Welcome to the Sensei Biotherapeutics Investor Webcast. At this time, all attendees are in listening-only mode. A question-and-answer session will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be made available on the Sensei website following the conclusion of the event. I'd now like to turn the call over to Mike Biega, Senior Director of Investor Relations at Sensei Biotherapeutics. Please go ahead, Mike. Thanks, Tara. Good afternoon, everyone. Thank you for joining Sensei Bio's Webcast. Today, we'll be discussing preliminary phase I dose expansion data for solnerstotug in PD-L1 resistant tumors that was released earlier today. Joining today from Sensei is John Celebi, President and CEO, and Dr. Ron Weitzman, Chief Medical Officer. We are also pleased to have Dr. Shiraj Sen join us today. Dr. Sen is a Medical Oncologist and Director of Clinical Research at NEXT Oncology in Dallas, Texas. Dr. Sen received his undergraduate degree from the University of Texas at Austin and his MD and PhD degrees from the University of Texas at Houston and MD Anderson Cancer Center Graduate School of Biomedical Sciences. His postgraduate training in internal medicine was performed at the University of Texas Southwestern Medical Center in Dallas prior to completing his Hematology and Medical Oncology Fellowship at the University of Texas MD Anderson Cancer Center. Dr. Sen is board-certified in internal medicine and medical oncology and is a recipient of numerous awards for his research, such as the Waun Ki Hong Award for Achievement in Clinical Investigation, the Marion D. Edwards Fellowship in Hepatic Oncology, and the American Society of Clinical Oncology Conquer Cancer Foundation Merit Award. He has also authored more than 30 peer-reviewed publications, presented his research at over 20 international conferences, and has served as a member of the ASCO Scientific Program Committee. He is a principal investigator on the ongoing phase I-II trial. Dr. Sen, I just want to thank you for taking the time to join us today. If you can move to the next slide, on this call, we will be making certain forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995. With that, I'd now like to hand it over to our President and CEO, John. John, please go ahead. Thank you, Mike. Good evening, everyone. Let me start by introducing the scientific foundation of the program. Solnerstotug is a potential first-in-class monoclonal antibody designed to selectively target VISTA, a unique immune checkpoint protein that plays a central role in immunosuppression within the tumor microenvironment. Unlike other immune checkpoints, VISTA is expressed across a broad range of solid tumors and operates in a pH-dependent fashion, engaging only under acidic conditions. These are the conditions found in tumors. This pH-sensitive mechanism allows solnerstotug to engage its target only where it matters most, inside the tumor. The goal? To reverse immunosuppression while minimizing the off-tumor effects seen with first-generation VISTA-targeted therapies. What makes this opportunity especially compelling is the breadth of VISTA expression. As you can see, VISTA is broadly expressed across the majority of solid tumors, even more so than PD-1 and PD-L1, particularly in indications with high unmet medical need. The market potential here is significant. PD-1 and PD-L1 inhibitors are among the most successful classes of drugs in oncology. With solnerstotug, we believe we're well-positioned to bring the next wave of immunotherapy to patients that currently lack effective options. This is not a straightforward target. Prior attempts to drug VISTA were halted due to toxicity and poor pharmacokinetics, largely driven by off-tumor binding. These early efforts demonstrated the biologic potential of VISTA inhibition, but they fell short of delivering a viable therapy. solnerstotug was intentionally designed to overcome these hurdles, binding selectively in the tumor microenvironment and showing no detectable off-tumor engagement. This is a crucial distinction and the foundation for what we believe sets solnerstotug apart. Now, let's take a closer look at how solnerstotug works in practice. The problem with earlier VISTA antibodies was their inability to distinguish between tumor and healthy tissue, leading to dose-limiting toxicities and unpredictable pharmacokinetics. Solnerstotug was designed to avoid those pitfalls. It binds VISTA only under acidic conditions, which are present in the tumor microenvironment but not in normal tissue. The image you see here shows just that: rapid accumulation in the tumor and no detectable binding in the periphery. This selective mechanism supports a cleaner safety profile and more predictable PK, both critical for clinical success. To summarize, solnerstotug is a rationally designed tumor-selective VISTA antibody that's overcome many of the obstacles that halted earlier programs. The science is compelling, and the preclinical promise has thus far translated into a differentiated safety and pharmacokinetic profile in the clinic. The real question is, can it deliver clinical activity in patients who've progressed on standard immunotherapies? To walk you through that early activity data from our phase I study, I'm pleased to hand it over to Dr. Ron Weitzman, Chief Medical Officer at Sensei, and Dr. Shiraj Sen, the principal investigator leading this trial. Ron? Thanks, John, for covering that so nicely. You cover a lot in very few slides. This is Ron Weitzman. I'm a Medical Oncologist, also the Chief Medical Officer of Sensei. I want to thank all of you who have joined us and made time to hear our story again. Here's the update. The slide you see before you is basically a recap of what we shared