Good afternoon, and welcome to the Xilio Therapeutics Virtual Program Spotlight. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentations. If you would like to ask a question, you may do so at any time throughout today's program by using the Q&A function below the webcast player. As a reminder, this program is being recorded and a replay will be made available on the Xilio Therapeutics website following the conclusion of today's event. At this time, I would now like to turn the call over to your host, Stacey Davis, Chief Business Officer at Xilio. Thank you. Good day, everyone. Welcome to the Xilio Therapeutics Virtual Spotlight event, focused on XTX-101, a novel Fc- enhanced tumor-activated anti-CTLA-4. Thank you for joining us today. This is Stacey Davis. I'm our Chief Business Officer, and I'll be moderating today's call. Before we get started, I'd like to remind everyone that the statements we make on this conference call will include forward-looking statements. Actual events or results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in the Risk Factors section of SEC filings. In addition, any forward-looking statements made on this call represents our views only as of today, and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statements. Today's agenda. In today's program, we will be covering 4 main areas of discussion. First, a deep dive into the CTLA-4 blockade biology and the opportunity associated with Treg depletion. Second, Xilio's XTX-101 molecule, which is a novel Fc- enhanced tumor-activated anti-CTLA-4. Third, monotherapy data for XTX-101 from the ongoing phase 1 clinical trial and an associated patient case. Lastly, our development plans for XTX-101 in combination with an anti-PD-L1 in advanced microsatellite stable colorectal cancer, commonly referred to as MSS-CRC. After the formal presentation, there will also be a Q&A session. During the presentation, you are invited to submit questions via the chat function to be addressed during the Q&A. Today on our call, we are joined by Dr. Diwakar Davar, who is Associate Professor of Medicine and Clinical Director, Melanoma and Skin Cancer Program, UPMC Hillman Cancer Center. He specializes in the management of advanced melanoma and the development of early phase studies to test novel immunotherapy approaches to treat advanced cancers. Dr. Davar is also an investigator in the ongoing phase I clinical trial of XTX-101. From the Xilio leadership team, we are joined by René Russo, the Chief Executive Officer, Uli Bialucha, our Chief Scientific Officer, Katarina Luptakova, our SVP of Medical, and Martin Huber, President and Head of our Research and Development. I'd now like to turn it over to René Russo to kick off today's discussion. Thank you, Stacey. Good day, everyone, and thank you for joining our call today. It's clear that advancements in the field of immuno-oncology or IO, have had a truly transformational impact for certain patients with advanced cancers. However, the treatment potential for many exciting IO targets have been limited by systemic immune-related toxicity for patients. At Xilio, we are seeking to change this paradigm by developing medicines that utilize the tumor's own dysregulated biology against itself to trick tumors into activating their own treatments locally within the tumor, while simultaneously sparing healthy tissues and cells from unintended side effects. We call this approach tumor selective activation. Our tumor-activated molecules are designed to make cancer therapies more effective by concentrating and focusing their power exactly where you want it, inside the tumor microenvironment, and at the same time, making them better tolerated by now allowing the active cancer medicine to distribute all over the body and attack, and attack healthy cells. The way we go about this, this goal of geographic precision is through our proprietary technology that we call GPS or Geographically Precise Solutions. We use this novel approach to build tumor-activated molecules, including monoclonal antibodies, cytokines, and multifunctional biologics that are designed to localize the anti-tumor activity within that tumor microenvironment and optimize the therapeutic index for patients. You can see here on the right a few of our key design components of some of our molecules that make this possible. First, we start with highly potent IO molecules, and in some cases further boost their potency through engineering. Second, we put these molecules under very tight regulation through a protein-engineered blocking domain or masking domain, seen here in orange, and that is to shut down the activity of the molecule and bring it under tight control while the molecule is circulating outside of the tumor. Third, we design the equivalent of a switch, called a protease cleavage site, seen here in green. That switch or site is what releases the blocking domain and turns on the molecule's activity, but only once it's inside the tumor microenvironment. Using our GPS technology, we are currently advancing multiple tumor-activated IO treatments in clinical development, as well as programs in preclinical development. The focus of today's discussion is XTX-101, our clinical stage anti-CTLA-4, which is a high-affinity, Fc- enhanced tumor-activated molecule.... XTX-101 has completed the phase I monotherapy dose escalation, we have selected a recommended phase II dose. Today, we'll be reviewing encouraging initial data from this study, including anti-tumor activity and safety data. Earlier this week, we also announced that we've ventured into a clinical collaboration with Roche to study XTX-101 in combination with atezolizumab in patients with metastatic microsatellite stable colorectal cancer, or MSS-CRC, including patients with metastatic disease to the liver. MSS-CRC represents a population with limited treatment options and no approved IO therapies available for patients with MSS-CRC today. Our second clinical stage program, XTX-202, is a tumor-activated beta-gamma engineered IL-2 molecule. Earlier this year, we opened the XTX-202 phase II monotherapy trial in patients with advanced renal cell carcinoma and advanced melanoma at an initial phase II dose of 1.4 milligrams per kilogram. In parallel, we continue to explore higher doses in a phase 1A dose escalation, where we're currently dosing patients at 4.0 mg per kilogram. In early November, we plan to share initial clinical data for XTX-202, including safety, PK/PD, and anti-tumor activity data. Our third clinical stage program is XTX-301. This is a tumor-activated IL-12. We initiated a Phase 1 dose escalation in the second quarter of this year, and we anticipate sharing preliminary safety data for this program in the fourth quarter of this year. Finally, I'd like to take a minute to mention our preclinical