Good morning, and welcome to the IMV Research and Development Day. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded, and a replay will be made available on the IMV website following the conclusion of the event. I'd now like to turn the call over to your host, Dr. Jeremy Graff, Chief Scientific Officer of IMV. Please go ahead, Jeremy.
Thank you very much, Tara, and welcome to everyone joining us today, whether it's morning or afternoon where you are. It's a great pleasure really to take a few minutes to talk with you about the science underlying the DPX platform, the foundation of IMV's entire scientific technology. If we can toggle to the next slide, please. We'll introduce you first, of course, with our forward-looking statement. We'll take a few moments here to give you an opportunity to review that forward-looking disclaimer. All right, Delphine, next slide, please. To the introduction, please. All right. With today's research and development day, we'll really try to work first through a historical perspective of therapeutic cancer vaccine efforts that'll be given by our keynote speaker, Dr. Michael Kalos. We'll take a lot of time to renew and update the scientific understanding for the DPX delivery platform.
Just why is IMV's DPX delivery platform so effective at delivering instruction to the immune system? We will show you what we think are the distinct advantages of DPX in educating a very specific, persistent immune response. Lastly, we'll review the translational and clinical data on our lead DPX product, maveropepimut-S. We hope that you leave today's conversation understanding how unique DPX is in educating a very specific, persistent, and robust immune response, directing the consumption of immune education, specifically through the primary sites of immune priming, specifically the lymph nodes. Let's talk very briefly about today's speakers so that you know who everyone is. My name is Jeremy Graff, Chief Scientific Officer for IMV. I joined IMV last summer. I have a history with innate immune oncology, having led Biothera Pharmaceuticals since 2014, ultimately to an acquisition.
Prior to that, I worked with Eli Lilly and Company for almost 17 years throughout the entire spectrum of cancer drug discovery and development. The next speaker from IMV will be Dr. Heather Hirsch. Heather joins us as well last summer, a long, distinguished career really focused on translational sciences. Heather's last stops included CRISPR Therapeutics, Jounce, and Merck. Lastly, our IMV speaker, Stephan Fiset. Stephan is our Vice President and Head of Clinical Research. He will detail for us the clinical experience with the DPX lead product, maveropepimut-S. Stephan comes to IMV. He's been at IMV now for about five years, having formerly led significant efforts in the clinical space at Medicago and GSK. With that, I wanna turn and introduce our lead speaker today, Dr. Michael Kalos. As many of you may be aware, Dr.
Kalos is a pioneer in the field of cancer immunotherapy, specifically focusing on T cells. We are pleased that Dr. Kalos joined us last summer as part of IMV's board of directors. He has held significant leadership positions in a wide variety of companies, including smaller biotech companies like Arsenal Biosciences. He was VP of Immuno-oncology at Janssen. He was Chief Scientific Officer for Immuno-oncology at Eli Lilly. On a personal note, Michael and I spent a number of years together working at Eli Lilly, and it's a pleasure for me to have an opportunity to work with Michael again. You can see with his extensive peer-reviewed publication list, scientific advisory board membership, et cetera, how deeply ingrained Michael is in this entire field.
We're really, really happy that we have an opportunity to have Michael kick off for us a review of cancer vaccines, of cancer immunotherapy in general. Michael, take us away.
Thank you, Jeremy, for the kind introduction. I'm grateful to be here today to take part in this R&D day for IMV. I'll tell you, I've been a board member for the company for close to a year now. I specifically and exclusively joined the board because of what I saw in the emerging clinical data from IMV and the potential I saw not only for that data, but the platform. As Jeremy indicated, I followed cancer vaccines for, my goodness, almost three decades, so I had a reasonable sense of the potential of what this platform could be. I'd like to focus today's introductory session on three topics with an intent to really lay down the basic scientific groundwork for us to understand how the IMV platform might fit into our universe of cancer vaccines.
We're gonna talk about the biology behind vaccines in general terms, the role of immunotherapy in the fight against cancer, and finally focus on the history and promise of developing therapeutic vaccines in cancer. Next slide, please. Vaccines, of course, trigger, as we all know, both arms of the adaptive immune system. They trigger the humoral arm, and that's B cells to make antibodies, and also the cellular arm that is T cells to target and eliminate cells that express target antigens. In cancer, T cells are now recognized as the most important player, hence the focus of this discussion on T cells. In cancer, T cells are understood to play a key role in controlling the diseases. Checkpoint therapy, we're all familiar with, anti-CTLA-4, anti-PD-1, anti-PD-L1, unleashes an existing T cell repertoire against cancer, and we all understand how important that can be.
Cell therapy, we're also familiar with the infusion of engineered T cells that recognize cancers and its profound results, at least in liquid tumors, is another example of the critical role of T cell. Finally TIL therapy, taking tumor-reactive T cells from tumors, growing them up and giving them back, has, again, profound clinical data in solid tumors. The evidence that T cells really matter in cancer is broad and compelling. On the other side, in infectious diseases, of course, the field recognizes that vaccines have triggered the expansion of target-reactive B cells and T cells, and that these players play key roles to eliminate many infections. I don't have to talk about the data with COVID, for example, that we're all familiar with. One of the fundamental questions about cancer and vaccines is. How can we effectively apply vaccines to treat cancer?
A number of bullets, three that I'll talk about here. Cancers, especially in the advanced stage, is a chronic condition, so there's immune suppression to deal with. Now, checkpoints work well in many cases in that context, right? Most of cancer is self. What we seek to recognize in cancer is an issue because, as we'll talk about in a little bit, our ability to target self is controlled by our immune system. Third, the immune system is often malfunctioning in cancers. How do we trigger something that isn't quite working as well as it should? Next slide, please. I wanna give you a little bit of an overview of scientific, scientifically technical to help us understand what we're talking about. First, I'll say the first principle of both medicine and the immune system is first, do no harm.
When something looks funny to the immune system because of a therapeutic intervention, its default position, I would say to you, is don't do anything. I think this plays really critically in how the to-date efforts have been pursued in cancer vaccines. Two topics, antigen processing and presentation, and T cell activation. This is how the immune system works in general term. Antigens, proteins are processed inside of cells. They're chopped up into small pieces, and they're put on the surface of cells in the context of HLA. And that complex of a small peptide derived from a protein and an HLA molecule is what the immune system, and specifically T cells see. Right? In the thymus, during T cell development, when a T cell sees this peptide and MHC complex, it gets deleted. Why?
That's a repertoire to self. We don't wanna cause ourselves damage. What comes out of the thymus is a repertoire, T cell repertoire, with the ability to see what's not self. Okay? Now, this deletion is a result of the strength of the activation of the T cells in the thymus. In the periphery, something else happens. A T cell that recognizes an MHC peptide complex with the right strength is stimulated, it responds, it expands, it proliferates, and it goes after the target cells that express that antigen. This is called T cell priming in the periphery. On the right panel, I'm showing you an overview of a T cell activation process. There's the MHC peptide complex that's recognized by T cells and a bevy of receptors that are called costimulatory receptors.
That integration of signals defines whether a T cell is gonna respond or not. The point I wanna make here is when we talk about targets that are overexpressed in cancer, the density or the amount of MHC peptide on the surface of cells is dramatically increased 'cause there's more peptide there. That can trigger a repertoire of T cells that otherwise wouldn't be triggered because of tolerance. Next slide, please. If you go back, please let me just make this point that I wanted to make sure. Each naive T cell in our body has a single and unique primary specificity. Its raison d'être, as you will. It has to be triggered in the right place and manner to be activated. Next slide, please.
Now, establishing an effective and specific cellular immune response against cancer is really a very complex and coordinated process, and I'm gonna take you through the steps in general terms. When looking to recreate this biology, it's fundamentally important to understand that the first do no harm concept is paramount. We need to make sure when we try to do this ourselves through, for example, a vaccine, that each step resembles a natural process. This issue has plagued, as I will tell you, most vaccine efforts to date. This, in fact, is where IMV's differentiation may lie. So click, please. The first step of the process physiologically is an infection in cells and tissues. This causes an inflammation and an infiltration into the tissues of these scavenger cells we call these professional APCs to the tissues.
These cells take up dying and dead material by the APC from the cancer cells. The process called phagocytosis. This triggers these cells to migrate to the lymph node. This is really important for vaccines. The lymph node is where the priming of the immune response happens. This is where it's the right environment, the right milieu for priming to occur. When priming occurs, as we talked about it, the presentation of MHC and peptide, there's a triggering of an immune cell, an expansion and movement of these cells into the periphery. Click again, please. When they go to the periphery, they migrate into tissues and they mediate their effects. Understand how complex this pathway is, understand that the initial inflamed condition needs to be physiologic.
The uptake of antigens, the migration to lymph nodes, the priming in the lymph nodes, the expansion, the efflux, all of those have to conform to what happens physiologically. Otherwise, first do no harm principle comes in place and the immune system basically shuts down with a suboptimal response. Next slide, please. So ideal vaccines would recapitulate this biology. Please click one more time. So this is an example from the literature of what the response to the vaccine looks like from a T cells perspective. Vaccines aim to recapitulate the natural process of presenting targets to the immune system. We talked about that. If you look at the kinetics of a yellow fever vaccine response in the peripheral blood of a person who received the vaccine, this is what happens. Initially, you have an activation event. Ki-67 is a measure of proliferation.
By about 10, the square indicates a yellow fever specific T cell response. We can detect that using a detection reagent. By day 10, about 5.5% of the peripheral T cell repertoire is specific for yellow fever vaccine. By day 15, that continues to expand a little bit. Eventually, the response contracts. This is our body's way of making sure that we don't have an ever-increasing number of T cells in our blood as we encounter more and more pathogens. There's a residual army called the memory effects phase, which are persisting, and they stay around for a long time. In case you get another infection of the same kind, that recall response results in very robust re-expansion of the cells. Note that you start out from essentially nothing.
You end up having often double digits of a peripheral repertoire that recognizes your vaccine, and that goes away. You'll see some data later on, I believe, from Stephan or Heather, that talks about how this looks like in the IMV context. The idea then is to activate and expand a specific and potent T cell response against target proteins. Next slide, please. I wanna take you through a little bit through the history of vaccines 'cause it really matters in terms of how we think about them today. The birth of cancer vaccines really was in the early 1990s. A group in Belgium was led by Thierry Boon discovered in the blood of patients with cancer, T cells that could recognize proteins from these cancers.
There was an aha moment for the field, and people then many groups said, "Hey, we can use vaccines since we know what the proteins are to stimulate and expand these cells and go after cancer, and everything is gonna be good." There were a multitude of trials, we're gonna summarize them in a couple of slides from about 1993 to 2007, using every possible available and known approach to generate, to trigger these T cells to go after cancer. Now, there were occasional responses and unfortunately many, many failures. I have here on the left two of the initial papers that say, "Hey, there's T cells in patients that recognize targets expressed by cancer." A review, an article in The Atlantic from I believe 1997, that basically hailed the coming end of cancer through vaccines, right?
Life was really great at that point. It was the apex in science. We often have peaks and valleys. This is one of the peaks. Next slide, please. This is just a snapshot, a historical summary, if you will, of the major cancer vaccine trials in the space. I've sort of bracketed these in terms of a category of vaccines and targets that used long peptides. The cell presents a nine or 10 amino acid peptide, 10 residues. These long peptides were 15, 20, 25 amino acids long. A series of trials that employed short peptides underneath there. A series of trials that employed whole protein or some version of this protein, and then a series of trials that employed cells that were engineered to have taken up these protein as a matter. Everything here essentially failed with one exception.
