CUE - NASDAQ

Greetings and welcome to the Cue Biopharma Update Call. At this time, all participants are in a listen-only mode. A question-and-answer session will follow the presentation. [Operator Instructions] As a reminder, this conference is being recorded. I would now like to turn this conference over to Mr. Dan Passeri, Cue Biopharma's Chief Executive Officer. Thank you, sir. You may begin.

Thank you, and good afternoon everyone. Just to remind you, as we proceed through the presentation we'll convey which slide we're on and you can advance the slides directly. We appreciate your time and interest in our update call regarding our ongoing trials of CUE-101, as well as CUE-102. Our initial representative drug candidates of the IL-2-based CUE-100 series. Joining me on today's call is Dr. Anish Suri, our President and Chief Scientific Officer; Dr. Ken Pienta, our Acting Chief Medical Officer; and Dr. Matteo Levisetti, our Senior Vice President of Clinical Development; and Kerri Millar, our Chief Financial Officer. This conference is being recorded and will be available on our website for the next 30 days. As a reminder, and as shown here on Slide #2 of this presentation. An overview may contain some forward-looking statements, and any forward-looking statements made during the call represents the company’s views only as of today, August 23, 2022. So Our agenda for today's call is shown on the next slide. As an introduction and each will provide a synopsis of our progress to date, as well as describing our strategic and competitive positioning prior to turning the call over to Ken and Matteo who will each provide a summary and status update of the data associated with observations from our ongoing Phase 1 trials of CUE-101, as well as the recently initiated CUE-102 trial. Following Ken and Matteo, I'll provide an overview of our corporate strategy and additional pipeline expansions within the CUE-100 series. Kerri will then provide a brief update of our financials, after which I'll return for closing remarks and then open up the call for a Q&A session. With that, I'll now pass the call over to a Anish.

