Welcome to the Immuneering fourth quarter and full year 2022 financial results and corporate update conference call. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will hold a Q&A session. To ensure that we have ample time to address everyone's questions during the Q&A session, we would ask for a limit of one question and one follow-up question per person. To ask a question at that time, please press star followed by one one on your touch tone phone. As a reminder, this call is being recorded today, Monday, March 6, 2023. I would now like to turn the conference over to Laurence Watts of Gilmartin Group. Please go ahead. Thank you, operator. Joining us on the call today from Immuneering are Chief Executive Officer, Ben Zeskind; Chief Scientific Officer, Brett Hall; Chief Medical Officer, Scott Barrett, and Vice President of Finance and Treasurer, Mallory Morales. During this conference call, management will make forward-looking statements, including statements relating to guidance and timing of data readouts for IMM-1-104 and IND submission of IMM-6-415. These forward-looking statements are based on the company's current expectations and inherently involve significant risks and uncertainties. Our actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties. Factors that could cause results to be different from these statements include factors the company describes in the section titled Risk Factors on our annual report on Form 10-K, filed with the SEC today, March 6, 2023. Immuneering undertakes no duty or obligation to update any forward-looking statements as a result of new information, future events, or changes in its expectations. With that, I will now turn the call over to Chief Executive Officer, Ben Zeskind. Ben? Thank you, Laurence. Good afternoon, everyone, and thank you for joining our fourth quarter and full year 2022 financial results conference call, the first such call we are hosting in our company's 15-year history. Let me start by assuring you that we do not plan to host an earnings call every single quarter. We will probably do them more than once every 15 years, though, maybe somewhere in between. Today, we have a lot to say, though, about our plan for the upcoming year and about the timing of our ongoing clinical trial. Our goal is to create medicines for large populations of cancer patients, and we took one giant leap in that direction in 2022 as the first patient was dosed in our phase I/I I-A trial of IMM-1-104 for the treatment of RAS-mutated solid tumors. We are proud to be a clinical-stage oncology company, thanks to years of hard work by so many Immuneers, and we are looking forward to sharing updates as the trial proceeds. Before I cover our achievements in 2022 and recent events, let me first take a step back and give everyone context on our counterintuitive approach to drug development. It is our belief that the name of the game in cancer therapy is not how do you kill cancer cells, it's how do you kill cancer cells with less risk to the healthy cells? It's all about therapeutic index, and historically, that has been really hard, and that's why cancer drugs are so commonly associated with such bad side effects, such poor tolerability. At Immuneering, we are developing what we believe is a fundamentally new way to achieve therapeutic index, a novel way to hit the tumor hard while going easy on the healthy cells. We think it'll enable us to develop treatments with the potential to benefit large numbers of patients globally with RAS-driven cancers. Most companies either go narrow by developing medicines that target specific individual RAS mutations, such as KRAS-G12C, or they go broad and hit wild-type RAS in healthy cells, and they hope to find a dose that harms the tumor more than the patient. In other words, unfortunately, this approach frequently leads to high toxicity. They say, "No pain, no gain." We believe cancer patients deserve better. They deserve less pain and more gain. We are working to rewrite the rules, to develop therapies that are designed to help patients with any mutation, be it KRAS, NRAS or HRAS, and that aim to provide more durable effects with better tolerability. Our approach utilizes a novel mechanism called deep cyclic inhibition, which is designed to maximize therapeutic activity while providing improved tolerability and durability. We aim to do this by taking advantage of the fact that the cancer cells are always on. They need the MAP kinase pathway all the time, whereas healthy cells use the pathway more intermittently, and I'll have more to say on that shortly. But first, we needed to figure out how to describe our approach, and there really wasn't an existing prefix or a suffix that worked. The closest ones were multi and pan, and it's not wrong to say we see pan-RAS activity preclinically, but pan is a prefix from the ancient Greek, and it sounds like cookware, and it just doesn't capture the excitement and the newness of what we are trying to accomplish. Importantly, both pan and multi tend to be associated with therapies that do not distinguish between the wild-type RAS in healthy cells and the mutant RAS in cancer cells, which raises concerns about therapeutic index and long-term tolerability for those therapies. So we adopted a phrase that aptly describes this uniquely broad approach and our fundamentally new way of achieving therapeutic index, and it's Universal-RAS. I'm being a bit lighthearted about the name, but let me assure you that we believe the potential for universal-RAS activity is incredibly serious and incredibly important to cancer patients and to their oncologists. The potential of our approach is supported by our preclinical data, and we are sharing some of our modeling data this week at the AACR Targeting RAS Conference. As described in our poster presentation, we tested 132 different cancer cell line models in our proprietary humanized 3D tumor growth assays in our labs in San Diego, including 75 models with RAS mutations. 