That's Sipuleucel-T, the first item on the last collection there. That's the Dendreon product, dendritic cell loaded with peptides to a prostate-specific antigen. The responses even there, I would say today are modest, but nonetheless, there was an approved molecule. The point here is that everything was tested in every possible way that was understood at the time. No rhyme, no reason, and fundamentally, no adherence to the principle of let's try to mimic what happens physiologically. The adjuvants that were put in, the inflammatory agents were not immunologically relevant. These cells were presented or provided the treatment was provided systemically, not in the lymph nodes. All sorts of reasons why these responses should not have worked, and ultimately, frankly, they didn't work. Next slide, please. Is there a click to the next slide? Am I connected? Oh, great.
Thank you. In 2004, a paper, a review article came out, an opinion paper in Nature Medicine. It was by an esteemed group at the NCI, Nick Restifo, Steve Rosenberg, and James Yang. They basically said, "You know, nothing's working here. There's too much that we don't know or understand. There's other immune therapies that look like they might be working. Let's stop focusing on vaccines for now, and let's focus on things that we think have a better su-- have a better probability of success." This was sort of a bomb thrown in the space of vaccines, in the field of vaccines. A pause, trials that were ongoing continued to go, but very little was done in this space for a few years. Click, please.
The take home messages from this review and from an assessment of the field, if you don't mind clicking one more time, please, were the following. We're oversimplifying biology, as we talked about before. We're delivering these vaccines systemically. They really need to get to the lymph node very effectively. In fact, when you deliver them systemically, the immune system says, "Shut down. This is not what's supposed to happen." We're overwhelming the system in more times, this philosophy that more is better, which really doesn't take place in the immune system. We're using adjuvants to stimulate the initial response that aren't biologic. In fact, we're also going after the wrong targets. We're going after targets that are expressed, of course, in cancer, but not expressed by every cell. They're expressed sporadically.
You can't have a complete response if target cells don't express the antigen. Really, an underappreciation of the power of thymic selection. The repertoire to self-antigens is fundamentally impacted, and we have to deal with that in a specific way. Next slide, please. As with most things in science, there was a resurgence in vaccines, and really it came in the first decade of the 2000 decade. The reset was based on the better appreciations of the barriers for success, the identification understanding of new targets. Truncal targets means targets that are expressed by every cell in the cancer mass. This notion of neoantigens, the stuff that tumor makes that's different from what normally happens.
New delivery strategies, and an opportunity to combine with immune therapies that had advances then PD-1, CTLA-4 and the like. I'll highlight one paper that I think was really defining for the field and important from the BioNTech group. You may be more familiar with them today from the COVID vaccine effort. They published in Nature a letter that said, "You know what? We can create a vaccine that's delivered to the lymph node because we injected in the lymph node." That's really an inefficient way, but that's what they did. When we give this vaccine that contains peptides from neoantigen-specific targets, we take patients with melanoma that have failed successive lines of therapy and focus on the figure there on the pre-vaccine. The triangles are where we have relapses. After we give them the vaccine, they stop progressing. They have stable disease. They didn't get worse.
They didn't really get better. The vaccine in this context stabilized their disease. Now recognize that every time you get a successive treatment in cancer, your progression is more rapid, typically. The fact that there were no progressions but stable disease in these patients was really important. They detected peripheral T-cell responses like we're gonna show you. This really was one of the series of promising early data for how we can move forward in the vaccine space. Click, please, if you don't mind. One more time. Now, this approach used mRNA to personalized neoantigens, and they injected the nanoparticles to the regional lymph nodes. Still, questions about the quality of the targets, and still you have to appreciate that injecting into a lymph node is an invasive non-physiologic.
It's better than systemic, but it isn't where we need to be. Nonetheless, this work and work from a few other groups showed us that if we think about the biology more systematically and carefully, there is the potential to actually make a real difference in the context of cancer with vaccines. Next slide, please. To summarize, if we take us to the year 2022, there's been an evolution in terms of how we think about cancer vaccines in terms of targets, tumor overexpressed, but overexpressed robustly and by all the cells in the tumor mass. Cancer/testis antigens, driver mutations and neoantigens are the two new players in the space. If we think about how to deliver the vaccines, heterologous prime-boost with viruses, they were around back in the day. They've now come to the forefront once again.
mRNA, liposomes, oncolytic viruses, and of course, as you'll hear today, the DPX platform that we're developing. In terms of delivery, moving from systemic into an intranodal mechanism, and the use of adjuvants that are physiologically more relevant. Of course, the ability to combine with combinations of PD-1, CTLA-4, CD40 ligand. All of these trials are in phase I and phase II, I would say at this point, with some encouraging data. Next slide, please. Significant lessons learned, but we're still largely potentially simplifying the biology in most of these cases. One more slide, please, if you don't mind. I would finish off this presentation by saying, what's the differentiation thesis for IMV and the DPX platform? As I hope you'll see today, this platform uniquely mimics the physiologic condition of exposing the immune system to target antigen.
It's a targeted and physiologic delivery of a vaccine payload to the lymph node to trigger the immune response. We have a robust activation of T-cells, and I would put to you potentially unprecedented clinical data sets, as I hope you'll see later today. One more click. I would put to you also that the DPX platform is really a plug-and-play platform that can be leveraged across oncology, and also I would argue, across therapeutic areas to deliver appropriate cues to the immune system in a physiologic and effective way. That's what I had to share with you today. I believe that in the presentations that follow, these points will be illustrated and expanded on and form the basis for an informed discussion session to follow these presentations.
Jeremy, with that, I thank you for your attention, and I'll pass it back to Jeremy.
Fantastic, Michael. Very much appreciated. That was really a beautiful review of the field. A beautiful review, really of why cancer vaccines historically have not been terribly effective. I think that helps us launch into an understanding of why we think DPX is a very different delivery platform for immune cargo, for the vaccine cargo that you just discussed. Let's go one slide forward, please. Like Michael, I joined last summer in large part because I was very attracted to the science of this DPX platform. The first characteristic of the platform that's different is that unlike other formulations to deliver this information, the DPX platform is a unique lipid and oil non-emulsion formulation that helps keep the product at the site of injection. Let's click once, please. That physicochemical nature of the product effectively spoon feeds instruction into the antigen-presenting cells that Michael mentioned before.
The product does not leach out into systemic circulation. It doesn't leave the site of injection, and that's really very distinct from other methodologies of delivering cancer vaccines systemically. Next click. The activation of the immune system, as Michael has shown us really with DPX, mirrors the physiologic condition to drive both a T and B cell response, priming of the response in the lymph nodes directly. Next click. We provide within the DPX product specific stimulants for the innate immune system. In our lead product, that specific stimulant is Poly-ICLC. You'll see some of the other products that have been developed over time use different innate immune stimuli, including Pam3Cys. Next click, please. All of this effectively allows for antigen presentation. I think importantly, within DPX we include what we consider to be CD4 T helper peptides.
When we instigate a more robust CD4 T cell response, I think of those particular CD4 T cells as being the CEOs of the adaptive immune system. We simultaneously allow for the maturation of antigen-presenting cells, and we allow for a persistent CD8 T cell response. Last click for this slide, please. As you'll see when we walk you through a variety of examples of the DPX science, there is broad therapeutic applicability for this platform, primarily because of the way it feeds information into the immune system. We can take cargo to specifically engineer a T or B cell response that are peptides. That's really where we spent most of our time. Cargo can be whole proteins. We know cargo can be viruses or viral-like particles, nucleic acids, including mRNAs, small molecules, et cetera.
There's a versatility to this platform that allows us to apply this science in many different directions. I think importantly, we rolled out last fall that our distinct focus at IMV is an immuno-oncologic focus. I will take you through some examples today of some of our older infectious disease products because they're instructive as we try to understand the DPX platform and how it educates a very specific immune response. I want to be very, very clear. Our focus is immuno-oncology. Next slide. I think instructive is to first appreciate what our product actually looks like. I said it's a unique lipid and oil non-emulsion formulation. You can see what DPX looks like on the left-hand side after lyophilization, after we dry it down. We call this the cake.
We take the cake at the site of administration, at the clinical site, and we reconstitute this in an oil known as Montanide ISA 51. That product then is really a clear solution. Contrast that with a conventional emulsion. Next clip, please. Conventional emulsions effectively mix both oil and aqueous phases. You can see on the right-hand side of this that the emulsion will actually begin to phase separate and can do so in vivo as well. As you phase separate, cargo that prefers to be in the aqueous phase versus cargo that prefers to be in the oil phase can begin to separate from one another. In the aqueous phase, the cargo disperses more readily, more quickly, and is effectively lost.
There's a very distinct difference that's based upon the physicochemical characteristics of the DPX platform and unique to this particular platform. Next slide. Let's talk about a few additional attributes that we think provide advantages for DPX-based delivery relative to aqueous delivery and relative to conventional emulsion delivery. First and foremost, the particle size for DPX. Particle size is fairly homogeneous, five to 10 nanometers. With the standard aqueous delivery formulations and the conventional emulsions, the particle sizes are very heterogeneous and may be much larger. The size of the particles that can be consumed by antigen-presenting cells actually matters. The stability of the product, so that it can be shipped around the world, so that it can be shipped without definitive cold chain storage, like some of the mRNA vaccines, is extreme with DPX, more than three years.
Our lead product, in fact, has a stability of five years. Aqueous and conventional emulsions are much shorter stability. Do the products leak from the site of injection? This is critically important because this is one of the reasons information fed through DPX ends up in the lymph node for priming in a more physiologic way. From DPX, we don't see leakage, and I'll show you some examples of that in a second. Aqueous delivery, the leakage is almost immediate. The cargo that comes in through aqueous delivery leaches out into systemic circulation very quickly. Conventional emulsions were built to make more gradual that leakage, but they still end up systemically dispersing the product. The uptake by the immune system is very different. For DPX, the uptake is active.
Antigen-presenting cells across time actually take bites of the cargo, if you will, and take that cargo back to lymph nodes to instruct a very specific response. With aqueous and conventional emulsion formulations, you can get active uptake, but as the product disperses. You also get passive interaction with the immune system, passive interaction that can trap T cells, passive interaction that can defeat an effective immune response. Lastly, as Michael so eloquently described for us, we target immune instruction to the lymph node when we use DPX. That's not necessarily true with aqueous and conventional emulsions. Next slide, please. So this, I think, is a very instructive cartoon diagrammatic to explain to you how DPX is consumed by the immune system, how it's processed through the immune system, et cetera.
You can see at the bottom of this graphic in point number one, we inject our product by subcutaneous administration, typically in the thigh of our patients. At the site of injection then we attract antigen-presenting cells, in particular immune cells to that site. Those antigen-presenting cells, by virtue of the phagocytic action that they carry, consume parts of that cargo and traffic back to the lymph nodes. This is point number three on this slide, where they can begin to educate an appropriate immune response. Once educated, those T cells and B cells can then circulate in the periphery, honing in on their specific target. T cells, of course, enter into tumor tissue and can mediate direct killing. B cells can also enter into tumor tissue, but are largely responsible for making the antibodies that then coat and flag a tumor cell for recognition and destruction.
We can inspire both the T and a B cell response using DPX. We can inspire a very specific flow of traffic through the lymph nodes. Next slide. This, I think, is a very illustrative example of the difference that DPX brings to distribution of vaccine cargo. Here we did a really simple experiment. We took a blue dye, and we administered it to mice in an aqueous delivery platform. What you can see in the first picture is just one day after, if we look in the serum of these mice, it's almost entirely blue. The dye has leaked completely into systemic circulation. You can see at seven days post-injection, you still see an enormous amount of that dye in the serum.
You can actually see, if you look at the far right picture, the paws of the animal and other tissues of the animal are visibly blue. So an aqueous delivery immediately casts out cargo into the systemic circulation. That cargo is lost. It's not fed through the immune system in an appropriate way. By contrast, quickly click to the next, please. DPX holds the cargo at the site of injection. The best way to visualize this is actually the picture on the far right. You see the blue dye just sitting there at the site of injection. If we look at serum at day one after injection and serum seven days after injection, you don't see evidence for that blue dye having made its way into circulation.
