First of all, thank you very much all of you for attending. This is a great turnout on a Sunday night, at least I think it's Sunday.
I'm not sure what day it is. I've lost track. But we appreciate you all coming. We have, I think, a very interesting agenda for you tonight. As you know, we presented, I think, a really beautiful paper this morning presented by Doctor.
Luke, who's joining us this evening. Doctor. Luke, of course, did this work while at the University of Chicago, but he's recently moved to the University of Pittsburgh. So if you're a Steeler fan, you'll be happy. The paper today that Doctor.
Luke presented makes me extremely proud of the work of our collaborators and the work of people at our company. For those of you who were there, it is and I've been doing this for like 30 years, It was a great, great demonstration of a really nicely conducted Phase I study that had beautiful safety early assessments of efficacy and beautiful correlative biology and immunology. It doesn't get any better than what you saw today, in my opinion. And I think others in the room who are also our collaborators, who I'll introduce in a bit, would agree. That really doesn't get any better than this.
So what I want to do tonight is, I've asked Doctor. Luke to run through the presentation again because I know a lot of people, ASCO is very busy and a lot of people probably didn't have time to attend this morning. So we'll run through the presentation quickly. The slides are up on our website, so you don't need to take pictures or take notes because it's all there for you to look at and download and do what you want. So I'd ask Doctor.
Luke to run through the slides. I'd like to hold questions until he's done, and then we can open it up for questions. I also have some slides that I want to run through that sort of put the data in context. As you know, anti CD73 antibodies are sort of a hot area now. There's or targeting CD73.
There's probably 10 or so companies working on this. And what you saw today in our presentation was really very, very novel unique behavior of this antibody. And I'll go through what those things are and why we think they're advantageous and why we think that they're going to play a great role in therapy, both in oncology, perhaps even other diseases as well. So with that, and it's already getting late, I want to turn it over to Doctor. Luke.
But before I do, I want to just make some quick introductions. We're also joined by Doctor. Mehrdad Mobasher. He's our new or not our new anymore. He's been with us a few months.
He's our Chief Medical Officer Janet Koh, our Director of Product Development Dan Hunt, VP of Business Development. Also joining us tonight is the most distinguished person of all, Lauren Harshman, who is from Harvard. Lauren is from Dana Farber Cancer Center, and she's a genitourinary cancer expert, renal cell cancer and prostate cancer. And you'll see why we're interested in those diseases. So I'll have to be careful what I say because Lauren's here.
Lauren also trained at Stanford. So we know she's very well trained oncologist, right? What's that? Jason was not trained at Stanford, but nonetheless, he's still a pretty good oncologist. So with that, let me turn it over to Jason.
He did? I was at Harvard before she was.
Is that right?
Awesome. So appreciate all of you taking the time to come out. As was mentioned, we're going to go through the slides of the presentation. A bit less formal, like, than the actual talk. So if you want to interrupt, you want to ask questions, it's fine.
We're trying to just get through the slides, so if it's depressing to ask, otherwise we can wait. But sort of just to hit the highlights of the slides as we presented them. So CPI-six obviously is the molecule anti CD73. Really talking about immunomodulatory properties of that and then the Phase I results as they've been described so far. So to set the stage on this, you can see on the right hand side this cartoon that's busy but important in identifying several aspects of what we think is important in this biology.
Obviously, everyone is aware of the importance of CD73 in this conversion of AMP to adenosine in the tumor microenvironment, adenosine being known to be immuno metabolism of AMP to adenosine. But more broadly than that, CD73 is expressed on a number of different cell types, including T and B cells and has a number of other functions related to lymphocyte adhesion and migration and activation. We highlight that here where CD73 is known to interact with other ligands and potentially can act as a co stimulatory molecule for T cell activation. So that's another aspect of CPI-six that's important. The antibody itself is a humanized IgG1 Fc gamma receptor deficient anti CD73.
