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.