Noon. Welcome to the Compugen virtual Investor event. At this time, all participants are in a listen-only mode. A Q&A session will follow the formal presentations. If you would like to submit a question, you may do so at any time throughout the event by using the Q&A function at the bottom of your webcast player. To our Analysts in the room, please raise your hand to indicate you would like to join the queue. At this time, I would like to turn the call over to your host, Anat Cohen-Dayag, President and Chief Executive Officer of Compugen. Please go ahead. Good morning and good afternoon, everyone. We're delighted to welcome you to our special call today with the man that likely needs no introduction, Professor Drew Pardoll. Drew is the Chair of our Scientific Advisory Board and a world expert on the DNAM-1 axis. Drew's research had a major contribution to the development of the first anti-PD-1 therapy which made a breakthrough in cancer treatment. No doubt, this class of drugs is transforming patient lives. It represents a greater than $35 billion market to date. There is so much more that needs to be done for the majority of patients that are still not responding, for those that are suffering and are resistant to these Immunotherapies. Drew is heavily involved in trying to identify mechanisms that are associated with resistance, like we do at Compugen. Drew is a world expert in the possible role of the DNAM-1 axis addressing resistance. As you know, Compugen's hypothesis behind the DNAM-1 axis role suggests that in many patients and in many tumor types, all three pathways of the DNAM-1 axis, PD-1, TIGIT, and PVRIG, may be needed to be blocked in order to maximize the immune system response to fight cancer. Before we hand over to Drew, Eran will set the scene explaining our DNAM-1 axis hypothesis and how we're quickly advancing it from a hypothesis to reality. As reflected in the clinical data we've presented with a combination of COM701, our potentially first-in-class anti-TIGIT, anti-PVRIG, COM902, our potentially best-in-class anti-TIGIT, and PD-1 inhibition in patients typically not responding to immunotherapy. Following the presentation, our Chief Medical Officer, Henry Adewoye, and I will join Eran and Drew for the Q&A. Next slide is our usual forward-looking statement. Now over to you, Eran. Thanks, Anat. Compugen is using its pioneering computational discovery platform to identify new targets and new MOA to address immunotherapy resistance and fight cancer. Our platform is validated because we already took all the way to preclinical POC, and as you'll see today, initial signs of clinical activity. The three major assets in our pipeline right now are COM701, 902, and COM503. COM701 and 902, which will be the focus of today's discussion, which are blocking the DNAM-1 axis. COM701 is a potential first-in-class anti-PVRIG antibody. COM902 is a potential best-in-class anti-TIGIT blocker antibody. I will not discuss COM503 today, but just in two words, it's really novel target coming from our discovery platform, another approach to harness cytokine biology to treat cancer. Again, today we're gonna focus on the DNAM-1 axis. We are studying this pathway for more than a decade now. We identified TIGIT the same time Genentech did. A few years later, identified PVRIG that had no literature around it by the time we discovered it. We're the first to take PVRIG into the clinic. Following our understanding of the biology of the DNAM-1 axis, we decided to develop then COM902 to be combined with PVRIG blockade because we understood the synergism potential. We generated COM902 with a non-Fc effector function because we believe following our understanding of the pathway that you actually want to reinvigorate CD8 T cells without the risk of depleting those. This property of COM902 in combined with the superior binding and affinity and function, positioned COM902 as a potential best-in-class. This is actually validated by the choice of AstraZeneca to select COM902 as the TIGIT arm of their PD-1/TIGIT bispecific antibody. They also chose a non-effect Fc effector binding for their antibody. They recently announced that in addition to the multiple phase ll they are having for this molecule, they're gonna advance into phase lll later this year. These are our main wholly owned assets. Now let's deep dive a bit more into the DNAM-1 axis. PVRIG and TIGIT are both expressed on T and NK cells, and they are negative checkpoints. Meaning that upon binding their ligands, they deliver inhibitory signal inhibiting the T and NK cells from attacking the tumor. They are part of DNAM-1 axis because actually they have a shared ligand. Both of their ligands are binding a shared molecule, which is DNAM-1, which is a costimulatory molecule, which actually is giving positive signal for T and NK cells to attack the tumor. PVRIG and TIGIT actually hijack these ligands of DNAM-1, and actually not only by themself deliver inhibitory signal but also prevent activating signal by DNAM-1. In addition, PD-1 intracellularly dephosphorylate DNAM-1 and actually also prevents activity. What we understood that if you triple blockade all these three components of the DNAM-1 axis, which is PD-1, PVRIG, and TIGIT, and this is what we saw preclinically and we started to see clinically. We get the most optimal T cell activation and antitumor effects. While PVRIG and TIGIT are parallel pathways in the DNAM-1 axis, and they share some similarities, they're also very different. PVRIG 2, the