This is a very simple experiment, but I think illustrative of how well DPX holds cargo at the site of injection. Next slide. Okay, so we took this a little step further. We wanted to ask a little bit more about how it is that antigens move through the system after DPX delivery. What we've done here, we've taken what we call a model antigen, ovalbumin, an antigen that mice will readily recognize and react to. We've labeled this antigen with FITC, so a fluorescent label. We inject mice at day zero. Two days later, we terminate some of the mice. We look at the sites of injection. We also look at regional lymph nodes. Where is the labeled antigen going?
At day eight, we sacrifice the rest of the mice, and we ask whether or not we've effectively inspired a response, an immune response to the ovalbumin antigen. Next slide, please. Okay, so I think this is illustrative. The PBS control is represented on the left-hand side, so this is just an injection control, if you will. We're looking at the site of injection. We're trying to understand what immune cells exist at the site of injection, and are those cells more prominent after delivery of DPX? I think in this donut graph you can see that there are many more colors. Those colors represent different types of immune cells when we inject DPX with the ovalbumin labeled antigen.
I think what's really notable is the cells that are primarily responsible for picking up antigen in tissues and delivering that antigen to the lymph node are the antigen-presenting cells and most notably, the macrophages and dendritic cells. You can readily see here, just two days after injection in green, the preponderance of the macrophages. If you look closely, you can also see in orange the dendritic cells, and then the other colors that pop are innate immune cells, NK cells and neutrophils. Click one more. At day eight, the rush of immune cells into the site of injection gets more profound. You can see that in the bottom right-hand side donut with DPX-based delivery of ovalbumin, you see an expansion of those green macrophages. You see an expansion of the dendritic cells in that salmon color.
In fact, what we can recognize when we do this experiment is roughly 40% of the cell composition, of the immune cell composition at the site of injection are made up of these antigen-presenting cells, the macrophages and dendritic cells. What this tells us is we are specifically recruiting these cells to the site of injection, and these cells, which are so important for trafficking information back to the lymph node, pick up the product, and I'll show you in a second, take it directly to the lymph nodes. Next slide. The first graphic here is effectively what you saw in the donut plot. We've just stacked these into a bar to give you a sense for what this looks like in a bar graph format. You can again really see the preponderance of the macrophages now coded, now color-coded in blue two days after injection.
Click one more time. That's the site of injection. At the site of injection too, we can look for the specific label that we've attached to the antigen. That's shown in green in this bar graph. What you see very quickly and very obviously is macrophages as early as day two are consuming the antigen. That's the smaller green bar that you see on the left-hand side of the graphic. You can see by day eight, they've consumed even more of the antigen. The only other cell that appreciably consumes the antigen are the dendritic cells, the other flavor of antigen-presenting cells that we're concerned with. You can see they do actually pick up a bit at day two. It's very tiny and hard to see on this graph, but you can very readily see they're picking up more and more of it by day eight.
We're getting recruitment of cells to the site of injection, the SOI. We're getting antigen uptake by the antigen-presenting cells at the site of injection. Next slide. We can track dispersal, we can track the trafficking, if you will, of the labeled antigen in the lymph nodes. Here we've taken lymph node tissue, the regional lymph node tissue, and we've looked for effectively the FITC-labeled antigen. You can see very prominent increase in the antigen within the lymph nodes just two days after injection. Click one more time. Now you can see a very specific ovalbumin-driven immune response within the spleen at day eight. Let's click one more time, and we'll kinda click through this next slide fairly quickly. This is the flow of antigen that Michael mentioned before, a more physiologic flow of antigen from the site of injection. Click once.
Consumption of antigen at the site of injection. Click again. The accumulation of the antigen within the lymph nodes. Click one more time. The resultant specific immune response that DPX delivers. Next slide. Okay, those are the basics of why DPX spoon feeds information into the immune system in a way that mirrors the way the immune system normally consumes antigen. I wanna take you now through a number of examples, proof of concept preclinical studies, if you will, that help articulate and illustrate what DPX, especially as we compare it to other delivery formulations, what DPX can do as we think of packing a variety of different cargo into DPX.
The fact that DPX can elicit both B and T cell responses depending upon what you pack within DPX, and then we'll spend time at the end of the talk really honing in on our lead DPX product, maveropepimut-S. Next slide. The first example is a product that we made ultimately to provide a vaccine for the viral infection RSV. The product is DPX packed with a B cell epitope, a 23-mer epitope, to this small hydrophobic ectodomain antigen or the SHeA product. The SHeA antigen is expressed on the surface of infected cells, and the intent for this product is to limit infectivity by RSV. A note, this is a product where we use the TLR one-two agonist to stimulate innate immune functionality. This agonist specifically is Pam3CSK4. Next slide.
What this slide really shows us is that when we administer this RSV product into different species, mice, rats or rabbits, DPX-based administration produces a much higher antibody titer and does so uniformly across species. Here in the mouse experiment, you can see we've compared DPX to a more standard adjuvant that's commonly used and has been commonly used for many, many years, the alum adjuvant or aqueous. You can see neither one of those approximates the antibody titer that DPX delivers. You can see effectively the same differentiation in rats and the same differentiation in rabbits. Next slide, please. We wanted to understand how important each of the components of DPX are.
When we think about DPX, it's not just packing antigens into a lipid and oil formulation, it's antigens, it's instruction to stimulate innate immunity, and it's T helper peptides that enable a CD4 T cell response. Here we're taking away various components to see what that does to influence the immune response DPX can orchestrate. You see on the top line what the fully loaded product does to elicit a very strong and profound antibody titer across more than 20 weeks in this particular experiment from a single injection. You can look at this on the chart on the right and compare it back to the lines in the graph. If we take away the oils, we simply don't feed information into the immune system appropriately.
If we take away oils and lipids, again, we defeat the ability to execute an effective immune response. Of course, if we take away lipids, oils and adjuvant, the product doesn't look very strong at all in eliciting an immune response. We know that we need more than just the antigen packed in DPX. We need all of the components of this product. I'm not sure that's been articulated fully in the past. Next slide. In this particular case, we're asking whether or not this product can be efficacious in a preclinical setting. We're really challenging mice with DPX-RSV, the fully loaded RSV product, directing an immune response to SHeA. We're looking for antibody production. That's what you see on the left-hand panel in the triangles. You can see antibody production after DPX-RSV administration.
We're comparing this to another way that's commonly used in preclinical studies to incite an immune response, and this is taking the SHeA antigen from RSV and conjugating it to another protein called KLH. We know historically in preclinical settings that will induce an immune response, and you can see here that we do in fact see an immune response. The response to the DPX product is more profound by a log order. If we look at efficacy, we can challenge these vaccinated mice. We can then harvest from their lungs and look for the number of plaque-forming units. We want to see a reduction in plaque-forming units if we have an efficacious product. You can see the PBS control in the gray bars. This is now the right-hand panel. We have plenty of plaque-forming units from the PBS control.
It looks very similar with the RSV KLH conjugate, but you can see a vast reduction when we've immunized the mice with the RSV product packaged in DPX. Again, DPX providing superiority to delivering effectively the same antigen, but through a different, more historical modality. Next slide. We actually took this product into phase I clinical study in healthy volunteers looking for immunogenicity. The actual trial involved a comparison for the DPX-RSV product against the same antigen delivered in the standard alum-type adjuvant. What you can see on the top panels is the high-dose DPX or alum product, and on the bottom panel, the low dose.
If you look at the left-hand panels, you can see in each of the patients dosed or each of the subjects dosed with the DPX-RSV product, a robust antibody titer that can be evident as early as just a few days after the first injection. You can see this in the far left of those graphics. We dose again at about day 50, and you can see a boost of the immune response. I think importantly, whether you're looking at the high dose or the low dose DPX-RSV, you can see that this antibody response persists across time. In this graphic out beyond 250 days. Contrast that DPX-RSV effectiveness with the same antigen delivered by the standard alum-type adjuvant. You can see that the response to alum in healthy human subjects is variable.
Some, very few, show antibody titers, but those titers don't approximate the titers we get with DPX-RSV. You can see that in the context of the alum adjuvant, those titers don't persist either. One more slide to help emphasize this particular separation. The advantages here of delivering this or antigen by DPX versus alum. This is now a mean or an average antibody titer across time from this phase I study. The bottom lines represent either placebo or the two different doses of the alum RSV product. You can see that early on, around day 50, you get a small bump of antibody from the alum product, but you can see that then recedes and effectively is flatlined for the remainder of this entire time course, out to about 420 days.
I think what is striking when we look at the DPX-RSV product at either dose, the upper two lines in this graphic, you can see that the immune response, in this case a B cell response to the antigen packaged in DPX, persists now beyond 400 days. That's a very impressive immune response to this particular antigen. Next slide. I want to take you through another example. This is an example where we've developed a product historically against flu. There really are two products we'll talk about. In the one case, we've packaged a recombinant protein, hemagglutinin antigen, into the product. This is a whole protein. We've also packaged within the product the TLR3 agonist Poly (I:C) to incite an innate immune response. The HA antigen is of course expressed on the surface of flu virus, and so we're trying to defeat its infectivity.
The second product we'll talk about very briefly is what we call DPX flu. In this product, instead of a whole protein, instead of a singular antigen, we've packaged the entire virus, heat killed, but the entire virus. Next slide, please. Of course, again, much like I showed you for the RSV product, we compared the response to the DPX hemagglutinin product to the alum-based adjuvant, which is very common and has been historically used. Again, you can see in this mouse study a very profound increase in the antibody titer elicited from a DPX injection versus an alum injection. You can see this persists out in this experiment to 12 weeks from a singular injection. Next slide. When we think about respiratory viruses, we're certainly front and center with COVID, but we're also thinking about flu.
We're thinking about any number of respiratory viruses, and we know that older individuals, in this case mice, tend to have more problem eliciting an immune response to vaccines than younger. In this experiment, we tested both young and old mice, and we tested to see whether or not DPX would be effective at eliciting an immune response in the older, more immunocompromised mice. In fact, that's what you see. The two purple lines on the top of this graphic show you the antibody levels that were generated by the DPX injection in young mice, that's the top line, and in older mice, that's the second line down. Both of those antibody titer show us a greater response than alum can produce even in the young animals.
Alum produces an antibody titer response, but it takes a while for that antibody titer to build up, and it does not necessarily reach the full levels that we get with DPX. I should point out, in this particular experiment, we've given a single dose of the DPX HA vaccine and compared that to two doses of prime, and then a boost dosing for the alum-based vaccine. DPX here again shows superiority versus this more classic means of administering a vaccine. Next slide. We wanted to look at efficacy of this type of product as well, right? Can we defeat infection by flu? This is a bit of a complicated slide, so I'll take you through it slowly. This is that second flu product we've packaged within DPX, the whole viral particle heat kill.
We're giving the entire roster of antigens to the immune system to process. In this experiment, we've packaged within the DPX product, the whole virus from the H1N1 strain here, the Puerto Rico strain, hence the moniker PR. You can see when we sham treat, so the controls in the dotted lines, the mice are dead after challenge within 10 days. If we treat with an alum-based version of this vaccine, about half of the mice are dead at 10 days. We contrast that with treatment using the DPX whole virus vaccine, and you can see virtually all of the mice are alive during this time period. That's a very profound and distinct difference in efficacy. We can take this another step further, and as a scientist, this is a particularly interesting aspect of DPX.