program, which is a multifunctional tumor-activated PD-1 IL-2 molecule. Our goal with this molecule is to deliver a synergistic combination of a full-dose PD-1 and a full-dose IL-2, directly targeted to the right immune cells within the tumor microenvironment. A key feature of our approach is that the IL-2 component is designed to remain inactive until it is unmasked locally in the tumor microenvironment using our tumor activation technology. Earlier this year, we presented exciting preclinical data from this program at AACR, demonstrating the potential of tumor-activated synergistic effects, specifically enhancing tumor-reactive antigen-specific T cells. Furthermore, we presented preclinical data showing minimal peripheral activity and superior exposure compared to unmasked multifunctional molecules. We see great potential for leveraging our platform and capabilities to enable more multifunctional molecules of this nature, and we look forward to sharing more about this specific program in the future. Now, let me turn it over to Dr. Davar. Next slide. CTLA-4 is a very exciting target in cancer and cancer immunotherapy. CTLA-4, you know, which stands for cytotoxic T-lymphocyte-associated protein four, also known as the CD152 protein receptor, essentially is the negative counterregulatory counterpart of CD28. CTLA-4 was actually first identified in 1991 by the labs of Tak Mak and Arlene Sharpe, who published their data independently. What they identified was that this was a key receptor that formed part of the immunoglobulin receptor superfamily, and it was actually the second receptor for the T-cell costimulatory ligand B7. Essentially, what we now know about CTLA-4 is that CTLA-4, along with CD28, represent a unique spectrum by which the immune system is able to tune immune responses following T-cell recognition. It's constitutively expressed by Tregs, but also very importantly, it can be upregulated by other T-cell subsets, particularly CD4 T helper cells, upon activation, which is particularly critical in the context of cancer. The way it works is that it competes with CD28 for binding to CD80 and 86, the aforementioned ligands. Given its greater binding affinity for the ligands, CTLA-4 effectively diminishes signaling and mediates immune suppression. Now, CTLA-4 may also mediate immune suppression through other means, including the removal of CD80, CD86 on APCs via transendocytosis and other mechanisms, and it's important to clarify that the mechanisms by which it elucidates and mediates immune suppression are not completely elucidated at this point in time. Now, very importantly, CTLA-4 blockade preclinically, is being shown to be associated with anti-tumor immunity, with the development of immunological memory. The development of these agents is essentially what led to the Nobel Prize being awarded to Jim Allison. Next slide, please. Now, in the context of cancer immunotherapy, the promise of this blockade was really heralded by the use of monoclonal antibodies. Again, as mentioned by Jim Allison, that demonstrated that effective blockade preclinically resulted in anti-tumor activity as well as immunological memory. The first advances in the context of cancer happened more than a decade ago when the CTLA-4 blocking antibody, ipilimumab, known then as MDX-010 and Medarex 010, was developed by Medarex, and it produced durable responses in a small fraction of extensively pretreated melanoma patients. This was demonstrated both as a single agent and also in combination with peptide vaccines in pivotal NCI trials. I show you an example of such a responder highlighted in a paper by almost a decade ago in 2014 by Steven A. Rosenberg's group. What you can see is, you know, what we now know to be the hallmark of cancer immunotherapy, which is you see a effect upon both regression of lung lesions, multiple lung lesions, and very interestingly enough, even though this was not demonstrated until relatively recently, a regression of an untreated brain met in panel E and F. This led to subsequent dose-finding trials that confirmed that multiple doses were effective, particularly doses three and 10 milligrams per kilogram, and identified two schedules that were taken into subsequent clinical trials. This 022 trial demonstrated single-agent response rates of about 4%-10% and also an iRAE rate of about 5%-18%. Very interestingly enough, the promise of CTLA-4 blockade heralded some very important principles of cancer immunotherapy that include the fact that unlike with checkpoint inhibitor, PD-1 checkpoint inhibitor therapy, the schedule and the dose actually does matter. This is a drug, this is a checkpoint, and this is a drug for which there is dose-dependent efficacy, and there's also different schedules that potentially may be efficacious, and that's why identifying dose and schedule is very, very important with CTLA-4 blockade. Next slide, please. The early developments of CTLA-4 and single-agent responses that were seen in the previously mentioned 022 trials led to two pivotal Phase 3 trials. The first was essentially a Phase 3 trial of ipilimumab plus minus gp100 vaccine in pretreated melanoma patients. This was conducted by Steve Hodi and his colleagues, and published more than a decade ago in 2011. In this pivotal paper, essentially what Dr. Hodi and his colleagues showed was that the response rate in heavily pretreated melanoma patients was 11%. Most importantly, even though the responses were 11%, up to a quarter of patients, a fifth to a quarter of patients, 22% of patients who were treated with ipilimumab were alive more than two years later. Firstly, not everybody who had a radiographic shrinkage counted towards the benefit, indicating that there was a proportion of patients who did not have cancer regression, at least cancer regression as, as we knew it in 2011, but who also had evidence of benefit because they did not pass away. This subsequently led to a Phase 3 trial in PD-1 and CTLA-4 and previously un- treatment-naive melanoma patients, what is known as the O 2 4 study. In that O 2 4 study, ipilimumab at 10 milligrams per kilogram was studied in combination with dacarbazine and demonstrated a response rate of about 20%, with about 47% of patients with the combination being alive and well at approximately two years. In this pivotal phase 3 trials, what we learned was that, one, both IP-3 and IP-10 are active. Both IP-three and IP-10 produce responses. Despite differences in schedules and differences in doses, we see a durable tail to the curve. This is what led to both the FDA approval for ipilimumab in advanced melanoma, but also some key principles that have guided immunotherapy drug development over the last decade. Being notably being that not all radiographic responses result in cancer shrinkage, but