and presented at ASCO last year in Chicago. As you know, or as you may know, this phase I dose, this was the phase I dose escalation portion of our study. You're going to hear about the cohort expansion in hot tumors from Dr. Sen shortly. In the dose escalation portion, we consciously and deliberately had very broad entry criteria, owing in large part to the fact that we believed, based on peer-reviewed literature and our own results, that VISTA may very well play a role in both the cold and hot tumor settings. We had broad entry criteria that allowed both cold and hot tumors to come onto the phase I escalation. As it turned out, just about 90% of the tumor types that came on were what we would call cold tumors or generally unresponsive to immunotherapy. On the upside, we were able to enroll very quickly, which is what we did. We covered five monotherapy dose levels in short order, as well as three combination dose levels, tracking right behind that. Within about a period of seven to eight months, we completed dose escalation. As you may recall from ASCO, we showed an absence of severe CRS. This is important because our predecessor competitor agents were basically shut down, or at least the J&J molecule was shut down due to this very toxicity at extremely low dose levels. Coinciding with that, with that severe CRS and that target-mediated drug disposition, those agents had very short half-lives, especially so for a monoclonal antibody. We, on the other hand, were able to show a very favorable PK profile. As a result of the lack of severe CRS, we were able to dose escalate to doses as high as 15 mg/kg, which I think we'll show you now are pharmacologically relevant dose levels. Therefore, for the first time, we believe we were able to test the VISTA hypothesis in the clinic. Next slide. Great. Okay. In phase I, we showed a very well-tolerated monotherapy and combination profile of our drug. As you recall, we combined with Regeneron's Libtayo or cemiplimab. That's a PD-1 targeting agent, which has approvals in several indications, including lung cancer. We, I believe, were able to show a commercially acceptable and potentially best-in-class PK profile. We, as a result, became the first and only agent to be dosed at pharmacologically relevant levels. We pivoted after ASCO and after completing, actually, even before ASCO, but after completing our phase I dose escalation, we pivoted to expanding into hot tumor types. You can go to the next slide. Sorry. What I want to show you here on this slide, slide 11, is you can see in perforated red there below on the right is the hot tumor basket. In the expansion cohort, we focused on three different populations. Number one, we focused on the microsatellite stable colorectal cancer population treated with monotherapy. There, we expanded to 10 patients. We did not observe any relevant or important clinical activity there. We're not going to talk about that today, but I'm just letting you know about that. We also tested the combination of Libtayo and SNS-101 in microsatellite stable colorectal cancer. Again, the same cold tumor population, 10 patients. We did not see responses there. We're not going to spend time talking about that here today. Most importantly, we enrolled or plan to enroll 40 patients in what we call the hot tumor basket, made up primarily of non-small cell lung cancer, squamous cell cancer of the head and neck, and malignant melanoma. We did also have language in the protocol that allowed us to consider other tumors of interest, ideally in the hot tumor category. This was 40 patients. This alternated doses between 3 and 15 mg/kg. Both were confident are pharmacologically relevant doses. You can go to the next slide. I'm going to hand this over to Dr. Sen. All yours. Thank you so much. On this slide here, you can see the patient disposition of the patients that were enrolled on the left-hand side in the entire expansion cohort. You can see on the right-hand side the patients we're going to focus on who were enrolled in the basket of "hot tumors" that Ron just described. On the left-hand side, you can see that patients across both the monotherapy as well as combination had similar dispositions. Patients were enrolled and came off of study for similar reasons. What I'll just briefly comment on is the reasons for discontinuation, mostly being disease progression or progressive disease, as this is very common across our phase I studies that we enroll. On the right-hand side, what you can see is, again, patients did receive two different dose levels of the experimental drug at both 3 mg/kg and 15 mg/kg. What I'd like to highlight is that in 23 of the 40 patients, or 58% of the patients, treatment is still ongoing. As you can see in the bottom half of the slide on the right-hand side, the reason for discontinuation most commonly was disease progression, as we commonly see in this patient population. Next slide, please. Again, focusing on the patient demographics of those patients who had "hot tumors," you can see that these patients had a median age of about 70 years old, which is, again, typical of this patient population. Patients' ECOG performance status was largely 0 to 1, mostly being 1. They had had a prior median lines of therapy of 2, which is, again, fairly standard for this patient population. What I really want to highlight here, though, is that 90% of the patients had previously received and no longer were benefiting from a PD-1 or PD-L1-based therapy. That will be, again, very important as we talk about the next few slides. In about 60% of the patients, that therapy was what they had just immediately received preceding going on to this clinical trial. On the right-hand side of the slide, you