Cue Biopharma, Inc. (CUE) Earnings Call Transcript & Summary

Greetings, and welcome to Cue Biopharma Third Quarter 2020 Earnings Call. [Operator Instructions] As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Dr. George Zavoico, Vice President, Investor Relations and Corporate Development. Thank you. You may begin.

Thank you, Doug, and good afternoon, everyone. Thank you for joining us on today's investor and analyst update call. Joining me today on the call are Dan Passeri, Cue Biopharma's CEO; Dr. Anish Suri, President and Chief Scientific Officer; Dr. Ken Pienta, acting Chief Medical Officer; and Kerri-Ann Millar, Chief Financial Officer. Before we begin, I'd like to remind you that various remarks that the company makes during this call about the company's future expectations, plans and prospects constitute forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of the company's annual report on Form 10-K filed with the SEC on March 12, 2020, and the most recent quarterly report on Form 10-Q filed with the SEC on November 9, 2020, as well as other filings made by the company with the SEC from time to time, which can be accessed on the EDGAR database at www.sec.gov. In addition, any forward-looking statements represents the company's views only as of today, November 17, 2020, and should not be relied upon as representing the company's views as of any subsequent date. While the company may elect to update these forward-looking statements at some future point, the company specifically disclaims any obligation to do so even if the company's views change. Please be advised that today's call is being recorded and webcast. The slides we're presenting today and the recording of our call will be available on our website for the next 30 days. With that, I would now like to turn the call over to Cue Biopharma's CEO, Dan Passeri.

Thanks, George. Good afternoon, everyone, and thanks for joining us today for a review of our ongoing progress and third quarter financial results, which are available in more detail in our Form 10-Q filed with the SEC on November 9. I'd like to begin by emphasizing our gratitude to our employees for their constant professionalism and dedication to advancing our programs of promising biologics to address the needs of patients suffering from debilitating diseases. We've continued to make significant progress during the continuing ongoing challenges of the COVID pandemic. Importantly, we have made meaningful progress in the clinical development of CUE-101 by continuing our monotherapy dose escalation study and second-line and beyond recurrent metastatic HPV+ head and neck cancer patients and launching our combination study of CUE-101 with KEYTRUDA, which is the standard of care for frontline HPV+ head and neck cancer patients. The data emerging from the clinical development of CUE-101, to be presented in further detail by Ken momentarily, is representative of our IL-2-based CUE-100 series. While our analysis of the emerging data is still early, we believe that our data -- the data from this ongoing dose escalation study is demonstrating that CUE-101 is capable of delivering and presenting a tumor-associated antigen directly to the targeted T cell receptor or TCR, together with the co-stimulatory cytokine, in this case, an IL-2 variant, specifically and selectively to activate disease-relevant T cells directly in a patient, thereby potentially eliciting a clinically meaningful response without dose-limiting off-target adverse events. Our primary objective is to create drugs that can benefit patients through the systematic demonstration of what we believe could be a breakthrough and disruptive approach for tolerable and selective immunomodulation, again, directly in the patient's body, for our off-the-shelf immune-mediated therapies. We believe that achieving this objective would create meaningful shareholder value. Our near-term goal in the ongoing CUE-101 dose escalation trial is to demonstrate tolerability, which should be to benefit of our entire CUE-100 series of molecules. For reasons that Ken will discuss shortly, we believe that we've already achieved this goal. Importantly, we also believe the clinical data generated with CUE-101 to date is supportive of our belief that CUE-101 is clinically active as a single agent and has a potential path forward as a monotherapy in second-line and later HPV+ head and neck cancer patients. We continue to observe dose proportional pharmacokinetics or PK, evidence of relevant pharmacodynamic or PD activity and encouraging metrics supporting the premise that CUE-101 is clinically active as a single agent. Moreover, since our last earnings call, we've advanced through cohort 6 and following authorization from our safety review committee last week, we're now enrolling cohort 7. Furthermore, we continue to broaden our strategic plan to address patients suffering from HPV+ head and neck cancer patient -- cancer by initiating a CUE-101 trial in combination with the anti-PD-1 antibody, pembro or KEYTRUDA. This program launched in late October and is currently screening and evaluating patients for enrollment. We believe that we are well positioned, with CUE-101 establishing highly supportive data sets for defining paths forward, and more importantly, setting up the potential for a substantive breakthrough if the current dose levels and expansion studies generate further evidence of antitumor activity in these highly compromised and challenging patients. It is our belief that through the ongoing development of CUE-101, we have the potential to be positioned as a pioneering breakthrough biopharmaceutical company that can transform immunotherapy through our targeted immunomodulation, including delivery of an IL-2 variant. Additionally, we believe we are well positioned to demonstrate the competitive advantages and market positioning of CUE-101 as a monotherapy as well as enhancing our patient reach and market potential by moving upstream in combination with KEYTRUDA in frontline patients. Furthermore, we continue to develop a robust and growing pipeline of additional targets from the CUE-100 series.. And now turning to Slide 3, as provides our agenda for this call. First, Dr. Ken Pienta, our acting Chief Medical Officer, will provide a substantive update on our clinical development progress and plans. After Ken's update of clinical progress, Dr. Anish Suri, our President and Chief Scientific Officer, will describe the clinical PD data in further detail and will provide an update of our continued progress with additional programs in oncology, including our next candidate, CUE-102, which targets Wilms' Tumor 1 or WT1 antigen. Following Anish's update, Kerri-Ann Millar, our Chief Financial Officer, will review our current financial status, and then I'll come back, provide concluding remarks and followed by a Q&A session. I'll now turn the call over to Ken. Ken?