Thanks, Dan. I'd like to start today's presentation by reminding folks of the genesis of our company's quest and the mission we seek to accomplish. Our mission is to address a very fundamental and consequential question for immunotherapy, which is, can we selectively and specifically activate anti-tumor T-cells, while avoiding the carpet bombing of the immune system to maximize efficacy and minimize toxicities. This is a very basic yet fundamental distinction from how other may be approaching the challenge of turning the immune system against cancers. To accomplish our objective, as shown in Slide 4, we envisioned exploiting the one unique marker of an anti-tumor T-cell, which is the tumor-specific T-cell receptor or TCR. We have engineered an innovative biologics platform termed Immuno-STAT, that generates TCR selective engages to deliver immune activating signals to tumor-specific T-cells. The figure on the left in Slide 4 depicts the core structure of an Immuno-STAT, which is essentially an antibody FC-based biologic containing stabilized tumor peptide HLA molecules to selectively target tumor-specific T-cells, along with desirable activation signals that are consumed by those T-cells. This framework provides a molecular basis for improved specificity for anti-tumor T-cell activation, while minimizing off-target toxicities due to systemic immune activation, which by the way, it continues to be a key impediment for many other broadly targeted immunotherapeutic approaches. On the right side of this slide, you can see a figure depicting the CUE-100 series, which is designed to selectively deliver IL-2 to tumor-specific T-cells over a relevant T-cell, hence generating a therapeutic index for IL-2 which as of yet has been a challenge. We believe this is a superior approach for harnessing the fullest potential of IL-2, especially since the tumor specific T-cells are present in a very low frequency. Our current clinical candidates, namely CUE-101 and CUE-102 are derived from the CUE-100 series and share the core IL-2 framework as depicted here. The next slide, Slide 5 summarizes the key and impactful takeaways that highlight the progress and clinical validation of our approach. Ken and Matteo will provide detailed insights into the clinical data and patient benefit that support the conclusions noted here. To summarize, we have engineered a novel biologics platform Immuno-STAT for selective targeting of anti-tumor T-cell activation. As an initial drug construct, we chose to deploy IL-2 as the targeted activation signal. IL-2 is a well-characterized and validated therapeutic target, but has suffered from significant safety liabilities due to lack of a therapeutic index. We have successfully generated a therapeutic index for IL-2 as evidenced by the fact that we have observed clinical activity between 1 mg per kg and 4 mgs per kg and have dosed up to 8 mgs per kg with no MTD. Most other IL-2 variants that are in the clinic have been dosed in the low-microgram per kilogram range due to unwanted adverse side effects. Our first clinical candidate, CUE-101, targets IL-2 to HPV specific T-cells to attack HPV-driven cancers, such as head and neck cancer. Our clinical experience with CUE-101 highlights several important findings for our technology platform. Our molecules are well tolerated with no evidence of systemic IL-2 toxicities, such as vascular leak syndrome or cytokine storms. The exhibit drug-like properties, including favorable PK, on target PD signals and monoclonal antibody like manufacturability to support desirable cost of goods. We have demonstrated clinical efficacy as monotherapy in late-stage cancer patients that have failed numerous prior therapies, including checkpoint inhibitors. Ken and Matteo will describe these signals in detail, including an emerging benefit in overall survival. The observed clinical benefit is supported by mechanistic signals demonstrating T-cell infiltration, which catalyzed our ongoing neoadjuvant trial in head and neck cancer. We have evidence prolonged benefit and anti-tumor activity in patients remaining on therapy for long periods, which underscores the extended kinetics for evolution of a beneficial immunotherapy response, as also noted previously by others. And lastly, early data from our first clinical experience in combo with the checkpoint inhibitor supports the potential for significant expansion of patient benefit. All these metrics will be described in greater detail in the ensuing clinical discussion. Importantly, since the core IL-2 framework is conserved across the CUE-100 series, we believe the clinical derisking obtained by CUE-101 has essentially derisked our entire platform. The recent IND acceptance for our next clinical candidate CUE-102 targeting Wilms’ Tumor 1 or WT1 underscores the strategic advantages of platform derisking accomplished by CUE-101. The FDA accepted the CUE-102 IND with no requirement for preclinical talks and has authorized us to initiate the trial at 1 milligram per kilogram, a dose that has demonstrated clinical activity in the CUE-101 trial and is a significantly higher starting dose than the 0.06 mg per kg starting dose for CUE-101. These metrics highlight the resource, time and operational efficiencies gained by the platform derisking by CUE-101. To end, we believe the modularity of our platform, coupled with the clinical validation, positions us to generate a rich repository of therapeutic molecules targeting many cancers. As one evaluate the potential of IL-2 per cancer immunotherapy, we believe our platform has cracked the code for selective targeting of the cytokine to the tumor specific T-cell repertoire. Dan will address this in context of our corporate growth strategy towards the end of today's presentation. With that backdrop, I'll now pass the call to Ken for the clinical update. Ken?

Thanks, Denise, and good afternoon to all listening to this call. We're excited to be presenting our updated data from the ongoing CUE-101 Phase 1 trial as both a single agent monotherapy and third-line and beyond head and neck cancer, as well as the encouraging emerging early data from the combination study with pembrolizumab in first-line patients. As previously and consistently stated, we believe CUE-101 Q1 mechanism of action is evidenced by the ongoing data generated to date provides effective and tolerated dose levels enabling selective stimulation of tumor specific T-cells. Recurrent head and neck cancer is a tough incurable disease. The data we have observed throughout the monotherapy trial enhances our confidence that CUE-101 is stimulating cancer specific T-cells in a subset of these patients with a resulting anti-tumor effect. Furthermore and more importantly, we continue to observe an evolving trend of enhanced survival. And while this data is still maturing, we are encouraged by the observations to date. Clinical observations beyond overall response rate and median overall survival continue to bolster our confidence in the anti-tumor effect in CUE-101. For example, we have observed patients experiencing tumor reduction after prolonged periods on drug where no [resistance] (ph) based objective response was initially observed by imaging. This observation consistent with observations made by other demonstrates the kinetics of T-cell anti-tumor activity that manifest over a longer period of time. This pattern can be seen in the tumor measurements plotted out on Slide 6 for a patient receiving CUE-101 at 2 mg per kg where we can see that the first several months appear to demonstrate tumor growth even beyond the 20% threshold used by resist criteria. However, we -- based on the overall clinical status, the patient was continued on treatment after we changed the protocol to allow this. So after approximately six months the tumor began to shrink and the patient remains on therapy 14 months after starting treatment with CUE-101. The data presented on Slide 7 from a patient treated with RP2D at 4 mg per kg demonstrates stable disease lasting close to 12 months and ongoing with sustained reductions of cell free HPV-DNA, a biomarker that may reflect disease activity in patients with HPV-positive cancers. And in fact, this is a test that is increasingly being used by experts to guide treatment in these patients. This may represent a pattern suggestive of a pathologic CR. Taken together, these data build our confidence in the therapeutic potential of CUE-101 and in the potential path forward for registration study as a monotherapy in patients that have failed prior chemo therapy, as well as checkpoint inhibitor therapy. We plan to present additional data at an upcoming medical meeting. I'll now turn this over to Matteo to talk more about this and our other data. Matteo?

