Sensei Biotherapeutics, Inc.

Your conference call should begin momentarily. Thank you. Thank you. Good afternoon. My name is Sally, and I'm the facilitator today. At this time, I would like to welcome everyone to the Sensei Biopharmaceutical Virtual Vista Science Symposium. All lines have been placed on mute. After Sensei's presentation, there will be a question and answer period. To ask a question during that time, please press star 1 on your telephones. If you'd like to withdraw your question, please press the pound key. I would now like to turn the conference over to your host, Mr. Shellaby. You may begin.

Thank you, operator, and welcome everybody to our VISTA Science Symposium. We're really looking forward to today's meeting. We think it's a great nexus between deep immunology and biopharma drug development, and great timing coming on the heels of the CITSE annual meeting, where we presented some new data We're really, just a reminder before we get started, that we are a publicly traded company, and we may be making forward-looking statements today. I want to review the agenda with you. I'm going to make some opening remarks regarding our TMAB platform and mission. And then we'll be joined by Professor Robert Schreiber, a professor at the Washington University School of Medicine and a member of our scientific advisory board. We'll then turn it over to Dr. Robert Pierce, our Chief Scientific Officer, and Edward Vonderhorst will be available for question and answers. Edward Vonderhorst is our Senior Vice President of TMAB Antibody Development. Together this team has vast experience in VISTA biology and antibody development, and we're really excited to share our program with you today, and also what we've learned along the way. So just as we move forward, I want to share with you what the mission is of our TMAB platform. TMAB stands for Tumor Microenvironment Activated Biologics. And the mission of this platform is really to develop and leverage unique features of the tumor microenvironment to selectively activate biologics that unleash clinically meaningful anti-cancer immune responses. And the feature we're really going to be focused on as we talk through our lead program is pH. Although there are others, we're going to be focused on pH today. There is a huge need for new drugs to address this space. As you can see on slide five, the global immune checkpoint market is poised to become one of the biggest drug classes in history, and it is growing. However, only a minority, about 20 to 30% of patients have survival benefit from checkpoint therapy. And so there's obviously a huge need for these patients that aren't responding to checkpoint drugs. And on slide six, you can see that over the last decade or so, we've learned a lot about why certain patients don't respond to checkpoint therapy. And if I focus you in the panels on the right, you can see that some of these patients that don't respond correlate to one of two phenotypes, either the tumor is cold an immune desert phenotype, or it is immune excluded. And here at Sensei on slide seven, you can see that we've developed two platforms to focus on these two mechanisms. These are two of the key mechanisms that are involved in the resistance to checkpoint therapy. On the right is our Immunophage platform, which is designed to generate new anti-tumor T cells. And then on the left, which is the focus of today's discussion, is our TMAD platform, And that's really focused on unleashing anti-tumor T cells. And in this case, we're going to be talking about blocking alternate immune pathways that may suppress the tumor microenvironment. And the target of choice, we're going to be, our first target that we've selected is VISTA, B-domain Ig suppressor of T cell activation. It's been known for quite some time that VISTA is an important immune target. It's got very extensive expression on normal myeloid cells, but it has been traditionally very challenging to develop effective antibodies targeting VISTA. And we're gonna be talking a little bit about some of those challenges and how we believe we've overcome them. We've leveraged our extensive understanding of VISTA biology to develop a differentiated approach that really focuses on three salient features. One, a fully human monoclonal antibody that selectively binds to the active form of VISTA, which is the low pH form of VISTA, but doesn't bind to the inactive VISTA that's found in the blood, that physiologic pH. The second feature is that it's a potent inhibitor of the interaction of VISTA to its receptor on T cells, PSGL1. And the third is that this is an FC-competent framework, which really delivers a positive kick to suppressive myeloid cells in the tumor microenvironment. So together, those three features form a triumvirate that we believe is required for an effective anti-VISTA antibody. And we've done all that by building a really amazing team with decades of experience in immunology, antibody drug discovery and development, translational medicine, and the business of biopharma. And we plan to move other programs forward using this type of an approach. So without further ado, I'd like to turn it over to Professor Schreiber to take you through VISTA Biology. Bob?