Thanks, Dan, and good afternoon, everyone. Once again, I'd like to first begin by thanking all of the participating clinical centers and associated oncologists shown on Slide 4, who despite the ravaging COVID-19 pandemic, have continued to be actively screening and enrolling HPV-16+ head and neck cancer patients to participate in our ongoing trial. Turning now to Slide 5. As a brief status update, we have fully enrolled Cohort 6, representing a dose concentration of 4 milligrams per kilogram, and the safety review committee has recently granted us permission to enroll into Cohort 7 at 8 mg per kg and backfill other cohorts at our discretion to further build out the data set to inform selection of the appropriate dose of the part B expansion of the trial. At Cohort 6, CUE-101 delivers about 32-fold higher amounts of an IL-2 variant on a molar basis than wild-type IL-2, delivered by the approved dose of Proleukin. And at Cohort 7 at 8 milligrams per kilogram, the same would deliver approximately 64-fold higher dosing. Turning now to Slide 6. This slide shows a high-level summary of the design and dosing cohorts for our ongoing Phase I dose escalation trial. As a reminder, the trial is designed to enroll second line and beyond patients that are HLA-0201 positive with recurrent or metastatic head and neck squamous cell carcinoma driven by HPV, specifically HPV-16. All but 2 of the 25 patients enrolled in this trial to date have previously failed both platinum-based chemotherapy and checkpoint blockade and entered the trial receiving CUE-101 as third or fourth line or more treatment for their metastatic disease. This trial is designed with the primary end points of safety and tolerability, while concurrently defining the PK parameters of CUE-101 with secondary end points of pharmacodynamics, evidencing the drug's mechanistic activity on T cell activation and proliferation as well as assessing signs of clinical activity by RECIST radiologic and exam criteria. The trial is a standard 2-part trial, with part A designed as a typical 3 plus 3 monotherapy dose escalation trial. Patients receive CUE-101 with a dosing cycle of once every 3 weeks via IV infusion. However, as I have noted in previous earnings calls, the trial protocol also provides the opportunity to dose up to 9 patients in any given cohort where we see evidence of clinical activity or pharmacodynamic effect. We designed the trial in this manner to be able to assess and choose the most appropriate dose for the part B expansion as well as the presumed recommended Phase II dose or RP2D if we had no evidence of dose-limiting toxicity, while simultaneously seeing evidence of dose-dependent PK plus evidence of agent-specific PD plus evidence of clinical effect. Since the last earnings call, in addition to enrolling the first 3 patients of Cohort 6, we have now expanded Cohort 4 to 8 patients and Cohort 5 to 5 patients. We will continue to expand these cohorts as we enroll patients in Cohort 7. Once we determine the most appropriate dose based on the drug's safety PK/PD and clinical activity data from the dose escalation part A, we will accrue a total of 20 patients at that dose level during the part B expansion phase to further evaluate and confirm the recommended Phase II dose. I'm happy to report that to date, 25 patients in Cohort 1 through 6 have received a total of 77 infusions of CUE-101 3 weeks apart without reaching a maximally-tolerated dose. As discussed above, we've been able to administer doses of CUE-101 in Cohort 6 that deliver about 32-fold higher amounts of an IL variant on a molar basis than wild-type IL-2 delivered by the approved dose of Proleukin. Importantly, while not observing the common adverse side effects associated with IL-2, we are observing positive PD effects on targeted CD8+ T cells as well as observing evidence of clinical activity, particularly at the higher dose cohorts. As we show on Slide 7, the PK data from the first 5 cohorts reveal dose-dependent PK that is sustained across multiple doses. In patients that received multiple cycles of CUE-101, we continue to see no evidence of a decrease in exposure of CUE-101, which suggests a lack of immunogenicity of drug-clearing antidrug antibodies or ADAs. We believe that sustained increase in exposure with incremental doses of CUE-101 bodes favorably for CUE-101's mechanism of action. It follows that with enhanced exposure, CUE-101 should continue to be present in blood circulation for longer periods of time at concentration levels favoring engagement and activation of the target cells. To date, we have observed confirmed stable disease in 4 patients, with 7 patients presently on study. Just to remind you and to clarify, the designation of a confirmed stable disease is determined with 2 consecutive scans representing a minimum duration of at least 12 weeks. 2 patients had stable disease for over 18 weeks and 2 other patients with current stable disease remain on study. Anish will give an example of PD from one of these patients shortly. I would like to emphasize here that these observations are highly encouraging for what I consider to be 3 primary reasons. Number one, as I stated, these are heavily pretreated patients who have had 3 to 6 prior lines of therapy for their metastatic disease. Number two, we are still in the dose escalation phase of this trial and have not yet defined our optimal expansion dose, the part of the trial where we would expect to catalog responses. It is highly encouraging to me as a physician that we have already observed clinical benefit in antitumor activity before we have defined the biologically-effective dose of CUE-101. In addition, it is also encouraging and intriguing to me that while this Phase I trial has been open for over 1 year now, we had only 1 documented death in the patients treated with CUE-101. Based on our observations to date, this suggests to me that CUE-101 has the therapeutic potential to enhance overall survival. And number three, as will be discussed in more detail by Anish in the following section, with the higher doses of CUE-101, we are seeing PD activity on the cellular immune compartment that seems to correlate with increased drug concentrations. Taken together, the totality of the current metrics continue to be supportive of tolerability as well as biologic and clinical activity of CUE-101. We remain encouraged by the supportive data generated to date, and we believe that a tolerable, clinically-active dose will be determined both for our ongoing monotherapy trial and our KEYNOTE-A78 combination trial. Speaking of KEYNOTE-A78, slide 8 shows our collaboration with Merck for KEYNOTE-A78, our frontline therapy Phase I trial to evaluate CUE-101 in combination with pembrolizumab or KEYTRUDA for patients with HPV+ head and neck cancer who are also HLA-0201 positive. This trial opened last month with initial patients already having been screened. This trial will also be a dose escalation and expansion trial with CUE-101 starting at a cohort dose -- Cohort 4 dose of 1 mg per kg. The dose of KEYTRUDA will be fixed at 200 milligrams per kilogram every 3 weeks. We believe this is a very attractive starting dose for the combination trial as Cohort 4 manifested a favorable tolerability profile as well as a confirmed stable disease patient who remained on study for 21 weeks. We have also expanded our plans for initiating neoadjuvant trials in the first half of the next year with patients newly diagnosed with localized head and neck cancer. These trials are designed to provide us with further insights into CUE-101's mechanism of action as a monotherapy as well as in combination with KEYTRUDA by directly studying the tumor tissue post resection to assess infiltration and proliferation of HPV-specific tumor-infiltrating lymphocytes or TILs. The analysis of TILs in tumor tissue is especially meaningful based on the recent report published by our collaborators in Nature Methods in October of 2020 that highlighted the finding that the core scaffold of an Immuno-STAT can penetrate solid tumors and directly engage the antigen-specific T cell repertoire. In summary, our initial focus is to pursue the monotherapy trial for mechanistic evidence of targeting and activation of HPV+ CD8+ T cells with the potential of defining a registration path for second-line or later HPV+ metastatic head and neck cancer patients and subsequently expand our patient reach through our trial in frontline patients in combination with the current standard of care KEYTRUDA, and to further our understanding of the biologic mechanisms of CUE-101 through the neoadjuvant trials via access to surgically excised tumor tissue. We expect that the totality of these data should provide greater insights, allowing us to further develop additional programs in the IL-2-based CUE-100 series in a streamlined and efficient manner. I will now hand the call over to Anish to discuss other advances in our pipeline and platform. Anish?