We can show cross-protection to other viral strains, so other flu strains. Let's go to the next click. We're vaccinating the same way. It's the same DPX product, engineered to encapsulate, to incorporate the Puerto Rico whole killed virus. We're now challenging these animals with the H3N2 Hong Kong strain. Let's walk through the experiment. Again, in the mice that did not receive any treatment in the dotted lines, you can see that they have all perished within 10 days. If they instead got the alum vaccine to the Puerto Rico strain, they also die just like the vehicle control. The Puerto Rico strain in the alum preparation does not provide cross-protection.
If you now look at the two top lines, you see on the very top line, the alum preparation of the Hong Kong virus, so specific for the virus we've used to challenge these mice. You see right with it, the DPX product with the Puerto Rico strain. That's a fairly complicated experiment, but what it really tells us is that the DPX product to the Puerto Rico strain is providing an immune response that cross-protects to the Hong Kong strain. If we're thinking about vaccination, if we're thinking about eliciting an immune response, the ability to elicit a diverse immune response that protects is very, very important against multiple strains. Next slide, please. Okay, so I've spent a bit of time providing examples for you of our B cell-oriented immunoinfectious products that have been worked on historically.
Again, I wanna emphasize our focus is immuno-oncology, and when we think about immuno-oncology, what we're trying to do, as Michael articulated so well before, is incite a T cell-based response. We're packing immunogenic peptides that can elicit a very profound T cell-based response. I'll show you data from a tumor model we use pre-clinically called C3, and the antigen specifically is called R9F. I'll show you data from our second product, a product that is just starting clinical trials now, DPX-SurMAGE, where we're actually targeting two different cancer antigens simultaneously, and then we'll spend the rest of the talk with maveropepimut-S, our lead DPX product. Next slide. This is just a great example, packaging a variety of different T cell-oriented peptides in DPX and comparing the response we get to conventional emulsion. On this slide, CE means conventional emulsion formulation.
You can see on the left-hand side, we're using maveropepimut-S, our lead product. You can see when we dose maveropepimut-S, we get a robust immune response. You can see that in the purple bar on the far right side of the left-hand graphic. You can see if it's delivered, those very same peptides are delivered in the conventional emulsion, you don't inspire much of an immune response. Similar pattern, if we look at seven different tumor-associated antigen peptides that are restricted to the HLA-A2 allele. Again, this grouping of peptides we simply call 0907. You can see if in DPX-0907 produces a very robust response, when in the conventional emulsion, 0907 produces a very marginal response by comparison.
The last graphic shows you if we target a mutant-specific neoantigen in the C57 mirroring background, DPX delivers a much more robust response than the standard aqueous delivery, the standard PBS-based delivery. All three of these are just different examples of eliciting a very robust T cell response to distinct peptide antigens. Next slide. Let's turn a little bit to the C3 model. To give you a sense for what this model is, we take these cells, and we inject them subcutaneously into the flank of mice, as you can see here in the middle panel of the graphic, and then those tumors grow. What we're trying to do at first is just understand whether or not by eliciting an immune response to antigens specific to this tumor model, we can control tumor growth.
The antigen we're specifically using is called R9F, and it comes from the HPV-16 E7 protein. This is a human papillomavirus-driven model. The innate immune activator we use in this product is Poly( dI:dC), and the helper peptides are either PADRE or F21E. Next slide. The left-hand panel shows you the base efficacy we get when we vaccinate, if you will, an animal against the C3 antigen R9F. Animals are injected with the tumor, then they are vaccinated with the DPX-R9F product. You can see the untreated animals in the dotted lines with the Xs grow tumors very effectively. You can see that in the purple line, the animals that had received the DPX-R9F vaccine simply don't grow tumors nearly as well. What's really, really interesting as a scientist is that we can actually take T cells out of animals that have been vaccinated with the DPX-R9F product.
These are now educated, activated T cells. We can transfer those. We can effectively give those cells in an adoptive transfer modality to other animals that are already growing the C3 tumor, and we can limit tumor growth in that setting. That's what's on the right-hand panel. In the pink are the animals that received the adoptively transferred T cells from a prior vaccination of donor animals. In the other two lines, you can see the control animals that are growing the C3 tumor much more robustly. The ability to adoptively transfer these activated and educated T cells has a profound effect on tumor growth as well. It's a very nice piece of data pre-clinically. Next slide. Again, with this product, this is the DPX-R9F product.
We also wanted to appreciate the contribution of the other components of DPX. It's not just antigen, it's antigen plus an immune stimulation plus T helper activation. If we take away T helper activation, this is on the left-hand panel, we limit or lose the effectiveness of this vaccine in controlling tumor growth. You can see the untreated in the dotted line. You can see the DPX without the T helper peptide in the solid gray line, and you can compare that and contrast that with the fully loaded DPX in the purple line. This is a survival curve. Almost all the mice survive with the fully loaded DPX, but they look just like the untreated controls if we've taken away the T helper peptide.
Effectively, the right panel shows you the same thing, but in this case, we've taken away the adjuvant to activate innate immunity. You can see the vehicle control again, all the animals are dead with about 42 days after injection. In the dotted lines, you can see that DPX without adjuvant in the gray lines looks very similar to that vehicle. You can see 100% of the animals living if they've got the fully loaded DPX with adjuvant. Next slide. Let's talk about our second product. The second product is DPX-SurMAGE. Both survivin and the MAGE-A9 proteins are well-known tumor-associated antigens. They are upregulated in poor prognosis bladder cancers in particular.
We wanted to develop a product and test whether or not DPX could deliver instruction to the immune system to inspire an immune response to two different cancer-associated antigens simultaneously. Packed within SurMAGE are peptides that are restricted for the HLA-A2 allele, the most common allele in the human population, to both survivin and MAGE-A9. I'll show you here in a second that we do elicit a robust response to both antigens simultaneously with this product. Next slide. This slide shows you really at eight days after the last dose and 29 days after the last dose, that we can inspire a very specific T cell response to both survivin and MAGE-A9. Let me tell you a little bit about the specifics of the experiment.
We dose the DPX-SurMAGE product at day seven, 28, and 49 with and without low dose intermittent cyclophosphamide, a way that we dose in the clinic. Then we harvest splenocytes for T cell reactivity assays, either eight days or 29 days after that last dose. You can see if we then challenge these splenocytes with peptides either to survivin or peptides to the MAGE antigens, we can inspire a very robust induction of T cell-based immunity. You can see that it's durable even 29 days after the last dose. Next slide, please. One of the things we wanted to understand about this particular product was whether or not the packaging of both antigens into a single product would limit the effectiveness, for instance, of our survivin antigens that are used in our lead product. Really that's exemplified by this experiment.
We've challenged the animals at day zero. We harvest at day eight, lymph nodes and spleens. We look for T cell reactivity by our standard interferon-gamma ELISpot activity assay. We're inducing T cell reactivity using antigens to the survivin protein. The essence of the experiment is to ask whether or not the survivin T cell reactivity is as good in SurMAGE as it is in DPX-Survivac or MVP-S. In that first set of bars, you can really see with the SurA2M that this, the MVP-S response or the response in the MVP-S vaccinated animals in the darker green, is the same as the response to this very same survivin antigens when given in the DPX-Montanide product.
This gives us confidence that being able to pack multiple antigens into DPX does a good job at simultaneously inspiring a robust immune response, doesn't limit the response to one antigen in favor of another. Next slide. Let's turn to the final phase of the talk. We wanna talk about the lead DPX product because I think our experience with this product really helps provide proof of concept for the activity and the unique special activity of the DPX platform. For maveropepimut-S or MVP-S, formerly known as DPX-Survivac, we've added peptides to the cancer antigen survivin, five different peptides that target the most common HLA alleles in the human population. We think this now covers virtually all of the human population, at least 85% or so. We've added the PolydIdC innate immune activator and the helper peptide known as A16L.
That's what's in maveropepimut-S. Next click, please. As we'll show you, and this is just a 30,000-foot view of our clinical experience, this product is in mid-phase II clinical development, angling toward registration trials. We've now dosed more than 300 patients in the clinic with this product. It is very well-tolerated. Typically, we only see grade 1 and 2 AEs, injection site reactions predominantly. We dose typically with low-dose intermittent cyclophosphamide, a way to help condition the immune system, and we've seen objective clinical responses and objective clinical benefit in the form of complete response, partial response, and long-term stable disease. We've seen this in multiple cancer types, diffuse large B-cell lymphoma or DLBCL, as well as recurrent platinum-resistant ovarian cancer and advanced metastatic bladder cancer. Next slide.
The survivin antigen, Michael touched on this a little bit before about how antigens that in and of themselves are not reflecting mutant oncogenes can be very good antigens if they are homogeneously upregulated. If they're upregulated to a level where the immune system can distinguish these antigens against itself. Survivin is one such antigen. We know the survivin protein is commonly upregulated by many, many cancers. Whether those cancers are liquid cancers like DLBCL or whether they're solid cancers like ovarian cancer. Survivin, as the name implies, is critically involved in the incredible survival the tumor cells acquire as they progress and as they ultimately escape chemotherapy. Survivin is commonly upregulated in multiple different tumor types. Its upregulation presents a very attractive immunologic target, and the beauty of targeting survivin is the cancer cells are using survivin.
They cannot readily just stop using survivin without also diminishing their survival. Next slide. The next two slides really help articulate exactly what we mean when we talk about the power of the DPX platform and how it's distinct from standard conventional emulsions or other means of administering immune instruction. The slide here that you see, we've packed peptides to the mouse version of survivin into a conventional emulsion, those at the left-hand side of this panel, or into DPX. I think you can fairly readily see that in DPX we get a robust T-cell based immune response we do not in a conventional emulsion. Next click. We can do the same experiment, but instead of using the mouse version of maveropepimut-S, we actually use the clinical product in mice that are transgenic for this HLA-A2 allele.
When we administer MVP-S, which are the two left-hand bars, we can see a really pronounced activation of T-cells specific to the SurA 2 peptide. But you don't see that if those same peptides are packed into a conventional or CE Survivac product, conventional emulsion product. Two different examples that are similar to what I showed you before with T-cell peptides. In DPX, the T-cell response is much greater. We think, as Michael articulated earlier, that reflects the fact that DPX promotes a flow of antigen through the immune system that mirrors the physiologic condition through lymph nodes. Next slide. I think this is very important. As we think about maveropepimut-S as a lead DPX platform product, the experience we've had with it is instructive. We took these peptides, these are the very same peptides that Merck KGaA pushed into a phase I study.
They vaccinated people in a conventional emulsion. Their experience, published in 2014, was that they could only see a T-cell based immune response in 14% of patients. Our experience with these very same survivin peptides now packed into DPX has been robust and more effective. Next slide, or next click, I should say. In our hands, in advanced cancer patients, nearly two-thirds of all patients show a robust T-cell based response to these very same survivin peptides. The only difference here really is DPX delivery versus a conventional emulsion. Click one more time. This also is associated with a difference in the clinical activity. The original report for these peptides in the hands of Merck KGaA was that the best clinical response achieved was stable disease.
As we'll walk you through in just a second, we have achieved clinical responses that include complete responses, partial responses, and long-term stable disease in multiple different cancer types, hematologic and solid cancers. This in and of itself is a great example of the plug-and-play nature of the platform. Take peptides that maybe did not work in other formulations, put them into DPX, elicit a much more robust response, and ideally a more robust clinical response as well. Next slide. Okay, I'll sum this up very quickly. The DPX delivery platform itself, as Michael helped us understand, really promotes the flow of immune instruction through the immune system to the lymph nodes, where priming really begins, in a way that mirrors physiologic conditions more readily than prior vaccine formulations have ever done.