Thanks, John. It's a pleasure to be here today. Just a quick little introduction of me. I am the Andrew M. and Jane M. Burski Distinguished Professor of Pathology and Immunology at the Washington University School of Medicine in St. Louis. I'm a tumor immunologist. I run the Burski Center for Human Immunology and Immunotherapy Programs, and I am the co-director of the tumor immunology program of the Siteman Cancer Center at WashU. So my job today is to tell you a little bit about VISTA biology and give you an indication of why VISTA has been difficult in the past to drug. And then I'm sure Rob, after my talk, will tell you some of the really cool things that have been done to develop antibodies that are highly specific to the active forms of VISTA. So if we go to the next slide, please. So as John mentioned to you a moment ago, Immunotherapy is really showing enormous promise in terms of an effective therapy for cancer. It obviously is a way of using the body's own immune system to attack cancer. This is an immune system that can detect a single amino acid difference in a normal protein and an abnormal protein. And so it's a very powerful tool. And in addition, it really capitalizes on the criteria of an immune response which is basically specificity, long-term memory, and adaptability. And the idea would be that this should be able to provide us with durable cures. And in some examples that you'll see in a few moments, it has provided durable cures with hopefully minimal toxicity or at least a toxicity that could be controlled. But the challenge that we're finding now is in the patients that have been treated with at least certain kinds of immune checkpoint therapy, that only about 20% respond with durable responses. And that leaves a large number of patients who do not achieve the desired durability. What's become clear is that in the past, most of the work has been done to try to drug the T cell compartment And these are where the two big immune therapies really have been focused. But it's now clear that in cancer, there is a very immunosuppressive tumor microenvironment. And this needs to be controlled or reversed in order to probably boost that number of 20% of patients getting responses to a much higher number. Obviously, we'd like it to be 100, but certainly there's a lot of room for improvement. And one of the key components in the tumor microenvironment are these myeloid cells, which have been shown to be highly immunosuppressive. So next slide, please. Now, myeloid cells themselves have a number of different, in cancers, have a number of different immunosuppressive moieties. But one of the ones that has proven to be quite interesting has been VISTA. Here are two beautiful publications by Padmani Sharma from MD Anderson and Gordon Freeman from Harvard that show and talk about the importance of VISTA as an inhibitory immune checkpoint. And then this is all based on the mouse work that others have done going forward. So next slide, please. So here's some examples in both humans and in animal models of the importance of VISTA. This one, a correlation found in patients with melanoma who are either treated with ipilimumab or Nevo, so anti-CTLA-4, anti-PD-1. On the left, you can see that When you look in the circulation of these patients, those patients who have very high levels of these inhibitory myeloid cells that have been called myeloid derived suppressor cells, or MDSCs, you can see that they have a lower overall survival than patients that have lower numbers of these MDSCs in the circulation. And this is independent of the type of checkpoint that is used. Now, that's just a correlation, but it is an interesting correlation with you can see a highly significant degree of, a high degree of significance. The other thing that has been seen with human patients is that when you treat a cancer patient, in this case, prostate cancer patients, with a checkpoint, you see on the left that the level of their cells of VISTA on their myeloid cells, identified as CD68 positive cells, goes up quite significantly, whereas the level of VISTA that goes up in T cells is significant but of a much lower magnitude. Next slide, please. And then finally, this really shows it probably better than anything where we're looking now at patients with non-small cell lung cancer. And these cells from the patient's peripheral blood are stained with either anti-VISTA or other markers of cell lineages. And so you can see on the upper panels When you look at normal cells from peripheral blood, from a patient without cancer with their peripheral blood cells, you see you get a few