Thank you for standing by. This is the conference operator. Welcome to the Cue Biopharma First Quarter 2021 Earnings Call. As a reminder, all participants are in a listen-only mode and the conference is being recorded. After the presentation, there will be an opportunity to ask questions.

[Operator Instructions] I'd now like to turn the conference over to George Zavoico Vice President, IR and Corp Development. Please go ahead..

Thank you, Shannon. Good afternoon, everyone. Thank you for joining us. On today's are Dan Passeri, Cue Biopharma's CEO; Dr. Anish Suri, President and Chief Scientific Officer; Dr. Ken Pienta, Acting Chief Medical Officer; Dr. Matteo Levisetti, Senior Vice President of Clinical Development; and Kerri-Ann Millar, Chief Financial Officer. Next slide, please.

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 Factor section of the company's annual report on Form 10-K filed with the SEC on March 09, 2021 as well as other filings made by the company to 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, March 17, 2021 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. Live and archive versions of the event can be accessed via the company’s website for the next 30-days.

I'd now like to turn the call over to, Dan Passeri, Cue Biopharma's CEO.

Dan?.

Thanks, George. Good afternoon, everyone. And thank you for joining us today for a review of our ongoing progress, as well as our first quarter of 2021 financial results, which are available in more detail in our Form 10-Q filed with the SEC on May 10th. Our agenda for today's call is shown on the next slide, which is Slide 3.

I'll first provide a brief overview of ongoing progress since our last call, highlighting recent developments across our programs with an emphasis upon our lead clinical program CUE-101. After the introductory update, I'll turn the call over to Dr.

Anish Suri, he is our President and Chief Scientific Officer who will provide a summary of progress and additional platform developments, in both oncology as well as our autoimmune disease programs. After Anish provides an overview, Dr. Ken Pienta, our Acting Chief Medical Officer and Dr.

Matteo Levisetti, our Senior Vice President of Clinical Development will each provide a clinical update and review associated data on our ongoing CUE-101 Phase 1 monotherapy dose escalation trial.

Ken and Matteo will then turn the call over to Kerri Millar, our Chief Financial Officer, who will provide a summary of our financial results for the last quarter, and then I'll come back and provide a brief closing summary prior to opening the call for questions.

So to begin, I'd like to remind you of our foundational mission, which is stated on Slide number 4, which is to design, develop and bring to patients in need rationally engineered biologics that restore immune balance by harnessing nature's own cues, hence our name for selective and specific modulation of disease relevant T cells directly in the patient's body.

Through this approach, as shown here on Slide number 5, we aim to restore balance to the patient's immune system by activating targeted T cells in the case of oncology and infectious disease, or dampening or inactivating T cells associated with autoimmune disease. Again, Anish will provide further context and updates on these approaches momentarily.

I'd like to first begin with CUE-101, which is our lead drug candidate. It's currently in a Phase 1 monotherapy clinical trial, or a second line and beyond HPV positive recurrent or metastatic head and neck squamous cell carcinoma, and is representative of our Immuno-STAT platform, engineered for targeting and activating cancer relevant T cells.

Recently, we reported a confirmed partial response or PR, from the Phase 1 dose escalation part of the CUE-101 trial for a refractory heavily pretreated patients.

We view this resist confirmed partial response in the monotherapy dose escalation portion of the Phase 1 trial as an important de-risking event, providing evidence of the potential ability of single agent CUE-101 to selectively engage and modulate T cells in a challenging patient population.

While still early in development, we believe this promising data supports the potential of CUE-101, having a registrational path forward as a monotherapy in second line and beyond HPV positive head and neck squamous cell carcinoma patients.

As the drugs mechanism of action is based upon activating HPV E7-specific T cells, we also believe this recent data supports the premise that CUE-101 may also enhance patient reach in therapeutic benefit for frontline HPV positive head and neck cancer patients in combination with pembrolizumab or KEYTRUDA, which is currently a standard-of-care for these patients, who have a composites positive score, or CPS greater than one for PD-L expression.

The combination trial referred to as the KEYNOTE-A78 trial is presently enrolling patients, and we look forward to providing an update on this combination study at the next quarterly call.

In summary, we believe that the emerging data from the ongoing monotherapy trial have the potential to be transformative for Cue Biopharma, as it provides objective evidence of clinical activity as a monotherapy and a late-stage prior treatment refractory patient population.

We also believe that this data differentiates our lead drug product candidate CUE-101, as well as our drug candidate pipeline from competing IL-2 to modalities and vaccine programs. Ken or Matteo will provide further details on a compilation of supporting clinical data to date.

So, as we continue to generate data in our ongoing Phase 1 dose escalation trial, it's important to recognize that if favorable, these data provide risk reduction and validation for CUE-101, and also by implication, the entire IL-2 base CUE-101series. This principle is shown on the next slide, Slide number 6.

As demonstrated here on this slide, the underlying framework for the IL-2 base CUE-101series remains essentially the same across programs with the primary difference being the nine to 10 amino acid antigenic epitope in the MHC, our HLA binding roof.

Our second drug product candidate from the CUE-101 series is CUE-102, which targets the Wilms' Tumor one protein or WT1, which is an onco-fetal protein expressed in a number of solid tumors as well as hematological cancers, which is being developed in collaboration with our Asia territory partner LG Chem.