75. We're not saying that every single RAS mutant model responds, but 64 of the 75 models tested, or approximately 85%, did respond, and at least one model displayed response to IMM-1-104 for each observed RAS mutation, regardless of the mutation position or amino acid substitution. This preclinical data suggests there's no RAS mutation we know of that's off-limits to IMM-1-104. For our clinical trial enrollment criteria, any solid tumor patient with any mutation in KRAS, NRAS, or HRAS is eligible to be screened for our phase I trial. As a result of these broad inclusion criteria and the robust preclinical data we have generated to date, we're seeing great enthusiasm from our clinical investigators, and one indicator of that is the fact that we dosed the first patient less than two months after receiving IND clearance. With enrollment ongoing, we are today providing guidance on when we could expect to report initial data readouts from the trial. Currently, we expect to share initial PK and safety data in mid-2023. Initial, initial pharmacodynamic and updated PK and safety data in the second half of 2023, the announcement of a recommended phase II dose and additional safety data in mid-2024, with additional trial updates on a periodic basis. We believe human PK data is a particularly important milestone for IMM-1-104, because PK is such an important part of how IMM-1-104 achieves universal-RAS activity in preclinical studies. I mentioned earlier that malignant cells depend on continuous signaling of the pathway, while the healthy cells can tolerate more interruptions. But one of the rules of targeted cancer therapy has been chronic pathway inhibition, which means if a pathway is locked on by a driver mutation, you must lock it off or chronically ablate it 24/7. And the problem with this approach is that healthy cells use the MAP kinase pathway, too. We have this pathway for reasons other than for cancer to hijack it, but the conventional wisdom is you make drugs with long half-lives, and they're dosed in such a way as to always maintain target occupancy, to maintain a drug trough. And it's intuitive, right? To shut down the pathway 24/7. But if we keep doing the intuitive thing, we'll keep getting the same result. The old no pain, no gain philosophy. So we decided to rewrite the rules in the design of IMM-1-104. IMM-1-104 began with a counterintuitive observation from our disease-canceling technology platform, that earlier time points did a better job of reversing disease at the transcriptomic level than later ones. And that helped us to realize that you may not actually have to shut down the pathway 24/7. You just have to prevent it from being on 24/7. So we designed IMM-1-104 to pulse the tumor with a manyfold higher free fraction Cmax, or in plain English, a very high peak drug exposure. Yet, we also have a short half-life in order to enable sufficient inhibition of the pathway while still achieving a near zero drug trough, to allow the drug to clear the system and reset the pathway each day, a process we call deep cyclic inhibition. So our approach aims for every day to be a drug holiday for the healthy cells and every day to be judgment day for the tumor. IMM-1-104 has demonstrated preclinical activity with strong tumor growth inhibition in each animal model we have tested, including KRAS- G12C, KRAS- G12F, KRAS- G12B, KRAS- G12V, as well as NRAS mutant animal models. As I said earlier, we can now also say approximately 85% of the 75 RAS mutant models we tested in our humanized 3D tumor growth assays responded to IMM-1-104. This positions IMM-1-104 to be the first and only MAP kinase pathway inhibitor with the potential for universal-RAS activity. Achieving that in humans depends on good tolerability with a short half-life and a high Cmax, and that's why the PK and safety data we expect to share in mid-2023 is so important. If IMM-1-104 achieves in humans anything like what we have observed preclinically, I believe it has the potential to be truly game-changing for large numbers of cancer patients in the near term. This is also a serious responsibility, and it requires our full focus and our undivided attention. So we have made the decision to suspend our early-stage neuroscience programs and focus ongoing development activities solely in oncology. Suspension of our neuroscience programs, as well as other non-core adjustments, extends our projected cash runway by one quarter into the fourth quarter of 2024, which is reflected in the updated runway guidance we have provided today. The oncology pipeline, which is now our sole focus, started less than five years ago as a research project by an extraordinary consultant named Brett Hall, who subsequently became our Chief Scientific Officer. Let me now turn the call over to Brett