Thanks, Ken, and thank you all for joining us on this update call today. I hope all of you and your families continue to be safe and well. I'd like to further elaborate upon Ken's comments on emerging PD data from the current monotherapy trial with CUE-101. Now a direct measure of CUE-101's mechanism of action is its ability to engage and expand HPV-E7-specific CD8 T cells, which are a rare population as described in numerous previously published studies in literature. Slide 9 here shows additional examples of patients where increases in the E7-specific CD8 T cells in blood were observed postdosing with CUE-101. The left panel indicates full increase of the frequency of E7-specific CD8 T cells over the predose frequency in different patients. Notably, the patient from Cohort 4 with confirmed stable disease, that is patient 14 in this bar graph, also demonstrated increase of E7-specific CD8 T cells. We also evaluated for the proliferation status of tumor-specific CD8 T cells by staining for Ki-67, which identifies actively proliferating cells. And as demonstrated in the right panel on this slide, E7-specific CD8 T cells exhibited significantly more proliferative capacity than the non tumor-specific CD8 T cells. We believe that this particular observation, albeit a snapshot at a specific time period, supports the rationale behind the molecular design of CUE-101, which was intended to seek and selectively engage the tumor-specific T cell repertoire. We also believe these early observations in the peripheral blood compartment will be further strengthened with analyses that target tumor tissue where localization and activity of the anti-tumor T cells is most evident and relevant. Slide 10 recaps the key observations from totality of the emerging data, including the points that Ken stressed with our clinical experience with CUE-101 thus far. We believe that the current progress with CUE-101 in the ongoing Phase I trial demonstrates clinical proof-of-concept for the broader Immuno-STAT platform. We continue to demonstrate tolerability at the current higher dose levels. We continue to observe dose proportional increase in exposure of CUE-101 that enhances its ability to engage and act upon the desirable population of immune cells. The sustained exposure of CUE-101 upon repeated dosing in the same patient supports our belief regarding the absence of drug clearing antidrug antibodies. Early metrics of PD activity in tumor-specific T cells continues to strengthen our belief regarding the on-target activity of CUE-101. And finally, the early evidence of clinical activity, albeit still in the dose escalation stage of the trial, provides support for mechanistic activity. To the last point, it's important to remind ourselves that CUE-101 by design has no direct impact on the survival or proliferation of the target tumor cells. Rather CUE-101 acts via an intermediary cellular immune compartment that must exert pressure on tumor growth and survival. Hence, the measured signals of PD activity of CUE-101 on the immune cells, including the tumor-specific CD8 T cells as described earlier, further bolster our confidence in this molecule. Moving along, Slide 11 highlights key emerging data sets from other studies that provide additional support for the mechanism of action of CUE-101. First, the specificity of E7, similar to what is targeted by CUE-101, is very pertinent for antitumor immunity in HPV-driven epithelial cancers. In a TCR T cell therapy approach, infusion of large numbers of ex vivo manufactured T cells expressing a TCR for the E7 antigen is able to target HPV-driven cancers. Secondly, recent data with adoptive TIL therapy demonstrates that head and neck tumors harbor tumor-specific T cells. And lastly, a recent paper in Nature Methods from Drs. Hidde Ploegh and Steve Almo, who is the co-founder of Cue, demonstrated that the core scaffold of an Immuno-STAT can localize into solid tumors and directly engage HPV E7-specific T cells. The last point is a significant mechanistic differentiation for the Immuno-STAT platform. Taken together, the data support the target specificity of CUE-101 and its potential to directly engage and activate tumor resident T cells. As mentioned previously by Ken, our planned neoadjuvant trials in localized head and neck cancer patients is an attractive opportunity for us to evaluate this activity of CUE-101 in the tumor microenvironment. I'll now move on to Slide 12 to further elaborate the progress with our broader pipeline and assets. Our next asset from the IL-2-based CUE-100 series is CUE-102, which targets Wilms' Tumor 1 or WT1, a well-recognized oncofetal antigen for cancer immunotherapy. We've made significant progress with this program with recently preclinical data highlighting activity of CUE-102 with primary human T cells disclosed at the SITC meeting last week and at the earlier AACR meeting. We currently anticipate IND filing for this program with the HLA-A*02 allele in the fourth quarter of 2021. In addition to CUE-102, we've also made significant progress with our KRAS G12V program that is initially focused on HLA-A11. We've successfully generated HLA-A11 Immuno-STATs expressing the mutated KRAS glycine 12 to [ bailing ] T cell epitope and we've observed that these Immuno-STATs can activate T cells expressing KRAS G12V-specific TCRs. Data demonstrating this activity was also presented at SITC. We anticipate initiating IND and labeling activities for this program in early 2021. Besides the CUE-100 series programs, we continue to make solid progress with our Neo-STAT platform, which allows us to generate a core generic scaffold for any HLA via a single cell line and then use the scaffold to conjugate various epitopes of interest based on the disease to generate therapeutic candidate molecules. We anticipate that the fact that only a single scaffold needs to be generated will save us significant resources in both time and cost for generation of clinical-grade material for any new program. And lastly, via our collaboration with Merck we continue to generate data demonstrating the road for Immuno-STAT in modulation of autoreactive T cells. In wrapping up the R&D update, I'd like to reiterate that the Immuno-STAT and, by extension, the Neo-STAT platform, are designed to address a fundamentally immunological challenge, which is how does one maintain selectivity and specificity of a desirable response without breaching or compromising patient safety or creating toxicities. We believe the data emerging to date both from the clinical and our preclinical assessments supports our approach that is built upon rational protein engineering that offer a very promising solution to patients suffering from cancers, autoimmune diseases and threats from pathogenic infections. With that, I'll now pass the call over to Kerri-Ann Millar, the Chief Financial Officer of Cue Biopharma. Kerri?