ligand of PVRIG, is more dominant to certain tumor types, like Ovarian Cancer. While TIGIT is most dominant on exhausted T cells and regulatory T cells, actually PVRIG is not so highly expressed on regulatory T cells, and it's much more dominant on stem-like memory T cells, the cells which have very strong proliferative capacity. We'll talk about the importance of this for PVRIG biology in the next slide. Exactly in correlation to that, the ligand, again, of PVRIG, PVRL2, is very dominant on Dendritic Cells, the same cells that interact with TSM to stimulate their proliferative. Most checkpoints are expressed on these T cells, exhausted or effector cells in the Tumor Microenvironment directly interacting with the tumor. We know from TIGIT studies until now, at least, that the most activity for TIGIT blockade in combination with PD-1 is seen when you have sufficient enough amount of T cells in the tumor microenvironment. If you're looking into patient with immune desert or just PD-L1 low indication, which have less T cells inside to begin with, then most checkpoints will be less active. Specifically, until what we've seen till now, the PD-1 TIGIT combination is not sufficiently potent to drive immune activation and Anti-Cancer Therapies in these settings. While PVRIG is also active in this stage of T tumor cell interaction, actually the dominant expression of PVRIG, but that is different from all the other checkpoints, is on these stem-like memory T cells, which have a very strong proliferative capacity. Our understanding now of the PVRIG biology, that if you use COM701 to block this interaction of TSM with dendritic cells, you have the potential to unleash now additional waves of effector cells coming out from the Lymph Node in TLS and now making less inflamed tumors more inflamed. If you combine TIGIT with PD-1, PVRIG blockade actually kind of sensitize the tumor to respond to PD-1 and TIGIT blockade. Now you have a full-fledged triple blockade activating the T cells while they're already in the tumor microenvironment. They say that the proof is in the pudding, so this is exactly what we start to see in our clinical trials. From Monotherapy to combination with PD-1 to triple combination. We see this activity in places where you wouldn't expect checkpoints to work. We see activity in indications which are non-inflamed. We're seeing activity in patients which have desert, immune desert tumors. We see activity in patients who failed prior checkpoint treatment, normally not responding to additional checkpoint. We see it, for example, for the Monotherapy, where the patient with Ovarian Cancer that had immune deserts before treatment, and that patient responded clinically to COM701 Monotherapy and stayed for more than 18 months on the study with deep response. We see all of these, and we're gonna cover some of it today, of responses in platinum-resistant, in MSS-CRC, again, in patients who failed prior checkpoint treatment. If we look in Ovarian Cancer. Platinum-resistant Ovarian Cancer is a very difficult indication. These patients have the standard of care is a toxic chemotherapy with over response rates of 12%. The option of immunotherapy for these patients is quite poor. PD-1, even in combined with TIGIT, actually give less than 10% overall response rate and specifically 0% in PD-1 negative tumors. If you focus especially on the triple blockade, when you use COM701 plus nivolumab plus the BMS TIGIT that we use these days, you can really see here 45% disease control rates. Four patients in the time we reported, all of them were ongoing at the time we reported with deep responses and ongoing responses, which is really supporting the activity of the triple blockade in this difficult to treat and checkpoint-nonresponsive indication. For example, this patient. This patient, she had seven prior lines of therapy. She actually received in one of these lines nivolumab, and she progressed on nivolumab. She had no response, not even stabilization on nivolumab. Then she came to the treatment of the doublet COM701 plus nivolumab. You can really see here the partial response that later on even deepens. Again, talking about the PVRIG biology, driving T cells into less inflamed tumor types. You can really see the increase in T cells on treatment following this doublet combination study. The signal that we see in MSS-CRC, an even more difficult indication, especially for checkpoints, but even the standard of care in the last line of patients that are getting into these trials is over response rate of 1%-2%. There's a huge unmet need here. 70% of these patients have liver metastases. Here the unmet need is even huge, even bigger. Checkpoints are very close to 0% response rate in general in Microsatellite stable Colorectal Cancer, in the patient with Liver Metastases, their response is really, I mean, overall, even in combination, is 0% response rate. In our study, we had 17 patients with liver metastases in MSS-CRC. In two of those, we have partial responses, which gives an overall response rate of 12%, which is encouraging compared to any type of historical data that we have seen. What is interesting is, we'll not go through all the details here, but for example, that patient, she had a immune desert before treatment. Again, MSS-CRC, this is biopsy from the liver metastases. You can see on treatment, following treatment of COM701 plus nivolumab, this is not even the triplet yet. We are gonna start the triplet soon. The doublet combination really