to say a few words about our unique approach and our latest data. Thank you, Ben. I'd like to start off by highlighting a key factor that we believe truly differentiates Immuneering from other biotech companies in the oncology space. Our aim is to develop drugs for larger patient populations using translational bioinformatics and humanized 3D tumor growth assays. We believe this approach enables us to design drug candidates with distinguishing features that select for a favorable activity and toxicity profile. One example of this application is the pharmacokinetics and target engagement of our lead asset, IMM-1-104. IMM-1-104 was designed to have a short half-life that can lead to manyfold higher free-drug fraction while still achieving near zero drug trough. We believe this profile enables deep cyclic pathway inhibition. We also designed IMM-1-104 to overcome resistance from CRAF bypass. We said that we project approximately a two-hour half-life in humans, which is much shorter when compared to other MEK inhibitors in the space that have up to multi-day half-lives. Our preclinical data suggests potential for robust activity in pancreatic cancer, melanoma, non-small cell lung cancer, colorectal cancer, and other solid tumors with RAS mutant disease. Using humanized 3D tumor growth assays, followed by select in vivo studies, we have identified NRAS-driven melanoma and KRAS-driven pancreatic cancer as two potential high-priority indications that we believe are both largely unaddressed and may be broadly sensitive to IMM-1-104. But as Ben mentioned earlier, we have reported on 132 tumor models that span over a dozen tumor types with various mutational profiles, and we observed broad activity in 64 out of the 75 models, or approximately 85%, that display mutant RAS. There was no specific RAS mutation where we didn't see potential activity. Additionally, our translational research team is further evaluating KRAS mutant lung cancer and KRAS mutant colorectal cancer to identify biomarkers that enrich for highest potential for monotherapy response. In 2022, Immuneering presented three abstracts on two programs, two at the American Society of Clinical Oncology, or ASCO, in May of 2022, and one at the SITC Annual Meeting in November of 2022. The first abstract, a head-to-head comparison of IMM-1-104 versus sotorasib or adagrasib in KRAS mutant pancreatic cancer, demonstrated lack of tumor growth inhibition by both sotorasib and adagrasib in the KRAS- G12V mutant Capan-2 pancreatic ductal adenocarcinoma tumor model. In contrast, IMM-1-104 observed tumor growth inhibitions of 49%-84% across all doses and schedules tested. Consistent with other IMM-1-104 in vivo studies, median body weight was no more than 3%-6% at the top doses. The second abstract we presented at ASCO found KRAS mutant pancreatic cancer and NRAS mutant melanoma were the most broadly sensitive to IMM-1-104 in patient-aligned 3D human tumor growth assays, and thus are included among the expected target indications for Immuneering's phase I/II-A clinical trial. Finally, the third abstract presented at SITC highlighted the preclinical activity of our second pipeline asset, IMM-6-415, as a single agent, as well as a combination therapy with checkpoint inhibitors in RAS mutant colorectal cancer and non-small cell lung cancer models driven by diverse MAP kinase pathway mutations. IMM-6-415, in combination with immuno-oncology agents, may have the potential to overcome resistance in the MAP kinase pathway and to provide deeper and more durable responses. We expect to file the IND with the FDA for IMM-6-415 in the fourth quarter of 2023. As Ben mentioned, for IMM-1-104, we expect to share initial phase I pharmacokinetic and safety data in mid-2023. With that, I'll turn the call over to Scott to share an update on our phase I clinical trial program. Brett, Brett, thank you, Brett. Just before you do that, if I could just say that, that Scott joined our team in 2019, and at the time, everyone said: "Why do you need a chief medical officer when you're a few years from the clinic?" And we said two reasons, we want a clinician's perspective in our preclinical development, and so we can lay all the groundwork to really hit the ground running in phase I. I'm really proud of what a great team Scott has built and what a great job they've done getting our trial up and running. With that, over to you, Scott. Thank you, Brett and Ben. I'm delighted about the progress that we're making in our first human clinical trial evaluating IMM-1-104 in a phase I/II-A open-label study designed to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy. IMM-1-104 is administered as a once-daily oral monotherapy for adult cancer patients with RAS mutated solid tumors in an advanced setting, and our trial requires that they've already failed at least one line of systemic standard of care treatment. This phase I open-label study utilizes a Bayesian mTPI-2 escalation design for IMM-1-104. This includes a dose escalation phase and a dose evaluation phase in order to evaluate safety and establish an optimized recommended phase II dose, or RP2D, candidate in mid-2024. This is expected to segue into a phase II-A dose expansion in approximately 160 total patients in four parallel cohorts, which independently evaluate monotherapy treatment effect in RAS-mutated melanoma, pancreatic cancer, non-small cell