To expand patient reach and potentially address resistance mechanisms, we've also derivatized the CUE-101 series, providing us with Neo-STAT to address tumor heterogeneity, and redirected Immuno-STAT or RDI-STATs to address resistance mechanisms of HLA loss in tumor immunogenicity.

Importantly, we believe that positive clinical results for CUE-101 have the potential to provide mechanistic support for the entire CUE-100 series in derivative platforms.

First, Anish will provide an update on our drug candidate pipeline expansion, and provide an overview of the platform's modularity and flexibility to potentially address both oncology and autoimmune disease.

Following Anish's pipeline update, Ken and Matteo will provide a clinical update, including a discussion of the recent confirmed partial response.

Through focused execution of our corporate development strategy, we believe we are well-positioned to potentially demonstrate the transformative nature of our protein engineering approach, to provide breakthrough immunotherapies for patients in need of more effective therapeutics. With that, I'm now going to turn the call over to Anish..

Thanks, Dan. I'd like to start with a broad perspective on our platform and evolving pipeline, which should also provide a helpful context to the important clinical metrics, emerging from our current trial with CUE-101. To remind everyone, Slide 7, shows you the overall molecular structure of our IL-2 based CUE-100 series.

The CUE-100 series was designed with a key focus on the objective that the IL-2 activating signal was selectively delivered to tumor specific CDA T cells. The presence of bivalent tumor peptide HLA loaded molecules, which is Signal 1, as shown here, allows for selective targeting of tumor specific T cells.

This molecular scaffold is designed to potentially minimize systemic activation of non-tumor related T cells, which constitute the vast majority of the T cell repertoire in an individual. The four IL-2 molecules are conserved within the CUE-100 series, and have two key modifications.

One, abrogates binding to IL-2 receptor alpha, which avoids the bias towards regulatory T cells or Tregs, and minimize the safety liabilities. And the second attenuates binding to IL-2 receptor beta, which favors activity towards TCR engaged anti-tumor T cells.

As shown previously, and will be highlighted later in today's presentation of the clinical data, we have observed CUE-101 selectively activating tumor specific T cells. We believe this exemplifies the power and potential of targeted versus systemic approaches for cytokines, such as IL-2 for cancer immunotherapy.

In addition, a key strength of the Immuno-STAT platform is its versatility and modularity, with respect to swapping different tumor derived T cell epitopes to change the indication of interest.

As an example, CUE-101 targets HPV E7-specific T cells, while CUE-102, our next clinical candidate for which we anticipate filing IND in the first-half of 2022 targets Wilms' Tumor 1, as mentioned by Dan earlier. The majority of the molecular framework including the IL-2 molecules are identical between CUE-101 CUE-102.

The next slide, Slide 8, provides a more holistic view on the clinical experience of CUE-101, and its impact on various pipeline and platform enhancements.

We believe that the encouraging metrics with CUE-101 with respect to tolerability, favorable PK and exposure and PD data, and now tumor response clinical data support multiple therapeutic opportunities, as shown here.

First, as mentioned before, it is our belief that the Immuno-STAT pipeline assets, including CUE-102 targeting Wilms' Tumor 1 and the KRASG12 valine molecules have a reduced risk profile due to clinical observations of CUE-101.

Second, we also believe that the Neo-STAT platform, which is a derivative of the IL-2 based CUE-100 series, and as designed to address tumor heterogeneity, also directly benefits from the CUE-101 clinical data.

To remind you the Neo-STAT platform allows us to generate the core generic scaffold of the IL-2 based CUE-101 series without a tumor peptide, that is an empty stabilized HLA molecule to which the desirable tumor epitopes can be efficiently conjugated. This strategy allows us to target multiple tumor antigens, maximizing time and cost efficiencies.

From a clinical application perspective, we believe the current clinical data sets with CUE-101 provides strong support for Neo-STAT since the core IL-2 molecules and HLA allele remain the same.

Third, we also believe that the development of the Bi-specific redirected Immuno-STAT or RDI-STATs designed to address tumor escape mechanisms of HLA loss, or antigen presentation defects also derive benefit from CUE-101, since the core IL-2 framework is essentially the same. We have evolved the RDI-STATs based on two key observations.

One, a significant fraction of human cancers up to 30% in some cases, will undergo loss of HLA molecules and antigen presentation defects, which makes them essentially invisible to tumor specific T cells.

And two, observations from cellular analysis of human cancer tissues have revealed a significant presence of virus specific memory CDA T cells in the tumor tissue.

To that end, the Bi-specific RDI-STATs contain the two key components, viral T cell epitopes to engage anti-viral T cells, along with a tumor targeting arm that allows for binding to a tumor cell surface antigen, such as a Trop2 to mesothelin, HER2 et cetera.

In this manner, the cancer cell bound to RDI-STAT appears as a virally infected cell, which can be recognized and killed by the anti-viral T cells in the patient. We believe this approach may provide several unique advantages from a mechanistic efficacy and safety perspective.

The novel Bi-specific format of RDI-STAT is very distinct from other Bi-specific molecules that indiscriminately activate T cells resulting in systemic cytokine release and toxicities.