We promote recruitment of cells to the site of injection, uptake of the cargo within DPX by antigen-presenting cells, the trafficking to the lymph nodes, and then, of course, the specific immune responses. It's a versatile platform. I've shown you examples today of packaging peptides of all different sorts, whole proteins, whole viruses. We have examples within our preclinical work of packaging nucleic acids. We can swap in and out, as you've seen, with Poly- dIdC, Poly-IC, Pam3CSK, different innate immune activators. This is truly a plug-and-play platform, and our experience with MVP-S helps us appreciate that. With that, I'm gonna hand this over to Heather. Heather's gonna take us through our clinical experience, the science in the clinic for DPX, to help you appreciate more deeply exactly the mechanism of action in our patients. Heather, take us away.
Thank you, Jeremy. Just wanted to start out by saying I'm very excited to be able to be here today and speak to everyone about the exciting science that we have ongoing in our clinical trials for our lead products. Just to set up just a little bit before we go to the next slide, some of you may have seen some of the data that we're gonna talk about today. We have been kind of highlighting bits and pieces at different meetings and different press conferences.
What I'd really like to do today is integrate the data that we have that you may have seen in different places, but integrate that so that I can start to draw kind of a connected dot story to walk everyone through what we know in the clinic and the data that we have to support MVP-S mechanism of action in our patients themselves. On the first slide, what we've shown just briefly is to talk about kind of how are we gonna do this in the clinic. During the clinical trial, we set up these trials so that we are taking clinical samples from patients both prior to treatment and while on treatment, and we do that in two major buckets.
We take blood draws at various times throughout the trial to harvest products such as PBMCs, plasma, serum. We kinda do the standard things that you would do in any clinical trial, but also importantly for us, we use these cells to do assays downstream to understand the changes in the immune system and the periphery, and understand the changes that are brought about by having survivin specific immune cells being initiated from our treatment in the clinic. Additionally, we also do take tumor biopsies. We take a biopsy before a patient comes on trial, and we try to get patient biopsies on treatment as well to be able to learn more about the tumors that we're trying to treat, but also learn more about what MVP-S is doing to those tumors in the patients in our trials.
We look at that in a couple ways. We look at that by RNA sequencing to understand kind of on the global perspective, we look at gene expression, we look at gene signatures, and we look at signatures of specific cell types. We also do multiplex immunofluorescence. It's gonna help us better understand the types of cells that are in our patients' tumors, both prior to treatment and while on treatment. We can also do things that are more DNA-based methods that will help us understand correlations with HLA. It'll help us understand things around tumor mutational burden. Importantly, some of the sequencing we can do from the DNA will help us understand the T-cell repertoire that was spoken about earlier in this discussion.
That's gonna give us a really good handle to understand kind of the diversity of the T-cells that we're seeing in the tumors in the patients that we're treating. Thank you. Next slide, please. Just to bring this up really quickly again, Jeremy's already taken you through this and shown the beautiful data that we have for our mechanism in the preclinical setting. We're gonna talk a little bit today about how we measure this in the clinic and what we've learned so far. We've already kind of been through the site of injection, recruitment of our particles by APCs that then go to the lymph node where additional immune education occurs.
They leave the lymph nodes, they traffic out, either through the blood system or in other methods to be able to either send their survivin specifically activated cells to the tumor or do things like B-cell component where they might be releasing antibodies. Again, these two very important concepts and pathways around the T-cells and the B-cell is really what I wanna talk about today and how they may be working together to affect change in the tumor. First of all, we're gonna break this into kind of up into sections along the lines of this mechanism and kind of zero in on a couple things. If you can hit the next clip, please.
The first thing I really wanna talk about is the evidence that we have in the clinic that immune cells have been educated by MVP-S now have a survivin-specific response, and they're going to traffic out into the periphery on their way to going to the tumors and doing their work there. What we're gonna look for first in our clinical samples, we're gonna look for evidence that we can find survivin-specific T cells that have been educated by MVP-S. We're also gonna wanna look for activity of B cells. B cell is a little bit more difficult to look at from a cell perspective, but we definitely can go in and measure the antibodies and other products that they generate. We'll look at that as well. Can we go to the next slide, please? Okay.
First of all, let's look at the evidence that we have that says that we can detect in patients in our trials survivin-specific T cells that come about, get activated, and expand after being exposed to MVP-S. The way that we do this is a couple of different methods actually, and we'll talk to you about two of those today. First of all, to kind of assess the activity of survivin-specific T cells, we do what we call an ELISpot analysis, in which we take PBMCs from our patients prior to treatment and then along the course of their treatment. Then along the course of their treatment, they're getting MVP-S, they're getting educated, they're having memory forming in these T-cell compartments.
Once we harvest those types of cells while the patients are on treatment, we can take them back to the lab, and we can stimulate them using the antigens that are the exact same antigens that we put into our MVP-S to kind of activate those cells. In this way, we're getting a very survivin antigen-specific response that we can measure by looking at how much interferon a T-cell is expressing in an ELISpot assay. That's what's shown here on the left-hand side.
If you look at this first line chart that's kind of on the top left-hand side, what I'm showing here is some comparisons within patients between what we see for the interferon production at baseline in our survivin specific T-cells versus what we would consider a best response when we're measuring those interferon responses on any of the days, any of the points post-treatment. What I want you to take away, because there's a couple things, is first of all, we do see a fairly dynamic range. We do see it's not just small changes in T cells that we observe. We do see a very dynamic range. Secondly, for the most part, most of these samples are going up higher in the post-treatment.
Again, if it's higher than baseline, then we are having evidence suggesting that this is a MVP-S specific response because those are survivin specific T cells that we see only in the post setting. What will also become a little bit more obvious in the next figure over in the box plot, we've measured kind of the best, the highest peak that we see by ELISpot in any of the patients in this trial. What we can kind of see if we plot that as a box plot is we do really see a correlation between much higher best responses in our PRs and our SD patients as opposed to those patients that have progressive disease. The very bottom pie chart here is kind of more of a quantitative view of that particular box plot.
That box plot gives you quantitation. This is gonna give us more of a yes or no answer where we've said a patient is positive if they've had at least two positive ELISpots, otherwise they're negative. What I wanna show here is that if you look at that green part pie chart, which is our partial response, we see 75% of those patients have elicited a survivin specific T-cell response. We see 63% in the stable disease, and we see only 33% in the progressive disease. Again, very much correlating to having more of that survivin specific T-cell response in our patients that are getting benefit from MVP-S. Next clip please. We have a secondary assay that we also measure that survivin specific T-cell activity.
In this case, we're attempting to count the number of survivin-specific T cells that we would see in the periphery. We do this by taking labeled tetramers and basically, you know, labeling survivin-specific T cells, and then they get counted in the flow cytometry. There's a couple of things that I want to point out though. First of all, if you look at the light green lines and that purple line, those are our partial responders as well as our stable disease. If you look at those, a couple of things I wanna point out, you can see that they have a fairly high induction of a T cell response there. The second thing that I want to point out is especially look at these last two.
There's one partial responder and one stable disease where we are still detecting survivin specific T cells all the way out to day 420. Not only are we inducing this robust T cell response that's survivin specific, it's also very persistent and we see this persisting for quite some time on patients that are, you know, getting that benefit from MVP-S. Can we go to the next slide, please? To kinda come back, you know, I like to think of what we're talking about today as T cells being a yin and the B cells being the yang of kind of the mechanism we're talking about today.
If we're looking at the yang side of this and looking at the B cell component, as I kind of alluded to earlier, it's a little more difficult to go in and kinda track down survivin-specific B cells. However, what we can do is we can monitor the types of antibodies that those B cells are producing. We can look for antibodies that specifically bind to survivin peptides kind of as a whole, but then also survivin peptides that are ones that are specifically in our MVP-S formulation. What I'd like to point out here is, on both of these plots, we're looking at induction of antibody specific to survivin as a whole or to our peptide that is designed to be specifically displayed by HLA.
All of the green dots and lines on these plots are patients who have clinical benefit as defined by having at least a 10% tumor reduction. Anyone who has purple lines and dots on the spot is someone who has not had that 10% reduction or is in that progressive disease category. First takeaway is we can definitely see induction of antibody titers that we do not see at baseline for many of our patients that are having some clinical benefit. We see those in the green lines. Very interestingly, we see no induction in the patients that we've tested so far that don't have a clinical benefit. We do not see these survivin specific antibodies getting produced in these patients.
This is highly indicative that the B cells are playing an important role in the mechanism of our drug, and we do have that evidence that it's survivin-specific based on the types of antibodies that we're seeing in the patient's periphery. Next slide, please. Okay, very quickly, I just wanna bring you back to our mechanism of action. We've already kind of talked about the evidence that we have that suggested, you know, that the B cells and the T cells are leaving the lymph nodes. They're going out in the periphery and trafficking to different areas of the body where they're needed to start performing their jobs.
The next thing I wanna talk about, which is also a very important concept when thinking about our mechanism of action, is once we produce those T cells that are survivin specific, they leave the lymph node, they've migrated to the tumor. Can they actually get into the tumors? Can we actually see them migrating into that tumor environment where they can go in and affect a change in the tumor? The way that we're gonna look at that today, and I think if you wanna click one more time. There we go. We can actually go and ask ourselves a question. Can we see survivin specific T cells in the tumors of patients who have had an on-treatment biopsy where we see survivin specific T cells post-treatment, but we don't necessarily see them in the pre-treatment space.
If you go to the next slide, I'd like to tell you a little bit about the experiment and how we approached that. The way that we are looking at this is to do T cell repertoire analysis. Again, we've already talked about that a little bit today, but this is a sequencing-based type of experiment in which we really can go through and kind of look at the clonal diversity of the T cell population in the patient, either in the periphery or in the tumor, and kind of understand the expansion and collapse of different types of clones over time in the blood, in the tumors. That's what we're gonna start out doing to try to identify survivin-specific T cells in the tumor.
What we can do is we can go to [inaudible], we can do the same type of tetramer analysis that we talked about before, where basically we're labeling a survivin specific T cell with a tetramer that's labeled, and then we can sort those cells. We then take those sorted cells, we send them to our partner who does the TCR repertoire with us. They sequence those, and we get the TCR beta sequence out. But because we purify the population up front, all the sequence that we get from those samples should be TCRs from survivin specific T cells. That's step one. Step two is to do something similar in our tumor biopsy.
In this case, we just take the tumor biopsy themselves, harvest the DNA, send them to our partner for TCR. In this case, we really can't sort them. They're FFPE, they're standard tumor slides. Basically, we sequence everything until we get the whole full clonal diversity of every T cell that's in that tumor back both prior to treatment and while on treatment. The final step of this to understand if you see survivin-specific T cells in the tumor is to take all the data that we get, and Gee, click the button one more time. We compare the overlap. Everything we have coming in from the peripheral blood should be survivin specifics.
We have a list of sequences that are survivin-specific TCRs, and then we take that huge list that we get of every TCR in the tumor, and we compare them and look for the overlap. Basically, we can start doing those counts and say, yes, we've seen this sequence come up specifically after MVP-S treatment in the blood. If we see it in the tumor, the suggestion is that specific clone that was in the blood has now migrated through its path and come back and has homed to the tumor. If you do one more click, I'd like to show an example of some of that data. This is one of the patients that we looked at using these methods. You can see kind of in the pretreatment, there's not a lot going on there.
That's not unusual. However, post-treatment, you can see kind of a stacked bar chart where this is all survivin-specific sequences for TCR. You can see that there are many clones in here. We also know that those clones are, you know, you can see the expansion of those clones just by nature of the kind of volume of those boxes. One thing I'd like to point out really quick, in some patients, we see anywhere of survivin-specific T cells being just to make that last point, the survivin-specific T cells do make up a fairly significant amount of the population. Say like somewhere between 1% to 3% to 10%, which doesn't sound like a lot, but when you think about how many T cells are actually there, that is pretty significant.