Thanks, Ken. The goal in our CUE-101 monotherapy study was to first prove safety for this first in man biologic, and second to prove that we could demonstrate activity. In addition to the data just described by Ken, we have observed in our 20 treated patients at the recommended Phase 2 dose in our monotherapy trial, one PR and seven patients with durable stable disease for an overall clinical benefit rate of approximately 40%. The next slide, Slide 8 shows the patient with a PR and they're supporting pharmacodynamic metrics. This heavily pre-treated patient has completed 17 cycles of CUE-101. You can see in the two upper right panel that the patient demonstrated a nine-fold increase in cancer specific T-cells, but did not demonstrate an increase in the general CD8 positive T-cell population, which might cause unwanted side effects, including immune related adverse events. The patient also demonstrated a transient and modest increase in Tregs that return to baseline by day 15. Patient demonstrated a sustained increase in NK cells, a positive attribute for an anti-tumor response as the NK cells may assist in tumor killing. We observed similar pharmacodynamic effects across many patients. On the lower right portion of the slide is a graph showing a rapid decrease in circulating cell-free HPV DNA, corresponding with the decrease in tumor burden observed by imaging. We had made the same observation with several other patients who have demonstrated antitumor activity and continue to monitor cell-free HPV DNA as a possible predictive biomarker. The next slide, Slide 9 conveys our ongoing survival [swimmer] (ph) plot for the 20 patients dosed with the recommended Phase 2 dose of 4 milligrams per kilogram. We have taken the liberty to draw a median overall survival line at eight months, which is reflective of the median overall survival observed in both the KEYNOTE-40 and CheckMate 143 trials of pembrolizumab and nivolumab in second line patients. As any experienced oncologist understands the survival with third-line treatment is expected to be less, as the disease has further developed and become more unstable. Our evolving data continues to support the premise that treatment with CUE-101 is clearly trending to increased survival in the third-line setting for patients with head and neck cancer. This data has encouraged our principal investigators and they are aligned with our position that this potentially provides us with a promising path forward to a registrational trial. The demonstration of monotherapy activity bolsters our belief that we should see complementary mechanistic effects in combination with pembrolizumab. As a reminder, the data from patients treated in monotherapy clearly supports that CUE-101 increases the number of antigen specific T-cells. It is likely that these T-cells will have greater freedom to kill with inhibition of the PD-1 pathway, a major mechanism used by cancer cells to prevent immune-mediated killing. Slide 10 demonstrates the spider plot. As shown at ASCO this past June of first-line patients treated in the dose escalation cohorts of the ongoing study. Early data and signs of activity of CUE-101 in combination with pembrolizumab are encouraging. With one patient each in cohorts 2 and 3 experiencing a confirmed PR and an additional two patients experiencing durable stable disease. We are continuing to expand patient enrollment at the recommended combination Phase 2 dose and look forward to presenting additional data at an upcoming meeting. Slide 11 shows the patient from cohort 2 demonstrating a decrease in all four of their target lesions, including two liver lesions. I want to emphasize that this is not just shrinkage in lymph nodes, but shrinkage of visceral tumor disease. To any oncologist this is a significant and meaningful response. This patient has also demonstrated a clearing of the circulating cell-free HPV DNA, which is ongoing. As mentioned before circulating a tumor DNA continues to be developed and used by our principal investigators as a potential surrogate for response. As shown in Slide 12, the patient with a confirmed partial response from cohort 3 also demonstrated reductions in all four target lesions, including two [indiscernible] lung lesions and clearing of their circulating cell-free HPV DNA. We are excited by the preliminary data in this ongoing combination study, along with maturing data from our monotherapy and new adjuvant studies and look forward to presenting additional data at upcoming meetings. I'm also happy to report that we have treated our first patient with CUE-102, which targets Wilms’ Tumor 1 positive tumors in a trial that is enrolling patients with advanced colorectal, gastric, pancreatic and ovarian cancers. As shown on Slide 13, CUE-102 and CUE-101 shared 99% amino acid sequence identity. This enabled us to significantly increase the development time and cost of CUE-102 as we were not required by FDA to repeat IND enabling toxicology studies for CUE-102 and we are also able to initiate the Phase 1 dose escalation study at 1 milligram per kilogram, the dose at which we observed clear signs of biologic activity with CUE-101. As Slide 14 shows and as mentioned just a moment ago, we are performing the CUE-102 dose escalation study in colorectal, gastric pancreatic and ovarian cancer patients. This designed offers us the ability to do monotherapy expansion studies in all -- any or all of the indications being evaluated in the dose escalation phase of the trial. This trial is actively accruing and will be opened at 15 sites around the US. I will now turn the call over to Dan to talk more about our pipeline. Dan? Yeah. Thanks, Matteo. As just described by Anish, Ken and Matteo, we've made significant progress towards the establishment of CUE-101 and by implication, the entire CUE-100 series as a breakthrough therapy for stimulating patients’ immune system against cancer. And remind you that stimulating the immune system directly in the patient’s body. As we continue to progress forward with CUE-101and CUE-102 as our lead programs, we also have the potential to rapidly expand our pipeline and productivities as conveyed in the schematic shown on Slide 15. However under the current market conditions where capital is constrained and resource prioritization is paramount, we've streamlined our operational footprint and taken prudent measures to foster a focused and strategic prioritization of clinical development and those activities associated with pipeline development, fostering strategic partnership. Our core approach is to validate and derisk the IL-2 based CUE-100 series through the emerging data and associated metrics from our ongoing 101 and now 102 clinical trials and position ourselves with greater leverage for retained value creation for our shareholders. We have promising preclinical data from our KRAS program, which is an extremely important target covering a broad set of cancers with expanded allele coverage into HLA-A03 and HLA-A11 and have preserved this clinically important program for potential strategic partnering to be catalyzed by our emerging data from our 101 trial and our 102 trial, as well as a possible registration submission in 101. We have also positioned ourselves for enhanced productivity and efficiencies with the development of CUE-100 series derivative, referred to as Neo-STAT entailing a stabilized molecule as the MHC HLA binding pocket with the epitope fits in, that's been stabilized for covalent chemical attachment of an identified cancer epitope. This will allow for the manufacturing of each allele framework, for example, HLA- A02, A03, A11, et cetera, with an empty binding pocket, whereby the epitope may be subsequently attached chemically rather than made as a single fusion protein. This will provide us with cost savings, production efficiencies and greater flexibility for epitope selection in combination, such as in the case with tumor instability and heterogeneity. Furthermore, we envisage that Neo-STAT may be an enabling innovation to realize the potential of personalized cancer immunotherapy where one could sequence the tumor and identify particular epitopes and chemically attach those to a Neo-STAT. So while we are currently prioritizing and strategically focusing internal efforts on the development of our CUE-100 series drug candidates for treating cancer, we're also actively engaged in strategic discussions with third parties to further develop CUE programs outside of oncology, including the CUE-400 series for treating autoimmune disease. These activities aim at ensuring optimal use of our internal resources on our most advanced programs, while augmenting and enhancing our capacities with third-party relationships to further develop promising assets beyond our core focus. I'm now going to turn the call over to Kerri, who will provide a brief overview of our current financials and I'll then return to briefly provide some closing summary remarks prior to opening the call up to questions.