Last week, at the New York Academy of Sciences Frontiers in Cancer Immunotherapy meeting, we presented early data indicating that RDI-STAT exhibited equivalent killing of target cells, compared to CD3 Bi-specific molecules, while avoiding systemic activation and cytokine secretion.

For autoimmune and inflammatory diseases, we have exploited the same IL-2 variant from CUE-101 design a novel first and class molecule for induction and expansion of regulatory T cells. As shown here, this molecule CUE-401 contains the two key signals an IL-2 variant and a TGF beta variant for induced Treg or iTreg differentiation.

Importantly, and in contrast to other approaches, focus on expansion of natural Tregs the IL-2 variant is not biased towards IL-2 receptor alpha.

We have previously presented data indicating that an in vitro assays CUE-401 can induce and expand regulatory T cells derived from healthy human subjects, and from patients suffering from rheumatoid arthritis and inflammatory bowel diseases. More importantly, these T cells exhibited suppression of effector T cells in vitro assays.

More recently, we've generated additional data in Vivo Animal Models that support the mechanism of action of CUE-401 in inducing an expanding Tregs, and the persistence and in vivo activity. We will plan on sharing additional details of these exciting datasets in a future scientific forum.

In summary, the following slide, Slide 9, outlines our broad vision on the autoimmune front. Our core strategy here has centered on two key approaches, antigen-specific and pathway-specific.

The antigen-specific approach deploys Immuno-STATs to modulate auto reactive T cells in diseases with well-characterized or few auto antigens, such as Type 1 diabetes.

In contrast, the pathway-specific approach, as exemplified by CUE-401 in the previous slide, is focused on induction and expansion of regulatory T cells, and additional tolerogenic pathways for broad applications.

We've been collaborating with Merck on the antigen-specific approach focused on two autoimmune diseases, and have made significant progress, which underscored the extension of our relationship last year to focus on optimizing potential lead clinical candidate molecules.

Earlier this year, we presented a progress update on these efforts via a presentation at the antigen-specific tolerance meeting. Those data slides are available on our website.

And as discussed in the previous slide, for the pathway-specific approach, we continue to make strong progress with our lead CUE-401 asset for generation and expansion of regulatory T cells directly in the patient's body.

We believe CUE-401 provides a unique opportunity to reset immune balance for numerous autoimmune diseases, graft versus host disease and even transplant rejection. With that summary, I'd like to pass the call to Ken and Matteo to provide a clinical update on CUE-101.

Ken?.

Thanks, Anish, and good afternoon, everyone. As always, I'd like to say thank you to all of the participating principal investigators, their names are shown on the next slide, Slide 10.

As we have noted on previous earnings calls, we have continued to screen and enroll HPV-16 positive head and neck cancer patients to participate in our trial throughout the COVID-19 pandemic.

We have fully enrolled through Cohort 7 at the 8 mg per kg dose without reaching a MTD, or maximally tolerated dose, and have now completed enrollments of Cohorts 5 at 2 milligrams per kilogram, and 6 at 4 milligrams per kilogram to nine patients each in anticipation of selecting our expansion cohort dose in the near future.

The next slide, Slide 11, shows a high-level summary of the clinical design and dosing cohorts for this ongoing Phase 1 trial of CUE-101, enrolling second line and beyond patients that are HLA-A0201 positive with recurrent or metastatic head and neck squamous cell carcinoma, driven by HPV-16.

We have now completed enrollment in the Part A dose escalation portion of this trial.

As I have noted in previous earnings calls, this escalation phase of the trial protocol provided the opportunity to dose up to nine patients in any given cohort, to provide and bolster evidence of clinical activity or PD effect in order to enhance our ability to choose the most appropriate dose for the Part B expansion, and presumed recommended Phase 2 dose.

The next slide, Slide 12, shows some of the details about our enrolled patients today. The vast majority of our patients more than 90% have been treated with CUE-101as third line of greater therapy after failing both platinum-based chemotherapy and a checkpoint inhibitor.

Many patients also failed treatment with the epidermal growth factor inhibitors cetuximab. Several observations give us confidence that our data is maturing to allow us to make an informed decision to choose our expansion dose. First, as shown in Slide 13, our data to date demonstrates the tolerability of CUE-101 in patients.

We have treated through Cohort 7 at 8 mg per kg as I mentioned, without reaching an MTD. All of the SAEs AEs observed today are consistent with those that are observed with IL-2 administration, or typical of those observed with immune modulators in the treatment of cancer patients.

The most common AEs observed include fatigue, anemia, and decreased lymphocyte counts.

Second, as reported in the previous earnings calls, our pharmacokinetics or PK data is shown in the next slide, Slide 14, reveals dose dependent exposure without any evidence or effect of anti-drug antibodies on PK, and exposure in patients that have received multiple doses of CUE-101.

Third, again, as reported in previous earning calls, the sustained increase in exposure with increasing doses of CUE-101 has led to observed pharmacodynamic effects, including early evidence of proliferation of tumor-specific CDA positive T cells, versus the broader CDA positive T cell component, and an increase in natural killer cells or NK cells.

We have previously shared early data on the increase of E7-specific CDA positive T cells, and NK cells in patient blood samples at various time points, after dosing of CUE-101.