lung cancer, and colorectal cancer. The primary endpoint of the phase II trial will be response rate, as defined by objective radiographic response assessment, measured by radiographic imaging changes from pretreatment baseline. This is first observed for each patient at two months and continues every eight weeks thereafter for patients receiving benefit from study drug for up to 48 weeks of treatment. Overall, we've received great enthusiasm from our investigators across five clinical sites in the United States, who are all eager to enroll patients as soon as possible. In fact, we have a robust wait list for patients. Our phase I program is now open to all comers with evidence of any RAS mutation, including KRAS, NRAS, and HRAS, as IMM-1-104 has been designed to be broadly active in tumors addicted to MAP kinase pathway signaling. In November 2022, we successfully dosed our first patient in the trial. For the time being, that's all we've disclosed, but I expect to have much more to say in the coming months as we begin to share data from the trial, as Ben has laid out in today's guidance. So with that, I'll turn the call over to Mallory to cover our fourth quarter and full year financials. Thank you, Scott. In addition to the financial results summarized in our press release we issued earlier today, I will share some key financial highlights on this call. You can also find additional information in our Form 10-K that was also issued earlier today. As of December 31st, 2022, our cash, cash equivalents, and marketable securities were $105.5 million, compared with $150.2 million as of December 31st, 2021. Operating expenses for the fourth quarter of 2022 were $14 million, compared with $11.1 million for the fourth quarter of 2021. Full- year 2022 operating expenses were $51.9 million, compared to $34.8 million for full- year 2021. The increase in total operating expenses in 2022 was primarily due to the advancement of IMM-1-104 through IND and into our phase I/II-A clinical trial, as well as employee-related costs due to increased headcount. Net loss attributable to common stockholders was $13.2 million for the quarter ended December 31st, 2022, compared to $10.8 million for the quarter ended December 31st, 2021. Net loss attributable to common stockholders for full- year 2022 was $50.5 million, compared to $33.5 million for the full- year 2021. As of February 27th, 2023, we have 26,436,109 shares outstanding. In terms of our cash runway, management expects our cash, cash equivalents, and marketable securities to be sufficient to fund operations into the fourth quarter of 2024. That concludes the financial update, and I'll now turn the call back over to Ben. Thank you, Mallory. Mallory and her team are doing a phenomenal job, and we're very lucky to have them. Let me wrap things up by saying that nobody should be dying of cancer in 2023. I'll say that again. Nobody should be dying of cancer in 2023. Cancer doesn't work by magic. It's not some paranormal force. It operates by a set of biological mechanisms that are actually well understood. It's just really good at hiding among the healthy cells, and it essentially hijacks a person's body and takes them hostage. The challenge is, how do you kill the hijackers with less risk to the hostages? How do you achieve a therapeutic index? To date, companies have either gone narrow by targeting a single mutation, such as KRAS- G12C, or they've gone broad, but in a way that hits wild-type RAS in healthy cells. At Immuneering, we believe it's time to go broad, and we believe that deep cyclic inhibition represents a fundamentally new way of focusing the activity against the malignant cells, of taking out the hijackers with less risk to the hostages. It's time to make medicine with the potential for universal-RAS activity. In the past twenty-four hours, we've released new preclinical data we'll be showing at AACR Targeting RAS this week, which is a tour de force in demonstrating the universal-RAS activity of IMM-1-104 in preclinical models. Our clinical trial is moving forward rapidly because our enrollment criteria are truly universal-RAS. Soon it will be time to share data showing how that deep cyclic inhibition is playing out in humans. We believe 2023 is shaping up to be Immuneering's breakout year, and we aspire to make 2023 a year that marks an important turning point in the battle against cancer. With that, I'd like to thank all of our patients, clinical investigators, and stakeholders for their continued support of Immuneering, and I look forward to updating you all in the coming months on our progress towards our goal of a universal-RAS therapy for cancer patients. I will now open the call up for questions. Operator? As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Swapnil Malekar from Piper Sandler. Great. Thank you for taking my questions. I have a couple of them. First one is, can you comment on how many patients have been dosed in the 104 trial so far, and what is the extent of the data that will be presented, in the mid-2023 update? Hey, Swapnil. Thanks, thanks for the question. We're really pleased with the progress of the trial, and you know, I think we provided very, very detailed guidance today, probably more, more granular than many companies often do. And, you know, we're really, really excited to share the initial PK and safety data in mid-2023, and the rest of