Thank you, Anish. Turning now to Slide 13. I'd like to provide a brief update on our financial results for the third quarter ended September 30, 2020. We finished the quarter with approximately $91.8 million in cash, cash equivalents and marketable securities and working capital of approximately $79.3 million. During the third quarter of 2020, we extended our cash runway with $14.3 million from the sale of shares of common stock under our aftermarket equity offering through Stifel, Nicolaus & Company, who acted as our sales agents, bringing the total raise through ATM equity offerings for the 9 months ended September 30, 2020, to approximately $56.7 million. We believe our cash, cash equivalents and marketable securities as of September 30 will allow us to support the development of our Immuno-STAT platform, including the clinical development of CUE-101 into the second quarter of 2022. We recorded collaboration revenue of approximately $704,000 from our collaborations with Merck and LG Chem during the third quarter of 2020, which is a decrease of approximately $280,000 from the same period in 2019. Research and development expenses were $7.5 million for the quarter ended September 30, 2020, as compared to $5.3 million for the same period in 2019. This increase in R&D expenses was primarily due to an increase in clinical trial activity, drug manufacturing costs and stock-based compensation expense. These increases were offset in part by a decrease in travel expenses due to the COVID-19 pandemic, which continued to hamper travel throughout the quarter. General and administrative expenses were $3.3 million for the quarter ended September 30, 2020, as compared to $2.8 million for the same period in 2019. This increase in G&A expenses was primarily due to increases in stock-based compensation expense and legal fees incurred in the third quarter of 2020. Despite the ongoing challenges presented from the COVID-19 pandemic, we've continued to enroll patients in our clinical trial and have extended our cash runway through disciplined spending and investor support via our ATM facilities with Stifel. 2020 has presented everyone with a variety of challenges, and I'm really impressed with the creativity and the discipline that we have applied to our business operations throughout the year that has allowed us to end this year in a strong financial position as we plan for a successful 2020/21. I'll now turn the call back over to Dan for closing remarks.

