, very small fraction, okay? So with that, we took this forward into the clinic. The first molecule is CUE-101 that targets HPV-specific T cells. This is in head and neck cancer. CUE-101 shown on the left there, it's got an epitope from the HPV16 E7 protein. This is a viral proto-oncogene. We took it initially in late stage, second-line, and beyond recurrent metastatic head and neck cancer patients as a monotherapy. These are patients that have failed several lines of prior therapy, including checkpoints, cetuximab, chemoradiation, et cetera.
In the frontline recurrent metastatic setting, we've combined this with Keytruda, and both of these datasets are looking extremely promising and exciting, and we just gave an oral presentation focused on this at ASCO a few days ago. In the locally advanced setting, we have a new adjuvant trial that's ongoing with Washington University School of Medicine, and we have plans to do an adjuvant study in the near future. So let's get into the data. This is monotherapy and the dataset that's quite mature at this point in time, looking at the recommended phase 2 cohort treated with CUE-101, where the median overall survival at this point in time is about approximating 21 months.
This is quite a notable signal when you compare this to the historical second-line treatments from Opdivo, BMS's anti-PD-1 nivolumab, or Keytruda, which are roughly about 7.5 to about 8.5 months. So really, we think a very exciting signal for monotherapy activity in this instance. In the frontline setting, where Keytruda is the standard of care, we've combined CUE-101 with Keytruda, and this dataset is still maturing, but at this point in time, we have an overall response rate of 46%, which is greater than a twofold increase over Keytruda alone in the KEYNOTE-048 study, which is 19%. Importantly, as you look at the patients across, half of head and neck cancer patients are CPS low.
CPS low patients, which is less than 20 for PD-L1 expression, generally do not respond well to checkpoint inhibitors. So in the case of the Keytruda, for example, the CPS low response is roughly about below 15%. In that particular cohort of CPS low, we've seen a response rate of 50%. So that's quite notable that you're seeing responses across both CPS high and CPS low and not just focused on CPS high, which others have pointed to. Okay. Continuing with the clinical response in the frontline setting, the progression-free survival is maturing. At this point, it's 5.8 months and maturing. This is again, approximately double of what was seen with Keytruda, which is about 3.2 months. And an estimated overall survival at a 12-month time point right now is at about 96%. So really great metrics.
We're sort of really excited to continue to develop this program forward. As a mechanism of action, I just put this slide in here to make the point that in patients where we've had biopsies, as you can see on the right there between the pre-dose and post-dose, you can see clear evidence of T cell infiltrates coming in, and these T cells are activated as evidenced by the presence of granzymes, and that's shown in green. T cell is in red, and the overlay is yellow, as you can see by the immunohistochemistry. On the left, there are examples from patient blood samples showing tetramer positive staining for tumor-specific T cells in blood, again, pre-treatment and post-treatment.
And the point being, again, a marker of PD activity, showing clear induction and expansion of the right population without broad immune activation and systemic activation, as one would expect if this was not targeted to the T cell receptor. Okay, the second program we followed up behind that is Wilms' tumor 1, CUE-102. This molecule is essentially 99% sequence identical to CUE-101, except the peptide here. Now, instead of the HPV epitope, is an epitope from Wilms' tumor 1, which is a prominent tumor antigen across a variety of solid and heme malignancies. We've taken this into colorectal, gastric, ovarian, and pancreatic as a monotherapy. These are cancers that have been traditionally refractory to checkpoint blockade, and again, the data from here continues to develop quite nicely.
This is just to make the point that this is a pretty significant unmet medical need in cancers that express WT1. You can see gastric, ovarian, pancreatic, and colorectal on the left, and on the right in blue, you can see additional cancers, hematologic and solid tumors that are high expressers of WT1. So again, a really quite a significant market opportunity when you look at what you're trying to address with this molecule. Again, as we had seen with 101 and now the same signals emerging as a monotherapy with 102, you see selective expansion of the right T cells in blood, and there are two examples of two different patients shown here. We've seen this across many, many patients.