gave a huge influx of new T cells. What is interesting to see is really the fingerprints of the PVRIG biology of this in the T cell before treatment, and then massive increase of T cell proliferating in the tumor microenvironment and coming probably from the Lymph Node from inside the tumor microenvironment. All of this in this indication that normally would not respond to any treatment, especially in patients with liver metastases. Before handing over to Drew, what is next for Compugen? We're focusing now on these two studies. In addition, of course, to AstraZeneca that they are progressing with their bispecific and going to start phase three soon with the PD-1 TIGIT antibody based on COM902. We're focusing now on two triplet studies combining COM701 with COM902 and pembrolizumab. Based on the biology of PVRIG and based on the previous data that some of it you have just seen, and the translational data, all supportive of a potential for chemotherapy-free option for these difficult indications and with a very favorable safety profile and what you start to see, like, really responses and T cell infiltration in places where normally other treatments would not work. The unmet need here is very clear, and we really think that this might be the right combination to transform patient lives in this indication. With that, I will hand over to Drew. Great. Eran, can you hand over the screen, maybe? Drew, you'll need to share your screen. Yeah. It's saying that I'm viewing Eran's screen, and it's not giving me the option to share screen. Okay. Eran, you can end your screen share. Drew, you can try it. Okay. I'm still not. My screen sharing is not. Oh, there we go. Perfect. Great. Thanks so much, Eran, for that great introduction. Thank you so much, Anat, for that extremely embarrassing introduction of me. Just for disclosures. Our group has received research support from Compugen for the PVRIG and TIGIT-related scientific research. This has been a 10-year collaboration which has been extremely productive, and I'll say at the outset that I am certainly an enthusiast based on the data, both preclinical and also the early clinical data, that this is a very promising opportunity. I, as Anat mentioned, chair Compugen's SAB. I have no intellectual property relevant to this presentation nor any personal equity in Compugen. What I hope to do just with a few of these bullet point slides is to give you a little bit of a sense of my take on not only the pathway but also to address some of the questions that are out there in the community. This will hopefully stimulate questions from some of the folks on the Zoom. Really, I've been a strong advocate to Compugen and am very happy that Compugen has really come to focus on really this triplet. For a number of scientific reasons, I think PD-1 blockade is foundational, so I think it's important that that's one piece of this. Also, as Eran mentioned, PVRIG and TIGIT really are parallel pathways. While blocking one or the other may very well add some activity, if you only block one, that leaves the other checkpoint intact. It really makes scientific sense to block these concordantly. There as Eran mentioned, differentially but preferentially expressed really on the two populations that we know of, sort of precursor populations of tumor-specific T cells that can be when properly unleashed and unblocked, become activated antitumor effector cells. I'll show you just on the next slide, one piece of data from my colleague here at Hopkins, Sudipto Ganguly, showing that knockouts of both PVRIG and TIGIT in animal models have additive and in some cases synergistic antitumor activity in multiple aggressive mirroring tumors that are resistant to anti-PD-1. Does that guarantee success in the human? No. If you look at the successful immunotherapies of all sorts, they all started by demonstrating activity in challenging poorly immunogenic murine models. Then also oftentimes not appreciated, even above, in thinking about translation of mouse data to the human, there are actually three reasons to predict that PVRIG will play actually even a larger relative role in humans than in mice. It's expressed more highly in humans than in mice. It's also developed a full item in the human that it actually doesn't have in the mouse, which is the conventional strong inhibitory signaling motif that binds particular phosphatases. Also human tumors have, some of them, including Ovarian Cancer, have very high expression of the ligand for PVRIG. The top just is a reiteration of the fact that there are these two populations, stem memory and exhausted T cells. Stem memory particularly have high levels of PVRIG, lower and exhausted where, but where you have higher levels of TIGIT and PD-1, which upon multi-checkpoint blockade, essentially can activate cells from these two pre-existing tumor-specific populations. This is B16-F10, a very classic, highly non-immunogenic mouse model looking at the various knockouts. You can see either looking at tumor growth or survival, that the combination of knockout of, which is the genetic form of blockade of PVRIG and TIGIT, generates stronger antitumor responses than knocking either of those out alone, which do certainly have activity. Similarly, the combination knockout has longer survival in an extremely aggressive Ovarian Cancer model in human. This is the ID8 model expressing VEGF. Again, I think all the preclinical data strongly supports this as a promising triplet. I think it's worth just putting on the