can, again, see that we enrolled a wide variety of patients. That does, again, represent patients of a variety of hot tumors, but also helps to explain some of the heterogeneity of some of the results that we're going to show here. Most commonly, patients had head and neck squamous cell cancers, non-small cell lung cancers for the most part. Next slide. Now, the reason on the last slide that I wanted to really highlight the% of patients who had previously received PD-1, PD-L1 therapy and had no longer benefited from it is shown here on this slide. Here, you can see a series of four studies that have described how patients historically do once they have received a PD-1 or PD-L1 inhibitor therapy and at some point are re-challenged with the same treatment. You can see, again, in the red circles below that the response rates to this can vary from, again, 0% to at most about 8.3%. For the overwhelming majority of patients who have progressed on a prior PD-1 or PD-L1 inhibitor, we generally do not expect there to be much benefit to re-challenging them on that drug alone. This, as stated at the very bottom, is aligned with the Society for Immunotherapy of Cancer definition of acquired resistance to this class of medications, which defines there being about a 5% or less chance of benefit with immune checkpoint inhibitor therapy once they have already had disease progression or no longer benefited from the drug. Next slide, please. Here we show the preliminary efficacy data in this population of patients with "hot tumors" whose tumors are already refractory to a PD-1 or PD-L1 inhibitor, meaning patients who had already had a PD-1 or PD-L1 inhibitor and had demonstrated that drug was no longer benefiting them. What you can see is two things: that there were a number of patients who did have some degree of tumor shrinkage on this combination therapy after already having no longer benefited on a PD-1 inhibitor alone. There were two patients that you can see on the far right-hand side who both had Merkel cell carcinomas, one patient who to date has already had almost a 45% decrease of their tumors, and a second patient who at this point has had a 100% decrease of all visible tumors on scans and on, again, a dermatologic exam, this being a Merkel cell carcinoma patient. Notably, also, you can see that on about half the patients, they still have treatment that is ongoing. If you can go to the next slide, we can go into a little bit more detail of why that's important. Again, to set a historical kind of context, these patients, when they receive further immunotherapy with a PD-1 or PD-L1 inhibitor, generally, as shown earlier on, historically do not do very well and do not have many responses. If they do respond, the durability or the length of time that they tend to respond to those therapies is not very long. What you can see here in the 21 individuals who had received a prior PD-1 or PD-L1 inhibitor that then went on this clinical trial is that a number of them, shown with the arrows, with the black arrows on the right-hand side of the bars, have had a benefit to the treatment that, again, goes well beyond what we would expect with many therapies in this refractory setting. Most notably, at the very bottom, you can see that there are a handful of patients who have, at this point, already been on for well over six months of treatment with ongoing benefit. Next slide, please. Now, we want to highlight a few specific cases that sort of bring home this point of not just the degree of benefit, but also the duration of benefit that these patients are receiving. The first one here is, again, an elderly gentleman, 85 years old, with a Merkel cell carcinoma of the skin originating in the right nasal side wall. This patient was diagnosed in 2022, had, again, received a prior checkpoint inhibitor, avelumab, for quite a while until January of 2024, started treatment on this combination in April of 2024. You can see on the right-hand side, looking at the tumor assessments, had quite a rapid and steady decrease in the size of their tumors until, again, at week 18, they no longer had any visible tumors on their scans. That response has now been maintained for 42 weeks and counting. This is despite, as you can see with the little asterisks on the bottom, this patient having missed a couple of cycles of treatment due to an extended vacation, which, just to highlight, is a whole reason we treat and try to help these patients on these therapies so they can just go on to live not only a longer life, but also a healthier one where they can essentially take vacation and enjoy life. Next slide, please. The next patient is, again, another woman, a younger woman now, 58-year-old, with a metastatic Merkel cell carcinoma. She was also diagnosed in 2022. Unlike the prior patient, this one had, again, received a number of different checkpoint inhibitors. Sort of like we discussed, despite that, is receiving benefit from this combination. Specifically, she initially received Keytruda or pembrolizumab in the adjuvant setting after having an initial resection of her Merkel cell carcinoma. Unfortunately, despite receiving that adjuvant therapy, she had new lesions pop up that were biopsy-proven to be disease. She then went on a different combination immunotherapy of Opdivo plus Yervoy or nivolumab plus ipilimumab. She got four cycles of induction therapy before then going on to maintenance nivolumab or maintenance Opdivo. Again, in April of last year, she had new lesions that had popped up. She then went on a different experimental monoclonal antibody to which she did not have any sort of meaningful tumor shrinkage and response and stopped due to disease progression. Here on this therapy, despite having