Thanks, Dan. Turning now to Slide 16, I'd like to provide a brief update on our financial results for the three months ended June 30, 2022. The Company reported collaboration revenue of approximately $26,000 and $2.7 million for the three months ended June 30, 2022 and 2021, respectively. Research and development expenses was $9.6 million and $8.8 million for the three months ended June 30, 2022 and 2021, respectively. The increase was primarily due to an increase in laboratory and drug substance manufacturing costs, as well as clinical expenses related to our CUE-102 Phase 1 dose escalation clinical trial that was initiated during the second quarter of 2022. General and administrative expenses were $3.8 million and $4.3 million for the three months ended June 30, 2022 and 2021, respectively. The decrease was due primarily to a decrease in stock-based compensation and professional and consulting fees incurred during the second quarter of 2022 as compared to the same period in 2021. We ended the quarter with approximately $66.1 million in cash and cash equivalents and working capital of approximately $60.7 million. Importantly, we took proactive steps to decrease the company's office and lab footprint and restructure specific functions, which will afford us significant cost savings that can be allocated to our clinical programs. We believe our cash and cash equivalents as of June 30, 2022 will allow us to support the development of our Immuno-STAT platform, including the clinical development of CUE-101 and CUE-102 through the through the third quarter of 2023. I'll now turn the call back over to Dan for closing remarks. Dan?