Fourth, as noted in a previous earnings call, is shown in Slide 15, histopathology from biopsies of treated patients has revealed evidence of anti-tumor activity, including necrosis and T cell infiltration, as shown on the left hand panel, as well as in the right hand panel evidence of PDL-1 expression on the tumor cells, as shown by the brown staining, and a market infiltration of cytotoxic CDA positive T cells, as shown by the pink staining cells.

Fifth, in the dose escalation phase of the trial, we have had five heavily pretreated patients, patients that receive CUE-101 is third, fourth and fifth line therapy with confirmed stable disease after receiving CUE-101.

In addition to these five patients with stable disease, as announced last week, a patient in Cohort 6 at the 4 milligram per kilogram dose had a confirmed partial response. We believe that the partial responses observed in this patient, demonstrate single agent activity of CUE-101, something rarely seen in mono immunotherapy treatments.

We believe that this clinical observation provides supporting evidence that CUE-101 is an active agent with promising potential for HPV positive head and neck squamous cell carcinoma patients, which is further bolstered by the supporting pharmacodynamic data, in which we have observed activation of disease specific T cells, and NK cells in the blood of our treated patients.

I will hand the call over to Matteo to describe some of these data in greater detail.

Matteo?.

Thanks, Ken. The next slide, Slide 16, shows some of the data associated with the confirmed partial response in this patient. This patient had previously failed cetuximab and pembrolizumab systemic therapy for their recurrent disease, and was treated with CUE-101 as third line for their metastatic cancer.

At their first scan, after two cycles of therapy, the patient had an approximate 50% decrease in the size of their target lesions. And this was confirmed on their second scan after four cycles of therapy. The associated pharmacodynamic data for this patient correlates with this clinical response.

The middle panel demonstrates the slight increase in Tregs at cycle one day eight that returns to baseline by day 15, that we have observed in other patients. Similarly, as we have seen in other patients, we see a marked increase in NK cells on cycle one day eight that persists through day 15.

The right panel demonstrates the nine-fold increase in E7 positive specific T cells, in the cycle one day eight peripheral blood sample from this patient. These data support the mechanism of action of the Immuno-STAT platform, and supports to further develop meant not only of CUE-101, but the entire CUE-100 series and beyond.

On the next slide, Slide 17, I also wanted to share with you new histology data which also supports the mechanism of action of CUE-101. Granzyme B is a serine protease, most commonly found in the granules of natural killer cells, instead of toxic CDA positive T cells. It's a weapon utilized by these cells to kill cancer cells.

Slide 17, demonstrates biopsies from a patient in Cohort 5, before and after administration of two doses of CUE-101.

In the post-treatment histo micrograph on the right, and quantified on the graph on the far right, you can see a marked increase inside of toxic T cells that are secreting granzyme B, again, providing valuable validating data supporting the mechanism of action of CUE-101.

These results are also supported by the preclinical data published late last year in Nature Methods, where an immuno-PET imaging demonstrated that the core scaffolds of an Immuno-STAT consisting of the peptide MHC components could penetrate solid tumor tissue, and directly engage tumor infiltrating lymphocytes.

Hence, mechanistically the Immuno-STATs have the potential to directly engage TILs and NK cells, which may also alter the local tumor microenvironment to favor anti-tumor immunity.

As noted in previous earnings calls, we also continue to monitor progression free survival and overall survival closely, and continue to observe what appears to be an enhancement to the survival of patients in the CUE-101 dose escalation trial.

Our clinical trial protocol amendment for the expansion phase will, once cleared by FDA one allow patients to remain on study at investigator discretion if they demonstrate radiologic progression, but are clinically stable, two add assessment of response by iRECIST criteria to the exploratory endpoints, and third, allow for collection of data regarding subsequent anti-cancer treatments patients may receive to gain further insights into our preliminary survival observations.

I will now hand the call over to Kerri to discuss first quarter financial results..

Thank you, Matteo. Turning now to Slide 18, I'd like to provide a brief update on our financial results for the three months ended March 31, 2021. The company reported collaboration revenue of approximately $1.6 million and $0.9 million for the three months ended March 31, 2021, and 2020, respectively.

The increase in revenue was due primarily to revenue generated from the extension of the Merck research program in November of 2020, from which we are receiving additional financial support to further research and develop promising preclinical biologics with the objective of identifying clinical candidates for the treatment of Type 1 diabetes, and an additional undisclosed autoimmune disease.

Research and development expenses were $9.8 million and $9.9 million for the three months ended March 31, 2021, and 2020, respectively. The decrease was primarily due to a decrease in laboratory costs and travel-related expenses.

General and administrative expenses were $4.3 million and $4 million for the three months ended March 31, 2021 and 2020, respectively. The increase is due primarily to stock-based compensation and legal fees incurred during the first quarter of 2021, as compared to the same period in 2020.

We ended the quarter with approximately $73.3 million in cash, cash equivalents and marketable securities, and working capital of approximately $60.8 million.

In April, we extended our cash runway with approximately $10.4 million from the sale of approximately 907,000 shares of our common stock, under our at the market equity offering through Stifel, Nicolaus & Company, who acted as our sales agents.

We believe our cash, cash equivalents and marketable securities as of March 31, 2021, along with the funds received in April, through the ATM will allow us to support the development of our Immuno-STAT platform, including the clinical development of CUE-101 into the fourth quarter of 2022. I'll now turn the call back over to Dan for closing remarks.

Dan?.