the data as we've outlined. Got it. Okay. And then I have one follow-up. So regarding the AACR poster tomorrow, what additional data does the poster include that has not been previously presented? And from this, from this new preclinical studies, are you seeing any specific trends, related to tumor types or mutation status that could inform your ongoing clinical trial in terms of patient selection? Thank you for taking my question. Sure. Thanks, Swapnil. I'll hand it over to Brett in a second to see if there's anything he wants to add. But the poster is available already on our website. You know, and I think, you know, one of the key takeaways from the poster is really the universal-RAS activity that we're seeing. The fact that about 85% of the cell lines that we tested with RAS mutations in the humanized 3D tumor growth assay, you know, are really responsive to IMM-1-104, and there's really no mutation that's, you know, that's not responsive, right? Every mutation has at least one model within that's responsive. But let me see if there's anything Brett would like to add there. Thanks, Ben, and hey, Swapnil. Yeah, I would, I would add that, you know, the poster is really a deep dive into a broad panel of tumor models that we've evaluated that have RAS and other MAP kinase pathway and non-MAP kinase pathway-driven mutations. And it really is a deep look or a deep dive into our core platform, our humanized 3D tumor growth assay platform, that we've used, and have vetted additionally with in vivo studies on the back end. So including, you know, those that we've discussed before, like MIA PaCa, A549, SK-MEL-2, and others, have all basically been vetted both in the 3D tumor growth assay as well as in vivo. So it just really. Thank you, Brett. Yeah, so Swapnil, it just really broadens the scope of models that we've released publicly, and I think all of this contributes to the really the universal-RAS activity that we've seen preclinically, and frankly supports the enrollment criteria for our clinical trial, which is truly open to patients with any mutation in KRAS, NRAS, or HRAS. So with that, thanks for your question, Swapnil. Thank you. One moment for our next question. Our next question comes from the line of Michael Yee from Jefferies. Hi, guys, this is Dina on for Mike. I just had a couple of quick questions, and congrats again on the progress. What doses are you using right now to dose escalate? And are the low doses that you're starting at therapeutic at all, where we could potentially see responses in that mid-2023 or second half update? I know you just only said that you would be sharing PK, PD, and safety data, but just wondering if there is a potential for efficacy data or dose response data that we'd see there. I guess another thing, if you could just share some more color on the PD modeling that you are planning to share in the second half, what does that entail, and what type of, you know, biomarkers are you really looking to share there? Thank you. Sure. Yeah, thanks, thanks for the question. I can take the first part, and I'll maybe hand it over to Brett to speak a bit to the second part. But again, you know, we're really pleased with the progress of the trial. And I, you know, I think we've provided some really granular guidance today, that should hopefully be helpful in, you know, really knowing when, you know, when we're gonna share data. So, you know, I think that's really what I'd say about the trial. And then, Brett, maybe you want to speak to some color on the PD modeling. Yeah, absolutely. Happy to. So we're looking at two orthogonal pharmacodynamic assays. One is an induction-based assay, PBMCs, and the other is a oncogene-driven PD assay, where we're looking at reduction from baseline of a KRAS-driven model. And so the key thing that we're looking for there, of course, is attenuation of the MAP kinase pathway at the level of MEK and ERK. I believe that was the only question. I'll turn back to you, Ben. Yeah, thank you. I guess just a quick follow-up on safety. I know you guys are going to be sharing a lot of that data this year. Given that it's like a cyclic MEK inhibition, what kind of tox profile are you guys looking to see that kind of, you know, gives you confidence around the hypothesis of cyclic inhibition, if you don't mind? Thank you. So yeah, I mean, look, the tolerability that we've seen in preclinical models has been really quite good. So, you know, we've described that across the, you know, multiple animal studies that we've run, each of which have shown very strong tumor growth inhibition in different, you know, models with different mutations in the RAS pathway. You know, in each of those, we've seen very little body weight loss, so no more than 3%-6% body weight loss. So really good tolerability, and I think that, as you heard in my comments, is really, you know, really kind of the key thing. You know, I think seeing a short half-life is really important to that as well, right? I mean, I think that's fundamental to the deep cyclic inhibition mechanism is seeing the short half-life, seeing the high Cmax, meaningfully higher Cmax. And, you know, so these are some of the things. But let me just see if Brett wants to add anything there. No, I think, you covered it well, Ben. Thanks again for that question. Let's take the next one. Thank you. One moment for our next question. Our next