Yeah. Thanks, Kerri. As you've heard on this call, we continue to execute and make significant progress towards further advancing our lead and representative candidate CUE-101 towards a potential path for registration. And through the clinical development of 101 we've clearly demonstrated the ability to selectively target and activate defined anti-tumor T-cells, while not compromising patient safety. As seen on Slide 17, we have successfully executed and continue to execute on defined strategies providing risk reduction and validation of the CUE-100 series and its derivatives. As such, CUE-101, which is targeting the HLA-A02 allele has clearly demonstrated tolerability and single agent activity. And remind you, with no maximum tolerated dose emerging from the dose range of 0.06 mgs per kg, all the way up to 8 mgs per kg. We've seen clear evidence of pharmacodynamic effect on targeted tumor specific immune cells, that is T-cells as well as natural killer cells, obviously, the properties that we want to see in the immune compartment. Clinical activity demonstrated from 1 mg per kg to 4 mgs per kg with 4 mgs per kg being our recommended Phase 2 dose. And clear evidence of anti-tumor activity, which we've gone through some of these data showing of a prolonged effect having to do with the kinetics of the stimulating the immune system, immune system then dynamically interfacing with cancer. So clear evidence of that anti-tumor activity manifested as a confirmed PR, seven durable longstanding stable disease with one potential pathologic complete responder that Ken reviewed. Also we appear to be providing a survival benefit, this obviously needs to be determined as to what the median overall survival is, but it is clearly trending in a positive direction, and we believe it will provide us with a potential path forward for registration. 101 in combination with pembrolizumab is showing encouraging early signs of activity, which we look forward to presenting further details at an upcoming medical meetings later this year. CUE-102, the IND was accepted at 1 mg per kg starting dose and we consider this to be a major achievement, basically underscoring the quality of the supportive data, but also kind of underscoring the risk reduction and validation that we believe we've achieved with the data emerging from the 101 trial. We have evidence of -- any evidence, I should say, that emerges in the 102 trial of clinical activity will be a further catalyst for validation and value creation regarding the platforms analog nature and modularity. And just to remind you, Wilms’ Tumor 1 is expressed in a significant range of tumors representing a very significant market potential and multiple tumor types. So we believe those two programs add significant validation and value for our shareholders, and then coupled with Neo-STAT representing a derivative of the 100 series as a next generation construct providing scale and flexibility, one that allows us to address tumor heterogeneity, but also just as importantly, it should substantially decreased our cost of goods and provide us with flexibility that we may even be able to go into personalized medicine. And again, to remind you the attachment of the peptide is in the HLA pocket, that's a covalent attachment. We have attractive preclinical proof of concept data supporting that premise and look forward to providing you with updates as we continue to progress. We are positioned very well strategically and anticipate several important milestones throughout the coming year, including the potential of a registration path for CUE-101 as a monotherapy. These milestones has conveyed the next slide, include CUE-101 monotherapy with a median overall survival date by the end of the year. Clarifying, this is a potential start of registrational trial in the second half of ’23. CUE-101 plus pembrolizumab combination, the preliminary overall response rate data reading out in the second quarter of next year, ‘23 and the 102 monotherapy data, which we've just recently initiated, data from the dose escalation will be reading out mid-23. And to remind you that is a major significant market opportunity, so any evidence of clinical activity will represent a significant perspective value increment. Also and importantly as we focus our efforts and resources on the clinical development of 101 and 102, we believe that further clinical datasets will catalyze significant business development and corporate development opportunities for pipeline expansion. We look forward to providing further details on these trials at an upcoming medical conference later this year. We'd like to thank our employees and clinical principal investigators whose dedication to our mission through their commitment and professionalism allows us to continue progressing our goal of helping patients in need. And we'd like to thank our Board of Directors for their support and guidance. We want to thank our shareholders who provide us with the essential resources to continue this important work, developing promising immuno therapies for patients. And most importantly, we want to thank the patients who are participating in our trial and their families for their coverage and willingness to be part of clinical study, allowing us the opportunity to assess and determine the potential therapeutic benefit of our promising drug candidates. I'd like to thank you very much for your attention and interest. I'd now like to turn the call back over to the operator for questions.

