My name is Ted Tenthoff. I'm a senior biotech analyst at Piper Sandler, and thank you for sticking around for our final presenting company of the day, Cue Biopharma. Before I begin, I'm required to point out certain disclosures regarding the relationship between Piper and Cue that are posted in the back of the room and also at the registration desk. Q is developing novel immunotherapies called Immuno-STAT, and I'm pleased to have Anish Suri, President and CSO, here with us, since he was really the architect of these designs and really several of the constructs that Q is working on. Really, really cool stuff. I think one of the most elegant ways to present antigens to the immune system. So Anish, start off by describing CUE-101. How does it activate tumor-targeted T cells with IL-2?
Sure. Well, first of all, Ted, thank you for having us here, and thank you to Piper for hosting us. Really glad to sort of see people in person, face to face again. I'll give a brief background, Ted. We started on this sort of adventure several years back by focusing on the two sort of fundamental immunological constants, which is the frequency of any disease-relevant T cells is relatively rare.
Yep.
The only unique marker on a disease-relevant T cell is the T cell receptor.
Yep.
That is what qualifies a tumor-specific T cell, because it has a tumor-specific T cell receptor.
Yep.
A virus-specific T cell has a virus-specific T cell receptor. So Immuno-STATs were built from the lens of a T cell. They are TCR selective engagers of the tumor-specific T cells, and by virtue of that, For, you know, what that allows us to do is selectively deliver immune modulating signals-
Yep.
to the right T cells while sparing the broad carpet bombing of the immune system. So CUE-101 is our flagship leading clinical candidate, which has presented some really exciting recent clinical data. It is designed with an HPV epitope, such that is HPV from human papillomavirus, to selectively engage and activate HPV-specific T cells to eradicate HPV-driven cancers like head and neck cancer and others. We are in the clinic in head and neck cancer with that. The module that it uses to activate the T cell is an affinity-tuned IL-2 molecule. So IL-2, as you well know, validated target, but a lot of challenges in the field with creation of a therapeutic index, toxicities, lack of tolerability. A number of companies have attempted to sort of derive IL-2 variants, the not-alpha variants
Yep.
These have been tough, and they've been tough because those interactions are unique to the IL-2, IL-2 receptor interactions, but not specific for the disease-relevant T cell, and that's what the Immuno-STATs are able to accomplish. So we believe for the first time in the history of that cytokine, we're able to create a very meaningful therapeutic index, which, by the way, that principle will hold true for any given immune activation signals. It could be IL-2, IL-7, IL-12, cell surface receptors, but it proves the concept out. CUE-101 targets HPV-specific T cells and is derived from the CUE-100 series, which is our IL-2 base series.
Yep.
What makes it very unique is then from going from one molecule to the other, all you have to really swap out is the tumor antigen specificity-
Yep
The core IL-2 framework remains the same.
Yeah, so it really is modular. And again, the data that you've reported, which we're going to talk about now on CUE-101, really does de-risk the platform.
It does
... with a novel, antigen.
We firmly believe that, Ted, and thank you for highlighting that. And that was actually also in many ways endorsed by the FDA as we brought forward our second product-
Yep
... in the clinic last year, where, based on the safety of CUE-101 in the clinic with head and neck cancer patients, we were not required to do any further IND-enabling toxicology.
Yep.
Could start that second molecule at a clinically active dose-
Yep
... which saved us a year's worth of dose escalation.
Yep.
And that, you know, when you look at the development efficiencies and the regulatory efficiencies, that's actually a pretty, we believe, a significant win for the platform.
Agreed. So Anish, walk us through the phase I monotherapy and the Keytruda combo data that you've reported to date in recurrent metastatic head and neck squamous cell carcinoma.
Sure. So we started the trial with CUE-101 as a monotherapy, Ted, initially in late-stage head and neck cancer patients for two reasons. One, there is a significant unmet medical need.
Yep.
These are patients that are mostly in the third line and beyond. They've failed multiple lines of prior therapy, including checkpoint inhibitors, cetuximab, chemoradiation. But the point of going initially mono was to firmly demonstrate single agent activity.