there are proportion of patients who benefit who do not have radiographic responses. Two, that at least in the context of CTLA-4 development, drug and dose and schedule do matter. Next slide, please. What we have learned since then are some important preclinical aspects of the biology of CTLA-4 that were not known when the drug went into clinic. The reason for that is probably to do with some unique human-specific factors that were not identified in the preclinical models. That starts with, it has always been thought that, given the expression of CTLA-4 on Tregs constitutively, that Treg depletion is very important for the efficacy of the drug, and therefore, Fc mediated Treg depletion, that is ADCC via an Fc IgG1 backbone, is critical to the function of CTLA-4 antibodies, and this was known preclinically. What we then realized was that there may be, in addition to Treg depletion, an additional role for the Fc, Fc gamma interaction in terms of improving APC function via receptor clustering. This data came out of several pivotal papers, including by the Agenus group in a Cancer Cell paper in 2018, but also in another paper in that same edition of Cancer Cell by Sergio Quezada, who's actually Jim Allison's postdoc, demonstrating that Fc, Fc-gamma interactions were very important to the efficacy of ipilimumab or Fc active CTLA-4s. Now, very interestingly, in the same paper, Dr. Quezada and colleagues demonstrated that the clinical efficacy of ipilimumab was associated with particular single nucleotide polymorphisms on CD16, that is Fc-gamma high affinity, that were known to have higher binding affinity and increased ADCC, and this is a high-affinity polymorphism. Now, all of that led to the development of a Fc-enhanced CTLA-4 molecules, such as the Agenus 1181 molecule, known as 1181 or botensilimab, that specifically binds to not just high, but also low affinity Fc-gamma and demonstrates clinical activity in cold tumors. As you can see here, what we know about the Agenus 1181 data is that there is this, you know, rather remarkable signal of efficacy in Microsatellite stable colorectal cancer, but very interestingly, complete absence of any efficacy in liver metastases, an important, biological factor that is of significant importance to patients. Now, as it turns out, the deep durable responses seen come at a cost, and that cost is side effects. The Agenus data, while exciting, has to be taken, has to be taken in light of the fact that the drug is associated with a very significant incidence of at least 30% Grade 2 or greater immune-related adverse events, particularly colonic inflammation, that sometimes can result in therapeutic cessation of the drug because of the need of how severe the side effect is. Overall, what we have now come with CTLA-4 is we've, you know, basically, completed the immunotherapy revolution. We started with it. This was the drug that actually kickstarted the IO revolution with the deep durable responses that were seen in a very, very select subset of melanoma patients. Now, with improved understanding of how the biology works in humans, we have ways in which we can potentially improve upon the efficacy of the drug as well as the toxicity of the drug through some novel mechanisms. Potentially, the tumor microenvironment selective activation of this agent would be very exciting because it could potentially overcome some of the aforementioned limitations of other Fc-enhanced CTLA-4 agents. Thank you, and I'll turn it over to our hosts. Thank you, Dr. Davar. That's a great segue for us into moving to discuss the design of XTX-101. If we can go to the next slide. What we're looking at here is a structural representation of our antibody molecule, XTX-101. On the left-hand side, we are showing the molecule in its inactive masked state, and on the right-hand side is the active unmasked state. I'll note up front, the antibody that we're using here is a novel CTLA-4 antibody. It is not ipilimumab. We selected this antibody specifically for high affinity, and it is a CTLA-4 blocking antibody. When activated, XTX-101 has about tenfold higher affinity for CTLA-4 compared to ipilimumab. Now, once we selected the unmasked antibody as our lead, we next use our platform to discover a unique and customized mask highlighted here in orange. This peptide mask blocks the antigen binding region of the molecule and prevents it from interacting with its target, CTLA-4. We then use a combination of computational as well as structural biology approaches to optimize how we connect that mask to the rest of the antibody and incorporated a cleavage element here shown in green. This cleavage element is what tumor-associated proteases act upon for activation of the molecule. Now, the final feature that distinguishes this molecule from ipilimumab and other first-generation CTLA-4 antibodies is that we incorporated mutations in the Fc region of the antibody that enhance the affinity of the molecule for activating Fc-gamma receptors, thereby enabling the antibody to elicit enhanced antibody-dependent cell-mediated cytotoxicity, or ADCC. In the context of XTX-101, the enhanced ADCC drives potent T-reg depletion, as this cell type features elevated levels of CTLA-4 expression, particularly in the tumor microenvironment. I'll note that the work that has gone into optimizing the cleavage site for XTX-101 was quite extensive. That's probably where we leveraged most of our unique expertise. What we wanted to do is dial in the right selectivity for tumor-associated proteases. Also the right degree of specificity and efficiency of cleavage. We designed the molecule to be at steady state, about 90% masked and around 10% activated. We did that with CTLA-4 biology in mind, with the understanding that we want some activity in tumor-draining lymph nodes, as well as peripheral lymph nodes, to facilitate efficient T cell priming. Now, on the right-hand side, you'll see the active state of the molecule. The masks have been released following proteolytic cleavage of the linker. The antibody is now able to do two things. It will bind CTLA-4 with high affinity, it will block the checkpoint. The antibody will drive potent ADCC against Tregs, which express CTLA-4 at high levels in the tumor microenvironment. To sum this up, the masking approach is designed to minimize activity of XTX-101 outside of the tumor microenvironment and improve tolerability. Once activated by tumor-associated proteases, the two mechanisms of action, potent blockade of CTLA-4 and Treg depletion, combine to enable antitumor activity. I would like to show you some preclinical data for XTX-101. On the left-hand panel here in the upper graph, we are focusing on antitumor activity with XTX-101, we are comparing that to activity with ipilimumab in the lower graph. In response to a