At this time, we'll be conducting a question-and-answer session. [Operator Instructions] Our first question comes from the line of Stephen Willey with Stifel. You may proceed with your question.

Yeah. Good afternoon. Thanks for taking the question and thanks for the update here. With respect to the updated CUE-101 data, do you have a median duration of treatment at this point? I think it looks to be about two months just in terms of eyeballing it, but just wanted to know if that's correct? And then also, can you just broadly speak to post-study therapy that these patients may or may not be receiving following discontinuation of CUE-101and I guess your confidence that post-study therapy is not impacting extended OS time that you're seeing off treatment? And then I just have a quick follow-up on CUE-102.

Okay. Thanks, Steve. Ken, you want to take those questions?

Yeah. Hi, Steve. So the median therapy is two cycles, meaning half the patients got two cycles and came off. I would just point out that that's basically the same as second-line, we see what second line checkpoint inhibitors is. So it really comes down to what did those patients do as far as overall survival, because the progression-free survival just doesn't correlate as you know. As far as follow up therapies, we are still collecting that data and really don't have that to report yet. We do know some patients they haven't -- that are doing quite well off all therapies. So we just don't know that data yet. Sorry.

Okay. And then just on CUE-102, I know that dose escalation portion and presumably expansion is requiring WT1 antigen positivity. Is this just kind of like a binary yes/no type of assay that's, I'm guessing, IHC-based or is there some kind of graded expression that a clinic needs to have in order to be eligible?

Yeah. It is IHC-based and it is grated, but our sort of minimal requirement is that 1% of the tumor cells are expressing WT1.

Okay. I'll hop back of in the queue. Thank you.

Our next question comes from the line of Reni Benjamin with JMP Securities. You may proceed with your question.

Hey, good afternoon, guys. Thanks for taking the questions and congrats on the progress. Maybe just starting off, can we talk a little bit more about the biomarker data that you generated. I see the circulating -- sorry, the HPV-DNA going down considerably better, and then -- but the tumor shrinkage is occurring, but not clearly as much. And I think you may have called out a pathological CR. I'm not too sure if I understand how well that's being correlated. And so can you talk to us a little bit about that? Would you use that going forward? And what other sorts of biomarker activities are you planning for these studies, both for 101 and 102?

Okay. Ken, you want to take the first part of that and then have Matteo cover the second half.