Thanks, Kerri.

In conclusion, the confirmation of clinical activity of CUE-101 as a monotherapy in this challenging and heavily pretreated patient population, is an important step forward and supports the potential of not only our CUE-101 drug product candidate for oncology, but for our follow on drug candidates as well, such as CUE-102, from the IL-2 based CUE-100 series, and provides valuable proof-of-concept of the Immuno-STAT platform to activate and expand disease, relevant T cells and NK cells directly in the patient's body, as a method to treat other cancers.

We anticipate a number of important milestones throughout this year, with the potential of further data to support the possibility of a registration path for CUE-101 as a monotherapy.

These milestones include the planned selection of a recommended Phase 2 dose of CUE-101, by mid-2021, for further development as a single agent treatment for HPV positive second line and beyond head and neck squamous cell carcinoma, our to support initial Phase 1 results from the combination study of CUE-101 with pembrolizumab in the second-half of 2021, and our plans to initiate a neo adjuvant study to evaluate the effects of CUE-101 on the tumor microenvironment, which is also expected to launch in the second-half of the year.

We continue to execute our corporate strategy in a focused and deliberate manner, with the aim of demonstrating clear competitive advantage and market positioning of the Immuno-STAT platform and associated programs.

We believe that CUE-101 monotherapy trial provides a potential registration path forward as a single agent therapeutic, and the combination trial with pembrolizumab also known as KEYTRUDA provides the prospects to enhance patient reach and market size, by moving upstream to first line patients where we anticipate the potential for significant mechanistic synergies, as demonstrated in our preclinical studies.

We look forward to providing the trial status update at our next earnings call. Finally, we'd like to thank our employees whose dedication to our mission through their commitment and professionalism, allows us to continue executing our corporate development strategy.

I'd like to thank our board of directors for their support and guidance, and want to thank our shareholders who provide us with the essential resources to continue our important work, developing promising therapeutic candidates for patients in need. But importantly, we want to thank those patients and their families involved in the clinical trials.

Their courage and willingness to be part of a clinical study allows us the opportunity to assess potential drug activity and assess the potential therapeutic benefit of our promising drug candidates. With that, I want 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.

Operator?.

Thank you. We will now begin the question-and-answer session. [Operator Instructions] Our first question comes from Tom Shrader from BTIG. Please go ahead..

Thank you. And let me be the first, but hopefully not the only to congratulate you on the response. It's been quite a push. So congratulations. I have kind of a general question probably for Anish.

How many patients do you have blood levels of tissue-specific T cells and tumor-specific levels? And are you getting to a point where you can start to define the curve as to what levels in the blood might mean in the tumor, at least for this specific example? And then I have a Tregs question, if I can..

Yeah, sure. Thanks, Tom. So, in the data points that we have evaluated so far, Tom, we've been able to detect E7s in about, clearly in about a third of patients.

And, I caveat that by the sampling times, because our major bleed is at day 21, after injection of the drug at day zero, so there's a fair bit of things that happen in the middle of T cells once they get activated, expansion and extravasation from blood. So, we view that as a significant positive just by doing these first pass analysis.

Remember, this is just direct detection from the blood with no ex vivo expansion, et cetera, or looking at additional protocols. Having said that, as you saw here, when Matteo presented, this was about a nine-fold increase. We'd also reported I think about a seven-fold increase in a patient with stable disease in a prior presentation.

We just need to do enough and have additional data to be able to make any sort of hard conclusions Tom, whether these numbers at the end of the day are correlating with an objective response.

And I say that simply because of the fact that it's a wonderful read in the blood for mechanism of action and PD activity, but ultimately, we think have a deeper insights into the target tissue will reveal more meaningful sort of outcomes. And that's been the general narrative in the field as you will have follow that out.

This is actually one of the reasons why we've pushed for the neo adjuvant study, where we have guaranteed access to the blood and the tumor tissue, post-surgical resection pre and post CUE-101 administration. So, I think the blood data is fascinating, it's very positive from a PD perspective.

But I think as we go through the rest of the year, and start gathering the metrics on the neo adjuvant study, we will hopefully be able to strengthen and make those correlations. The biopsies in the current trial are not mandatory. As you're well aware, these are optional.

So we're very grateful and thankful to patients that have provided us those, although there have been fewer events there. But nonetheless, the data that can present and Matteo discussed is just fascinating to see the immune effector mechanisms sort of start to kick in after the drug is administered..

And then quickly on the Tregs program, your RNA data is presumably a model where you know exactly the antigen.

Do you think in a disease like RNA or RA, you will need exactly the Tregs antigen? Or, can it be one of several and you just get enough Tregs in the joint that you would have some sort of anti-inflammatory effect, any data there yet?.

No, it's a fantastic question, Tom. So especially in the cases of chronic autoimmune diseases like RA, like lupus, like IBD, where the diversity of antigen is vast, and it's not well-characterized.

And in many cases, I think having this CUE-401 asset is extremely beneficial, because it expands Tregs globally, and the hope is that they would then, turn around and modulating control or reactivity. In fact, that's what has been seen. And that's what we've seen in a role in vitro assessments of activity of these cells.

That is in contrast to the Immuno-STATs, we're deploying with Merck in our collaboration, for example, for diseases like DID, with focused antigens, like proinsulin in that case. But those diseases are a handful where some of those antigens are really dominant or well-characterized.