single dose of XTX-101 at the low dose level of 0.3 milligrams per kilogram, we saw robust antitumor activity, including complete regressions in a subset of the animals. We also saw activity with ipilimumab in this model. At least 3 milligrams per kilogram, a 10-fold higher dose of ipilimumab were needed to drive a similar level of activity to that of XTX-101. This is a key preclinical demonstration of the 10x improvement in potency with XTX-101. In the middle panel, we're focusing on the mechanism of action and what is happening in the tumor. Specifically, we're looking at tumor-infiltrating immune cell changes in response to treatment. The top panel here shows CD8 cells, and you can see that XTX-101 at this time point was very effective in inducing an influx of CD8 positive T cells, which are known to be key mediators of antitumor immunity. In the bottom middle panel, we see that XTX-101 treatment resulted in a decrease of immune suppressive regulatory T cells, or Tregs, consistent with the ADCC enhancement built into XTX-101. We also see that ipilimumab, in contrast, did not deplete Tregs. It's important actually to take the two together, the increase in CD8s and the depletion in Tregs. This essentially results in a robust increase in CD8 to Treg ratio, and is exactly the pharmacology you would want to see with XTX-101. Now on the right-hand side here, we actually had an opportunity to make a replica of the Agenus molecule, Agenus 1181, and we profiled XTX-101 against Agenus 1181, as well as ipilimumab, and ran ADCC assay, as shown in the top right graph. As expected, ipilimumab did not signal in the ADCC assay, whereas the Agenus molecule did show robust ADCC, as an Fc-enhanced molecule would be expected to. Importantly, XTX-101 matched the level of activity of the Agenus molecule in this assay when activated. However, what we have seen from Agenus 1181, and as noted by Dr. Davar, in the clinic, there is a toxicity profile that is consistent with what we would be expected from a systemic. The classical T cell activation assay. Here, both the Agenus molecule and unmasked XTX-101 compared favorably relative to ipilimumab, which demonstrates the robust checkpoint blocking function of XTX-101 in this model system once activated. I'll now turn it over to Katarina Luptakova to walk you through the clinical data from our phase 1 clinical trial of XTX-101. Thank you, Uli. The phase I trial is a multicenter, open label study designed to evaluate the safety and tolerability of XTX-101 as monotherapy in patients with advanced solid tumors, and to determine the recommended dose and schedule of XTX-101 for phase II. Part 1A was the monotherapy dose escalation that is now completed, with patients ongoing and in follow-up. Part 1B is the monotherapy dose expansion, designed to collect three and on treatment tumor samples in order to assess the pharmacodynamic profile of XTX-101. Part 1B is ongoing at the recommended phase II dose of 150 mg every six weeks. To date, 29 patients have been enrolled and treated in the XTX-101 study across parts 1A and 1B. Note, we are including 27 patients in this data update, as two patients are still too early to include for safety data at the time of August 3rd data cutoffs. The patient population reflects a typical first in human oncology population, with a median age of 67, and a heavily pretreated population with a range of up to 12 prior lines of therapy and a median on four prior lines. In fact, for most patients enrolled in the study, the choice has been between seeking end-of-life care in hospice or enrollment in a clinical study. Almost half of the patients previously received immunotherapy, and the remaining patients typically have tumor types that would not be considered for IO treatment as per standard of care. The tumor types treated in the study include a range of various histology, as expected for an oncology phase one study. Of note, in the most recent six months, our investigators increasingly started enrolling patients with colorectal cancer. In terms of patient disposition, the predominant reason for treatment discontinuation was progression of the underlying disease, including consent withdrawals as patients moved to hospice and investigator decisions where a patient exhibited clinical progression. Only four patients discontinued treatment due to a treatment-related adverse event, and in all four cases, this was related to an infusion reaction, which importantly, all occurred on a once every three week dosing schedule. On the next slide, we are looking at an overview of our dose escalation schema using an accelerated study design, transitioning to a standard 3+3 dose escalation, evaluating ascending doses of XTX-101 with threefold dose escalation between each dose level. We use flat dosing because this molecule is expected to have antibody-like volume of distribution and bodyweight dosing is not necessary. I'd like to remind you there is some accumulation of the activated molecule, which was intentional in the design process, as Uli mentioned earlier. Knowing this, we expected to see a certain amount of systemic activity and at higher doses, toxicity. For this reason, we designed the study to push the dose levels in order to understand the maximum tolerated dose. The second point I would like to point out is that we took into account our target dose. Based on the preclinical data, 60 milligrams every three weeks was intended to give us the exposure at the tumor that was on par with ipilimumab at 10 milligrams per kilogram. Those were the two key anchor points in the study design. One dose limiting toxicity of colitis was reported at 60 milligrams. This event was confounded by preexisting GI condition, with the patient experiencing diarrhea at baseline before treatment. At a threefold higher dose of 180 milligrams once every three weeks, 2 DLTs of grade three colitis were noted. At this point, we sought to optimize the dose and schedule to preserve the higher Cmax seen with the 180 milligram dose, while matching the AUC exposure of the 60 milligrams once every three week target dose. With this in mind, we evaluated dosing XTX-101 at 150 milligrams once every six weeks, where no DLTs were reported among five patients treated in the dose escalation portion of the study. As you will see in more details in the next slide, we did not observe infusion reactions nor colitis in the patients treated at 150 milligrams once every six weeks. We are now reviewing the summary of related adverse events in 27 patients treated in either Part 1 A or Part One B. First, it's very important to note that we have not observed any Grade four or five treatment-related adverse events at any dose. At the once every three week dosing, GI immune-related adverse events occurred in approximately one third of