On the right there, you see examples as a monotherapy showing reduction of metastatic tumor lesions. The left panel there is a gastric cancer patient which remained on study for over 6 months, -34% reduction across some of target lesions. On the right is an ovarian cancer patient with about -30%. So again, clinical activity as a single agent, again, demonstrating selective targeting of the right T cell repertoire in the patient. Okay, the platform is extremely modular, so what changes from one molecule to the next is really the T cell epitope, and the core IL-2 framework remains the same, and this creates enormous regulatory and development efficiencies.
For example, for the CUE-102 IND, the FDA allowed us to move forward with no further IND-enabling toxicology because you had de-risked that with CUE-101 and the IL-2 related any concerns. Similarly, we were allowed to start that trial at a clinically active dose of 4 mg per kg, which saved us almost a year's worth of dose escalation timeline. So these are pretty significant sort of read-throughs on every subsequent asset that one develops using this platform with the CUE-100 series. Behind those two clinical stage assets, we have validated Immuno-STATs that target mutated KRAS epitopes, T cell epitopes, G12D, G12V, PRAME, MAGE-A4, the collagen 6A3, NY-ESO-1, etc. So it's a very rich preclinical pipeline behind that can be developed quite readily.
Okay, so this summarizes the oncology side with the IL-2 immunotherapy on how we've approached the problem, which is selectively targeting IL-2 to tumor-specific T cells by harnessing the T cell receptor specificity, given the nature's recognition of the peptide HLA as the module. We've had a very productive discussion with the agency earlier this year, aligning on a registration path, following the FDA interaction. The platform de-risking, as I mentioned, provides significant regulatory advantages and development efficiencies to develop future candidates. The modularity allows you to swap in and out many different tumor antigens to go after many different cancers at will. We see this as a strategy for off-the-shelf immunotherapy approaches, as a patient sort of presents with different cancers, to know the antigenic expression and then tailor the therapy to what the tumor is actually expressing.
We also see multiple paths. While we've spoken mostly about recurrent metastatic setting, we do see a modality like these, this approach moving in the adjuvant/neoadjuvant setting, particularly based on the specificity and the favorable tolerability that we've observed so far through our clinical experience. Okay, I'm now going to switch gears and get into the autoimmune side of things, where we've got two wonderful ways of resetting immune balance. One is CUE-401. This is a bispecific focused on conversion and expansion of new population of regulatory T cells or Tregs, okay? The CUE-401 molecule is a bispecific. It has the IL-2 molecule on the N-terminus and a masked TGF-beta variant on the C-terminus.
The reason we went after this, and not just simply an IL-2 mutein as others have done, is because it's now known for about 3, 3.5 decades that IL-2 and TGF-beta together can convert your peripheral CD4 T cells into regulatory T cells by turning on the FOXP3 master regulator, okay? And that's what's shown in the cartoon on the right. So this provides a wonderful opportunity to really generate new waves of regulatory T cells, rather than just focus on the small population of pre-existing natural T-regs, okay? And that's exemplified in this cartoon here, where if you went in with the conventional approach of taking IL-2 muteins biased to CD25, that's highly expressed by T-regs, you focus on what nature's already given you, and that circuit is not working very well by the time the patient presents with autoimmunity.
In contrast, CUE-401 not only acts upon pre-existing, natural T-regs, but can convert non-T-regs into induced T-regs, and that's gives an opportunity to even reset the peripheral pathogenic repertoire into a regulatory phenotype, and that's a very attractive way of sort of looking at the paradigm of immunoregulation. This is a program that's partnered with Ono Pharmaceuticals. Ono partnered with this last year, and the collaboration is moving along quite strongly. We've released some data on this, and some of it is shown here. On the left here, you can see CUE-401 producing human Treg. This is from a GVHD assay in a dish.
Again, IL-2 alone, TGF-beta alone does not do it, but when you have CUE-401 with both components in, you see induction of FOXP3 and generation of regulatory T cells. On the right is an in vivo model of gastritis, where we have taken this compound in a collaboration with Rich DiPaolo's lab at St. Louis University, showing protection from autoimmune gastritis with only 2 doses that were administered in this model at day 1 and day 14, and the scores that you're reading out are at day 62. So really making the point of immune control that seems to have durability with an early intervention, and that's essentially the thesis here. If you think about the approach, CUE-401 does not do anything to the disease mechanism, except generating a potent population of regulatory T cells that can then control inflammation.