Good.
We wanted to make sure there were no doubts about the utility of the platform, the module, the drugs, to go after the T-cells and actually demonstrate a beneficial clinical activity in a meaningful manner. And what we just reported at SITC earlier this month is the fact that as we're tracking out our monotherapy RP2D dose expansion of about 20 patients, our median overall survival at this point is tracking at about 20.8 months. And that is quite remarkable when you look at the historical numbers for survival in that recurrent metastatic indication. For example, in the second line setting, the reported numbers with two different checkpoints, BMS's nivolumab and Merck's pembrolizumab, the median OS is between 7.5-8.5 months.
Yeah.
In a third line and beyond, we're right now at 20, you know, looking at 20+ months. So really a very meaningful sort of improvement, we believe, meaningful enough that we're preparing to engage the agency to get alignment on what a potential sort of next steps for a registration pathway look like. Now, in the frontline setting, but still talking recurrent metastatic, so this is where the disease has sort of spread to distal sites. KEYTRUDA was approved several years back, so that's the standard of care. And we combined CUE-101 in KEYTRUDA, with KEYTRUDA. And what we've noticed so far in that cohort of the recommended phase 2 dose, from I think the first 17 patients we reported so far, KEYTRUDA single-agent activity as a response rate is roughly around 19%.
This is from the KEYNOTE-048 trial that was reported back several years from a significant massive study with about 800+ patients. We're right now tracking at 47%, so more than doubling of the response rate when you add CUE-101 with KEYTRUDA. If you do further subset, the patients, Ted, because KEYTRUDA is utilized in patients that have a CPS score of greater than one. So this is the measure of PD-L1 and expression in the tumor tissue. If you look at those low CPS scores, KEYTRUDA single-agent activity goes down to around 14.5%-15%, and low CPS patients constitute about 50% of head and neck cancer patients. In that particular subset, we go to 56%.
Pretty significant, I think, not only enhancing the patient response, but also expanding it to a subset that is traditionally not very responsive.
Yeah.
We think that, you know, that could be very meaningful as we continue to develop this program.
I agree. I was really impressed by the response rate in the low PD-L1 expressors. So where are we here in development with CUE-101? What are likely next steps? Is it more likely that you would go in combination with Keytruda in frontline? Is it more likely that you would go in second line plus as monotherapy? Is there the likelihood you could do both? How do we progress from here?
Yeah, at this point, Ted, obviously the mono data is, is more mature than the combo. So that, you know, that allows us to at least map the path for it. We hold the optionalities for both, and that puts us in a, you know, in a, in a pretty strong position with looking at different lines of treatment. Where we are with combo, we've got the response rate that's coming through quite nicely. We've been reported on completion of the RP2D cohort, so we're just waiting for the data to continue to mature. What we have noticed, and again, was reported at SITC, is as you're looking at another metric of activity, which would be progression-free survival, the median PFS at this point in time has doubled over what we had seen with Keytruda alone. So that's another metric.
Survival, all patients are alive, so that's a good problem to have, except one. So, you know, I, I believe by the time we get to mid-2024, we'll have some metrics to put against that. But I think with that, puts us in a very strong position to be able to look at a frontline option in recurrent metastatic for patients that have failed all those options and have really nothing. There's no standard of care, really, you know, in the late stage setting, have an optionality there as well. So puts us in, we believe, in a pretty, strong position to be able to, look at both these optionalities.
Does it make sense to partner CUE-101 here to really maximize that? Or is this something you think, Cue could do yourself?
Well, so that's an area that's been a very active discussions, particularly, Ted, after we released the SITC data.
Yeah.
There have been. We are engaged in what I would qualify as significant discussions with CPI franchises.
Yeah.
That can be bucketed, as with franchises that have not only a dedicated interest in head and neck cancer, but also have...
Mm-hmm.
obviously an approved CPI. So
And more than just Keytruda, because it would work with other-
That's exactly right.
-as well.