table a couple of the things that are sort of out there in the community. The first is, has TIGIT been a clinical failure? The answer is, we don't yet know. There was clearly in the early roll-outs irrational exuberance about TIGIT, that was in turn followed by what I view as irrational skepticism. Just to point to a few of the trials that obviously everybody's looked at. Obviously the Roche trial, and important to point out that for their phase three, the PFS curves have not been reported out. OS is not yet read out. I think people assume that the endpoint is improvement over atezo alone. Actually, it's not clear that that is the endpoint, because if you're a pharmaceutical company like Roche, the endpoint is not a positive trial. The endpoint is they need to have a result with atezolizumab, which with all due respect, to Roche and Genentech, is not as potent a PD-1 pathway blocker as pembrolizumab. What they need to beat, obviously, is pembrolizumab alone for PD-L1 greater than 50% non-small cell lung cancer. We don't know that the trial, if the data is ever released, isn't gonna show an improvement relative to atezolizumab, which would demonstrate some additive benefit of TIGIT blockade. There was also a report of a failure in pembrolizumab chemo-resistant non-small cell lung cancer, that obviously doesn't say anything about what the first-line activity would be or what the activity would be in IO-naive patients. Then the Arcus trial, which I actually thought again, was those relatively small numbers of patients encouraging for demonstrating an improvement of the combination over their anti-PD-1. The fact that the anti-PD-1 alone arm so-called underperformed in my mind does not negate the value of the improvement relative to anti-PD-1 alone. This could be that their anti-PD-1 is less active than pembro, just like atezo. It may or may not. You know, I don't think anybody's actually compared them head-to-head. Also, I think it's very possible that there may be patient selection differences relative to the Merck approval trials, which could explain that so-called underperformance. On the right side, the question of does anti-TIGIT need to be quote-unquote, "Fc active," namely have an Fc region that binds Fc receptors. The answer is, it's actually unclear. I think likely not the case. There have been conflicting reports in mouse models. The first report actually from Vijay Kuchroo and Anna Anderson in the mouse reported synergy between anti-PD-L1 and an Fc inactive anti-TIGIT. Clearly, if you needed the Fc receptor-dependent effect, then you wouldn't expect to see an effect in TIGIT knockout mice. I just showed you that you do actually see an antitumor effect in TIGIT knockout mice. I might also remind you that with anti-CTLA-4 there in mice, the anti-CTLA-4 antibodies do have to be Fc active for the antibodies to have an effect. That actually is known to not translate in human because essentially Ipi has the same activity as Trem. Trem is Fc inactive. Ipi does bind to Fc receptors as a human IgG1, and there's absolutely no difference in their activity whatsoever. Fc active anti-TIGIT also concerns me because the effector cells also express TIGIT because you're trying to block TIGIT. What if you block TIGIT but also eliminate the very effector cells that you're trying to enhance their activity? I think they're real personally concerns as with regard to a so-called FC active antibody. The reality is, if you listen to the explanations as to why you would need the FC activity, with all due respect to some great scientists, it's all hand-waving. Finally, why do I think these particular trials that Compugen has focused in on are really strong trial designs? Firstly, as I've mentioned, the triplet prioritizes potency with three really excellent monoclonal antibodies. I believe that in drug development in cancer, the three most important things are potency, potency. Ovarian Cancer has always been known to have, in a large proportion, a decent lymphocyte infiltrate, yet it has a very low response to anti-PD-1. it's a high unmet need. Generally, the response rate is less than 10% in PD-L1 negative patients. I know at least one of the responders in the triplet trial of Compugen's is in fact PD-L1 negative. In the Merck study with pembro alone, there was a 0% response rate in the PD-L1 negative Ovarian Cancers. Ovarian has a very high expression of PD-L2, the major PVRIG ligand, and also some great opportunities for identification of biomarkers for further patient selection. Similarly, MSS colorectal cancer, high unmet medical need. Very, very low response to anti-PD-1 alone. You saw even the doublet had very small numbers but had some activity. Also, with liver metastases there, I think there are some good opportunities, for on-treatment biopsies, which I think is gonna give a lot of information, that will come out of the trial beyond simply, clinical endpoints. Also, again, there'll be opportunities for identification of biomarkers for patient selection that will be very important. With that, I will stop share and turn it over to Sarah to moderate the Q&A session. Wonderful. Thank you, Drew. At this time, we'll begin conducting our Q&A session. A reminder to the audience, you can submit questions on the Q&A function at the bottom of the webcast player. If you are in full screen mode, you will need to exit full screen mode to access those text boxes. To our Analysts, just a reminder, you need to raise your hand in order to indicate you would