received different, again, checkpoint inhibitor-based therapies, she does have a partial response that is, again, 12 weeks and counting. Next slide, please. Now, a very different tumor type, but one, again, that's considered a hot tumor, a microsatellite unstable or MSI-High colorectal cancer patient. This is someone who, again, a young gentleman, 51 years old, who had received initially chemotherapy plus an anti-angiogenic therapy called Avastin that he did not respond to at all. Then February of 2020, around the time when Keytruda was approved for patients with MSI-High colorectal cancer, went on Keytruda, had actually a great response, had a complete response to this until April of 2024, at which point he had new lesions that appeared and then came to see us in our clinic here in Dallas and has been on this combination since then. As you can see, despite having had a complete response to Keytruda monotherapy, which, again, has been well described in patients with MSI-High colon cancer, at the time of developing resistance to that Keytruda monotherapy or that PD-1 inhibitor monotherapy, went on this trial and now is once again having meaningful tumor shrinkage and is in a partial response. You can see that it's, again, been very durable. He's now been on treatment for 36 weeks and counting with ongoing benefit and really tolerating the drug very well. Next slide, please. Another individual here, this is a patient with renal cell carcinoma. Again, a 59-year-old gentleman who, again, was diagnosed back in 2017. I won't go through the extensive treatment history, but you can see, again, this individual also has been on multiple checkpoint inhibitors. Initially, a Keytruda plus tyrosine kinase inhibitor. Later went on to, again, a dual checkpoint inhibitor combination of nivolumab plus ipilimumab. You can see that, unlike the last patient that received this dual checkpoint inhibitor, this individual did not benefit from it and had disease progression quite essentially on probably the first scans that they had afterwards. Went on a number of different tyrosine kinase inhibitors and therapy since then, but has now gone on to this combination, again, although only in a stable disease, has had some tumor shrinkage. It does appear to be quite durable now being on treatment 18 weeks and counting. Next slide, please. This patient's another patient that's under our care here in Dallas that has a hepatocellular carcinoma that shows another is not only a story of someone who has benefited from treatment, but is someone who, again, had been treated with various different checkpoint inhibitors. Again, initially with Opdivo without receiving any benefit, later, largely because of a lack of good therapeutic options for patients with hepatocellular carcinoma. Then went on Keytruda who actually had some durable stable disease on there, but then had disease progression. Ultimately, interestingly enough, also under my care was on a different cemiplimab-based combination before coming on to this cemiplimab-based combination. You can see that on treatment, while he clinically did very well and had an appreciable benefit in the first few weeks symptomatically, initially had some growth in his tumors that corresponded with an increase in his alpha-fetoprotein marker, which is the standard tumor marker we use to track patients with hepatocellular carcinoma. Because he was clinically feeling well, looking well, and having improvement in symptoms, we continued to treat him past that and then saw a decrease in the size of his tumors, which has then slowly continued to occur with quite durability and had a corresponding decrease in his alpha-fetoprotein, again, consistent with the pattern of what is sometimes called pseudoprogression if the patient actually had tumors that had grown 20% or more. A phenomenon that's been described in patients with hepatocellular carcinomas on checkpoint inhibitors. Again, another individual who now is 30 weeks and counting on this treatment with benefit. Next slide, please. From a, which is just as important to discuss, from a safety standpoint, we can see here comparing the monotherapy to the combination with cemiplimab, you can see that there really is not any significant increase in any sort of treatment emergent adverse events, in any sort of significant adverse events, and of course, in any sort of high-grade adverse events. There are some patients who have had some immune-mediated adverse events. Again, there have been a small number of patients who have had very low-grade, grade 1 CRS events that were largely laboratory-based and qualitatively really hard to distinguish early on between CRS events and infusion-related reactions, but all of which were managed appropriately and without any sort of aggressive intervention and led to no significant safety events. Really highlighting that this combination with cemiplimab has been well tolerated, not had any increased safety concerns. The majority of adverse events have just been grade 1 or 2 and manageable by the investigators. Next slide. Lastly, on my end, the pharmacokinetic data, therefore, has supported how we've dosed this once every three weeks, which is, again, how we dose cemiplimab to be given in combination with cemiplimab. It has really demonstrated nicely that, unlike some of the prior non-pH conditionally activated VISTA monoclonal antibodies, which had a very short half-life, possibly or likely due to target-mediated drug disposition, here with this molecule, we are seeing a nice long half-life and that the drug's been detectable in blood for really thousands of hours, equating to weeks, and has supported the use of its combination every three weeks with cemiplimab. Again, looking at on