cells that are expressing VISTA seen in the red staining. But when you look at the bottom panels, a patient with non-small cell lung cancer looking at their peripheral blood cells you can see very high levels of homogeneous staining of VISTA and particularly across many different cell types. But mostly in the myeloid compartment. And this you can see at the very bottom of the left side is an example of a FACTS profile where you're actually able to quantitate that staining, showing significant staining in CD11B and CD14 positive cells. So these would be myeloid-derived cells that very selectively express the highest level of VISTA. Next slide, please. So this is also seen in mouse models of cancer. In this case, mice are injected with a syngeneic tumor. This is CT26. And as you can see that if you treat tumor-bearing mice then with an irrelevant antibody identified here as control IG, that tumor grows and those mice basically do not survive very long. If you use anti-VISTA by itself, you do get a little bit of an effect. If you use anti-PD1, L1, you get a little bit more of an effect. But if you use both together, shown in the open boxes, the combo, you see you actually cure the mice of their cancers. And it's this treatment shown on the right here which gives you complete durable responses. Next slide, please. This data together provides a strong justification for thinking about VISTA as an additional checkpoint that one might be able to drug, and because it is drugged on a myeloid cell predominantly, it really should be able to complement the work with anti-PD-1, say for example, or anti-CTLA-4, which you're drugging now receptors on the T cell compartment. So just to remind you, this is a B7 family. It's the same family as PDL1 expressed on myeloid cells. And myeloid cells can be thought of as the hub of immunosuppressive activity in the tumor microenvironment. VISTA is a key player in controlling checkpoint blockade and VISTA has been implicated in resistance to PD-1, PD-L1 inhibitors, and a major step forward has been made recently by identifying the physiologic and functional ligand for VISTA, which is, as John mentioned, PSGL1 that is existing on the T cell. Next slide, please. So, why then, if we know all of this, hasn't more advances been made in terms of drugging VISTA. So one of the issues becomes this very unique mechanism by which VISTA becomes activated or inactivated depending on where the cell that is expressing VISTA is. So tumors are typically lower in pH than normal tissues. And at low pH, key amino acids in VISTA become protonated. These are histidines, and that's right at the PI of the histidine. And so at pHs like around 6, you basically now protonate those, and now they have a charge. And that change of the charge likely changes the shape of VISTA, and this allows now VISTA to interact with PSGL1 on the T cells, and then allowing it to affect its checkpoint function. Next slide, please. This just shows you more graphically what's going on. On the bottom is inactive VISTA. This would be VISTA on a myeloid cell that's in the circulation, for example. And you can see since the VISTA is not charged under these conditions, it can't interact with the sulfate group on its ligand PSGL1, and so nothing really happens at this point. However, if you're in a tumor microenvironment where the pH, because of the metabolism of these tumor cells, is so high, you can see that now, sorry, so low, somewhere around between 6.3 and 5.9, Now, VISTA becomes activated because those histidines get protonated, and now you've got the positive charge from the histidine interacting with the negative charge from the sulfate group on the PSGL1, and you have interaction, and that interaction leads to the expression of the immunosuppressive activity of VISTA. Next slide, please. I want to just spend now the last couple of minutes describing why VISTA has been difficult to drug because of its activity. And this really just goes into a little bit more depth of what I've already told you. Here what we're looking at are fluorescence-activated cell sorter flow cytometer patterns. of VISTA expression on human peripheral immune cells. And we're looking at two cells in particular that seem to express the bulk of the VISTA, monocytes or monocyte-derived macrophages and neutrophils. And you can see that in the blue lines is the staining with the anti-VISTA antibody. And in the pink curves, is sustaining with a control antibody. And so you can see that there is substantial VISTA expression in both monocytes and neutrophils in normal peripheral blood. But remember, this is