like to join the queue. With that, we'll take our first question from Mark Breidenbach at Oppenheimer & Co.. Hi. Thanks for taking our questions and thanks for putting this presentation together. Just a couple from me, probably both aimed at Dr. Pardoll. I guess I'm wondering if TIGIT and PVRIG are somewhat redundant checkpoints that maybe can compensate for one another. Why should we be expecting a doublet, a PD-1 plus TIGIT antibody to have any benefit over PD-1 at all? What's kind of the rationale there? Maybe just what's the Occam's razor explanation for the divergence of clinical data we've seen from across the clinical trial space? I know that that might be a hard one to answer. I have one more follow-up after you after you field those questions. Yeah. If you're trying to activate a pathway, and you have two redundant upstream targets that you're trying to activate. There, redundancy does not buy you an advantage to hit both because if you hit one, you activate, if you hit the other, you activate. If you're trying to block a pathway, redundancy arguably requires that you block both. Just imagine you have a big, a bunch of steer in a rodeo or something, and there are two doors, and you wanna keep the steer inside, and you have two doors into the rodeo space. If one door is slammed shut, but the other door is open, even though it's a smaller door, the steer can get out. If you wanna keep the steer, in the, you know, in the pen, you have to shut both doors. That's sort of the... Similarly here, they're not, they're not totally redundant, but they are somewhat overlapping. Again, if you're a tumor, and you want to block the patient's immune system from getting at you, and you have two molecules, two receptors that are similar or related that will each send a negative signal to turn off that T cell, and you're making ligands that will hit both of those receptors, you come in with an antibody to block one of them, the other one is still open to be engaged by that tumor. That's the fundamental reason why if you're trying to inhibit as opposed to agonize, it's important with redundancy to block both. To your second question about why, you know, about the early trials looking like they're, quote-unquote, "all over the place." You know, if you've seen one cancer patient, you've seen one cancer patient. There you have to really go into the populations of patients that, not only just that are in the inclusion/exclusion criteria but really look at the characteristics of the patients that went onto a given trial. You need to look at the setting. You need to look at the antibodies. There are a lot of variables. I apologize, I work in an inner-city medical center. If you hear sirens periodically. Yeah, you're gonna have variability. This is why the big randomized, properly designed phase three approval trials are the trials that you need to ultimately answer. The question is, are we seeing signal? For first-line non-small cell, certainly what I look for with the TIGIT is signal above baseline comparator, which is anti-PD-1, or in the case of Roche, anti-PD-L1 alone. With the Arcus trial, again, there was clear signal by adding their anti-TIGIT, which is an Fc-inactive. In the Roche trial, we haven't seen the data on their phase three trial PFS. They've essentially announced that they didn't hit their endpoints for PFS. We haven't heard about OS, but it's not clear to me what they're what their endpoint was. Yes, it's an improvement relative to Atezo alone, how much improvement are they asking for? If, you know, if their Atezo alone has a PFS that's 10%-15%, which I imagine it will be because it's not as good a PD-1 pathway blocker as pembro. If it's 10%-15% below pembro, even on the phase lll, and adding their anti-TIGIT brings it up to the level of pembro alone in patients that are PD-L1 greater than 50%, that may be a positive trial, that's not the endpoint that matters to Roche. They need a strong enough result that not only do they get FDA approval, An oncologist says, "This is so compelling that I'm not going to any longer prescribe to my first-line lung cancer patient what I've been prescribing for the last seven years, which works pretty well, which is pembro. Because I'm not convinced that their data compared to pembro, it's not gonna get me to change my prescribing habits." That's really the operational endpoint, if you're Roche, that you need. It's not another The New England Journal of Medicine paper. That's good for us as academics, but... I think, again, those are some of the points that I would make to keep in mind, before just sort of writing off something based on a lot of, really small studies in terms of what's really been reported to the level that you can look carefully at what the variables, patient populations, and outcomes are, sort of under the below the level of the press release. On the design of the two triplet studies that Compugen is running right now, you know, we're testing three agents in tumor types where there's not a lot of single agent activity for any of the three components. I'm wondering, I would love to get your thoughts on potentially combining with chemotherapy in these maybe second or third line settings. Wouldn't that potentially be easier from a regulatory perspective than going after a triple combination, as the company is doing now? Yeah. In Ovarian Cancer, we don't really know whether the chemotherapy agents that are conventionally used in Ovarian Cancer, how they are going to play with