And an important point there is that there's no ADCC function. So when you see the later data, it's not that the cells are being depleted. So obviously, block this catalact activity. We can agonize immunomodulatory activity here. You're also aware that ciparatidant or CPI-four 44 is the A2AR inhibitor that's previously been investigated by Corbus with activity as monotherapy and in combination and importantly with this, gene signature, adenosine gene signature that correlates with treatment response, it really will be an integral biomarker moving into the future.
So all of this to say there are multiple roles where adenosine could matter, CD73 can matter, the interaction with antigen presenting cells is going to be important, particularly B cells throughout the data, the rest of the data that I show. And CPI-six can interact in a number of functions here. So just quickly, preclinically, looking at CPI-six in terms of CD73 catalytic activity, you can see that increasing dose, you get a decrease in free adenosine interrupting the catabolism as you would expect. Interestingly, the molecule has monotherapy activity. This is MDA MB-two thirty one is a triple negative breast cancer orthotopic model.
And from those tumors, importantly, when you take them out, if you expose them to a noncompetitive CD73, you can see that the antibody diffuses through the tumor and binds to the antigen. In the context of this competitive blocking acetate, the epitope is blocked, and the enzymatic activity is interrupted as shown on the right hand side. The immunomodulatory activities, as I mentioned, are really highlighted on this slide, which I really think is an interesting one. So these are healthy donor PBMCs treated overnight with the antibody. And what you can see is an induction of a number of activation markers, particularly on B cells, CD69.
And I'll also note that besides being an activation marker, this molecule is important in migration and trafficking of B cells. And again, that will become important in a second. But broadly, their activation markers, 69,8325, as you can see here, up regulated, as well as antigen presentation markers, 86 in Class 2 MHC. And interestingly, these effects up regulating these activation markers are independent of the adenosine axis, as shown on the bottom hand bottom panels here where 6983 are moved to the right here despite co treatment with this high potency adenosine agonist. So we're not moving that back to the left, which means a different effect coming here.
So these lymphocyte markers are consistent with activation of B cells, which a number of these markers associated with B cells and other antigen presenting cells. And so that led to the clinical trial design, which I won't belabor. It's a 3 +3 dose escalation. In orange, you can see the dose levels that have already been accomplished as monotherapy as well as combination. There'll be a third combination with pembrolizumab that will be initiated.
All of these are current and ongoing. Dose expansion groups in the middle. Just in terms of dosing, the molecule is 1 hour infusion every 3 weeks with cifuraditan as previously described. The eligibility is pretty standard for Phase I population. We will note the CD73 expression, which is not required in dose escalation, but is a potential marker to be integrated as a biomarker into the expansion cohorts.
Object is fairly standard and biomarker assessments are noted on the bottom. We'll talk about some of them kind of throughout the rest of the year. So talking about patients treated on the study. You can see monotherapy in the middle column and the combination on the right hand side for CPI-six or with ciforatedan. Again, it's a general Phase I population, but we'll note that 4 prior therapies on median for each one of these groups, these are heavily pre treated population.
If you look at the tumor types, I won't read them out, but these are tumor types that, generally speaking, are quite aggressive in the refractory setting. So this is a pretty heavily pretreated population. In terms of adverse events that we've observed, you can just look at the numbers and see that it's been very well tolerated to date with mostly low grade events. So all grades here in the middle, not so many, even in combination and grade 3 events really only just here with anemia. So it's been very well tolerated to date, and I think that's important as we start to think about adding in other therapies like anti PD-one or the combination of cifuraditan.
These are PK and receptor occupancy data. And what you can see is that with increasing dose, we have increasing exposure to the drug, as you'd expect. There's an interesting phenomenon here where clearance appears to decrease. It's not so clinically important, but it's an interesting PK profile. We see that the CPI-six is detectable at the 6 milligram per kilogram dose level out over 21 days.
And in terms of the receptor occupancy, this dotted line shows 100% receptor saturation. You can see that doses we've already gotten to, we get 100% receptor saturation at 6 mg per kilogram or higher. Again, similar to what we previously showed from the peripheral blood, you can see that upon binding of the antibody here, the total cell surface CD73 doesn't change. This is kind of important. Whereas the free cell surface goes basically to 0, which means that the epitope for binding is totally blocked, but the receptor is still there.