outside of any kind of tumor microenvironment, and so this is inactive VISTA, not active VISTA. And so, if you put in antibodies that bind to VISTA positive cells like these monocytes as physiologic pH, it would result in the rapid elimination from the circulation through targeted mediated drug disposition. And that removal of the antibody would not be associated with the kind of biologic and therapeutic effect that you would like. And so, In addition, the efficacious drug occupancy levels would be difficult to reach and potentially would narrow the therapeutic window. So this really presents a problem because of this rapid clearance that would be occurring and not leaving enough anti-VISTA in the tumor microenvironment to really do what you want it to do. Now here, next slide please, this is a close-up of the VISTA PSGL1 interface. On the bottom you see the VISTA surface and you see all these histidine molecules that accumulate right near where they're interacting potentially with the PSGL1. And so you can now see why it's so important that when you're at a lower pH and those histidines become protonated, now make a surface filled with positive charges that can interact with the various sulfation and hydroxyl groups of the tyrosines and other molecules that are present on PSGL1. And so this really explains the very unique interaction that is occurring here. It's an immune checkpoint that literally gets turned on when it is now focused in the tumor microenvironment because of the pH. Now, you may remember that J&J basically made an antibody against VISTA and used it in clinical trials. And they examined the, this is all published work, but they examined the need for the FC component of the antibody for VISTA to have the correct activity. What you see on the left is an FC-competent IgG1, the antibody that they used, I think, in their clinical candidate, which was the 61610588 in the red bars. And you can see if you compare that lower open bar just adjacent to the red bars, that's the control amount of T cell stimulation that would go on if you were to mix myeloid cells and T cells together. But as you add the anti-Zista into this, you can actually see you're allowing T cells to activate more and more. And so you have a very nice dose response, maybe a little bit of high-dose inhibition, but nevertheless, the more antibody you add, the more, in general, response you get. Now if you take an antibody like this one with the same FAB on it, but you silence the FC component, which would be this VSTB140 antibody, you can see that without, that ablates the ability of the FC to bind to FC receptors, and you see you lose all your stimulatory activity. So interestingly, you not only need to block the PSGL1 VISTA site, interaction site. But you also need to engage the FC receptors of myeloid cells in order to get the full therapeutic effect. And this can be seen actually in a syngeneic mouse tumor model where this is a bladder carcinoma model. And you can see on the right that if you put in low doses of the FC-competent anti-VISTA antibody, like five milligrams per kilogram, you get not much therapeutic effect. But when you double that dose, you completely ablate the inhibition that's there and you get the spontaneous rejection of this tumor. If you give irrelevant IgG2A shown in the black line, you get tumor growth as well too. But if you use the FC silent version of the anti-VISTA, then you can see that you lose all your therapeutic effects. So what we've tried to show you today then is that VISTA is expressed at high levels on monocytes and neutrophils. For a non-pH dependent blocking antibody, high expression on monocytes and neutrophils results in a suboptimal PK due to target mediated clearance and may decrease the therapeutic window. The VISTA checkpoint itself is only on under low pH conditions. VISTA's immune checkpoint function is only active, capable of binding PSGL1 at pH is somewhere around 6 and below. And other receptors for VISTA are active in physiologic pHs but don't appear to function as immune checkpoints. So that's an important consideration as well too. And finally, engagement of the FC gamma receptor may be a prerequisite for optimal activity of anti-VISTA antibodies. FC silent antibodies are not effective at T cell proliferation ex vivo. or anti-tumor activity in vivo despite picomolar binding affinity to VISTA, and engagement in the blood may result in an untowards off-tumor activation, so cytokine release syndrome, which is something that obviously you don't want. So having said that, I'm gonna turn it over to Rob, and so Rob, take it away.