the right, across these different graphs, we can see that there does not appear to be any major effects on pharmacokinetics when given in combination with cemiplimab compared to monotherapy. While there is some increase in pharmacokinetics in the PK data with repeat dosing, there has not been any concerning or clinically relevant notable accumulation of drug in these patients. Next slide. Okay. Solnerstotug in this study is being looked at in one of the most challenging patient populations. Again, those who have already progressed on PD-1 or PD-L1 therapy. That is very important context when interpreting our data because existing treatment options for PD-L1 resistant patients remain quite limited. The few checkpoint inhibitors that have been evaluated in this setting have shown modest response rates and durability, and none are formally approved for this indication. Against that backdrop, solnerstotug has demonstrated encouraging early signals of activity, a well-tolerated safety profile, and a mechanism that lines up well with overcoming acquired resistance. We believe these features position Solnerstotug as a next-generation potential immunotherapy with the opportunity to address a significant unmet need in immuno-oncology. Next slide. One of the things we wanted to touch on before we open it up to questions as well is biomarker data. In addition to what we shared at ASCO last year, we've been doing a lot of additional work. One of the ways we look at biomarkers is through gene expression. What you're seeing here is data from samples that were taken from patients at baseline, that is, prior to treatment. As you can see from the chart on the left, we looked at thousands of different genes at baseline. What we then did is we compared the readout of those genes at baseline by looking at patients of interest, i.e., those that have shown some form of interesting activity, and those patients that did not respond. When we looked at the data that way, we found four genes that stood out to us quite clearly. We're labeling them here, Gene A, B, C, and D. These are all statistically significant differences. You can see, maybe just focusing on Gene D here in the lower right, you can see there was a very clear difference in the baseline gene expression of Gene D in patients that responded or had some form of activity to the combination of solnerstotug plus Libtayo and those that did not. While early, we believe this data has potential to form the basis of a biomarker that could be used for patient selection in the future. Next slide. We're Ron here. I'll hand it back to you. Oh, sorry about that. Yeah. Are we on slide 26? I'm not on the webcast exactly. I'm calling in. Yes. Slide 26? Yes. Yeah. This is our phase II strategy that we're considering. I think one of the general concepts in oncology that has largely held true is that if you can show activity in a previously treated resistant setting, a convincing activity, that that same regimen would perform even better in the naive or treatment naive setting. That usually plays out, at least in my experience. There's even examples of that in the immuno-oncology space. Look no further than the activity of PD-1 agents in, for instance, MSI-High colorectal cancer, very active in the metastatic previously treated setting, even more active when you look at rectal carcinoma patients who have localized disease and receive a PD-1 agent neoadjuvantly. The CR rate was extremely high there and durable, I dare say, a cure. There is one example of a PD-1 therapy doing even better in the treatment naive setting. Our idea here is take our activity and bring it to the upfront setting in a hot tumor population, such as, just one example, non-small cell lung cancer or head and neck cancer or melanoma or renal cell. The idea would be to take roughly 80 patients and randomize them to SNS-101 at either 3 or 15 mg per kg in combination with an anti-PD-1 agent versus that same anti-PD-1 agent as the comparator. This kind of a trial design would work best in PD-L1 high, high patients, such as in non-small cell lung cancer or head and neck cancer. If you have very high PD-L1 expression, there's actually an FDA label that allows the patient to receive just the PD-1 targeting agent without chemotherapy. This would be one possible approach going forward. The endpoint would be fairly straightforward, progression-free survival and overall survival as a secondary endpoint, as well as safety and tolerability. In addition to this, given the signal we're seeing, for instance, in Merkel cell carcinoma, a much smaller tumor type, but an exquisitely sensitive IO tumor type as well, we could also consider a second indication where we do a single-arm study in parallel to this in PD-1 pretreated Merkel cell patients. That could potentially serve as a basis for accelerated approval, obviously, data permitting. Let me just pause there. Next slide. Great. Thank you, Ron. I think before we wrap up here, just wanted to remind everyone of our milestones ahead as well. We do expect to have full phase I dose expansion data by the end of this year and to initiate a phase II study in Q1 2026. With that, Mike, I'll hand it back to you. Thanks, John. Tara, can you poll for questions? Yes. To our audience, please hold for a brief moment. Our first question comes from Frank Brisebois at Oppenheimer. Please go ahead, Frank. Hi. Thanks. Can you guys hear me okay? Yes. Okay. All right. Great. Thanks for the question here. Congrats on the update. I was just wondering, going forward with the full data set, this preliminary data, there will be a full data set. What else would you like to see going forward? Is it kind of in line? Are we expecting better results or not? I will start