immunotherapy. For reasons that we're actually working hard to understand, there's no question that the platinum doublet, particularly, a platinum agent with pemetrexed in non-small cell lung cancer does have an additive, if not potentially synergistic effect with anti-PD-1. That's not the case with most of the other, even FDA-approved combinations of anti-PD-1 with other chemotherapy agents. You know, the chemotherapy agents are so diverse in terms of what they do, the targets they hit. You know, antifolates, intercalators, you know, microtubule agents, polymerase inhibitors. You know, might it be an easier regulatory path? Maybe, there's no data that it's gonna be the most effective. I'm a strong believer that the fastest pathway to market is the pathway that brings the greatest efficacy on behalf of patients. I really do believe that the market and the patient focused incentives are concordant here. I think that if the data from the certainly from the ovarian holds up four out of 20 patients, and I've been lobbying to really pay attention to effects in the PD-L1 negative ovarians, where essentially, you know, pembro has a 0% response rate. That, you know, results that are reproduce the results in the small 20-patient triplet are going to turn into a, you know, fairly rapid. It may be a multi-arm trial, but I think a fairly rapid pathway to approval. Similarly, MSS, it's the, you know, the bar is so low. There's just really so little. Again, right now, we don't know what throwing this checkpoint blocker combination together with sort of standard chemotherapy is going to do. I hate sort of closing, you know, just closing my eyes and hoping that I hit the bullseye. I got it. Thank you for taking the questions. I'll jump back into queue. Thanks, Mark. The next question comes from Tony Butler at EF Hutton. Sarah, thank you. Dr. Pardoll, thank you very much. My, my question for you and maybe Eran, is this. You could imagine that a tumor microenvironment which is refractory to previous therapy, would produce different cytokines or maybe little cytokines than one in which you do have an antitumor response. The question is, when you add the triplet, is there evidence that actually there is a change in those cytokines? For example, is there an increase in, say, IL-2 versus that pre-triplet TME? Moreover, the second part of the question might be, are there phenotypic changes in those T cells based upon the pathway being blocked by the triplet versus one in which it's not blocked? You might also consider, back to the previous question, what might happen if it's not the triplet, but two of the three components. Is there any evidence, cytokine or phenotypically, for that outcome? Thanks very much. I will say before handing it over to Eran, who's been very much obviously on top of the analysis of on treatment effects and Eran showed a beautiful slide of one example of changes with therapy. What I can tell you is that in the mouse models, and granted, you know, you can't take mouse models as absolutes, but the biology of the molecules in this pathway looks very similar between mouse and human. I think in terms of understanding what effects the pathways have in mouse, I think that is going to be at least partially translatable. Without taking the time to go into the detail, but my colleague, Dr. Ganguly, is writing this up now. He's been able to, in the mouse models, compare with the individual versus the combined knockouts. Which is really the ultimate clean genetic methodology to answer your question, at least in mouse models, which are inbred and more consistent. There are absolutely differences in terms of qualitative and quantitative differences in the in-tumor specific T cells that enter into the tumor. Without question. Why don't I hand this over to Eran to maybe say a little bit more about some of the information that's been gleaned from the clinical patients. Thanks, Drew. You know, about the question of patients who failed prior IO. I think it's really dependent on why they failed. I'm not sure if the triple blockade could rescue all of them. For example, if we didn't have enough T cells to begin with, and that's why we didn't respond, again, given also the unique biology of PVR gene driving T cell proliferation and infiltration, potentially triple blockade could more potently increase T cell numbers and then induce also clinical response. If, for example, they lost MHC as well or Beta-2 M, here, for example, PVR gene TIGIT are also NK checkpoints. While you don't have a lot of NK human tumor microenvironment, there are some indications for NK or maybe even gamma delta, which also carry PVR gene TIGIT, that can control some responses even when the MHC is lost. About the phenotypic changes following triple blockade, as Drew just mentioned, is probably easier to follow very precisely in the mice, but also in human subject, what we have shown that following the treatment, you see increase in Interferon gamma in the blood, and most importantly, in Interferon gamma signature in the tumor. Actually, we have some data of IL-6 reduction in responding patients. Definitely the triple blockade is being able to modulate tumor microenvironment, really changing not only the Cytokine landscape, but also increasing T cells, activated Polyfunctional T cells. This is what we see in patients, and again, in more details in Drew's studies. May I have a follow-up, if possible? Thank you both. Dr. Pardoll, back to your comments in mouse models. Can you say that