This is the kind of evidence that points to that, both by the histopathological measures as you see of the stomach mucosa and the compiled gastritis scores that you see in the graph on the right. Okay, now I'm gonna switch to one of the most recent areas that we've been developing, and this is a program we started working on almost about a year ago, a year and a half ago, called the CUE-500 series. And in light of the recent CAR-T data, B-cell depletion and autoimmune diseases, really positions a wonderful opportunity to be able to achieve a similar kind of efficacy of deep depletion of B cells via a T-cell-mediated mechanism, but doing it with a biologic.
Okay, so, the CUE-500 series essentially is developed off the CUE-100 series. On the left there, you can see the CUE-100 series that has the IL-2 and the tumor-specific peptide HLA. This molecule we've dosed now in over 120 patients. Validation data I just showed you in terms of efficacy. We've not seen any clinically relevant immunogenicity. It's highly manufacturable, and the tolerability looks great. On the right there is the CUE-500 series, which essentially goes after a very fundamental mechanism of repurposing your protective antiviral T cells that all of us harbor, and having them recognize B cells and destroy the B cells. And the way we do that is the peptide in the middle now is a virus epitope. Think about SARS-CoV-2, think about flu, think about CMV.
So you have a viral peptide HLA, and instead of the IL-2, you've got, you've got an scFv to a B-cell marker like CD19. So you essentially end up painting the B cell to make it appear like a virally infected cell. So, that allows you to really focus on the VSTs, the viral specific T cells. Why did we choose to do that? It's for several reasons. One, as opposed to the other pan anti-CD3 T-cell engagers, this is not broad anti-T-cell activation. This really goes after a very small subset of nature's robust killer cells that all of us have harbored for decades, okay? We know these are trained killer cells that respond very quickly upon seeing a viral antigen. They're present in high frequencies. We know from several different papers, they are localized in inflamed tissue.
They are not exhausted and have a robust phenotype, and most importantly, from a safety and a specificity perspective, this avoids broad immune activation, okay? Because you are selectively perturbing the nature's memory repertoire that the host harbors. This essentially shows you the mechanism of action. You have the CUE-500 series available here that would bind to the B cell in circulation. As shown here, the B cell bound to the CUE-500, essentially now is visible to the virus-specific T cell as a virally infected cell because the B cell is displaying a virus antigen peptide HLA complex on its cell surface. So this is the fundamental node of T cell antigen recognition, which then leads to B cell killing very effectively.
Here's an example of primary B cell killing from human blood that we've achieved, as you can see here in this instance. You see, with a CMV epitope, you can actually see excellent killing with a CUE-500 series molecule that is harboring the CMV peptide, which essentially kills maximal killing accompanied in the same range as you would see with the BiTE molecule. Except the fact is you're harnessing a very small repertoire as opposed to an anti-CD3 approach of a bispecific, which would be activating every single T cell. If you take the CUE-500 molecule and you make it with an HIV peptide, and most of us should not have HIV-specific T cells floating around in your body, nothing happens, and that's in blue.
So again, a very exquisite way of repurposing what all of us have already harbored and will continue to hold on to the rest of our lives, and using those kinds of T cells to destroy B cells via this mechanism, okay? We've done this with CMV, we've done this with SARS-CoV-2, and essentially, at this point in time, every donor that we've tested has T cells to SARS-CoV-2, which raises the, also the attractive opportunity that you could even enhance these T cells by commercial vaccines that are available, and then come back with a strategy like this to coat your B cells, and destroy the B cells.
We do see this as a program that has an enormous potential, essentially representing a pipeline and a product, not just in autoimmunity across different autoimmune disorders from neuroinflammation, rheumatology, hematology, endocrine autoimmunity, DERM, but also areas where B cell responses have resulted in pathologies, rejection of transplant, transplanted organs, severe food allergies, and perhaps even if one wanted to, you could take these kind of modalities into oncology, where B-cell engagers do exist. Importantly, one of the strengths of the approach is really significant differentiation and advantages over other approaches that have been attempted for B cell depletion. So going from left to right, we know ADCC drugs have been approved, so anti-CD20, anti-CD19s have been used.