with that, and then I will have a follow-up. Ron, I can start, and maybe you can help me supplement anything you want to add. As previously noted, Frank, especially, I think this stands out when you look at the swimmers' plot or the waterfall plot. All of the patients in this patient population that we've referred to, those patients that have PD-L1 resistance, all of the patients that have any form of tumor shrinkage are still on study. These results are early, but that fact does suggest the fact that these patients could continue to improve over time, especially when you consider the durability of the responses we've seen and the fact that, for example, the MSI-High colorectal patient that turned into a PR turned into a PR at the nine-month mark. That is not totally unusual for immunotherapy. It does suggest that we could continue to see additional PRs coming onto the study. Ron, do you want to add to anything I said? Yeah. Let me just say that PRs alone won't drive a favorable outcome of a future randomized study. Obviously, PRs are important. Tumors like these do not regress on their own typically. It is clearly a drug-related phenomenon as opposed to disease stability, which could be tumor indolence, etc. My point here is that we do have three PRs. We have 23 patients ongoing. If the first 21 patients that we showed data for in the swimmers' plot are any guide to how the latter, the remaining patients, some of whom are already on that swimmers' plot, but also quite a few others that have yet to have a first post-baseline scan, if the initial patient experience is any guide to how the remaining patients will do, I expect with longer follow-up where we can cover the entire data set with adequate follow-up, minimal adequate follow-up, I expect the results to look even better. I mean, that is my expectation, so. Okay. Great. I think such an important part of the VISTA hypothesis here is on safety. When there's the CRS that you did see, we talked about severity, grade one versus grade two. Can you help just frame what prior VISTAs showed on the safety front that was unacceptable and did not allow them to move forward versus what little signs of safety that you guys showed here? John, do you want me to handle that? Yes, please. Go ahead. Yeah, sure. Yeah, it's pretty simple. I think the best example that's out there in the literature because it was presented was the Johnson & Johnson molecule, which at a dose of 0.3 mg per kg resulted in grade three cytokine release syndrome. For those of you unfamiliar with the specific grading criteria, that's not just hypotension, hypoxia, neurologic. I believe at least one of the patients had neurological symptoms. Vasopressor support is often seen in the grade three setting. This was severe life-threatening CRS, which was a categorical showstopper. You cannot go above that. Even with maximal therapy, it is very hard to take a drug with that assortment of different toxicities. In contrast, none of our patients were prophylaxed with any medications at all. That was a protocol requirement because we wanted to see how our drug behaved. The worst grade toxicity we saw was a grade two. Most of the patients had a grade one. No patient required rescue with tocilizumab. No patient had to stop our study due to a low-grade CRS. The CRS that we saw in the handful of patients was really more or less a first cycle phenomenon. Let me just pause there. I do not know, Dr. Sen, if you have had a few patients experience some of that low-grade CRS. I don't know if you have anything to add in terms of your own personal experience with it. Yeah, I agree. I think, like I had sort of alluded to when I was speaking about it, in early days with this drug, we were sort of on the fence whether we even call it a CRS event or whether we call it an infusion-related reaction because it presented sort of similar to a delayed infusion-related reaction. I think we ended up calling it a low-grade CRS event after going back and looking at a cohort of patients who had this same phenomenon of elevated cytokines despite sort of normal tryptase levels, as well as the same sort of very delayed onset timing-wise of the symptoms that they had, the fevers, the chills. That is why we ended up calling it a CRS event. All again, we're grade one. Like Ron mentioned, no one hospitalized, no one needing tocilizumab. Most patients responsive to steroids. In subsequent infusions, since we did not pre-medicate patients upfront, we were able to, in those patients who had these sort of events, pre-medicate them with future infusions, and they tolerated it well. Yeah. I'll just add, as a drug developer, Dr. Sen treats patients. I used to. As a drug developer, I'm actually somewhat pleased to see some CRS. I'm very thankful that it's low-grade, that nothing bad happened to anybody. I mean, that goes without saying. To see sort of the classic class effect of this drug, otherwise, checkpoint inhibitors that are out there do not cause CRS. This one does. We know that. Ours did, but thankfully, very low-grade. I'll pause there. Hopefully, we've answered your question. No, that's great. If I could just jump in with one last one, I was just wondering, what is it about Merkel that seemed to work so well? Why not move forward with Merkel as a priority? Merkel cells is not the only tumor type that's responded, as you heard, MSI-H igh colorectal cancer as well. We have a host of other tumor types. It could very well be in five or six months from now, we'll be talking about other responders that aren't Merkel cells or MSI-H igh. For now, we have Merkel cells and an MSI-H igh. What's unique about those two? They're probably two of the most immunogenic or immune-responsive type tumors. The