patients, with four patients having Grade three diarrhea or colitis. Of note, these Grade three adverse events were driven primarily by the highest dose of 180 milligrams once every three weeks, which was well beyond our target dose of 60 milligrams once every three weeks. In contrast, in patients treated at the RP2D of 150 milligrams once every six weeks, only 1 related Grade three GI event was observed, which was diarrhea occurring after the second dose. 0ne case of Grade three dermatitis, which rapidly resolved with steroids, was also observed at the RP2D. The remaining safety profile for patients treated with the once every three-week schedule was unremarkable, with the exception of the Grade three infusion reactions, which all occurred during either the 2nd or 3rd infusion. Importantly, no infusion reactions of any grade have been reported to date in the once every six-week schedule. Finally, the infusion reactions did result in the four treatment discontinuation at the once every three-week schedule. However, no discontinuation due to treatment-related adverse events have been observed at the RP2D at this time. Data on the best overall response are presented here as the% change in the sum of diameters in the target lesions from baseline. This waterfall plot is showing the evaluable patients who had at least one post-baseline scan as of the data cut-off. Three patients had a reduction in the sum of their tumor measurements. One patient with squamous cell carcinoma of the skin had a stable disease with a maximum reduction of 5%. A second non-small cell lung cancer patient had a reduction of 7%, and one patient had a confirmed partial response with a reduction of 52%, and this patient was continuing on treatment at the time of data cut-off. This spider plot displays the change in measurements over time to evaluate the duration of effect. The blue line shows the tumor measurement for the patient I mentioned with squamous cell carcinoma of the skin, who was treated at 60 mg once every three week dose and maintained stable disease for 24 weeks. The lowest black line shows a slight tumor reduction for the patient with non-small cell lung cancer. This patient received XTX-101 at the 180 milligram once every three-week dose and had to discontinue treatment due to an infusion reaction during the third dose. Last, but certainly not least, the orange line at the bottom is the non-small cell lung cancer patient who was treated at 150 milligrams once every six weeks and achieved a confirmed partial response. At this point, I would like to turn it over to Marty to share more of the details related to this patient. Thank you, Katarina. I'm pleased to share more information on this patient, which represents our best observed response to date. Here we have a 66-year-old female patient with metastatic non-small cell lung cancer as the primary lesion, and as you can see, metastasis to the liver. The patient's molecular profiling was unremarkable. In addition, there was no PD-L1 staining in the tumor. She had previously been treated with chemotherapy, which resulted in a response, which then progressed after approximately four months. She was then enrolled in the XTX-101 phase I dose escalation at dose level five, which is 150 milligrams every 6 weeks. To date, she has received seven doses of XTX-101 at the recommended phase II dose, and a response was last assessed at the 36-week time point. The only treatment-related adverse events on XTX-101 have been Grade one fatigue. The patient developed clear evidence of antitumor activity at week nine in both the lung and liver lesions. Here you can see the CT images of the chest at two different levels, capturing the lung tumor. In the upper row, this captures the upper portion of the lesion, and as you can see, we are going across the chest approximately at the level where the trachea splits into two main bronchi. Going from left to right, you see a decrease in the tumor size from baseline through weeks nine and 18. In the lower cut, which represents the main portion of the tumor, which is measured for RECIST response assessments, you can also appreciate that the tumor becomes smaller at week nine and 18. Most importantly, you notice at week 9, significant cavitation, likely indicating necrosis in the center of the tumor. This is not reflected in standard tumor measurements by RECIST. These lesions continue to decrease through both week 27 and week 36 scans, and this resulted in a confirmed partial response. If we look at the next slide, however, this is where we really got excited. This is the liver lesions for the patient. As mentioned previously, liver metastases are not very responsive to IO treatment. This patient was noticed to have multiple liver lesions, as highlighted by the orange circles here. One of them, the largest one on the, on the posterior lobe of the liver, was 23 mm at baseline, and that's that large circle lesion on the lower image. The others are smaller, and then there were multiple lesions under 10 mm, which are non-target lesions. Notably, both the target lesion and all non-target lesions were described as absent in the follow-up scans at week nine and week 18. The lesions have disappeared. As of week 27 and week 36 scans, the hepatic lesions have not returned, so we've seen a complete reduction of the hepatic metastasis, which to us was a very striking in a setting of monotherapy with an anti-CTLA-4 in a PD-L1 negative lung cancer patient. The next question, is this being driven by tumor-specific activity or by systemic activity? This patient's case is supporting that XTX-101 masking has been effective. There was a lack of peripheral activity, as evidenced by the pharmacodynamic data. There were minimal changes in the peripheral CD8, CD4, and Tregs on treatment. At the same time, the clinical data support that there's tumor-specific activation, as evidenced by the clear tumor response in this patient. These figures show the PD data from the peripheral blood in this patient that was concordant with the partial response. The best way to look at this is fold change. If you had a systemically active anti-CTLA-4 present, you would expect to see at least two to three-fold changes in several of these markers. For example, you would expect CD8 T cell counts, as well as the subset of proliferating CD8 T cells, as measured by Ki-67, to increase more than twofold. As you can see here, pretreatment is shown in black, which is baseline, on treatment shown in orange at Cycle four, Day seven. In all of the values assessed, there is a less than two-fold change throughout, with minimal changes observed in any of the markers. This is consistent with the observation that we also were not seeing any immune-related adverse events in the periphery in this patient. I'd now like to change