So if you just put yourself what we believe the platform offers, Ted, as it—as evidenced by the 101 data, is a clear demonstration of enhancing CPI regimen and indication.
Mm.
We've proven that out with head and neck cancer, but I think strategically, as we're talking with partners, that is becoming more and more apparent, that the CUE-100 series could be a very synergistic molecular addition to an existing checkpoint inhibitor to really expand patient reach. And if you fundamentally think about the mechanism, it makes perfect sense, because the CPI application is a futile endeavor if you don't have the right T-cell repertoire there to begin with.
There's nothing to expand.
There's nothing to expand. So we are the precursor step-
Yeah
to that, we believe, with the IL-2 focused and the TCR engagement or the tumor-specific T cells. So this is a very, you know, it's a really interesting and attractive proposition, but also grounded on very solid scientific rationale.
And clinical data. So this is a perfect segue into your second candidate, CUE-102, which is targeting Wilms' tumor 1. Firstly, tell us about this program. How does WT1 address different cancers? Obviously, it's a different, different answer, but where is, where is that involved?
Yeah. So WT1, you know, we—as we were looking to expand the pipeline, Ted, we did a survey of many different tumor antigens, and WT1 really stood out for several reasons. One, as the NCI had done their own assessment of cancer antigens, you know, some years back, WT1 was ranked as the number one antigen for cancer immunotherapy because of its expression patterns, widely expressed, because of the fact it's an onco-fetal antigen, so it's restricted to the tumorigenic sort of, phenotype, and because of the fact that it is, has defined, well-defined T-cell epitopes. We made a choice with a particular amino acid segment that spans 37-45. And the reason I give you that granularity is a lot of the previous work, Ted, has been done with a different-
Yeah
... T-cell epitope from the 126 amino acid segment, which last year there have been three really remarkable papers that made the point-... that tumors can evade the presentation of the 126 epitope, but not the 37.
Yeah.
It appears that 37 was the right epitope choice that we made to incorporate it into CUE-102, CUE-101. As a framework at an amino acid level, CUE-101 and CUE-102 are 99% sequence identical.
Mm-hmm.
One has an HPV epitope, the other has a 101 epitope. That's, you know, that's the,
Go with it.
It's a molecular analog.
Yeah
... in many ways. The cancers we've gone in with this program initially, Ted, are ovarian, colorectal, gastric and pancreatic. Four cancers with high unmet medical need, four cancers where there's not really a big presence of checkpoint inhibitors. They've been tried and have not worked as well, so there's no approved checkpoints in a majority of these cancers. So we felt this was a pretty-
Yeah
... greenfield opportunity for us to have an impact. We can talk a little bit about the data-
Yeah
... but the early data on this looks actually very encouraging.
Let's pick up right there, because you just had a small data set very, very early. But tell us what you've reported so far, and when can we get more data on CUE-102?
Sure. So we reported at SITC, still in those escalations, so still very early stages. Haven't yet chosen an RP2D. We've not yet embarked on any dose expansions. But even in the dose escalation, we have seen clear evidence of not only disease stabilization, but tumor regressions.
Mm.
So we've got, I think in our second cohort of 2 mg/kg, I think our disease control rate is about 80% in the cohort. With 4 mg/kg, I think it's 75%. So really very strong numbers. We have a gastric cancer patient, failed multiple lines of therapy. And again, these are pretty late-stage patients. As a single agent, monotherapy and CUE-102, were at -29%, reduction of some of target lesions, almost a PR. That patient continues on study now going north of 6 months on treatment, which is quite remarkable when you look at the cancer and the line of treatment. We reported a case report with an ovarian cancer patient, where they have an unconfirmed PR of -30%.
So again, really, you know, several pancreatic cancer patients with long-term stable disease, where we've not seen much of growth, which our physicians and investigators tell us that is, that is something that is really very positive and encouraging. This is all as monotherapy.
Mm.
This is, you know, quite remarkable.
Yeah. So when can we get more data, and how do you sort of anticipate developing CUE-102? Because as you mentioned, you're already seeing signs of broad activity. Is this something where you would do expansion cohorts in each of these cancers, or how do you... What would be next steps?