That's important when I think Richard's going to talk about some other antibodies in class. This is different than what has been described to date for other antibodies. It's just a different mechanism. From tumor, we see very similar. This is a patient treated at 12 mgs per kg, colorectal cancer.
This is from a tumor biopsy. And again, we see the same phenomenon with the antibodies able to penetrate and bind to antigen. The epitopes blocked by this competitive antibody binding. In the context of competitive antibody binding and CD73 and the matic activity being eliminated. So really, we think about we've got preclinical tumor, we've got peripheral blood, and we've got the tumor from the patients.
They're all showing the same thing throughout, which I think is what Richard was alluded to. It's really the beauty of this study, which really goes from preclinical translation all the way through the patients. So these are the disease assessments for patients treated on the study so far, and you can see the dose for monotherapy and combo on the right and dose increasing here, here, here, so 1 through 12 milligrams per kilogram. Again, 6 milligrams per kilogram is 100 percent receptor occupancy on the dotted line here. And again, we highlight this is early in the study, right?
And we're just it's a 6 milligram per kilogram is the first dose where we're hitting the full saturation. But you can see, as we're going up, there's a suggestion here. It appears that we're getting longer term benefit in these patients and these patients being on this therapy for a long period of time. What I remember mentioned before, these were highly refractory patients, more than four lines of therapy. It's very unlikely that this is just stable disease because just because these are people who have progressed through a lot of stuff before they went on the study.
And then similarly, this combination even at earlier dose levels with cifuraditan, we're starting to see patients going out longer than you would really expect for just stable disease on a Phase I trial, as patients are out to 6 cycles on therapy. I would point out that there are a number of patients, renal cell that will be discussed a little bit later, that are ongoing on the study, and there's high hopes that this could be an interesting combination approach there. From the peripheral blood in patients, we see quite some quite interesting changes in peripheral blood profiles. You can see in the CD73 positive B cells, which was sort of mentioned a few times, there's this rapid reduction in the peripheral blood compartment of these cells. And there are also changes in T cells and other sorts.
And you can see CD73 positive and negative CD4s, which appear to go up. CD73 positive, CD8s are basically stable, and CD73 negatives are slightly lower. We and monocytes are also lower, consistent with the B cells. And we see that this is trafficking of the CD73 positive B cells out of the peripheral blood. We're really going to talk about that later.
And redistribution of both those B cells and monocytes into different compartments, and this is going to become important, as well as an increase in this ratio of 4:eight cells, and we think that, that could be important in
in terms of mediating antitumor activity as well.
Profiling these changes in B cells, we can see that after treatment, we see this initial drop and a return to a new steady state thereafter, and that's true at each one of the dose levels. This appears to be an on target effect independent of dose. Very interestingly, however, as I just mentioned, the B cells do come back to the peripheral circulation. And when they do so, they have a different phenotype, highlighted here from these 3 patients treated on the 6 milligram per kilogram dose cohort, whereupon return to the peripheral circulation, you have an increase in HLA Doctor, Class II MHC expression. So these are activated B cells that are ready to help prime an antitumor response when they return to the circulation.
We're going to talk about what that could mean, but we think maybe this is consistent with redistribution of these B cells into lymphoid tissues where they may be able to prime immune response. When they return, they have this profile. And this is a patient with prostate cancer, a 72 year old man treated with a 6 milligram per kilogram dose cohort, again refractory to standard therapies that are outlined here. You can see in this patient, we get this drop in the CD73 positive B cells. It returns, as I discussed, to a new baseline and continues then to stable out over time.
In this patient, we see a reduction in the patient's overall tumor burden with these peraortic lymph nodes decreasing. Upon initiation on the study, it's interesting we saw that the PSA velocity started to change, and then there were some fluctuations over, but the patient clearly benefited. The treating investigators report is this guy had fairly significant pain syndrome that essentially has resolved now. And this guy is going on now more than 11 cycles. Very unlikely this patient has stable disease on a Phase I trial for more than 11 cycles with an improvement in overall pain syndrome, like I mentioned.