Yeah. So essentially, what we're seeing is that, we have several patients with durable stable disease. And as you know, with the immunotherapy types of therapies, the IO type therapies, you often can see sort of a stabilization of disease that could be scar, it could be fibrotic tissue, it could be inflammatory tissue and we had the -- early on, we had the patient at 1 mg per kg who had stable disease and we ended up going to the operating room and seeing that patient and never has remained off therapy for now 14 months or 19 months. And then the data that we've been getting from these ongoing cell-free DNA assays, which didn't really exist when we started the trial, was that several of our TIs have started to follow virtually all of the patients with cell-free DNA to try and get some insight into their disease, especially when we don't know when somebody has an increase in their tumor, if that’s by resist, if that's more I resist, is that an inflammatory change that we should be following, what their cell-free DNA, is that going up or going down, suggesting it might be more inflammatory or with these stable disease patients do they have any active tumor left. And so, the data we talked about with this one patient who has very stable disease and the tumor is either just sitting there or what we think is not viable tumor is just sitting there like a scar and there cell-free DNA is zeroed out. So that suggests to us based on the other patients that that may be a pathologic CR if we took that out. And that is -- this whole area is evolving, especially in the head and neck cancer and our investigators are learning how to use cell-free DNA. It's not an accepted biomarker of response by the FDA by any means. But that's why we're trying to really figure this out and learn this and we are -- we don't have all the cell-free DNA back yet the data because we do and in batches. So we're very encouraged by it as a biomarker as our all of our docs, and we're going to continue to follow that and use that as a potential. We are talking about with one of our investigators in fact about doing an adjuvant study based on cell-free DNA responses in patients. I'll stop there and let Matteo talk about what we're doing with WT1.

Thanks, Ken. I believe that the questions have been well addressed at the point. I did want to add one comment regarding the previous question on the WT1 assay. Although we do use a binary results for eligibility, I just would add that we are paying very close attention and tracking both the nuclear inside of plasmic expression of WT1 by grade, so that we can correlate this data with potential patient outcomes.

And sorry, just kind of sticking with this thing for a second, are you seeing the converse accrue in that once patients are kind of progressing or off the study. Are you seeing HPV DNA – cell-free HPV DNA pick up in those patients as well or do they consistently stay low all the way through?

So, good question. What -- we don't have cell-free DNA on the patients after they come off study. We just are following them for survival and whatever therapies they have been on, et cetera. But what we can see is in patients who do progress there cell-free DNA actually will go up also. It's roughly correlates with tumor burden so we -- over it's dynamic, but that's why we're still learning about it as a biomarker, but we don't see people are truly progressing their cell-free DNA it does go up.

Yeah. I’d add as well, Ken, that this is an endpoint in the biomarker assessment that is gaining traction with FDA over the last 12 to 18 months. Whereas, it may be possible in the future to use it as a secondary endpoint and actually use it to inform decisions and adaptive trial design, but it's really not there yet. So that would an opportunity in the future to introduce that biomarker to sort of accelerate or perhaps enhanced decision-making in the next trial.

Got it. So second question is, when I look at the overall survival curves that you have, there are clearly those patients with durable FD, some obviously with partial responses. And then there are those that clearly have progressed. I mean they are surviving, right, but there -- I'm assuming that these that don't have a durable FD marker [indiscernible] their tumors are growing. And I guess the question I have is, have you guys been able to investigate what sort of mechanisms of resistance might be occurring? And as you think about that, what sorts of combination therapies are you thinking about that could maximize 101’s durability going forward?

Well, that’s the $1 billion question, it's a great question. We honestly don't know of the myriad of resistance mechanisms, which ones are at play. What I think is caught us, certainly surprise early on and caught all of our docs by surprise early on is, are these durable overall survival in these patients that are even have come off therapy fairly soon. I think obviously when we're increasing the number of cancer specific T-cells in the periphery and then the tumor itself, we're allowing for checkpoint therapies to work better. Certainly, we've seen some early indications of potential antigen spread which would suggest that combinations with further cytotoxic types of therapies that are going to increase neo-antigens to be seen by T-cells is certainly something that we'll consider in the future. As far as other mechanisms like HLA down-regulation, et cetera, we just don't know yet, we don't have that data, may be Anish wants to comment on this, but clearly we think there's going to be synergies. The obvious ones with checkpoints as well as with chemo.

Yeah, the only thing I'd add, it's a really important question, Ren, we have to look at these analysis. There has been all the way from operational resistance pathways because of the [TME] (ph) to cell types, to even the tumor intrinsically changing its immunogenicity profile, whether it is because of loss of HLA or loss of sort of components of antigen processing. We just need to sort of get a better grasp on this and that -- as a part of the ongoing analysis certainly enough in a sort of line of sight, we just need to gather the data and that will then dictate what possible other combinations can we bring in along with CUE-101 to further sort of extract even more benefit than what we've already started to see.