Bottom line there is that we can detect those survivin specific T cells that's running into the tumor. To parallel this a little bit, we also looked at whether or not we saw B cell recruitment into the tumors post-dose. I'm showing you an example of a pie chart here where we assess B cell component in the pre- and post-dose tumors by basically doing RNA analysis and doing cell type deconvolution to understand what type of B cells they are. The takeaway message here is if you look on the left-hand side or the green side, these are the number of patients who have increased numbers of B cells post-dose.
That dark green pie chart, you can see especially in the memory and plasma cells, many of the responding tumors have an increase in this type of cell type, especially compared to those patients that are not responding. Again, kind of emphasizing the importance of having those B cells there, during the tumor response. Okay, next slide, please. Last little thing I wanted to talk about before I show you a case study is one of the other things that we also like to understand is how much of the initial makeup of the tumor is important for how a patient responds to MVP-S, if there's something inherent about those tumors that's really important for our drug to work.
One of the first places you might start with something like this is you might go big global studies and say, "I'm gonna RNA-Seq baseline of every tumor that I have and see what it looks like." We did that, and just to highlight it really quickly, we saw a lot of, you know, gene correlations, cell signature correlations, but we also, a lot of the pathways and the cell types that we see coming up that are top hits for anyone in the, in the responding group, all have to do, you can see that here, T-cell polarity, lymphocytes, B cells. It's really obvious from even that first top-level pass that B cells, T cells, and immune cells are very important in those responding patients. Next slide, please.
To kinda dive a little bit deeper into that, we looked at individual patients, both by RNA-Seq, which is shown on the left-hand side here. This is just kind of a heat map showing an expansion of what we just saw. In this case, if you're yellow and orange, you're much higher expressing than you are if you're purple or black. The takeaway to the left-hand side is you can see that responding patients are really yellow and orange, so they're really high content for T cells as compared to the non-responders. We also look at that in our orthogonal assay. We look at this using multiplex immunofluorescence. Similar to what we saw in the RNA-Seq data, we see high enrichment for CD8s in those tumors that are responding as compared to the ones that are not. Next slide, please.
We did the exact same thing with the B-cell component. Again, RNA-Seq is on the left-hand side, that heat map showing that B-cell receptor signaling pathway is much higher in patients that are having a tumor response to MVP-S. The little box plots in the middle are showing some of the individual cell type markers for B cells. Again, all of those are higher, the statistically significant level in the responders than in the non. We also confirm that using multiplex immunofluorescence, in which you can see there's a higher B cell content for those tumors that are having at least a 10% regression. Next slide, please.
What we'd like to do next is kind of give you a case study of one patient where we can kind of tie a lot of these ideas together. If you go to the next slide, please. In this case, we've got a 65-year-old patient with high-grade serous ovarian cancer, stage three at diagnosis, BRCA 1 and 2 negative. They've had two prior lines of therapy, platinum sensitive, ECOG 1, and their best partial response is 57.8%. Okay, next part, please. Let's look, first of all, the very first thing we talked about is can we see evidence of a survivin specific T-cell response in the periphery of this patient?
What I've shown in the bar graph in green is kind of the full change in ELISpot between day zero as we go across the time course. What's plotted on that H2 of the plot here on the right-hand y-axis is showing the percent of tumor reduction. It's a really interesting overlay to see where you start to see that peak starting at day 28 for ELISpot. It really peaks by day 56. Looking at that overlay with tumor reduction really does show that having that T cell response is also associated with tumor reduction in this patient. If you go to the next slide, please.
We also looked at the antibodies in the periphery from this patient, and we can see definitely, especially the green bar right here, you can see that there's a spike in the amount of survivin specific antibodies that are showing up in the periphery of this patient as well. Next slide. Then I also wanted to show a little bit of the multiplex immunofluorescence we have for this patient. I'm gonna show you pictures of these tumors pre-treatment, non-treatment. The very first thing we're looking at is kind of what they call the tumor masking and tumor segmentation stage of doing some automated image analysis. What I wanna point out here is that anything in red is what they're gonna define as a tumor section.
Anything in green is what they're gonna define as non-tumor, and blue is kind of the space in between. The one really striking thing to point out here is how much fewer red areas you see in the anti-tumor biopsy, which I think that tumor is getting figured out. Next, please. These next two slides are showing the multiplex immunofluorescence that we did for these patients. If you kinda overlap what you see at the top and the below, our tumor marker is CK, so that's orange, and you really can see the tumor cells in the pre-treatment, and then you kinda have this little island left over of tumor cells on the post-treatment sample.
What I really wanna point out, especially post-treatment, is the teal color is B cells, and you can just see this line of B cells coming in and ringing around the residual parts of the tumor. We're looking for yellow CD8 cells, and we see a huge population up around the corners again, also interdigitating in with what's left of the tumor. If you do one more click for me, I have a quantitation on this. Again, just to bring back that point that the T cells and the B cells and elevation of that while on treatment is so important in our responding patients. You really can see that both the CD8 positive T cells and the B cells have increased on treatment with this patient. One last click on this slide.
We also see the same thing if you were to take our RNA data and do cell-type gene signature analysis. We see the exact same thing with that data. All right. Can we go to the last slide, please? I'd like to make a couple of conclusions here before turning this over to Stephan. First of all, first bullet, please. MVP-S induces a robust, persistent, and survivin specific T-cell response. Next point, please. MVP-S also promotes the infiltration of diverse survivin specific T-cell clones into the tumor tissue, as we saw in the TCR analysis. Next bullet, please. MVP-S induces survivin specific antibodies. We saw that in the periphery, indicating a B-cell activation. It also increases B-cell infiltration into the tumor itself upon treatment. Next bullet point, please.
MVP-S treatment shows clinical benefit in patients with preexisting immune responses within the tumor, as evident in other immunotherapies. What we're talking about here is we see more of a benefit, a clinical benefit in those patients who have existing levels of B and T cells in their tumors prior to the treatment. With that, I'd like to thank everyone and turn it over to Stephan Fiset, who's gonna talk to us about our affiliates program.
Thank you very much, Heather. I hope everyone can hear me well. Good morning, everyone. Very happy to provide an update on our clinical trials program. My name is Stephan Fiset. I'm the Vice President, Head of Clinical Research at IMV. Next slide, please. This first slide provided a 10,000-foot overview of our immuno-oncology trial portfolio. We currently have five trials at different stages, and I'm gonna cover more details in the upcoming slides, but you know, right now we do have a phase IIb trial in relapsed refractory DLBCL with maveropepimut-S, pembrolizumab plus or minus CPA. This trial is currently ongoing. Sorry. We have a phase IIb trial in platinum-resistant ovarian cancer. This trial is called AVALON.
Sorry, the DLBCL is called VITALIZE. The second one, phase IIb ovarian cancer is called AVALON. We also have the basket trial. We have announced that the enrollment is now over in the basket trial. There are still patients that are being treated in this trial, and they are being followed with long-term follow-up. I'm gonna provide a little bit of information on the bladder cancer cohort later on and what we are intending to do with this cohort. We also have another trial with maveropepimut-S and an aromatase inhibitor called letrozole in early-stage breast cancer. I will provide some details on that one as well. Finally, we do have a neoadjuvant study in non-muscle invasive bladder cancer with maveropepimut-S and DPX-SurMAGE .
Like, Jeremy and Heather mentioned, our lead compound, maveropepimut-S, have shown clinical benefits in multiple cancer types, with an exceptional safety profile. I'm gonna cover some of these in the upcoming slides. Next slide, please. Before talking about our current trial in relapsed refractory DLBCL trial is the VITALIZE trial. Yeah, I would like to give a refresher on you know what convinced us that we need to continue moving ahead, full speed ahead with in relapsed refractory DLBCL. I just want to give an update on just information and background on the SPiReL trial. SPiReL is an investigator-initiated trial led by Dr. Neil Berinstein in Toronto, Canada.
There's three main messages that we got from this trial that convince us that we need to continue moving ahead with relapsed refractory DLBCL development. This trial showed that MVP-S, pembrolizumab and CPA could lead to significant antitumor activity and long-term clinical response. This is especially true and remarkable in the PD-L1 positive patient population. If you look at the figure on the left, figure one, the top section here represent the PD-L1 positive patient, and you can see the responders. The three dark one and the three green one are complete and partial response respectively. You can see that six out of the eight patient with PD-L1 positive tumor responded to the treatment.
This is especially important knowing that PD-L1 monotherapy in relapsed refractory DLBCL has shown very limited activity. Also in several trials have shown that PD-L1 expression in DLBCL is frequently associated with a poorer outcome. This means like, you know, patients that are at a worse outcome, usually on conventional treatment, are responding well on the treatment. This is very important. Next slide, please. The second main message of SPIRAL is really supporting the need of maveropepimut-S in the treatment and the rationale for the mechanism of action of maveropepimut-S. What we've shown in the SPIRAL trial is that maveropepimut-S induced survivin specific T cell response is associated with clinical response.
As you can see in the pie chart here, the three patients who had a positive response have derived survivin-specific T-cell response, three out of four PR. If you continue with there is, there is only a very few in the MPD that have expressed survivin. This really supports, you know, the mechanism of action and the combination in using this trial. Last and not least, I think it's super important, this treatment, so this combination was very, very well tolerated. This is especially important in relapsed refractory DLBCL. You know, it's not all patients are usually older. Not all patients are eligible for CAR-T, or when they get CAR-T, they are more frail after. The need for very well-tolerated treatment is very important.
Based on, you know, the response that we are seeing, the duration of response, the survivin specific T cell response associated with the clinical response and the well-tolerated safety profile, you know, we're very excited to continue the development and move with our current trials. Next slide, please. This slide is our VITALIZE trial. VITALIZE is our phase IIb trial in relapse refractory DLBCL following the SPIRAL-1. It's an open-label multicenter two-stage trial designed with maveropepimut-S, pembrolizumab, with and without CPA. We wanna confirm if CPA has some activity in the mix. Really the main objective of this trial is to confirm the data from the SPIRAL trial.
This trial is designed for an all comers, so independent of the PD-L1 expression, but we will be looking at PD-L1 expression, trying to confirm what we have observed in the SPIRAL. The first part of this trial is really to confirm what we have observed in SPIRAL. Once this is done, we can expand and enrich in the PD-L1 positive population. The stage one will enroll up to 30 subjects. We are hoping to provide the preliminary data this summer, and we're hoping to have completed stage one enrollment by the end of this year. Currently the study is open in the US and Canada.
Enrollment is ongoing and we are in the activations phase with several countries, Australia, New Zealand, that should come on board anytime soon. We have Serbia, Poland, Spain and France that are coming on board, and South Korea as well. Next slide, please. Okay, moving to our ovarian cancer program. You probably have seen those data already. Those data have been presented several times, but this is very important for our current trial that is currently in startup. What we have shown is that in the DeCidE trial, patients with platinum-sensitive resistant or refractory disease could derive sustained benefits from maveropepimut-S treatment.
If you look at the waterfall at the left, you can see that, you know, the partial responders are depicted in green, and in purple are the stable disease. You can see that 15 out of 19 subjects had disease control on treatment, which is quite impressive in recurrent ovarian cancer. If you look at the swim lane on the right, you can see that several patients had clinical benefits for an extended period of time, for a long period of time. Seven out of 19 patients for more than six months and five out of 19 patients for up to or more than 12 months here.
The objective response rate in this trial was five out of 19, so 26.3%. With this set of data, what we did is we met with QLs, ovarian cancer QLs. We present them the data and we came up with a design for to move our maveropepimut-S in ovarian cancer. Next slide, please. We came up with, based on the data design feedback from the QLs, we have designed the AVALON trial, which is a phase IIb trial, single arm study with maveropepimut-S, intermittent low-dose CPA in subject with platinum resistant ovarian cancer. Really the goal of this trial is to extend, confirm the data from our DeCidE trial and then move forward towards registration.