Thanks, Bob. That was great. I'm going to amplify a little bit on what John and Bob have already gone into. And first, I want to just mention broadly about our TMAP platform. Our approach is really to kind of flip the script on those immunosuppressive features of the tumor microenvironment, taking advantage of unique features like pH, but you can imagine other ones, biochemical features that we can use to selectively activate biologics, in particular antibody-based biologics. This is perhaps VISTA as our first approach is made easier by the pH dependence of the biology, which Bob actually explained extremely well. But I do want to emphasize again that our approach really focuses on having understood that biology, we set out to design an antibody that really delivered on those three features of it had to effectively block PSGL1. It had to only do so under low pH conditions to attack that active form of VISTA, not the inactive form in the blood. and also deliver that kick to the myeloid cells through having an FC-competent backbone that triggers FC gamma receptors. So, next slide. So, the beauty of our approach, I think, is that by creatively designing very stringent screens, we could narrow down out of the, you know, from a yeast surface display library that has all of those potential antibodies, we could actually identify one that fit those stringent criteria. Now, this is a very iterative process, and it's hard to describe it all in a linear discussion. But suffice it to say is that the first key thing we focused on is do the antibodies bind VISTA, and then do we have antibodies that block that interaction between PSGL1 and and Vista, and Edward's group really generated a number of really great assays that could allow us to finally focus on those candidate antibodies of interest. And as these things go, first of all, there's an initial screen that basically tries to cover maximal epitopic space, and then we pick antibodies that have the features we want and then iterate on those to finally get to our lead, which is SNS-101. So on the left here is the assay, this so-called multimer assay, where we have multiple copies of VISTA protein on a string that is tied to a fluorescent marker. And this allows us to actually look at binding a VISTA to the target PSGL1 on cells. And of course, this only occurs at low pH. So this assay was performed at low pH. And you see over on the right in the upper two boxes, we have CD4-positive cells that are stained with this VISTA reagent in the presence of a control antibody that should be inert. And you can see in that bottom right-hand quadrant, you see that approximately 11% of those CD4-positive T cells bind VISTA. So they're interacting with PSGL1 on those T cells. On the right-hand side, under SNS101, you see what happens in the presence of our antibody. You get almost complete blockage of the binding of VISTA to PSGL1 at low pH. So this is exactly the phenotype we're scouring those libraries for. The bottom two boxes there, those dot plots, show the very same functionality of SNS101, but here against the interaction of PSGL1 and VISTA on CD8-positive T cells. And you see a very similar near-complete blocking of that interaction. So, next slide. So, once we chose candidate antibodies and then iterated, you know, on looking at the progeny of those antibodies, this is actually how we got to SNS11, because we had a number of antibodies that blocked that interaction. But remember, we were laser focused on one particular feature that was really important, which is we needed to be squeaky clean in the blood. We didn't want to see significant binding of our antibody to those VISTA positive cells that have inactive or high pH, physiologic pH VISTA. And so you see here, A number of different antibodies at pH 7.4, that's the pH in the blood, versus pH 6, that represents pH that converts VISTA into an active form. And there are lots of antibodies presented here, but really the two to really focus on, or three to focus on, are the top purple one, and on the right it says isotype control. So this is just the base case of no binding to cells in the blood. And then if you look at down below in the sort of, I don't know what you call that color, sort of pinkish red, that says SNS-101 parental. That's very interesting to focus on because it showed that great binding to VISTA, but it also is binding at pH 7.4. And this is exactly what we wanted to weed out in the progeny of that antibody. We wanted to find one that bound really well at pH 6, but lost all of the binding at pH 7.4. And that is in that green curve that's labeled with SNS 101. So this was kind of the linchpin final step to say, yeah, this is our candidate antibody because it's behaving exactly as we want to see it. And then the next slide. We can show the biochemistry really delving deeper into the affinity of our antibody binding under PH6 versus PH7.4. You see these with these sensograms that are showing the binding kinetics. SNS101 has beautiful binding at PH6. That's on the far left in the blue box. You see there that we have like 218 picomolar or sub-nanomolar binding, which is really extraordinary good affinity. And over on the right, you can't even measure the affinity under normal conditions. You have to increase the concentration of antigen very high to get any affinity measurements of all. But when we do that, we get 132 nanomolar. So if you look at the ratio of binding at 7.4 to pH 6, or rather pH 6, we have a 600-fold