But you're absolutely right, that's exactly the reason why we've had this dual strategy of an antigen-specific that deploys Immuno-STAT, and pathway-specific that's actually agnostic of the antigen identity, and goes after the vast regulation of the potential of Tregs..

Great. Thank you, and congratulations again..

Thanks, Tom..

Our next question comes from Mark Breidenbach from Oppenheimer. Please go ahead..

Hey, good afternoon. And let me add my congrats on the progress, and especially on the partial response. It's great news. I was wondering if you could tell us a little bit more about the responding patient, whether or not they were primary refractory to pembro.

Or, if this was a case of acquired resistance? And also, how long the patient had been off pembro before receiving CUE-101?.

Ken, do you want to take that question?.

Yeah. So, these patients, all the patients virtually have been on some kind of checkpoint inhibitor. And this patient failed pembro and it's controversial how long pembro sort of hangs in the system. But, what I think we can say for sure is, with a confirmed PR 12-weeks into treatment, that there wouldn't be any pembro in the system.

So the patient's still on study. And so, I'm hesitant to report too much more about the patient, but we'll be happy to share that in later calls..

Okay, fair enough. And one quick follow-up just on the really nice biopsies you showed us. I'm glad you were able to collect fair biopsies from the responding patient. I'm wondering if we can expect to see an analysis of pre and post-treatment TCR sequences from inside the tumor infiltrating lymphocytes. Thanks..

Yeah, Anish will take that..

Yeah, Mark. So that has been an area of very high interest for us.

As you well know, in previous sort of studies we have done a fair bit of single cell TCR analysis and expression, that's exactly the intention here is to get to a point where we can using the single cell platforms identify pair TCRs, express them, and then not only show functionality for the E7 epitope, but also show clonality for oligoclonal expansion.

Those are data that we've previously reported with Immuno-STAT in preclinical models in ex-vivo expansions. That is the very intention we intend to do with our clinical samples.

And in fact, again, coming back to the neo adjuvant study mug, that's one of the major goals there is to be able to characterize the tears [ph] with response to both clonality and specificity..

Okay, perfect. Looking forward to it, and congrats again on the data..

Thanks, Mark..

Our next question comes from Reni Benjamin from JMP Securities. Please go ahead..

Hey, guys, congratulations as well on the terrific clinical news. A couple of questions, maybe just starting off with the patient if we can.

Can you talk a little bit about prior to entry into the study was the patient progressing quite rapidly? Was he relatively stable or just slowly progressing? You mentioned that he's still on the study, is he overall, I don't know if you can make any comments, but is he doing fine? And, I guess, related to that, is this the highest CDA T cell count that you've seen to date peripherally? Or, were there other instances where we saw higher levels?.

Well, I'll let Anish comment on the CDA levels, but the patient does remain on study and is feeling clinically well. And what I'll say is, the patients progress and rate of progression is, I guess, a relative term. Patients' cancers grow in and that's not good. And so the patient went on study.

I think, because the patient is still active, I really would like to hesitate to go into a lot more detail about the patient..

And, Reni just to add on the T cell increase, we have seen T cell increases. Remember, this is fold increase Reni, so it's driven by the denominator of what you find initially.

But, I do want to caveat that, again, by sampling, in fact, one of the major amendments that we're trying to accomplish in that Ken and Matteo have driven is to get more blood samples at a time point, so we can understand the kinetics to be able to get deeper insights into this.

But, this is an area where we have noticed this sort of fold expansion in this range, even in prior samples.

And again, knowing well that as opposed to what we've done in preclinical models, where you can sample on a more regular basis and understand the kinetics of engagement, expansion and contraction that obviously is limited what you can do with patients in the situation.

And hopefully will gather more insights as the data continues to mature, but nonetheless, it is extremely positive to see these rare frequencies just emerge in a primary snapshot that we've been able to detect them..

Fair enough.

As we think about the recommended Phase 2 dose, can you just kind of talk us through maybe the metrics here or what you're considering? What are the metrics that are going to drive that decision? You have the nine patients that have enrolled, whether you see additional responses, I think then that decision becomes easier, if you don't, what other factors and what else do you need to see to declare recommended Phase 2 dose?.

Yeah, Ken, do you want to take that?.

Yeah, thanks. Well, it certainly becomes the totality of the PK data, the PD data, the clinical responses, as well as the safety data, all of which is maturing, literally as we speak for the later cohorts. And I do believe that we will have the data we need to choose that dose within the next month or so..

Got it. Okay. And then, I guess just one final one for me, probably for Anish.

Just could you give us a sense as to how the two programs the IL-2 TGF-beta and the Merck programs are progressing in the autoimmune front?.

Yeah. Sure, Reni. So on the Merck side with the antigen-specific approach, the teams focused with the proinsulin specific Immuno-STAT for Type 1 diabetes. We've made tremendous progress there, evolving that molecule towards a potential lead clinical candidate. And we're aiming to have those studies completed by the end of the year.

On this fascinating CUE-401, this is a fantastic asset. And this is really exciting for us, because of the breadth of application. So, we've generated foundational data. We actually have been invited to Forsus [ph] so we'll be presenting a talk on this in June as well.