This trial is in its startup phase right now. The protocol has been approved by the FDA, by Health Canada. We are in the site selection and site activation that is ongoing, and we are expecting to get our first patient in during the summer, early summer. Our goal is to get our first readouts of preliminary data by the end of the year. Next slide, please. The other trial that I want to talk about is a trial in early-stage breast cancer. Maveropepimut-S in neoadjuvant setting for the first time. Neoadjuvant settings are very interesting because we treat prior to the surgery.
This means like we can monitor the mechanism of action, you know, from the treatment and then get access to the tumor material where we can do some extensive translational work and deepen our knowledge on the mechanism of action. This trial is very interesting in that respect. Our collaborators at Providence Cancer Institute, Dr. Yong and Dr. Stanton and Page, have shown that survivin upregulation was strongly associated with resistance to aromatase inhibitor in early-stage breast cancer. This really provides a strong, rational, scientific rationale to use maveropepimut-S in combination with an aromatase inhibitor in an early stage trial. This trial is a three-arm investigator-initiated phase Ib trial.
The three-arm will be enrolled sequentially. The first arm is maveropepimut-S and letrozole. The second arm will treat with maveropepimut-S, letrozole and radiation. The third arm is maveropepimut-S, letrozole and cyclophosphamide. Like I said, this is very important because we have access to the tumor material, and we can do some complete translational analysis. The study is open. It's currently open. We have two patients that have been dosed right now. Our objective is really to present the preliminary data from arm B at the San Antonio Conference in December this year. Next slide, please. We have a second trial in neoadjuvant settings in non-muscle invasive bladder cancer.
We know that MAGE-A9 and survivin are highly expressed in bladder cancer. We know that bladder cancer is sensitive to immunotherapy with BCG being used for years and years now. We have designed a platform protocol to assess DPX-based products. Jeremy talked about our new product, DPX-SurMAGE. In this trial, we're gonna look at maveropepimut-S plus or minus CPA in study A, and we have a study B where we're gonna look at DPX-SurMAGE plus or minus CPA. The objective is really to further explore the mechanism of action of that combination and look at both treatments if we are seeing the same pattern. Translational heavy trials that will provide more robust data on our mechanism of action.
This trial is actively recruiting right now. Next slide. I talked about the basket trial early. I mentioned basket trial, I'm gonna talk about advanced and metastatic bladder cancer. In this cohort we have seen some important clinical benefits, including complete response, partial response, and stable disease. Some of the responses were observed in subjects who have failed prior checkpoint inhibitors, which is quite interesting. Based on these results, you know, we set up a bladder cancer advisory committee, and we're gonna have our first meeting, actually, QL meeting is scheduled for tomorrow, to discuss the design for the next trial in metastatic bladder cancer indication. I invite you to be present.
We were gonna have an oral presentation at AACR in the late-breaking abstract session. It's gonna be on Tuesday, April 12 at 2:30 P.M. CST. That completes my quick overview of our clinical trials, and I'm gonna hand it over to Jeremy for the wrap-up.
Thank you, Stephan. Click forward to the next slide, please. This is just a high level understanding of where our clinical program is this year. Maveropepimut-S, we will provide a first update on clinical study VITALIZE, the phase IIb study Stephan just took us through. You will see at the AACR in a podium presentation, the data for the bladder cancer basket trial, study that Stephan mentioned. We are just beginning to activate sites for the ovarian phase IIb trial known as AVALON. We will have clinical update on the neoadjuvant breast cancer study, as Stephan said, targeted toward the San Antonio Breast Cancer Symposium at the end of the year. Then our non-muscle invasive bladder cancer. A second opportunity to dive deeply into translational science will begin to open up here shortly.
It's actually opened at the site, and we're looking forward to enrolling patients shortly. Next slide, please. Let me just wrap up the day. First, I thank Dr. Kalos for a wonderful introduction to this entire day, Stephan and Heather as well for taking us deeply through our clinical data and our translational data set. Click forward, please. Just continue to click forward. We're really trying to help understand more deeply what DPX does, why it's such a novel way to educate an immune response. I think as Michael pointed out, it does so because it mimics the way physiologically the immune system wants to respond to antigens. Next click. I've shown you plenty of evidence today that it's a versatile platform.
We can pack within DPX peptides to different tumor-associated antigens like survivin, to mutant oncoproteins like KRAS, personalized neoantigens, whole proteins, viruses, virus-like particles, nucleic acids, and innate immune activators. There's all sorts of versatility associated with this platform that we think we can leverage. Next slide or next click. As a consequence, this really does present a really nice plug-and-play platform opportunity. We've mapped out a very rapid preclinical proof of concept schema, as well as a rapid progression through a phase I immunogenicity study. Lastly, I'll just highlight, go ahead and click forward, that our lead product, maveropepimut-S, exemplifies exactly what DPX can do. We're very excited about pushing this product forward to registration both in DLBCL, ovarian, and possibly as well metastatic bladder. With that, we'll wrap up. We'll take questions.
Joining us for the question and answer session will be our CEO, Andrew Hall. We're thrilled to take any questions you have, and we certainly can carry on a bit beyond 10:00 AM. or, yeah, 10:00 AM. Eastern Time as needed. We'll open up the Q&A session.
Great. Thank you, Jeremy. At this time, we'll be conducting our question and answer session. As a reminder, if you would like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. Please hold for a brief moment while we pull for questions. Our first question comes from Nick Abbott from Wells Fargo. Nick, you may go ahead and unmute your line.
Oh, good morning. Thanks a lot. Very interesting. You know, just going back to you know some of the data, preclinical data you showed. You know, we've got this you include this TLR. You didn't really talk much about you know which TLR agonists are better. And also, you know, in your preclinical studies, is there kinda evidence of improved opsonization you know with these TLRs, just kinda linking back to this you know newer data on B cells?
Nick, I think two different points in there. We are exploring, and I think it's a very good question, which TLR agonist or more broadly, which pattern recognition receptor agonist would help drive the innate immune functionality that we think is important as part of the DPX platform. We're investigating that deeply now. I think that's a very important point. On the concept of opsonization of tumor cells relative to the antibody production, that's also a very important point. It was really just at the latter third of last year that our translational data sets began to teach us that in fact B cells were involved and that in fact B cells were producing survivin-specific antibodies.
Those survivin-specific antibodies, as you're intimating, can certainly be responsible for binding the surface of cancer cells and flagging those cells for destruction, largely by innate immune functionality, by antibody-dependent cellular phagocytosis or cellular cytotoxicity, NK-mediated killing, et cetera. We're very excited to explore that more deeply. We have not explored it as deeply yet. We're in the midst of in fact doing that because this is a fairly new revelation for us in terms of what DPX can provide.
Okay. Thanks, Jeremy, and then a follow-up. You know, is it reasonable, you know, based on the ovarian cancer data to conclude that sort of baseline immune activity in the tumor is more important than platinum status, which is, you know, what most people focus on in ovarian. Given that, can you select for patients that have improved or, you know, above a threshold, immune activity against the tumor or prime it with localized radiation therapy, for example, to sort of kickstart that immune response before you vaccinate?
A couple of different points within that question, both very good again. You certainly could imagine priming a response before we begin to vaccinate. You could imagine doing that a number of ways, radiotherapy possibly, possible combinations with things that impact the immunogenicity of a tumor like bevacizumab or anti-VEGF strategies. That's a possibility. That's not the path forward at the moment. You know, it would be difficult, I think, to cobble together a precise way to define patients as having an immune response that preexists. That's what our data are telling us, and we're certainly interested in understanding that better, so that we can leverage that as we carry forward more deeply into the clinical development. But this wouldn't necessarily be a single biomarker play.
To then do patient treatment decisions based upon a multifactorial biomarker play that helps us appreciate the preexistence of an immune response certainly would be intriguing but might be very difficult to actually execute in practice. I don't know if Michael Kalos has any particular commentary on that.
Yeah. No, those are both really good points from Nick. I would say that, you know, as you pointed out, Jeremy, stratifying by such a complex compilation of markers is gonna be very challenging. I'd expect that as we see more patients treated in ovarian cancer, we may see responses in patients that, you know, who responds is gonna be further refined. I don't see this particular product being delivered in the context of a patient selection scheme like the one that was described. But I mean, that may be the future of this space in 10 years or so, let's say, once we understand what the immune signatures really mean. That's how I think about it.
Nick, you made one other point that I think was important, and I'm blanking out right now. It was the first point that you made, but I'll stop.
Thanks. Then just last one. In terms of you know, congratulations on getting an oral late breaker at AACR. That's terrific. You know, at that time point, how long do you think it'll be before you can communicate what the next steps are in bladder cancer?
I think, Nick, what we're walking through now, and as Stephan pointed out, we start tomorrow, KOL advisory board discussions of the data to gauge enthusiasm for the particular data and then define the path forward. I think that we'll have a refined protocol here within a quarter, and then once that protocol makes its way through the US FDA and Health Canada, we'll be able to begin activating sites sometime later on this year. You know, really the timing of that really depends upon the KOL discussions that start tomorrow and how long it takes us to refine and understand what the right trial design would be.
Okay. Great. Thanks, and I look forward to the presentation.
Thanks, Nick.
Thank you, Nick. Our next question comes from Brandon Folkes from Cantor Fitzgerald. Brandon, you may go ahead and unmute your line.
Hi. Thanks for taking my question, and thank you for the presentation today. You know, a lot of companies presented a lot of good data. Maybe just for Dr. Kalos. You know, given the failures you highlighted previously of previous companies, what data do you think IMV needs to show to sort of have you and your peers really validate that this is a different approach and that, you know, these cancer vaccines, while having a troubled past, you know, IMV has a fantastic platform. You know, is this just sort of a snowball of building data? Just I'd love to get your input in terms of where your peers are looking at cancer vaccines in general. Thank you.
No, it's a great question, right? I think at the end of the day, the first proof is in the pudding, right? It's the clinical data. The clinical data that has been generated to date, early but nonetheless the data set has been generating, is quite compelling, right? I think that's step one. Now this is DPX plus cyclophosphamide, right? It's hard to argue that it isn't the DPX that's doing the effect, given the translational data that's emerging that's showing mechanistically what's going on here in terms of the infiltration of the target antigen specific T cells, the B cells, all of the stuff that Heather described. I think that's how I'd answer the question. Proof's in the pudding. Objective responses, complete responses, significant responses, mechanistic association that makes sense.
That's what I'd like to see. Now, the preclinical setting, there's all sorts of stuff that can be done to support the mechanisms. I don't know if you wanna go into that or if it's the clinical data that you are more keen to understand.
I'd love to, if we've got time. Jeremy, let me know. Yeah, I think it's, you know, it all validates the platform.
Yeah. I think it's you know we've articulated or IMV has articulated five things that this platform delivers on, right? Generate the preclinical data that supports that that's the case. That the adjuvant that you're using, this was the point that Nick made, right? Choosing the right adjuvants, which I think is really important. I think we're on the right track, but is the adjuvant that we're using doing exactly what we're saying it's gonna do? Creating an inflammatory milieu that brings in the right cells, right? Are cells taken up? Are the phagocytosing cells really taking up the cargo and effectively delivering it to lymph nodes? Challenging studies to do in animals, but they're doable. If you can demonstrate that's a really important component.
The lymph nodes, are you getting the priming events that we're seeing clinically the output of that, but are you actually demonstrating the priming event? If you can start putting those pieces of data together, I think it'll be supportive in an important preclinical way to the clinical data that we're seeing.
Great.
To capitalize on that, I think, Brandon, we are in fact doing that series of preclinical experiments to really dissect precisely how the information from DPX is being consumed, by which immune cell subtypes it is being consumed, how we affect the functionality of those immune cell subtypes as they traffic back to and instruct a specific response in the lymph nodes. All of that is what our science team is tackling this year.