Thanks, Kerri. Since our last update call, we've made considerable progress with our ongoing Phase I dose escalation trial of CUE-101 as well as our pipeline. Importantly, we continue to demonstrate dose-dependent exposure, evidence of PD activity and tolerability at the higher dose levels. Furthermore, we're observing early signs of monotherapy clinical activity, including 4 patients with confirmed stable disease. One of these patients with confirmed stable disease, which is from Cohort 4, remain on study for 21 weeks. Presently, there are 7 patients remaining on study. 4 out of 5 patients from Cohort 5 remain on study with 2 of these patients remaining on study after 14 weeks, and all 3 patients from Cohort 6 also remain on study. Having advanced our trial to the current higher dose levels, demonstrating enhanced and longer exposure of CUE-101, we believe we are now beginning to see more robust evidence of clinical activity that will guide us to determining a recommended Phase Ib expansion dose and defining the Phase II starting dose. And to this point, we're pleased to have begun screening to enroll frontline therapy recurrent metastatic head and neck cancer patients in our Phase I trial of CUE-101 in combination with KEYTRUDA at a starting dose of CUE-101 at 1 milligram per kg. As these frontline patients typically have less compromised immune systems, we believe CUE-101 has the potential to improve upon the objective response rate reported for KEYTRUDA as monotherapy in this patient population. With 7 patients currently on study in patients being screened for enrollment in Cohort 7 as well as expanding enrollment of Cohorts 5 and 6 and commencing the combination trial with KEYTRUDA, we expect that in the coming months, we'll be generating important and informative data. Based upon PD and clinical activity we've observed thus far at these higher dose levels as a monotherapy as well as the launching of the combination study with KEYTRUDA, we believe we're now very well positioned to clarify the paths forward in clinical development. With that, I like to thank -- I'd like to close by thanking our employees, our Board of Directors as well as our shareholders for supporting these important activities. With that, we'd like to open the line for questions. Operator?