selectivity for VISTA at PH6, that active form of VISTA versus the inactive form. Also included in there are a PH-dependent benchmark, which is in the middle box, and a PH-independent benchmark, which behaves exactly as you would predict, that it actually binds quite well under both, it binds both the inactive and the active form of VISTA quite well. Okay, so next slide. So, as a further check of this, we stained monocytes, which Bob showed have very high levels of VISTA, and we wanted to check that our antibody really didn't bind them significantly at pH 7.4. And you see, again, the bottom row is SNS 101. The top curve is the control antibody. Our SNS 101 at pH 7.4 looks very much like the control. So, really no significant binding at pH 7.4. Now, Bob nicely pointed out why this is important, but it's so critical to our program that I want to run through it one more time with this figure that we've constructed here. Now, remember, the FC-competent framework, we believe, is required for optimal activity of the VISTA antibody because it also provides this positive kick through the FC gamma receptor. But FC gamma receptor engagement in the blood may result in untoward off-tumor activation, which can be seen, which we believe is the likely source of CRS that's been observed at pretty low doses in patients that are dosed with a pH-independent antibody or an antibody that sees the inactive form in the blood. So that's depicted up here in the top left. where it says non-pH dependent in the blood. What you can see, we depict in this cartoon, is the antibody is binding VISTA in the blood. And then because of that, you get clustering of that antibody, and then it can interact with FC gamma receptors on other monocytes. So you get this monocyte-monocyte stimulation in the blood, which can then result in in activation of those monocytes and potentially elaboration of inflammatory cytokines and downstream CRS. Now, in the tumor, which is below that, non-pH-dependent antibodies do their job, like we would like to see, in that they are activating, they are blocking PSGL1 interactions with macrophages. So there are sort of disinhibiting the T cell, and that's one part of the mechanism. And they're also activating macrophages, other myeloid cells that have FC gamma receptors appropriately. The issue there is that you don't want it in the blood, right? So it's working right in the tumor microenvironment, but you're presented with this issue with what we call a peripheral sync and activation of the myeloid cells in the blood. On the right-hand side of this is our antibody. whereby by virtue of it having no significant binding to VISTA physiologic pH, all we have is really inert antibody floating in the blood, not binding to cells. However, when the antibody gets into the tumor microenvironment, it can see that active form of VISTA and bind appropriately, delivering that really two-part activation that we think is critical, disinhibiting the T-cells, and also activating the myeloid cells in the tumor. So I hope that's clear, and we're glad to take any questions about that at the end. But I just wanted to end with the figure from our CITSE poster where we showed the in vivo screening of SNS-101. Now, we called this a high bar because we only actually dosed for one week, We were using this in a screening mode. This is an MC38 syngeneic tumor model in the human VISTA knock-in mice, and so it wasn't optimized to show a monotherapeutic effect or even to optimize the effect at all, but we knew that this model was capable of showing a positive combination effect with anti-PD-1, and we really were using it just to to check that our lead candidates, I actually used it to stratify some of our lead candidates, and SNS 101, not surprisingly, came out on top. And you see here that we're seeing a very nice combination activity with anti-PD1 in this model. Okay, so that being said, I think we've nailed the three features that make our program different from other programs that we're aware of. And it's really focused on what we consider is the salient mechanism of anti-VISTA antibodies in terms of the mechanism of action. Again, obviously we need to inhibit PSGL1 because we believe that that is the critical checkpoint that VISTA engages in the tumor microenvironment. We need it to be pH sensitive, meaning that it's actually seeing only the active form, not the inactive form in the blood. And we've described the reasons why that is important. And also, we need to have an FC competent framework that engages and activates the myeloid cells in the tumor microenvironment to get optimal activity. And you can see here on this slide, we've laid out what we know of some of the competitors. and how we feel that we're really the only antibody in development that we're aware of that really checks all three of those important mechanistic boxes. So, I've probably said this over and over again, and I'll just end with it one more time, that really we believe that the key to unlocking the power of the VISTA checkpoint are those three features. It needs to block PSGL1 and specific interaction with VISTA and specifically the low pH or active VISTA. And this will allow us, we believe, to obviate the problems with the target-mediated drug disposition and sort of on-target, off-tumor side effects in the blood. And we need that FC-competent framework to give those myeloid cells a kick in the pants. So with that, I think my part is done, and I'll hand it over to John again.