Got it. And just one final one for me. I probably missed this in the prepared remarks. I remember, we were talking about a neo-adjuvant study for quite some time and primarily what gotten me most excited about was the ability to have biopsy samples kind of before and after. I just wanted to get an update as to what was happening with that study.

So I'll give -- I'll make a few comments and then I'll probably turn it open turn it to Daniel to add on. So that study is going quite well at [indiscernible] when we've actually already recruited our first couple of patients, we got the biopsies in place, we've got plans in place to get a composite batch analysis going as soon as a few more patients are recruit, that's in locally advanced head and neck cancer, Matteo, please feel free to add more to it from your lens.

Thanks, Anish. That's really quite accurate. We've treated a bit more than a few, and we look forward to sharing the data in the future when it becomes available.

All right. Thanks guys.

Okay. Thank you.

Thanks, Ren.

[Operator Instructions] Our next question comes from the line of Mark Breidenbach with Oppenheimer. You may proceed with your question.

Hey guys, good afternoon and thanks for taking questions. Just a couple from me. First, with respect to upcoming interactions with the FDA, is the plan right now to have the end of Phase 1 meeting in conjunction with the availability of MLS data from your Phase 1 trial? And when can we kind of expect to hear their perspective on regulatory path forward? And then I guess I'm also just wondering why there looks to be kind of a gap between the availability of MLS data and the potential start of the registrational study? So that's one question for me. And the other one is just with respect to the CUE-102 trial. Does this protocol include a paired biopsy collections? I know that wasn't something that was included in the head and neck study. I'm just wondering if any changes have been introduced so we have more translational data from the CUE-102 patients.

Okay. So Ken, you want to take that?

Yeah. Sure, I can start with the question regarding the interaction with the regulatory agency. So as we've just covered here, we anticipate having a mature median overall survival data by the end of the year in the 20 patients dose at the recommended Phase 2 dose and we have designed a Phase 3 trial that we plan to present to FDA in the context of a subsequent registrational trial. And again, we're beginning to do preparations for such an trial at risk and anticipate that we could begin open that trial, which would be a global multi-regional trial sometime later next year.

[indiscernible] biopsies as well in the WT1 trial.

Yes. So we have -- you're absolutely correct. So we have made in the protocol paired biopsies optional. We've had a lot of productive conversations back and forth with investigators and we recruited some that are keenly interested and capable of arranging those. So we hope that in the tumor indications that we're enrolling in the 102 trial will have the opportunity to get paired biopsies perhaps in atomic locations in these indications that may be, if you will, more [indiscernible] and amenable to biopsy. But to your question, it is an optional procedure at this point, whereas in the new adjuvant trial by design we have an opportunity to examine pre and post-dose biopsies as a component of the patients interventional standard of care in the setting of locally advanced cancer that's undergoing resection with curative intent.

Okay. And just going back to the regulatory question. I just want to be absolutely clear, we wouldn’t hear until 2023 a regulatory feedback with respect to what a registrational trial might look like in head and neck cancer, is that correct?

I think that's correct. And I would say early 2023, of course, some of the interactions will really depend upon the timelines granted by FDA. But in this setting we're confident that requesting a Type B meeting request, but given where we are in the development that FDA would agree and be collaborative. So it's not to drive the potential of the development for this drug in this unmet medical need in third-line patients and beyond with head and neck cancer.

Okay. Thank you so much.

And -- this is Ken, we certainly I think the end of ’23 is our conservative estimate. We are -- we know what that trial, we want that trial to be -- as soon as we get the data we will be ready to go and hopefully be able to launch sooner at this point.

Got it.

Ladies and gentlemen, we have reached the end of today's question-and-answer session. I would like to turn this call back over to Mr. Daniel Passeri for closing remarks.

Okay. Thank you very much. I want to thank the research analysts for questions, very helpful and instructive. I just want to thank everyone for listening in and your ongoing interest and support of our activities and bringing these very promising therapies to patients. So thank you very much. Take care. And we look forward to providing updates throughout the year. Take care.