gears and talk about more where we're headed with XTX-101. In the United States, colorectal cancer ranks second as a cause of cancer-related mortality, and strikingly, is the leading cause of cancer-related death in men under the age of 50. More than 150,000 patients are diagnosed annually, and unfortunately, approximately 60% of these are not candidates for surgical resection due to the presence of metastatic disease. Chemotherapy and radiotherapy are used, but primarily as palliation in the metastatic setting. Recent advances in IO treatment with anti-PD-1 have shown great promise, but that is limited to the less than 5% of patients whose metastatic colorectal cancer is MSI-high, which is primarily associated with Lynch syndrome. Over 95% of the patients with metastatic colorectal cancer are classified as having microsatellite stable disease or MSS CRC. This is a clear example of a cold tumor, characterized by weak immunogenicity and limited immune cells. Unfortunately, previous efforts to bring checkpoint inhibitors to these patients have shown little to no efficacy, with previous studies yielding a 0-5% objective response rate. Based on these data, we estimate that there are approximately 85,000 patients in the U.S. alone with stage four metastatic MSS-CRC, who are currently not candidates for approved IO agents. In recent studies showing responses in patients with metastatic MSS-CRC with Fc- enhanced CTLA-4, as outlined earlier in this presentation, combined with a PD-1 treatment, the population with a clear benefit has been restricted to patients without hepatic metastasis, which is the most common site of metastatic disease in these patients. Therefore, approximately 60,000 patients in the U.S. who have MSS CRC and presence of liver metastasis are currently not candidates for IO treatment, even with the investigational Fc-enhanced anti-CTLA-4 agents. As Renee mentioned at the top of the call, our next step with XTX-101, will be to study it in combination with atezolizumab in patients with MSS CRC. Our approach is to determine the potential for XTX-101 plus atezolizumab in these patients without any current IO options. We'll start with the dose escalation cohort, shown here as Part 1C. To expedite study initiation, the Part 1C was added as an amendment to the ongoing phase 1 trial. In combination dose escalation, we will be allowing patients with a range of solid tumors to enable rapid dose escalation. As was noted earlier, we are seeing an enrichment for colorectal cancer patients already in the ongoing Phase 1, so we anticipate seeing a fair number of these patients in the study. Assuming that we have an acceptable toxicity profile for the combination at the initial dose, we'll explore XTX-101 at higher doses. Subject to the results of dose escalation, we plan to initiate a Phase 2 study of XTX-101 in combination with atezolizumab in patients with MSS-CRC. A key advantage of performing a proof of concept study in patients with MSS-CRC is that a randomized trial is not required to isolate the contribution of XTX-101. Given that this has an established response rate for anti-PD-Ls of less than 5%, an ORR of 20% or greater for the combination will be statistically significant and clinically meaningful in these patients, showing the contribution of XTX-101. Importantly, we intend to include patients both with and without hepatic metastasis. Based on the early antitumor activity observed in our patient with non-small cell lung cancer, our current goal is to activate this combination dose escalation by the fourth quarter of 2023. Let me recap what we have discussed. The totality of safety, efficacy, PK and PD data presented for XTX-101 supports continued development of this masked, tumor-activated, and Fc-enhanced anti-CTLA-4 molecule. With the completion of enrollment in phase 1 monotherapy dose escalation, the recommended Phase 2 dose has been established as 150 milligrams once every six weeks. At this dose and schedule, a favorable safety profile was observed, with only one incidence of reversible grade three diarrhea and one instance of reversible grade three dermatitis. Importantly, at the recommended Phase 2 dose of 150 mg every six weeks, we have not observed other immune-related adverse events typically associated with anti-CTLA-4 therapy. Further, with the once every six-week schedule, no infusion reactions were observed. At this dose level, a Cmax was reached that, adjusted for potency, would be twice as high as the Cmax of ipilimumab at 10 mg/kg. The antitumor activity observed in the patient with non-small cell lung cancer is notable for activity in both the primary lung lesion as well as in the liver metastasis. In summary, at 150 milligrams every SIX weeks, the clinical performance of XTX-101 to date is consistent with our target profile criteria, and what's really exciting for us as a company is that it also represents the first clinical validation of our platform, both in terms of safety and efficacy. Stacey? Thank you, Marty, for sharing that compelling overview of the patient case and the aspiration that we have to bring XTX-101 to patients with such great unmet need in MSS CRC. As a brief acknowledgement, we would like to thank the patients, families, caregivers, and investigators, and study site staff for the commitment to this trial, as well as to all of our Xilio employees. Now we're gonna turn it over to the Q&A portion of the program. Just a reminder to our audience, you can continue to submit your questions via the chat feature, and we will take those live now. The first question, Marty, is gonna be directed to you, to go a little bit deeper into the clinical trial design. Can you share some additional color on your plans for the XTX-101 combination study? How are you thinking about starting dose? Are you planning on starting the combination with the RP2D? Thank you, Stacey. As we move forward with the study, this is a novel combination, we are taking a fairly standard approach, is that you have to assume there may be some interaction from a toxicity point of view. We will start the initial dose level with a 50% reduction. We'll go to one-half of the recommended phase 2 dose that we saw with monotherapy. That'll be 75 milligrams every SIX weeks. Based on the safety data for the combination observed at the first dose level, we then plan to re-escalate to the higher dose. Importantly, even if we end up with the first dose level, being the recommended Phase 2 dose, we do anticipate this would be sufficient to move forward in a combination study, as the Cmax for XTX-101 at 75 milligrams is similar to the Cmax for ipilimumab at 10 milligrams per kilogram when adjusted for the 10x increase in potency. We think there's still the opportunity to have a highly potent tumor-selective anti-CTLA-4 combined