question comes from the line of Yaron Werber from Cowen. Hi, this is Joyce on for Yaron. Thanks for taking our question. Maybe just a couple on IMM-6-415. What additional preclinical data are you collecting right now? How are you thinking about your clinical development program and the potential design of a phase I trial? And how are you thinking about selection of focused tumor types versus what you're doing for IMM-1-104? Thanks. Yeah, thanks, thanks, Joyce, and we look forward to seeing you at the, at your conference tomorrow. So yeah, I mean, we're, we're really excited about, IMM-6-415. You know, it's, it's on track to, to file the IND by the end of this year. And, you know, just as we're calling, you know, calling, IMM-1-104 the universal, RAS program, we're actually calling 415 a universal, MAPK program. And, and that's because we, you know, really one of the key differences is that, that 6-415 has a, has a shorter half-life. So we, you know, we project that it'll end up being BID or twice a day in humans, versus 104, which is, which is, of course, once a day. And so we think that, you know, just kind of like tuning the dial on old-fashioned radio tunes in a different station with a different frequency, we think that different cadence will be optimized for unique biology. And we showed in our SITC poster late last year, you know, responses as a monotherapy in RAS and RAF mutant disease, so there's a universal MAPK as well as in combination with immuno-oncology agents. But you know, I think you can expect, you know, the clinical trial to really be focused initially on monotherapy. You know, that's really our initial focus, given the really nice data that we're seeing as a monotherapy. It's obviously a much, you know, much clearer path to start as monotherapy, and I, you know, I think, therapies that can do that too. So we're certainly excited to pursue it as a monotherapy. And, you know, the rest of the trial design, you know, we'll talk about in due course. But let me see, Scott, did I miss anything on the four one five design? Well, it's a work in progress. We're evolving it, but obviously, the objective is to integrate, you know, multiple aspects of the MAP kinase pathway, and that will include RAF, RAS, and RAS-driven disease. Thank you, Scott. Great. Thanks. Okay. Thanks, Joyce. Next question, please. Thank you. One moment for our next question. Our next question comes from the line of Jeff Hung from Morgan Stanley. Thanks for taking my questions. I have two on this week's AACR data. You indicated that no particular mutation position or amino acid substitution was exclusively found to confer resistance to drug exposure. So based on what you've seen, which mutations do you expect to be particularly challenging or relatively easier to treat? And then I have a follow-up. Sure. Hey, Jeff, thanks, thanks for the question. You know, universal-RAS means universal-RAS. You know, we've not seen any difference really among the different mutations at different positions in KRAS, NRAS, or HRAS in terms of sensitivity or resistance to 104. And, you know, I think that makes sense in that we, you know, we target MEK, so we're targeting downstream of RAS. So it's logical that, you know, we'd sort of be agnostic to the specific mutations. You know, where we do start to see differences in responses, it really has to do with the mutations in other parallel pathways unrelated to MAP kinase. So for instance, you know, we've disclosed that in our, in our phase IIa, in the colorectal cancer arm, we plan to look specifically at, at APC wild- type, patients who are KRAS- mutated. And that gives you a sense, for instance, that, you know, an APC mutation on a colorectal cancer model might, you know, might be a little more challenging. But let me see if, if Brett wants to add anything to that, and then I'll take your second question. Yeah, absolutely. Hi, Jeff. I would add, we've also discussed that really the drivers for resistance to IMM-1-104 are not really the mutation profile upstream, whether that's a BRAF or KRAS, HRAS, NRAS. It really has to do with the profile of mutations in the given model. And we've outlined this extensively, for example, in NRAS models, where the NRAS mutation, you know, is something that sets up for utilization or addiction, but addiction is really defined by how many compensatory mutations and parallel pathways exist. And so the more of those events that you see, the lower likelihood of single-agent response to IMM-1-104, and that's part of what's the mapping exercise for the AACR targeting RAS poster really starts to get at. Great. Thanks. And then the data were generated in 3D tumor growth assays. Would you expect some more broad activity in rodent models in humans? Thanks. Brett, do you want to, do you want to speak to that? Yeah, absolutely. So yeah, so we've actually also disclosed that. So for example, when you look at the depth of sensitivity or response in the 3D TGA, we've generally observed in the models that we've already published and disclosed that the deeper responding models, such as MIA PaCa-2, which is a KRAS- G12C pancreatic cancer model, as well as SK-MEL-2, which is a NRAS mutant melanoma model, which are highly sensitive in the 3D TGA and actually show regressions or mid-cycle regressions in vivo. For those that have an intermediate response profile, such as A549, which is a non-small