It's pretty impressive, if I can just say, the data that was generated historically at IMV, which was not frankly done in a particularly systematic fashion that supports the mechanisms that we're now articulating here, right? The teams are now, as I understand it, focusing explicitly in a systematic way to generate the supportive data that will really, you know, convince from a scientific perspective, the community that this is what's going on.
Great. Thank you very much.
Thank you.
Thanks, Brandon. Our next question comes from Joe Pantginis from H.C. Wainwright. Joe, you may go ahead and unmute your line.
Great. Hi, good morning, everybody. Can you hear me?
Yes.
Yes, I'm great.
Thank you. Thanks for all the information today. I guess, you know, my question wants to focus on one area. Thank you for the good background, Dr. Kalos. You know, when you look at the evolution of cancer vaccines, yes, there's broad reasons for all the failures. You discussed some of them even, you know, going back to, you know, studies that had high profile failures because they went into a tumor indication like advanced pancreatic, where, you know, patients weren't even alive long enough to, you know, mount an immune response. If you fast-forward to today, my question really focuses on, you know, the importance of combination therapy. Right now we're focusing on the anti-PD-1, for example, but the combination landscape is truly expanding at the moment.
How do you view, and I'd love to get the company's view as well, you know, the importance of combinations with it when it comes to unanswered questions around dosing, because you're gonna be combining things that take the brakes off or press the accelerator and, you know, the various potentials for immune related adverse events. Just wanted to get the sense of that.
Joe, that's an incredibly complex and important question.
Yeah
... as I'm sure you recognize, right? I mean, look, this is the truth about combinations. To date, it's basically been spaghetti on the wall. You throw things and you see what works, right? I will tell you that very few things have worked. If one goes back and tries to model mechanistically in a preclinical setting why these combinations work, you actually get some really valuable information, some of which is actually actionable clinically. It has to do with dose and schedule and, you know, let's not even go into agonism and the like. There's not an easy answer. If you're a company like Merck, you just do everything and see what falls out.
I would think that there's enough that we understand about today about the concept of vaccinations that a company like IMV could consider engaging in a thoughtful regimen of testing preclinical combinations. You know, CD40 is an important molecule, right? STING might be an important molecule. A lot of these, by the way, as Jeremy indicated, these can be co-packaged in a DPX, right? So if it's important to deliver STING to a lymph node or important to deliver CD40 to the lymph node, guess what? This platform uniquely can package these things and deliver them. So I think it's really a set of thoughtfully designed preclinical studies based upon the best information that's available out there, and with a specific defined endpoint of figuring out what combinations and how to interrogate in the clinic.
The other part of it, I will add to this, and I'm sorry for taking so much time, is in particular tumor types. For example, ovarian cancer. Mechanisms of immune suppression are reasonably understood, or at least some of them are. You know, Jeremy talked about bevacizumab, right? You know, TGF pathway is an important player in ovarian cancer, so you can rationally go into combination plays from that perspective also. Understand disease and go into it. The point you made about, you know, choosing the right indication and then the right combinations is so profoundly important in the clinical setting, right? That's why most things fail. The wrong indication was chosen or you didn't do the right combination. I'll stop there and happy to answer anything, any follow up for you, Joe.
Hey, it's Andrew Hall here. If I could jump into your answer. Joe, you asked for a bit of company perspective. I think we, as a company, strategically remain really curious about answering your question. What I don't want it to get in the way of, this is really important, is the shortest path to registration. Ovarian cancer is such an interesting field. As Michael said, it's becoming far better understood, but it's also a fairly familiar area for therapies to fail in. The data we have in specifying the specific population of platinum patients that we have, we think we have a really clear path to market there, and we don't wanna dilute that by overcomplicating it with combination therapies. That is not to say for a second that we are not exploring that. We're just not taking it off the critical path.
I think that's a really important element as well as in DLBCL and hopefully as well as in bladder cancer, that we maintain singularly focused on getting the products to registration and then looking to expand on its utility through combination strategically.
Great. Thank you very much.
Thanks, Joe. Our next question comes from Paul Stewardson from iA Capital Markets. Paul, you may go ahead and unmute your line.
Thanks for the presentation and also congrats on the AACR. Looking forward to that, of course. Just a couple questions from us on behalf of Chelsea here. Can we expect, you know, when we're looking at the muscle-invasive bladder cancer outlook, and I know this question might be better suited to be asked in a few days after the KOL onboard. I'll put it to you anyways and see sort of how you're thinking about it. You know, are you aiming essentially for a pivotal phase IIb kind of a large, you know, trial based on what you learned in the basket trial?
Is this more something that the next step is an intermediate phase IIa where you get more data on, you know, the specific how to organize it and maybe aim then towards a precise pivotal trial after that?
Paul, it's a great question. I think, you know, it certainly depends upon the output of our meetings with different key opinion leaders that start tomorrow, but I'll try to answer that given current perspective. I think the data are compelling enough. We would want to expand upon what we saw in the metastatic bladder cancer setting in the basket trial and use that maybe in a staged type of design, a stage one, stage two type of design, to graduate into a registration trial seeking accelerated approval. That would be the mindset right now. I think we have that possible path in front of us, but knowing that for sure really is dependent upon the conversations we have with the folks that are out there treating this devastating disease on a daily basis.
Okay. Yeah, that makes sense for sure. Just in terms of maybe a more general question about trial design strategy, it's great to start seeing some color on AVALON. You know, as we're going forward and we're really starting to see quite an expansive clinical data set emerge for MVP-S, is this something that we can expect to see kind of fewer arms in the trial because regulatory agencies already are content with single agent activity being shown in other indications? Or is this really something where, you know, every indication you kinda have to go back and show what's the effect of CPA, what's the effect of, you know, whatever the combo that you're testing is?
Just in terms of, you know, as we see more and more trials and larger and larger trials, towards registration, how do you anticipate the FDA addressing that?
You know, I think, Paul, we don't necessarily imagine having to explore every possible combination, variation on the theme. I think as we accumulate more and more data about the impact of MVP-S, as we buttress that data with the translational research that we do, we're going to be able to speed forward in a more homogenized patient population and a more homogenized, or if you will, focused treatment paradigm. So that's what we're looking forward to. You can take that, for instance, the DLBCL trial stage one to stage two graduation. We would imagine perhaps in stage two, we're able to hone in just on the PD-L1 positive patients, depending upon what stage one teaches us. That certainly will help us advance more quickly toward that registration path.
Right. Okay. Yeah, that's great to hear. Thanks, thanks again for the really interesting presentation this morning.
Thanks, Paul. Thank you.
Thank you, Paul. Our next question comes from David Novak from Raymond James. David, you may go ahead and unmute your line. David, you're on mute. Okay. That concludes our verbal portion of the question and answer session. I'll now turn it over to Andrew to read any questions that may have come over the web.
Yeah. Thank you, Tara. We've received a number of questions over the web, and unfortunately, time is gonna prevent us from answering all of them. What we will commit to do to those that have asked questions is get back to them in writing or in follow-up to this meeting. The first question, and I think it's probably the most foundational, and Michael Kalos, you've touched on this a little. Why have the cancer vaccines failed? You know, as elementary as you can, why have they failed? Perhaps why are we looking at this path with a little bit more enthusiasm on the back of some of the data we've seen today, but also some of the industry learnings that we've had?
You know, it's a great question. Quite frankly, they failed because people didn't contemplate or understand or consider the complexity of this biology. Each of us in our presentations today went through, in some schematic, the complex biology that's required to trigger an immune response effectively. The trials historically have not appreciated that. Like I said, first, do no harm. If things look funny, the immune system shuts down. It does not wanna cause massive destruction. Quite frankly, that's why. Then on top of that, you know, lack of critical thinking, perhaps I'd have to say. Number of big vaccine trials, for example, implemented recombinant protein to trigger T cell responses. It's well understood, or it was understood that that's not an effective way to prime T cell immunity, for example, right?
All sorts of reasons, but fundamentally lack of adherence to the principles of following the biology. I'll leave it at that.
Excellent. Next question, I'm curious about this myself. Why don't all patients show PBMCs with survivin specific response after getting DPX? Is there something unique in the biology that creates that delta that Heather talked about, where some patients show it, some patients don't? Jeremy, do we have initial thoughts on what's driving that selective response?
Most of our patients show some level of an immune response to survivin, and you can see that with the tetramer analysis. I think Heather showed a very specific panel in one of her slides, that almost 90% of the patients dosed get a survivin response of some sort. Now, Michael has tried to articulate multiple times, there's a lot of complexity into how the immune system controls its responsiveness, and a lot of that is influenced by a patient's individual status and about the way the tumor is speaking to and suppressing immunity in different patients. There's a lot of complexity here that we have to unravel. But the base immunogenicity of the program, of the actual DPX platform, the product is able to elicit a response of some sort in most of our patients.
It's really not selective in the response, it's how much that response then rolls over to shrinkage of disease, rolls over to control of disease with time. Those things are completely dependent on the complexity of the individual and how that individual's tumor and immune system are interplaying.
Jeremy, if I can very briefly add on to that, right? There's a temporal component to detecting these T cell responses in blood, right? That temporal component is different from patient to patient, so it's very difficult to say what we have to look at, I think, is the cumulative pattern, right? So in responding patients, we see those cells, in non-responders, we don't cumulatively. The maximum and the kinetics, we're probably missing them in most, if not all, patients, right? In some patients that responding, we're just too far off the slope to really see those responses.
Thanks, Michael, and we'll make this the final question and it relates to conversations of plug and play that I think Michael and Jeremy both alluded to. The question is, for therapies potentially introduced into plug and play, how quickly can IMV understand whether or not the DPX technology is enabling therapeutic improvement on those types of technologies?
I'll take that, and certainly we can comment, others can comment on it as well. We have been trying to map out a process by which we could take someone's antigens to say, let's model what we had done with the peptide antigens to survivin that we in-licensed from Merck KGaA. To understand that we have immunogenicity in mice after having built a DPX product with these new peptides would only take us a matter of months, maybe six months or so, to show that preclinical proof of concept. To then take that forward into an immunogenicity phase I study, much like what I showed you in the RSV example, we think is not very much longer than that, maybe another year. We have to, of course, go through the appropriate procedures, regulatory compliance to get product into people.
The build of the product itself, the demonstration that it elicits the immune response we intend, and that demonstration in people really is not a very long, protracted process.
I appreciate that, and I think it exemplifies the utility of DPX broadly and is certainly part of the IMV strategy as we move forward. Thank you, everyone, for your time today. We've gone 15 minutes over, and I appreciate those that have been able to stay on. As I mentioned, we will commit to get back to those that have asked questions through email directly. I'd also like to just summarize by saying that we've presented today, I think for the first time, a comprehensive summary of not just the DPX platform, but its potential utility, what it does, what it can do, and how it's potentially differentiated from all other approaches that have gone into this space.
There's been terrific illustration, I think, of both T and B cell responses in oncology, which we understand is important in the therapeutic advancement of this category. As a sort of launching pad for further IMV activity, particularly as it relates to public communications, we continue to lean heavily on our scientists to illustrate what it is that our technology is doing. Through this year and following years, we'll continue to stay very vested in better understanding, better directing our therapy into those patients that need it the most. I'd like to say a terrific thank you to Michael Kalos, to Jeremy, to Heather, and to Stephan for presenting the content today. As was mentioned at the front of this conversation, the content will be available on the IMV website, as a recording of this presentation. Thank you, everyone, for your time.
I wish you all a healthy rest of your Thursday. To all of the speakers and all of the questions, thank you very much for your interest, and we look forward to reconnecting in a couple of weeks for our quarter earnings. Thank you, everybody.