with an anti-PD-L1. All right, Marty, we got a couple follow-up components here. One additional challenge for novel combinations is always establishing contribution of components. How are you thinking about understanding the role of XTX-101 in the combination with atezolizumab, and how will you get a meaningful answer, without a randomized phase two study? Yeah, I think that's really one of the strengths of looking at MSS colorectal. If we were looking at another tumor type, like lung cancer, where the anti-PD-1, anti-PD-L1, or anti-PD-1s would have monotherapy activity, you would have to think in terms of a randomized trial. In this setting, where the anti-PD-L1 has very limited activity of, less than 5%, the sample size necessary to just in a single arm, see that a 20% response rate or higher is meaningful, is roughly 40 or 50 patients. If you see that, it's clear that's the contribution of the 101, because you would not expect to see that with either agent in monotherapy. Great. There's one more portion of this from Marc Frahm at TD Cowen. What portion of patients in the phase 1C dose escalation study do you expect will actually be MSS CRC patients? It's hard to give a precise number, but I think if you look at what's happened in Part 1B, the majority of the last patients enrolled have all been MSS-CRC. We think there's interest in this population, especially in the patients with hepatic metastasis, who are not eligible for some of the other studies out there. While we can't give an exact number, we think there will be a clear enrichment. Great. In terms of, this is a question from Michael at Morgan Stanley. Given the response in the PD-L1 negative lung cancer patient... what are we thinking about as far as, lung as an opportunity? I'm gonna give a quick answer, and then I'm gonna turn it over to Uli to think talk a little bit broader, how we're looking at the wider tumor types. With regards to lung cancer, that is an area, obviously an area of interest for us. I think the challenge there is that we would need to probably look at more of a randomized trial, et cetera, to get the clear proof of concept. That is something that we would see as a opportunity during via a collaboration. Uli? Yeah. Thanks, Marty. I think the only piece I would add here is that with the tolerability profile that we're seeing, so far, and the fact that our molecule is Fc-enhanced to elicit those two mechanisms of action that I spoke about, the potent checkpoint blockade and Treg depletion. I think there's a clear expectation that Treg biology matters in other tumor types. You know, we've done some internal work to actually understand where those signatures are present, and I would say that there is ample opportunity. Non-small cell lung cancer, for sure, has been mentioned. We also believe that head and neck and some other indications could be of high interest for the molecule. Thanks, Uli, and I think we wanna build on this question a little bit more. Dr. Davar, given what you shared us, with us earlier about CTLA-4 blockade and the profile that we've talked about with 101, we obviously just touched on lung cancer, and we're, we're advancing in MSS CRC. What are other tumor types or indications that you think would be interesting or important to explore with XTX-101 in combination with PD-1 or PD-L1? Okay. Thank you for that question, Stacey. I think the obvious points that were discussed were obviously of patient populations wherein CTLA-4 already has got an established efficacy profile, but wherein the efficacy profile could be improved, right? For example, we know that PD-1 CTLA-4 is efficacious in melanoma, cutaneous melanoma. Again, you know, CTLA-4, single agent response rate of about 15%. The combination PD-1 CTLA-4 has an efficacy rate of about 55% in frontline metastatic melanoma. In the perioperative space, there's no established standard beyond PD-1 monotherapy, and even then, it's not FDA-approved, it's just on NCCN. If you have a very effective PD-1 CTLA-4 molecule, particularly where the CTLA-4 has got, you know, clearly efficacy and has reduced toxicity, certainly studying that in the perioperative setting in melanoma opens up a whole new vista of being able to move the drug earlier in the life cycle of the patient, wherein the patients are PD-1, certainly PD-1 naive, right? The other areas, beyond the data in which wherein PD-1 CTLA-4 is already FDA approved, non-small cell lung cancer, say, kidney cancer, you can very easily start seeing that in many of these settings, PD-1 CTLA-4 with a novel CTLA-4 that has got a greater efficacy bar, could certainly improve upon the efficacy of PD-1 in this space. It is important to keep in mind that in many of these diseases, you know, for example, certainly in renal cell carcinoma, it is certainly thought that the CTLA-4 efficacy was lower than expected. Why that might be the case, we don't quite know, but it's certainly possible that this is... these are diseases, melanoma, kidney cancer, microsatellite, high colorectal cancer, wherein it's gonna be very advantageous to try to stack. One of the very important things that I think Marty brought up is also the idea that you really want to be hitting patients who are PD-1 naive. Therefore, you know, the standard dogma of drug development, which is to go as late as possible and then move the drug forward, is really being upended right now, wherein you can really do these smaller niche, niche trials and studying the drug in a perioperative landscape to try to get a signal in a PD-1 naive patient population. And really, that potentially is very efficacious because there is no CTLA-4 inhibitor outside of melanoma, ipilimumab melanoma, that is approved in the adjuvant landscape. So if you did have a PD-1 CTLA-4 combination and you studied that in the perioperative setting, your control arm would be something that you do not have to compare. The standard of care could be easy to beat if there is provocative data for the combination. So I think, short answer is, lots of exciting data. The areas that I would be thinking would be very interesting would be areas where CTLA-4 is already in the frontline setting, but could be expanded in the perioperative setting, in the PD-1 naive setting, and that would be melanoma, non-small cell lung cancer, and certainly potentially tumors, tumor types like head and neck carcinoma, wherein there are certainly signals for PD-1, and the perioperative setting are very hot in all of these areas. Thank you. There's, there's one more thread to pull on here, Dr. Davar, which is, if you thought beyond combinations with PD-1 or PD-L1, are there other molecules or other MOAs that you think would be interesting or important to study with XTX-101? Yeah, absolutely. I think that, you know, firstly, checkpoint is, we're