Yeah. Taking that point first, Ted, we started the dose escalation as a basket.
Mm.
So now we've got smattering of-
Yeah
... all four indications in there. I think our intention here is to identify an RP2D, which we will do likely very soon in the first quarter, actually, and then initiate dose expansion in an indication specific manner, along the lines of what you mentioned. That, we believe, gives us the best opportunity to build out a meaningful data set, to really sort of understand which indication and how one positions then the next sort of level of, development, both as monotherapy-
Mm
... and even potential combos-
Mm
... which by the way, may vary by the standard of cares that vary for each one of these indications.
Right.
Our cadence for data disclosures have been, we've usually aim for a major oncology meet in midyear-
Yeah
... and year end, we've done usually SITC.
Yeah.
Conventionally, historically, midyear, we've done ASCO.
Sure.
I think we're going to stick with that. I can tell you this, with the rate of accrual for 102 and the investigator enthusiasm, we actually have a wait list of patients that want to get on that. But-
Yeah
... since we're still in the dose escalation, 3 by 3 paradigm, you know, we can't accommodate all, but we feel that the recruitment for this trial, including the dose expansion phase, should go quite smoothly.
Right. So similar question in terms of partnering. You know, maybe taking a further step back now that we, we've introduced 102. You know, would you see this as 101 separate, 102 separate? Does the whole 100 series make sense for someone? What else can you do with Immuno-STATS beyond 101 and 102?
Yeah. So what we have sensed, and it's been actually quite remarkable, Ted, as we were going into SITC, we were obviously under, you know, having some early conversations, and as the data came out. There's a clear sort of interest in some parties for CUE-101, and these are establishments with an interest in head and neck cancer, as I mentioned, establishments with a, with an approved CPI. With CUE-102, this is a broad opportunity between Solid and Heme, and there are several partners that have expressed an interest in learning more about that program. And then we've had discussions where people want to apply the platform towards earlier stage assets. And a good example of that, where we've actually had a fair bit of interest, is our KRAS franchise.
So we have, as you well know, the mutated KRAS, the G12 hotspot mutation, lends itself to novel T cell neoepitopes-
Mm
... G12V and G12D. Both of these targeting via TCR T cell therapies as case studies, et cetera, have actually demonstrated pretty robust antitumor efficacy-
Yeah
... in humans. We have successfully made immuno-STATs with this. So our KRAS franchise actually covers 4 distinct immuno-STATs: G12V and G12D on HLA-A03, which is a highly expressed HLA in this part of the world, not as high as A02, but it's still up there. And the same mutations on HLA-A11, which is a very highly expressed HLA allele in Asia, China, Korea, Japan. So between those two alleles and the two mutations, we have, we have an opportunity to build out at least 4 distinct immuno-STATs for KRAS. As you well know, in pancreatic, 80% of pancreatic is KRAS mutated, about 30% of lung is KRAS mutated, and 30%-40% of colorectal is KRAS mutated. So the market opportunity is quite significant. So that's another set of business interests where we've had a very focused interest on a mutated primary cancer tumor gene.
Yep.
A validated one at this point. And by the way, if you compare to the G12C covalent inhibitors-
Mm.
you know, these mutations are far more prevalent-
Yeah
in these cancers. And then there are companies that are, as they're learning about the technology, that have their bespoke antigens, where they want to use the platform to drug those particular antigens.
Yeah.
So one of the strengths, as we talked about earlier, is the modularity. So we are not. At this point, we're not in the antigen discovery business. We are drugging-
Yeah
antigens that are well described, a lot of literature and clinical validation. However, there are companies that are in the business and of sort of detecting and discovering new antigens, and this framework lends itself to optimal drugging.
Yeah.
For building on top.
Again, you can even do beyond that with Neo-STATs, with neoantigens, and ...