cell lung cancer model, that KRAS- G12S, as well as Capan-2, which is a pancreatic cancer G12V model. Those have an intermediate response profile, and we see stable disease, or flatlining the tumor, if you will, in vivo. And so basically, when you start to look at the profiles and start to map out what those different response profiles are, and then compare them to also, we've disclosed on what we call offset plots, which are basically projections of the molecular characteristics that align with those models in patients, that, you see the broadest single monotherapy, response potential in KRAS pancreatic cancer and NRAS melanoma. We also see very promising single-agent monotherapy potential in KRAS mutant lung cancer, as well as KRAS mutant colorectal cancer. And thanks, Brett. And I would just emphasize, Jeff, this is a really unique and proprietary capability that we have. So the 3D tumor growth assays, you know, this is a proprietary assay that we have up and running at our labs in San Diego. And we highly encourage everyone to schedule a time to come visit those labs. We give a great tour, second only to Disneyland in popularity in Southern California. But you know, it really enables us to very broadly assess the response profiles of, you know, of different mutational profiles. And that proprietary view, I mean, 132, right? How many companies do we know that have run 132 models on their lead program? And then, you know, that really ties in elegantly with all the deep informatics capabilities that we've developed over the last 15 years to create these plots that Brett described, where we're actually projecting onto patient populations using real patient data to really identify and prioritize which, you know, which indications we think to kind of go after first. So it's really a, you know, it's a platform that I think is very unique to Immuneering that we're quite proud of. Great. Thanks so much. Thank you, Jeff. Next question, please. Thank you. One moment for our next question. Our next question comes from the line of Mark Breidenbach from Oppenheimer. Hey, good afternoon. Thanks for taking our questions. You know, the first one kind of goes back to something Ben mentioned. I mean, this is a drug that acts on MEK, which is, of course, downstream from RAS. I guess I'm finding myself wondering why we should be at all surprised that this activity you're observing is independent of specific RAS mutations. Shouldn't that be the case for any MEK inhibitor, or is there something different with this one? And the second question is just with regard to the timing of initiation of expansion cohorts. You know, if we're talking about identifying a recommended phase II dose by middle of next year, can we assume that's a prerequisite before initiation of expansion cohorts? Thank you. Hey, Mark. Thanks for the question. So, you know, you're right. In theory, MEK has always been a great target, right? But it really hasn't lived up to its potential yet. And I think really that's because the first generation MEK inhibitors have really had two main challenges. Number one, they've been limited mainly to RAF mutant disease, and secondly, they've really been quite toxic, very poorly tolerated. You know, and I think that's really because, in part, because they've all been developed in this same old chronic inhibition paradigm, where you shut down the pathway 24/7, you maintain chronic occupancy, you maintain a drug trough. You never, never let the drug level get to, get close to zero. And again, the problem is healthy cells need the MAP kinase pathway, too. And so, you know, these first-generation MEK inhibitors really just kind of harm the, you know, or create challenges for the MAP kinase pathway in healthy cells. And so I think that, combined with the fact that they're also all susceptible to a feedback loop called CRAF bypass, that makes it, you know, really, really challenging to go after RAF mutant disease. And so those are some of the design choices we made in creating 104. You know, we gave it the ability to block CRAF bypass. We gave it a, you know, the ability to, to, to cause a manifold higher Cmax to really hit the tumor hard. And then we gave it a very short half-life. So we've consistently said we projected two-hour half-life in humans. And the combination of those things gives it, you know, essentially, the ability to hit the tumor hard, but then allow the pathway to reset. It, you know, really the idea, as I said earlier, you know, every day is a drug holiday for the healthy cells, and yet every day is judgment day for the tumor. And so I think that's, you know, that's really why, you know, we've been able to go after MEK in a unique way, that we think certainly pre-clinically is really kind of living up to the full potential of MEK as a target. And you're right. Conceptually, you know, MEK is a great target to really target any, you know, any mutation in RAS and really achieve that kind of universal-RAS activity. Let me see if Brett wants to add anything on your first question, then we can talk about the second question. Yeah, just really quickly. Hi, Mark. So I would add the strength, our core thesis is that deep cyclic inhibition with the novel engagement mechanism that prevents or resists the CRAF bypass and other bypass mechanisms is critical. And I think here is where a good example of the existing MEK inhibitors, their