there were changes in the ID8 model with respect to cytokines, pre and post? Thank you. The answer is yes. The analyses actually that has been done and is actually ongoing is an analysis called single-cell RNA-seq, which gives you the whole transcriptome of each cell, and you can analyze 5,000 cells per tumor. You get a massive amount of information, and there are actually multiple pro-inflammatory cytokines that do go up being made by the T cells, and we haven't even started looking at non-T cells in the tumor microenvironment. Also, receptors on the T cells for cytokines that may be produced at low levels in the tumor milieu, such as IL-7, the IL-7 receptor levels go up. That indicates that these T cells in the tumor, particularly with the combined knockout, will be more sensitive to lower levels of cytokines that are in the tumor microenvironment. It's there are actually very, very large global changes as well also as with chemokines. I think this also makes the point that we hear a lot about a tumor immune exclusion, and the idea is if you could only get T cells into the tumor, then you could potentially enhance antitumor activity. one of the best ways to do that is to increase the level of the chemokines, which are essentially the chemoattractant cytokines, that are being made in the tumor, which again, some of which go up, in particular some of the-I won't bore you with the particular names because there are a lot of them. These are not individual cytokines. They're global changes that represent banks of cytokines that are commonly regulated by transcriptional programs. Probably more than you wanted to hear. No, sir. It's perfect. Thank you, sir. Thank you for the questions, Tony. The next question comes from Jeff LaRosa at SVB. Please go ahead. Hi, this is Jeff on for Dana. Thanks for taking our questions. To Dr. Pardoll, you hinted at the ovarian CRC trials being great opportunities for biomarker identification. I guess, like what are your thoughts on varying biomarker enrichment strategies for therapies targeting the GDAM-1 axis? Most sponsors today are generally following more inflamed tumor types and selection for PD-L1 expression, while Compugen is targeting more immunologically cold tumors. Given that these tumors are also more challenging to treat, do you think it will ultimately prove necessary to prospectively enrich for responses of biomarkers? Do you have any thoughts on specific ones that have been raised, such as PVRL2 or PVR? Might a gene signature type of biomarker strategy be more productive? Thank you. The way I view biomarker analyses and I wish for so many trials that the proportion of investment on the, you know, sort of patient entry and all the clinical aspects of the trial, which is obviously very important, that sometimes there is more investment in the trial put into looking at biomarkers. That said, I view them in two buckets. There are the biomarkers that make biological sense based on the science. Most straightforwardly here, there are the actual targets themselves and their ligands. You've got PD-1, TIGIT, PVRIG, and then on the other side you've got PVR, PVRL2, PD-L1 and PD-L2. What I would love to see is as much as possible a focus, and Compugen certainly has been working very diligently on developing immunohistochemistry and other antibodies for these markers. Those make the most sense and would be the ones, just like with PD-L1 and PD-1 blockade. Then there are all of the other potential biomarkers that only come from application of the high dimensional analyses that are now available to us. you know, things like, you know, whole transcriptome sequencing and others. Those are done retrospectively, they're done relatively agnostically, but they require biopsies to be able to perform those analyses. In general, because of the peritoneal studying and also the fact that it's relatively easy to draw ascites from Ovarian Cancer patients, and then also particularly with peripheral liver metastases, the morbidity these days with sono or CT-guided needle biopsies in the liver. The morbidity is very low. I've certainly been a strong advocate to try to collect that tissue, because once you have that tissue collected, there are these high dimensional exploratory analyses that you can do that will potentially reveal something that's not the obvious ones. Those are kind of the two buckets that I look at, as opportunities for biomarkers. Thanks. I guess one quick follow-up, since I understand you are a discoverer of NKT cells. Compugen showed a pretty striking increase in NKT cell proliferation in the phase 1 COM701, with Monotherapy and with nivolumab. What role might NKT cells play in the GDNF axis? Similarly, also, what are your thoughts on NK cells and gamma delta T cells in this axis? Yeah. Actually, my first paper in immunology was the identification of gamma delta T cells. I actually have two on my belt. There is certainly a growing interest in these so-called unconventional T cells. And actually we can throw in innate cells as another unconventional, sure, MAIT cells, all of which use a T-cell receptor, all of which can kill and can mediate anti-tumor activity. And they all express either TIGIT, PVRIG or both. I don't know specifically what role they may have. I look at that as an important area for discovery. We actually have a couple of projects looking at these in neoadjuvant settings. They are definitely potential killers, and they do express, TIGIT, PVRIG in some cases, and to a lesser extent