The intentions are to continue to validate and preclinical models have that solidified by the end of the year, to be in then a position to start initiating IND-enabling studies, et cetera, and position ourselves to start thinking about what a clinical development strategy would look like for chronic autoimmune sort of so the big indications, we're talking about RA and IBD, and lupus, et cetera, which stands out to us..

Terrific. Thanks very much for taking the questions..

Thanks, Reni..

Our next question comes from Stephen Willey from Stifel. Please go ahead..

Yeah. Good afternoon. Congratulations on the progress. Hey, Dan. So, I know in your prepared remarks, Dan, I think you kind of re-emphasized your confidence and monotherapy having a potential registrational path forward.

How are you guys thinking about pursuing that as of right now? And I guess, should we anticipate because of this, I guess extended event times that you're seeing in patients that a trial in this setting would most likely be something like CUE-101 versus best supportive care and salvage? Or, do you think if you see another response, or two, just given I think the low single digit response rate that's associated with current standard-of-care? Do you try to push forward in single arm study?.

Yeah, I'm going to just answer that, broadly, but I'll hand it over to Ken as well. So, I think you actually just summarized the answer to it, and that's how we're looking at it these patients. As you know, refractory, there is no standard-of-care, many of them are basically going on palliative therapy.

So, I think one, it's looking at the response rate to step another couple of PRs and would really bolster confidence. So we're confident by what we're seeing already to date, in that, we're seeing the molecules actively modifying the relevant immune components.

We're seeing again, in a dose escalation it was a five confirmed stable disease, a confirmed partial response as a monotherapy. And we're seeing what appears to be emergence of data suggesting as a survival advantage. So all of this is basically giving us confidence going forward.

And it will be continuing that type of data that will give us confidence going forward with a registration path, but at that, I'll turn it over to Ken if he wants to elaborate..

Well, I think there you said it. The bottom line is, if we think that we have a registration path as a as a single arm study, that's certainly what we're going to pursue. And I leave it at that. I mean, that's what we're hoping and that's what the data looks like is emerging..

So, in terms of the monotherapy expansion cohorts at the recommended Phase 2 dose, do you then I guess, have a conversation with FDA and potentially design that such that those Phase 1 expansion patients could be rolled into a registrational dataset?.

Short answer, yes..

Understood. And then, maybe just a bigger question here. You've got proof-of-concept established with the CUE-101 series, and you've got a lot of other interesting constructs that you're working on with Neo-STAT and the RDI-STATs.

But how do you just think about prioritizing each of the opportunities now within the pipeline? And because of the de-risking, I guess on 101, do you try to accelerate the WT1? Do you accelerate KRAS? Can you accelerate both of those things in the context of making progress on these constructs on the novel format? How do you guys think about that?.

It's a complex question, Steve. As you know, it has to do with resource access, resource allocation. Priority right now is focus on establishing a foothold or a beachhead with 101, which by implication applies, in terms of de-risking and validation to the 100 series.

So, we have 101, 102, and 103, partnered with LG Chem, so a strategy that incorporates the potential of looking at patients here in the U.S. as well as Asia, that's something we consider. So, I don't know if it's one priority, I think all of it is actually really important.

So we have to continue pushing forward with 101 as establishing the foothold, but then expanding out into 102 to make sure we're doing that in a timely manner. Right now, we are expecting the IND to be filed in Q1 of 2022. And KRAS is obviously a high profile program. So, we're putting our resources on that as well.

Going forward, beyond that, it's really going to be based on resource access and allocation. But right now, it's really focused on establishing the foundational principle of 101, and expanding out as efficiently as we can with the other programs..

Understood. Thanks for taking the questions..

Thank you..

Our next question comes from Brian Skorney from Baird. Please go ahead..

Good afternoon, everyone. And let me offer my congrats too on the single agent activity. It seems like it was really sports, a lot of Immuno-STAT platform, probably in particular, the 100 series.

So to that point, I guess, how do we kind of think about using 101 monotherapy in thinking through the design of Phase 1s in KRAS and Wilms? Does this give you any opportunity to sort of accelerate through dose escalation here maybe starting at a dose that would be closer to what you think would be relevant exposures for driving response in T cell activity?.

Ken, do you want to take that?.

Yeah, great question. We certainly believe that what we've learned from 101 will allow us to propose to the FDA, that we be able to start it, for example, higher doses than we were with CUE-101. And we have that as part of our pre-IND meeting.

Question set of questions is will the FDA accept the learnings from CUE-101 as part of what we do going forward? But I would also mention that, we really like this trial design that we've used for 101, which is based on the 3x3 design, but also lets us backfill cohorts as needed. So, I think we'll use that strategy again.

But we'll be able to get to clinically relevant doses much quicker based on the PK, PD and safety data that we've observed with 101..

And then maybe digging a little bit on the 101 PD data.

Are you -- is there anything on the PD side that shows kind of a clear dose relationship, maybe the increase in NK cells and/or E7-specific T cells? I'm just trying to get those level tests where you really don't see this activation, like Cohort 3? And is there a dose level where you sort of see it peek out in higher doses maybe Cohort 7, just aren't showing any additional activity?.

Anish, do you want to take that?.

Yeah. Brian, so, if you look at some of the emerging PD metrics, including the NK data, we think that Cohorts 5 and 6, you start to see the uptake at about Cohort 3 and 4, but at 5 and 6, they're very comparable.