That's right
... even redirect immuno-STATs. But I want to take some of the rest of the time that we have, because the other side of this immunology coin is obviously autoimmune disease. And you guys partnered with Ono Pharmaceutical for autoimmune and inflammatory diseases. Firstly, tell us, how would an immunostat work here? And then maybe remind us what you're working on-
Yeah
- and what the deal was like for Ono.
Sure. So for autoimmunity, the two broad areas are antigen-specific modulation in diseases where we have a high degree of confidence of primary autoantigens and very strong HLA susceptibilities. So examples here would be type 1 diabetes, proinsulin, celiac with some of the gliadin gluten epitopes, and so on. So in that instance, Ted, you can use an immunostat with an autoantigen, and now instead of an activating module, you have a module to quiet-
Yeah
... to dampen the T cell. And this, in that instance, of our 300 series, we've used the native PD ligand and shown POC, proof of concept, with proinsulin-specific T cells from type 1 diabetes individuals-
Mm
and some preclinical, supporting preclinical studies. So that's one part of the axis, is generating immunostats for selective targeting, dampening, and perhaps even depletion of the pathogenic rogue repertoire, while you do not carpet immunosuppress the entire patient.
Yeah.
Which is where the field tends to go. When you block multiple cytokines or if you're doing steroids, et cetera, you're bringing everything down.
Mm-hmm.
So that's actually a very important component. What we... The deal we have with Ono is actually for a novel bispecific we developed in-house. That is an IL-2 TGF-beta bispecific. That allows us to induce and generate regulatory T cells. So historically, it's known that Tregs are, of course, dependent upon IL-2 signals, but TGF-beta, in conjunction with IL-2, can generate new populations of regulatory T cells, also known in the literature or in the field as induced Tregs, iTregs. This is very different from the IL-2 muteins that others are developing that go after preformed natural Tregs-
Right
... that exist. We act upon those, but beyond that, we have the potential to convert a pathogenic CD4+ T cell into a regulatory T cell.
To a T, yeah.
So that's a very unique way of-
Yeah
- resetting immune tolerance, when you can take what has gone wrong and reset it to be regulatory in nature. And that's the molecule CUE-401 that Ono partnered with us. Or we partnered with Ono earlier this year, and that partnership is going very well. That actually what turned out to be a really excellent deal from the science and execution part for us, because Ted, Ono essentially covers 100% of our costs.
Yeah.
This is all off our books till we get to the decision, option decision point, which we anticipate by middle of next year. At that point, we still hold the optionality of opting in for 50% of co-development in the US-
Sure
... which we believe allows us to have a significant upside, should we choose to do that, depending obviously on how we're progressing with our other assets and how the company is progressing. So again, on the autoimmune side, I'm glad you brought this up.
Yeah.
We've not sort of talked about this much on the outside, but there's two axes here. Broadly, one is dampening, selective dampening of the rogue pathogenic autoreactive repertoire, and that would be through the TCR engagement of an Immuno-STAT format. Except instead of having an IL-2-
Yeah
As you would in oncology, you have a dampening module.
Yeah.
In this case, we showed it with PD-L1. The other is focusing on tolerogenic mechanisms with CUE-401 that goes after regulatory T cells, enhancing them, but very differentiated from just the CD25-
For sure
biased IL-2 muteins. And we've sort of shared some of that early preclinical data, but even a short-term treatment, and that's in a preclinical model of autoimmune gastritis, leads to long-term disease protection. 'Cause again, if you think about the paradigm here, Ted, you know, it's the regulatory T cells that are the ultimate drug.
Sure.
So, we don't foresee-
Yeah
... chronic treatment, 'cause once you get them in place and you situate them, they should control the inflammatory reaction.
Yeah. I mean, really, the same thing too, with how you're treating cancer.
That's exactly right.
Where the, you know, antitumor T cells are the drug. You're not a drug, you're actually just inducing the immune system to have that target.
Exactly right.
Great. Well, I think that's a good spot to end it. Anish, thanks so much for being with us. Thank you all for joining us for the second day of Piper Healthcare Conference, and we look forward to seeing you tomorrow for day three.
Great.
Thanks, everybody.
Thank you, Ted.