strength becomes their weakness, right? Their, there's 24/7 chronic inhibition, sustainably induces these adaptive resistance mechanisms that basically is kind of like having a snow plow where the snow builds up in front of the plow and eventually just slows down the ability, for you know, for the that truck to be effective and remove snow. Very similar with MEK inhibitors, and we can avoid that or reduce that significantly by the deep cyclic inhibition approach, where we reset the pathway every day, as well as the novel mechanistic engagement that actually resists the buildup in the first place. And I think those two, the one-two punch of deep cyclic inhibition with IMM-1-104, really stands apart, from the other MEK inhibitors. Okay. I guess I'm also just wondering if you included any of the more conventional MEK inhibitors in your screen against humanized 3D tumor models, if you saw any sort of difference there? I see your question. Yeah, so, so we, we haven't guided on that at this point. But what we, what we have actually run, and, and we've already mentioned that we do see a nice read-through of the 3DTJ into in vivo. And we did publish, for example, you know, in the head-to-head comparison of IMM-1-104 versus binimetinib, in the NRAS Q61R SK-MEL-2 model, where we saw mid-cycle regressions with 104, but really very minimal to no effect with full dose binimetinib. Okay, great. And then with respect to the timing on expansion cohorts? Yeah. Yeah, thanks. Thanks for that, that second question, Mark. So given that, that RP2D stands for, recommended phase II dose, you know, I'll ask Scott to confirm this with his decades of clinical experience, but I think it would be hard to start the phase II until we have that recommended phase II dose, but- I think Mark is asking in the spirit... Can you hear me? Yeah. Yes. Yes. Sorry. In the spirit of dose optimization, we're proactively volunteering to have a dose evaluation phase, what we're calling internally phase I- B. And so we'll come up with candidate dose or dose RP2 dose candidates, and then evaluate them further to make sure that we've selected the definitive one, before we start phase II- A. So yes, in answer to your question, Mark, we plan to complete those escalations before we formally evaluate two or more dose candidates. Understood. Thank you. Yeah. And thanks. That's a great point. And you know, I first heard about the Project Optimus from Scott and his team years before it sort of got popular and you know, gained a lot of prominence and attention. So we've been very focused on that from the early days. But thanks again, Mark, for your questions. And let's go on to the next question please. Thank you. One moment for our next question. Our last question comes from the line of Michael Schmidt from Guggenheim Partners. Hey, guys. Thanks for taking my question. Just maybe a quick follow-up on the phase I study. Based on the enrollment criteria, what tumor histologies would you expect to enroll predominantly? And, and based on that, you know, as you think ahead towards you reaching, more efficacious, or higher doses in the study, where would you expect to see, early clinical activity? Thanks so much. Hey, Michael, thanks for the questions, and last but certainly not least, appreciate the question. And yeah, look, I mean, our phase I enrollment criteria is quite broad, right? It's truly universal-RAS. Any, you know, any solid tumor patient with any mutation in KRAS, NRAS or HRAS is eligible to be screened. So we're not requiring or specifying particular tumor types as part of the phase I. You know, however, as you know, we've identified, you know, what we believe are the most likely phase IIa areas for dose expansion. And that's based on you know the use of these humanized tumor growth assays and the informatics that we described earlier. And so all our clinical investigators are familiar with those data. And in fact, we've chosen our clinical sites in part based on their expertise with those types of cancer. So you know I think you can expect you know you might expect to see a bit more of those in the trial. But again, you know, we have... And I'll hand over to Scott to comment, but again, we have very broad enrollment criteria to really cast a wide net. Scott, I don't know if there's anything you wanna add there? No, I think you covered it well. They're all the phase I investigators are clinicians and scientists that were involved in our protocol development and are very excited about the clinical proof of concept. And so they're basically, you know, actively looking to enrich for the tumor types that we built our model there for melanoma. Okay, thank you. Great. Thanks. Thanks, Michael. Thank you. At this time, I would now like to turn the conference back over to Ben Zeskind for closing remarks. Great. Thank you, operator, and thanks, everyone, for the great questions and to everyone who was listening in on the call. In the coming weeks, we plan to attend the Cowen and Oppenheimer Healthcare Investor Conferences, and we welcome your request for meetings at these events or directly through us. Feel free to reach out to Gilmartin if you'd like to schedule some time. With that, I would like to thank all of you for participating in today's call and wish you a good evening. This concludes today's conference call. Thank you for participating. You may now disconnect.