So, we think these, as you're looking around activity, appear to be very relevant cohorts is also what can and Matteo stressed, as you've heard about the dose expansion. We just have to mature on the T cell side with some of these emerging metrics.

And I think sampling more would help and obviously continue to make this strong, but already with what we're seeing, with the sustained increase in NKs, the notable sort of increase in the E7-specific and only a transient uptake on Tregs, that comes back to the baseline, I think provides a very strong case that these appropriate cohorts that seem to exhibit what we would, -- some indicate as very relevant PD metrics for us to be able to move forward..

That's helpful. Thank you..

Yeah. My pleasure. Thank you..

[Operator Instructions] Our next question comes from Zhiqiang Shu from Berenberg. Please go ahead..

Hi, good afternoon. Thanks for taking my question. I want to add my congratulations to the team as well..

Thank you..

The first I want to ask about the safety, I know it looks like the safety is quite favorable.

Just curious for the length of sight decrease, do you have an idea of why we've seen some grade 3 of insight decrease? Wouldn't be IL-2 supposed to be designed to activate T cells and NK cells in this manner?.

So, Ken, do you want to comment on that, and I can follow-up after Ken..

Alright, go ahead Anish..

So, again, the activity of IL-2 in peripheral lymphocytic populations, including T cells and NKs post activation, as you're well aware, the raise that has been noted for extravasation, you see these transient dips, I think that likely explained that these active doses is the most likely aspect, and consistent with what's been sort of seen in prior pharmacological measurements..

Yeah, it's a known IL-2 effect. Essentially, what it represents is the IL-2 moving -- the lymphocytes moving out of the blood into tissue in a non-specific manner at those early time points..

Okay. Understood. And then I also want to ask about the combination trial, PD-1 and CUE-101.

Based on your preclinical modeling, have you seen any synergies between them? As have you observed PDL-1 being upregulated upon to CUE-101 treatment?.

So, I can take that at least as of in the preclinical side Zhi, which is a very important component that not only supports, but provides a lot of good evidence for the synergistic. So first of all, as everyone appreciates checkpoint blockade like PD-1 and absence of the right repertoire is likely not very meaningful.

So the fact that CUE-101 elicits and activates the repertoire is actually very meaningful from that.

And in our preclinical studies that we published last year in Clinical Cancer Research, in a E7-driven aggressive TC1 tumor model, we saw monotherapy, the murine CUE-101 surrogate its activity, whereas PD-1 alone in that setting was no better than the vehicle.

However, when that monotherapy was then further combined with anti-PD-1 blockade and that model, there was a substantial increase in the observed efficacy in response in the animals.

Upon closer examination of the tumor tissue from those animals, we could again, very nicely locate tumor-specific T cells in both mono and combo, except that in combination therapy, those numbers were present in higher numbers within the tumor tissue.

And as Ken showed you from the histo path, from one of the patients in his section, we have done this from a model trial, where the tumors are expressing PD like and are infiltrated by CDA T cells.

So putting it all together, I think as we continue to build on a combination trial that data combined with what we've noticed preclinical, proven preclinical observations should really bode well and further sort of build favorable parameters for these patients..

Okay, great. And one final question is also a [Indiscernible] probably also for you Anish. For Neo-STAT, I understand it is empty HLA construct with IL-2.

So, I guess, is it designed to bind to any TCR regardless of what to antigen [ph] the tumor has?.

So the whole concept of the Neo-STAT, Zhi, is to have the scaffold to which we can then conjugate any tumor peptide, which we do using chemical conjugation, using established chemistry. So, it's a covalent linkage.

So, when the drug product actually gets made, it's not an empty HLA, but rather is conjugated with a desirable epitope or epitopes in cases of multiple antigens. And that's quite significant when you compare it to an Immuno-STAT, where each one of the epitope, like the HPV E7 or the WT1 is a fused peptide.

So in other words, each one of those antibody molecules is a separate drug molecule with a separate cell line for production and time there. With Neo-STAT, you have one cell line that can generate the scaffold that can then serve many different areas of interest and indications, based upon the tumor epitopes that one wants to conjugate.

So it's still very much antigen-specific, except that the versatility and modularity there, since it's empty, allows us to go after many different tumor T cell epitopes.

And the fact that it's a single cell line, obviously has significant implications for the time and cost to the clinic, is essentially an off the shelf scaffold that one can deploy in real-time to drug patients. That was a vision when we started on this about three years back..

Okay.

So essentially, it's a cancer vaccine turbocharged?.

Well, it's a vaccine in terms of specificity. Every single vaccine is dependent upon the APC, actually doing this job and antigen processing presentation, the right kind of membrane interactions, costings, et cetera. We've just bypass all that and that's a big leap in the space of immunotherapy..

Got it. That's very helpful. Thank you..

Okay. Thank you..

[Operator Instructions] This concludes the question-and-answer session. I would like to turn the conference back over to Dan Passeri for any closing remarks..

We want to thank everyone for your attention and interest. And we look forward to providing periodic updates, as we continue to make progress on these important observations and findings. So, thank you and we look forward to catching up sometime soon in the near future..

This concludes today's conference call. You may disconnect your lines. Thank you for participating and have a pleasant day..