PD-1. With this triplet they would certainly be potentially brought into play. Great. Thanks, Andrew, for all. That's good. That's it for me. Appreciate it. Thank you for the question, Jeff. The last question will come from Karina at Truist. Hi, this is Karina for Asthika. Dr. Pardoll, I have a question for you. Are you seeing any significant differences in response in ID8 pre-clinical model for ovarian given that it has high expression of PVRIG ligand and tumors? What's the response in terms of anti-PVRIG alone versus a triple blockade? A follow-up is, how do you see this translating in clinical trials? Thank you. The focus in the ID8, and it's a model actually where the original ID8 is transfected with a constitutively active VEGF gene. It's a version of ID8 that's more aggressive than the parental ID8 and less immunogenic. In fact, as it turns out, VEGF actually inhibits dendritic cell activation. This was shown decades ago by Dmitry Gabrilovich. There is absolutely tumor growth inhibition, I think that was on one of my slides, in the PVRIG knockouts alone. In that case, less so with the TIGIT knockouts, but when you knock out both PVRIG and TIGIT together, there is further tumor growth inhibition. Sudipto Ganguly, and I'm not sure where those stand now, has been now adding He actually uses an anti-PD-L1, which in the mouse models is equivalent to an anti-PD-1 on top of that. That does give you an added benefit in B16-F10. I'm not sure if he, if he has that data yet, in the ID8 VEGF model. Definitely with the knockouts there is an effect of just PVRIG knockout alone, and again, a greater effect when it's knocked out together with TIGIT. Okay. Thank you. Thank you for the questions, Karina. I think this concludes the Analyst portion of the Q&A session. I'll now hand it over to Anat for any questions that may have come in over the webcast. Yes. There is a question here from our covering Analyst, Stephen Willey, which is asking, "Can you speak to the efficacy thresholds you need to see in both ovarian and MSS CRC to justify moving forward in either setting? Specifically, what kind of efficacy signal emerging out of a 20-patient MSS CRC cohort would you like to see to believe you're fundamentally altering the trajectory of patient outcomes with the triplet regimen?" Drew, would you like to give your perspective on this? Yeah. Well, what I'd like to see is five of the 20 patients showing an objective response. I... Yeah, at the very least, I would, you know, like to see three or four responders. I think if you have two-- even though these are small trials, if you have two in a row, and you're-- This trial is gonna focus on liver metastasis only, I believe. Is that right, Anat? No, we're going to. Yeah. It's not only liver metastasis. Gonna be the all comers. Yeah. You know- The setting is, having liver metastasis, but we're not focusing only on this. As an academic, I would like to see as many on treatment biopsies as possible, so that we can learn. You know, I think from a de-risking standpoint, you know, I think three, four objective responders out of 20 in MSS would significantly de-risk it. Henry, would you like to give some perspective on MSS CRC and ovarian, or what would be the signals for us? Yeah, I think what Drew has said is something that most clinicians will be looking forward to. Especially more so if the patients that have the responses are patients who also have liver metastasis. Like Drew said in his, with his slides. The efficacy bar is so very low in patients who have Microsatellite stable colorectal cancer. That success can be judged, even though these are small studies, by the few number of patients with responses, including some other indicators of adverse prognostic features. For example, like KRAS mutation also. If you're seeing a confluence of those kinds of parameters in those patients, three, four, I think it's something that one should look into for colorectal cancer. Also for Ovarian Cancer. We're seeing good data as well at IO last year with the four patients with the partial responses, confirmed partial responses. Similar numbers I think will be helpful. Now, point to bear in mind, and I know it hasn't been part of the conversation, is that those patients with Ovarian Cancer, remember, are patients who have exhausted all available standard of care therapies. Even makes it even more challenging. We did report that there were four prior therapies in the platinum-resistant Ovarian Cancer setting, in the triplet last year at ESMO IO and also for six for the dual combination. It's a lot of therapies, and so we've seen those kinds of results. That's what I would just like to point out. Okay. Maybe I can sneak in something else there, Anat. I'm sorry. Something to do with the kinds of histologies that we're seeing in patients with Ovarian Cancer also. We're seeing diverse histologies, not just serous, we're seeing clear cell, or not just clear cell, we're seeing serous and mucinous. We reported this also. Thank you, Henry. Thank you, everyone. We're going over the hour, so in case we didn't get to answer your questions or you have more to ask, please don't hesitate to contact Yvonne, Head of Investor Relations, and she will facilitate contact with Drew. Drew, thank you very much for taking the time to be with us today. Oh, my pleasure. Thanks for the invite. Thanks to everybody on the line listening in and asking good questions. Thank you, everyone. This concludes today's call. You may now disconnect your line.