Thank you very much, Rob. Operator, we're happy to take questions now.

Thank you. Again, ladies and gentlemen, if you'd like to ask a question, please press star then 1 on your touchdown telephone. Again, to ask a question, please press star then 1. One moment for our first question. Our first question comes from Kevin DeGieter of Oppenheimer. Your line is open.

Hey, great. Thanks for taking my questions. And Dr. Shriver, thank you for joining us. Always a pleasure. I guess really Two questions, if I can start maybe with Dr. Shriver. As we think about, you know, monotherapy activity, I recognize, you know, in the preclinical models, that's not sort of the primary, you know, proposed development path here. But from your perspective, are there tumor types that you would like to see a sponsor look at as potentially interesting as a monotherapy, you know, with the MOA around VISTA, and then, you know, separately when we think about, you know, potential patient selection here, are there any biomarkers, you know, MDSCs or others that you think may be informative as we think about, you know, patient subtypes within given histologies?

Yeah, it's always good to hear from you, Kevin. So it's nice that you're here. So I... I think one thing that strikes me, of course, is this association with high levels of MDSCs being resistant to therapy, and this is where I might think that you might have the best chance of using this kind of anti-VISTA potentially as a monotherapy. My feeling would be, though, that perhaps I do like the idea of this looks like a very unique and relatively non-toxic combination of a blockade with PD-1, PD-L1 versus and the anti-VISTA either together or sequentially. And I think the fact that the anti-PD-1 raises VISTA levels on myeloid cells would make them then maybe easier to inhibit when you came in with the anti-VISTA. So I think that might be a very interesting thing. I know that the Pam Sharma paper was in, I think it was in prostate cancer, and they saw some activity of anti-VISTA there. So I think that this would be maybe a good place to start.

Can I jump in there, Kevin? Sure. You know, obviously we have an active program, you know, using multiplex immunohistochemistry to kind of get a landscape of tumor types and, you know, that have, you know, a signature that looks like VISTA is engaged. You know, I agree with Bob that I think we'll find a tumor type that probably responds to VISTA as a monotherapy, but actually in terms of Drug development, you know, it's almost easier to go into, you know, because PD-1 and PD-L1 are standard of care now in so many tumor types that to go into that population. But we're exploring all kinds of different responder hypotheses there. There was another thing I was going to say. Oh, yeah. So, you know, I think there are, you know, John mentioned threw up that slide about with the two different non-responder phenotypes. You know, there's, broadly speaking, this immune-excluded where the T cells are there. They're present but not voting. They're stuck in the stroma, right? And then there's the ones where there's just sort of immune ignorance. There's really not much of T cells present in the tumor. You know, we're looking very carefully at these different phenotypes and testing We think that, you know, and we're going to, well, let's just say we're going to be testing the hypothesis that blocking VISTA sort of breaks the cycle that keeps those T cells tethered in the stroma. So that kind of immune-excluded tumor is something we're going to be looking very closely at. And then lastly, before I left the Hutch, we published an interesting paper showing that neutrophils in the tumor, in fact, in the stroma, correlate with this immune segregation phenotype and lack of response to pembrolizumab. And, you know, given the high level of VISTA on neutrophils, I think that might be a very clear hypothesis to test early in clinical development, whether these, you know, neutrophil-rich tumors or patients that have high myeloid to lymphocyte ratios in the blood are whether they'll respond, you know, with a higher frequency to an anti-VISTA.

Great. And then as a follow-up question, as we think about a potential AE profile, I think your comments with regard to, you know, high pH and low pH were really clear, but I guess, you know, in the context of low pH, you know, on target, you know, AEs, you know, how should we think about you know, AEs that could be potentially interesting to watch for during a Phase I dose escalation? And perhaps a separate question that's a bit further down the line, but, you know, I get that from an overlapping tox perspective with a PD-1, you know, this looks like a really nice combo, but if we were to add in a triplet that included chemo, just kind of how do we think about a, you know, potential AE profile with a you know, chemo monocyte-directed, you know, antibody combo?

Yeah, that's a tough one. I think it's worth looking into and maybe modeling preclinically what the kind of chemo you'd be thinking about combining with whether or not it induces a low pH environment in non-tumor as, you know, as part of its mechanism, because that could certainly be or bring forward some AEs that would be due to, you know, the binding to active VISTA but not in the tumor. So that might be worth then avoiding. But, you know, we'll just have to think about that one a little bit more. In terms of other AEs of interest, you know, I certainly will be thinking about what kind of patients we would, you know, like to exclude from early clinical trials. Marie-Louise has given some thought to that, and I think we have some good ideas about, you know, exclusions, at least early on. Thanks for taking our questions. Thank you.

Thank you. Again, if you'd like to ask a question, please press star then 1. One moment, please. I'm showing no questions at this time. I'd like to turn the call back over to Mr. Shelby for any closing remarks.

Thank you, Operator. And thanks to everyone for joining us today. We're very excited about the potential of SNS 101, and we're looking forward to sharing more information as the program advances toward IND submission. Again, thank you for your time, and have a good evening.

Bye-bye. Thank you. Ladies and gentlemen, this ends today's conference. Thank you all for participating. You may now disconnect. Have a great day.