fact that when we add our agent to more PD-1 therapy, cemiplimab, to me, that suggests that in these very sensitive tumor types that acquire resistance to PD-1, maybe one of the mechanisms of that acquired resistance is VISTA. When you target VISTA with an agent like ours, you overcome that, and you allow the PD-1 to reestablish a solid, meaningful anti-tumor effect. By no means do I think that our effect is limited to these rare tumor types. I mean, we have a smattering of other much more common tumor types that have tumor regression that are on our study for quite some time, well beyond what you'd expect with just cemiplimab. For now, the Merkel cells and the MSI-Highs have caught our attention. I agree with you. I think in a world of more resources, we would focus on Merkel cells for the reasons you're intimating. Thank you. Sure. Thanks for the questions, Frank. Our next question comes from Sudan Loganathan at Stifel. Please go ahead, Sudan. Thanks. Can you guys hear me well? Very well. Perfect. Awesome. Great. Hi, John, Ron, Dr. Sen, and the Sensei team. Congrats on the data. Again, thank you in advance for taking my questions. My first one, specifically on the four patients that experienced CRS at the grade one levels, when did this effect arise in the treatment regimen? Was it kind of early on? Was it pretty obvious, or did it take a few cycles or a few treatments before it was obvious? For the patients that were deemed progressive disease and had lack of benefit and had to discontinue, was it based on the number of scans, or how long did these patients stay on until that was kind of deemed? What was the threshold there to discontinue? Yeah, I can take that. In terms of the timing or dynamics of the CRS, Dr. Sen, feel free to add or subtract from anything I say here. I would say the general impression, actually, all the cases occurred in cycle one and with the first infusion, if I'm not mistaken. That is very classic for CRS. That is one of the defining features of CRS. It tends to be a cycle one, often just a cycle one phenomenon. Sometimes it lingers into cycle two. For the most part, it is a cycle one phenomenon. The other notable feature of what we saw, again, consistent with CRS, was the slightly later onset, as in several hours after towards the end of the infusion or even after the infusion, like several hours after completing the infusion. I think we had one patient up to four hours after completion of infusion. That's another typical finding with CRS. Whereas with an infusion reaction, what you tend to see is soon after starting the infusion or in the middle of the infusion. In terms of your second question, really, it's just a smattering. I mean, some patients progressed at week six, those that did not respond. Others stayed on for months, many cycles, and then eventually progressed. It's really sort of a mixed bag there. It's hard for me to I can't characterize one prevailing sort of pattern for you. It's a spectrum. I don't know, Dr. Sen, if you have anything to add on that. No, not much to add. I'll just echo that. Again, even in my hands, it was often very early on, like Ron said, always in the first cycle. Got it. If I can squeeze in one more specific for Dr. Sen, based on your knowledge of your colleagues and even with your own knowledge, are medical oncologists kind of familiar with managing CRS at this point? Even with grade two or grade three CRS that may occur, can this be managed clinically? Or kind of what's the threshold there and what physicians are willing to be able to manage for their patients? Yeah, great question. As you know, a bit of a loaded question. In this, you've got two sets of sorts of oncologists, right? You've got, I think, 10-15% of practice in an academic center, and then about 85-90% in the community practice. In the community, right, oncologists see everything, right? The same oncologist who treats patients with Merkel cell, MSI-High colon cancer, are also out there treating patients with leukemias and lymphomas versus in the academic setting where people really kind of hone in on one tumor type or an organ site, for instance. Bispecific antibodies, for instance, that's sort of the class of drugs that are already commercially available where we often see CRS-like pictures or even CRS events. I'll tell you that in the community, right, with oncologists who have had their hands at some of these bispecifics, whether it's for, again, some of the hemolignancies or now with small cell lung cancer, people are slowly getting more and more familiar with how to manage it. More importantly, they are building sort of kind of protocols in place with hospital systems to manage these patients if they need to get admitted and receive whatever level of care they need and ensure drugs like tocilizumab are on hand. In the academic setting, contrasting to that, whereas the oncologists themselves may not be as familiar with it, right, unless they're treating those sorts of tumor types, the advantages, at least the hospital systems, are. They have got colleagues that they can turn to who use these drugs to help them learn how to manage it. I think as a field, folks are getting more to answer your question, it's a field that people are getting more and more familiar and comfortable managing these sorts of CRS and CRS-like events. If I could just add one word, one comment. I don't think oncologists like unpredictability. What they're looking for is if a drug does have a side effect, and in our case, it's a mild one, very modest severity. It's nice to know that when it does happen, it's likely going to happen, at least in the patients to date, at the very beginning. What we don't like to see are sort of idiosyncratic or toxicities