[Operator Instructions] Our first question comes from the line of Ren Benjamin with JMP Securities.

Congratulations on the progress. Maybe just starting off with the 101 study. When we're looking at the activity in expansion cohorts 4, 5 and 6 without an RP2D, I'm kind of curious, why even bother expanding in 4, 5 and 6? What exactly are you seeing that got you intrigued that wants you to flesh out those doses? Any sort of color to help us understand that?

Ken, do you want to take that question?

Yes. Thanks for the question. So again, the idea here is that we may not see a maximally tolerated dose. And we have to define the biologically effective dose. And that is going to require us to potentially look at we wanted the ability to look at more than 3 patients at any dose level. And the idea is we don't know if that's going to be dosed -- Cohort 4 or Cohort 6, and we wanted to be able to collect enough data to have enough confidence to pick that expansion dose without compromising our data from the standpoint of [indiscernible]. We don't see toxicity. What is sort of the minimally effective dose? Do we see more in 6 than in 4? Do we see the same as in 4 as in 6 as far as PD? So we use this Bayesian statistics approach to give us -- and we chose 9 there because that would give us the power to tell us if there's differences between the cohorts. And I want to emphasize, we haven't lost time by doing that because we're enrolling -- and backfilling the cohorts as we have patients already scheduled to get the next doses of the higher level. So we have for example, 3 patients scheduled for Cohort 7 already. As patients become available, we want to treat them, and so we'll start backfilling Cohort 6. And as we get data, we'll decide between -- what we're looking for, Ren, is we're really looking for the dose that's going to give us the biologic activity, clinical activity, but we also want to know what that minimum dose is. And that's why we're doing multiple different cohorts per se.

And just as a follow-up to that, Ken. Are there any other metrics, since you are expanding here, that you might try to flesh out? For example, I don't know, patients that are less refractory or have had less prior treatments in each particular cohort? Or anyone with a particular biological signature? Or not really, it's just kind of all comers?

Well, it is all comers because we can't constrain really what our -- who our [ PIs ] want to put on. We do track for every patient, how many pretreatments they've had. We also track -- they've all basically received checkpoints. So we look at how many doses of checkpoint they got, when was their last checkpoint dose, to see if that's at all relevant. So far, we don't have enough data to say if anything is more relevant than the other. But we are looking at what patients were dosed with before and when they were dosed with those agents. Obviously, we would like to get as healthiest patients as possible, but we're not trying to constrain to say, "Oh, you can only have been treated with 1 drug" or something.

Got it. And then just a second question regarding the combo trial. Can you talk a little bit about -- the trial has started, when you expect to begin enrolling patients? I know you're going through prescreening, but any sort of color as to how this is likely to evolve? And are the same sites that are currently participating in the monotherapy study also involved in this combination study? Are there new sites as well?