In this case, for ADCC, the effector cell is an NK cell, so there's a minimum amount of target receptor, you need on the target cell for effective ADCC. And this is why you don't have, you know, deep durability and deep responses and deep efficacy because you have escaped variants that down modulate the target like CD19 in the case of B cells and escape ADCC mechanism. In contrast to that, the T cell-mediated killing is highly sensitive. As few as 10-50 peptide HLA molecules are sufficient for a T cell to trigger killing, in contrast to 10,000-20,000 that are needed for ADCC. And these are hard numbers, right? So in the case of CAR-T, when we had this initial group of studies that being, being sort of shared, the early data looks extremely encouraging.
robust efficacy, robust durability, but there are challenges here. It's, it's autologous, complex manufacturing, conditioning regimens, even the continued toxicity risks, etc. Then on the right are pan-T cell engagers that would be modalities like anti-CD3, CD19, anti-CD3, anti-CD20. And again, here you're using a T cell-mediated mechanism, except here you have high risk for activation of the breadth of the T cell repertoire, risk for, cytokine release syndrome toxicities, not suitable for long-term dosing and at risk for even activation of your autoreactive T cell repertoire. That may be important as you think about disease mechanisms.
So in that context, CUE-500 series offers an off-the-shelf biologic to harness a T cell-mediated killing mechanism, but not have the cell therapy side linked to it in terms of the modality and the approach, and not have the breadth of T cell activation in terms of the pan-T cell engager strategies that have been deployed to some degree of success in oncology, for example, but may not be tolerated in the case of autoimmune diseases. So we are very excited about the CUE-500 and its potential to be able to deliver this deep efficacy of B cell depletion with a biologic while avoiding both the cell therapy side of complexities and the systemic activation as you would with pan-T cell engagers. Okay?
So I just wanted to end here, as you look at the technology and the company at this point in time, Immuno-STATs are a whole new class of biologics that are based off harnessing the T cell receptor specificity of disease-relevant T cells. Our progress in oncology, essentially with the two lead programs now across five different solid cancer indications, establishes and provides clinical validation for both mechanism and efficacy, as well as tolerability and safety. As the data are being generated, you can see, particularly in the frontline setting, but also as monotherapy, the meaningful increase in survival and early metrics of response look quite favorable to us. We think the applications both on the solid tumor side, but also on the autoimmune side, provide significant market opportunities as you think about the platform going on both ends.
I spoke to you mostly about the clinical data in oncology, but the autoimmune side, while still preclinical, we think has a tremendous opportunities in the near term as you think about both the regulatory T cell as a linchpin to reset immune balance, but also now looking at B cell depletion with a biologic that enables a T cell-mediated mechanism. So, I think that's my last slide. So with that, thank you again, Yao, for the invitation to speak here. We've got a couple of minutes here. I was on time if there's any questions, and happy to address them.
If you have any question from the audience, please feel free to raise your hand. In the interest of time, maybe I can ask the first question. In your phase two design, you're randomizing patients to pembro control with one or two doses, with one zero one, in combination with pembro. Can you talk about feedback from FDA on the trial design, alignment on the endpoint, and anything you can say to the path of registrational study?
Yeah. So we've spoken about this, Yao. We had the discussion with the agency presenting the data. It was actually a very productive and solid discussion in terms of guidance. There is broad alignment, and the trial you described is a phase 2 trial against pembro alone, which is important 'cause we right now, the data is from a single-arm study. Comparing that to actually two different doses of CUE-101, and that gets you a lot of confidence in a dose selection. FDA has been quite focused on Project Optimus. The current RP2D is 4 mg/kg, which we think is absolutely fine, but the agency asked us to consider another one. So it would really be two different doses, 4 mg, plus another dose chosen with pembro versus pembro alone.
A trial looking at about 25 patients in each arm. That, if that signal continues to hold, which we believe it will, as you've already seen, provides a very strong basis and confidence to go into the phase III registrational, but also with this, with the dose that you've qualified and selected.
Yeah, that makes sense. Well, maybe another quick one. For 102, your dose expansion here, planning on enrolling 28 colorectal cancer patients, and maybe some other patients. Could you maybe talk about the data update in second half this year and what the full data that you plan to show?
Yeah, I think we've been cut off, but we will be talking about a complete update at SITC.
Okay.
We're actually a pretty comprehensive update, and we're expanding after the last sort of dose escalation. We're expanding about four indications and feedback we've got.