that sort of have a life of their own and appear at some unpredictable point. That's one of the comforting features of this, at least in my opinion. Got it. No, I appreciate all the answers. Thank you so much. Thanks for the question, Sudan. Our next question comes from Ed White at H.C. Wainwright. Please go ahead, Ed. Ed, you might be on mute. Can you hear me now? Yes, we can. Loud and clear. Okay, great. Thanks. Thanks for taking my questions. The safety data looks good, as we've all mentioned this evening. How are you thinking about Project Optimus and what the FDA is going to require you to do? Do you think you're going to have to start pushing the doses a little bit higher just to fulfill that part of Project Optimus? I can take that. I think when I think about Project Optimus, first of all, that requires a discussion with FDA. I don't know that I'm worried or concerned that FDA would say, "No, 15 mg per kg isn't high enough. Go higher." I mean, with monoclonal antibodies, unlike small molecules and certainly cytotoxics, most of them do not dose to a maximal tolerated dose. Most of them dose to some predetermined maximal dose based on preclinical data, which is what we have done. Certainly, we have seen activity both at 3 and 15 mg per kg. Can I categorically tell you that a dose of 30 mg per kg will not show more activity? I cannot. I just do not think that it is worth pushing it that high, given our preclinical data that suggests that 15 mg per kg is well above where we need to be to see maximal activity. In terms of Project Optimus, usually when FDA, at least in my experience, when FDA has something to say in regards to Project Optimus, it is, "Okay, that is your high dose. Now tell us more about some lower, maybe less toxic dose. Is that every bit as efficacious and less toxic?" I think that's the key feedback that companies, sponsors often receive. In that regard, I'm not sure that they have much to react to here because I can't honestly tell you that there's a safety difference between 15 and 3. I look forward to that discussion with FDA to find out just how much more work we need to do because, as you heard, we've alternated 3 and 15 mg per kg. By the way, over the next few months, we'll follow all our patients and have a more robust data set at both 3 and 15 mg per kg. Maybe that'll be enough. Maybe FDA will ask for a third arm in that randomized study where we study 3, 15 in combination with Libtayo. We'll see. I don't know if I've answered your question, but that's the way I look at it. No, you did. You did. Thank you. Okay. Just with another question, you said full data by the end of the year. Are you planning on taking another? I said a few months. I said a few months, yeah. Okay. I think it might have been in the slide. That's what I was going to ask. Are we going to see another interim look in the near term? John, I don't know. Would you like to comment on that? It's possible. We haven't determined that. It really depends on the rate at which the data reads out. We're quite confident it'll read out before the end of the year. Okay. Thanks. Just the last question from me. What is your strategy going to be to lock into a lead indication? Obviously, you have more data to come, hopefully, in other indications with the next data set or at least by the end of the year. What is your strategy going to be? What's the most important thing that you're looking at to go after a certain indication for the phase II trial? John, do you want me to take that, or do you want to? Please go ahead, Ron. Yeah, sure. I think we're looking at at least one or two indications right off the bat. There are smaller indications. I wouldn't call them the lead indication, although they could get to the market sooner. Those would be Merkel cell and MSI-High colon. That's where we've seen the most profound and long-lasting anti-tumor effects. I think on the commercial side, and here I'll refer to that as the lead indication, I think checkpoint inhibitors, when they work in a particular setting, it tends to be sort of a broad effect. Just like you've seen with pembrolizumab, nivolumab, Libtayo, these types of agents in the IO space, they have remarkably consistent effects across basically identical indications: lung cancer, head and neck, melanoma, renal cell carcinoma. You've just seen our data across a heterogeneous group of different tumor types. Our underlying premise is that if we see activity in hot tumors, that that extends broadly to hot tumors. I have no concrete scientific reason to pick one hot tumor over another purely based on mechanism or probability of success. Therefore, my approach is, or my approach would be, unless I hear differently from experts like Dr. Sen and his colleagues, my approach would be, "Okay, it seems to work in hot tumors. Let's pick a hot tumor that's commercially at the beginning as a lead. Let's pick a hot tumor that's both commercially very attractive and easy to enroll with a more favorable regulatory space." That is not to say that we would not go more broadly. No, we would. Your question was lead indication. One lead indication, for instance, could be non-small cell lung cancer, or it could be head and neck cancer. We need to think, we need to evaluate that very carefully over the next few months as we see more data read out. Okay. Great. Thanks for taking my questions. Sure. Good questions. Thank you for the questions, Ed. This concludes today's Q&A session. I'll now turn the call back over to Mike for closing remarks. Thanks, Tara. That concludes the webcast for today. I would like to thank everyone for joining us today. Thanks, Dr. Sen, for spending the time with us tonight. Yes, that's it for today. Thanks and have a great evening.