Yes. So thanks. Yes, there are no -- all the sites that are enrolling in -- for monotherapy are also enrolling for this -- for the combo study. And the only site that's not open for enrollment yet is Hopkins because they came on late, but -- so they will be the only additional site per se. But all the sites that have been part of the monotherapy agreed to do the combo and we really didn't feel like we needed more sites at this time. Literally, we're -- actively have patients in screen and so the first patient to get through screen will -- could go on study anytime. So I'm hoping one of those patients in screen passes and then we'll start treating.

Our next question comes from the line of Mark Breidenbach with Oppenheimer.

Congrats on the progress. Just a few questions from us on some of the new pharmacodynamic data, probably everything is on Slide 9. I'm just wondering how you settled on C1D8 as the best time to collect peripheral T cells? And is the timing of T cell collection impactful on the PD analysis?

Yes, Mark. This is Anish. Thanks for the question. So Mark, as you remember from our earlier assessments, we've been looking at day 21, which is still our main time point for sampling every 3 weeks, just basically from logistics and convenience, the patients coming in to receive the cycle of dose, so before they get the next dose. We have started to look at the earlier time points as you picked up on day 8, primarily from some of the samples we've been collecting, and it appears that we can detect these cells there. And that's going to be a key area of focus as we continue to sort of build out this data set. But including with the proliferative sort of Ki-67 positivity that one can only detect at that early time point, as you well can imagine, because by the time we get to 21, it's an expansion and contraction phase. So by that time, the proliferative potential is not at its peak. In fact, it's waned away. So we believe that these sort of time points of analysis that we've started will now -- could be very relevant as we continue to build out the data sets.

Got it. And it's really nice to see a high proportion of HPV-E7 specific cells expressing Ki-67. I'm just wondering, just to be sure, are you seeing an increase in Ki-67 of that [indiscernible] themselves from baseline to posttreatment? Or can it not be measured pretreatment?

For some of them, Mark, they are not detectable. And for some of them, they are present at pretreatment, but the Ki-67 status goes up. So we have patients in both categories. But clearly, there are instances where you don't see anything at baseline, you see an uptick via the tetramer staining then you can gate on those and see what their status is. And you picked up on a very important point, which is this is exactly what one would expect, Mark, if the IL-2 was hopefully selectively delivered to what is still, by percentage of it, is a minor subset compared to the total CD8s simply by precursor frequencies. But it's nice to see that validation, and we would agree with you with that this sort of further validates the molecular rationale behind the build of being able to target this sort of an IL-2 variant to hopefully a very relevant repertoire. And that's a big differentiation we think also from the not alpha emerging landscape where even though the not alpha liability has been dialed out, the fact is you still have something that is equally available to every T cell.

And then just 1 quick follow-up on that. How would you say that the degree of Ki-67 positivity compares to what's achievable with other not alpha IL-2 variance? And would you expect sort of a correlation between Ki-67 status and clinical activity?

I would imagine, Mark, as we build this out, that's exactly the kind of relationship and activity we would like to understand better. But in some of these cases, and again, I qualified this by simply that this is a day 8 snapshot, Mark, simply because we don't have the luxury of getting it every single day. So whether there's something that peaked at day 6 or day 7, and that's now trending down, we're catching a snapshot here. So that is something we all have to consider. It's experimental medicine, as you well appreciate. But we do think that with the differentials that we're seeing here and continuing to build out the data set, we hope that not only that this continues to sort of strengthen, but there are then correlates hopefully with the company activity that one can start to tease apart, to the point that Ken made earlier on why one would want to continue to expand on these particular dose cohorts as we continue to dose escalate.

Our next question comes from the line of Madhu Kumar with Robert W. Baird.

So first one is kind of just making sure I understand the pembrolizumab combo trial. So it's in people who have not received PD-1 before, but they can have received prior platinum-based chemotherapy, correct?

That is correct. A lot of those patients will have seen platinum-based therapy around the time they were first diagnosed in the adjuvant -- neoadjuvant and adjuvant setting. But the likelihood is that the majority of them will not have received platinum in the first-line setting that they will be patients who will have gone to pembro as first line, and we will treat them with CUE-101 plus pembro in that setting.

Okay. So that's important. Then you would expect that there would be some split, but you'd expect most patients to receive no prior systemic therapy, no platinum chemotherapy kind of beforehand. Is that correct?

Not in the metastatic setting, no. Correct.