really, you know, at the, at the very early aspect, trying to unpack, unpack all of this potential combinations, right? Like, when you start thinking of what the biology of CTLA-4 is doing, really, you're priming, you're reducing Tregs, and you're priming. There are two sort of main areas that you think could be potentially efficacious. The first is to combine it with an agent wherein priming is important. For example, if you've got a CD3 bi, a CD3 bispecific, that's a T-cell bi-engager, that these are drugs from companies like Immunocore. The drug would be, say, tebentafusp, also known as Kimmtrak, which is the first CD3 bispecific that is FDA approved, in this case, for uveal melanoma. Now, the drug has got very minimal single-agent efficacy. It tends to be associated with improvement in overall survival and ctDNA reduction, and certainly better than the comparator, which is chemotherapy. The single agent efficacy of the drug certainly could be improved, it's modest, and this is an area where potentially a combination would be very exciting. The other class of drugs beyond the CD3 bispecifics, where you could potentially see some mechanisms of action that would be very interesting, would be to combine it with agents that are known to have synergistic effect upon Treg depletion. For example, looking at agents that are either administered in cold tumors such as uveal melanoma into the liver directly, or agents such as oncolytic viruses that are being used to prime cold tumors, such as intrahepatic administered RP3 from Replimune. These are all agents that wherein a priming agent CD that works on Treg depletion, but also CD4 priming, could be very important to augment the efficacy of these novel agents. I think that as classes, certainly CD3 bispecifics and also agents that are involved in oncolytic viruses and agents that are involved in APC priming, such as TLR agonists. Great. Thank you. The next question is gonna go in a slightly different direction, and this is going to be directed to Renee. If we take a step back and look at the long-term opportunity for XTX-101, how are you thinking about the collaboration with Roche, and how does this fit in with our overall partnering strategy? Thanks, Stacey. I think first off, we want to express how excited we are to have this collaboration with the Roche team. If you think about everything that's just been discussed here today, it's clear that the unmet need in MSS CRC is significant and that a combination of XTX-101 with atezolizumab really represents new potential for these patients that we feel is extremely important to explore, particularly in the subgroup with liver metastases. Beyond that, as we just heard from Dr. Davar, there are numerous additional tumor types and additional mechanisms and molecules that likely make sense to combine with XTX-101. What we think, you know, the best way to approach this, to be able to explore all of these different applications where XTX-101 may have an important role to play, will be through collaborations. We're very excited about this first collaboration with Roche, and we will be actively exploring, areas where additional, collaborative programs make sense for the molecule. Great. Thank you. I think we have time for just one more question, and we're gonna direct this one to Uli. Uli, there's a lot of activity and excitement about progress in the CTLA-4 space overall. Can you help us understand how you're thinking about XTX-101 in the terms of the competitive landscape versus other molecules that are in development? Yeah, I think great question. You know, I think if you go back to where the field started with ipilimumab, the two big things that we learned were, first, that increased dose demonstrated improved efficacy, but, you know, secondly, that the higher doses, such as 10 milligrams per kilogram, were not really tolerable. I think we've consistently seen that this dose-limiting toxicity that's associated with the, the first generation, that is, is still a limitation. I think as the field has advanced, there are molecules now in development that clearly aim to improve upon that, mostly on potency through, for instance, Fc enhancement. I think one example there would include molecules like Agenus molecule that we spoke about earlier, but with these types of unmasked molecules, they're still systemically active, so we would expect that toxicity could still be a challenge, particularly with molecules as they're getting studied in ever larger study cohorts. You know, on the, on the other side, more addressing the toxicity associated with those first-generation molecules, there are various approaches to conditional activation that are currently being explored. In some cases, people are trying to use conditional activation via a pH-sensitive switch, but at least from what we've seen to date there, you know, data on the molecules using that approach, they've not really achieved an optimal outcome. The other cases where we have molecules that are trying to use the protease-mediated switch, I think that is starting to look more promising. There are a few in development that use that approach. One of the examples, I think, is one of BMS's CTLA-4 molecules that currently remains in development using CytomX's technology. It was actually... It's interesting, it was announced earlier this year that BMS was discontinuing two of those three molecules that were part of this arrangement, which included a masked version of ipilimumab, which of course lacks the Tregs depleting MOA. They also discontinued the unmasked non-fucosylated version of ipilimumab, which we would think would face toxicity challenges as an unmasked molecule. The remaining molecule that's, that's moving forward, I think it's BMS-986288, which is advancing now into Phase 2, is a masked, non-fucosylated version of ipilimumab. So this molecule, in some regards, is really the closest in design to what we are doing with XTX-101, but we have to remember that it is still ipilimumab at the core, so we believe the potency of that molecule is not really fully optimized. Then maybe lastly, as we noted earlier, we designed XTX-101 to optimize both the potency and peripheral safety, including the design criteria for low-level activated drug in the, in the periphery, around 10%. With the optimized Cmax that we've been talking about, we've been able to achieve, through the Q 6-week dosing, what we believe to be in the XTX-101, really a molecule with best-in-class potential. All right, great. I think that's gonna wrap us up for Q&A today, and I'll turn it back to the operator to close this out. Thank you, everyone, for joining us today. As a reminder, the replay will be available on the Xilio website following the conclusion of the event. With that, you may go ahead and disconnect your line.