The treatment in the peripheral blood has also been associated with this cytokine profile that really suggests an immune activation phenotype. You can see early on treatment at a half hour and 2 hours induction of a number of cytokines consistent with an early inflammatory response. And these then sort of expand into a broader inflammatory response out at 24 hours 8 days. You can see that sort of here with this initial burst and then sort of a broader expansion of this phenomenon out over time, again, consistent with an inflammatory response to treatment associated with those changes in the blood cell types that I mentioned. So to try to put this together then, what do we think is going on here?
CVI-six is obviously anti CD73. So it binds and it can block this conversion of AMP to adenosine. So that's clear. And that's what many people have been focused on so far. But in addition, I think it's becoming very clear, and we try to show you here, binding of CD73, however, has the potential to lead to activation of multiple immune cells.
And so here we show B cells where you can have multiple pathways that can induce this activation with up regulation of CD69. If you remember at the beginning, I talked about CD69 being an activation marker, but also a migration and trafficking marker, and I think that's important. CD69 is a regulator of S1P1, which is a molecule that helps to mediate egress of B cells from lymph nodes. And so this biology is all starting to link up such that we think that after we treat, these B cells are going down. They're actually migrating into and being retained within the lymph nodes where they start to pick up this increased antigen presentation ability.
And again, returning to that cartoon then, that's why I mentioned before that we think antigen presenting cells, and specifically B cells then, are now into the lymph node where they can interact with T cells, help facilitate showing antigen to T cells, but then there's this additional co stimulatory function of CPI-six on CD73 in T cells. So it's an addition to helping the B cell become activated. It's also directly helping to activate T cells. And you put that in the context of sipiraditan eliminating immunosuppressive adenosine in the tumor microenvironment. We really think that this could be an attractive therapy.
And with the early data, we're quite excited about the potential here. So in conclusion then, CPI-six, novel immunomodulatory activity with dual mechanism. We talked about D cell trafficking quite a bit with increased expression of CD69 and other markers, an increased antigen presentation and obviously inhibition of CD73 enzymatic activity without internalization of the receptor and that being different than other antibodies. Molecule safe is throughout the study to date. 12 mg per kilogram is monotherapy and 6 mg per kilogram with silforaditan with no DLTs or MTD.
At doses of 12 mgs per kg, we get sustained occupancy in PVL with target saturation and inhibition of enzyme activity from tumor biopsies in patients. The treatment associated with peripheral blood serum cytokines consists with an inflammatory response. And the preliminary data suggests that there are patients already who are benefiting with extended stable disease that appears to be clinical benefit associated with reduction in pain, as I mentioned. And the study continues to enroll both monotherapy, combo and their further stages, as I outlined previously. So with that, I'll pass it back to Richard.
Well,
stay up there. I'm sure any questions for Jason or I have a question. So these B cells are in the blood. They leave. But what do they do when they get in lymph nodes?
What's the normal immunology?
Well, they're going to do a lot of things, right? So I mean, I think that's a
Well, teach me, I don't know what they do. So tell me what they do.
So obviously, B cells are one component of the antigen presentation compartment. So they will go and on some level educate T cells. We commonly think of that as being from dendritic cells, but they'll also become and be educated to differentiate into other cell types to make obviously, to differentiate the plasma cells to make antibodies. And so I think there's probably multiple things that I mean, I'm not sure 100% where you're going with this. There's lots of things that they could be doing.
But I think sort of the spectrum is multifold.
So since I give some of the lectures on immunology to freshman medical students at Stanford, So the lymph nodes are not just these little things that are kind of hanging out there. They have a very characteristic architecture. And B cells come out of the bone marrow, and they float around in your bloodstream. And when there's a site of inflammation or a bad guy who's entered your body, they go to the lymph node and they get stuck in there. And when they're in there, they get exposed to the antigen.
And then interesting things happen. They start to differentiate, and they do a couple of different things. One is some of the B cells differentiate into what are called plasma cells and make antibodies. One of the questions today from, I think, one of your former colleagues was, have we found any of those antibodies yet? Well, that's a really good question, and we're going to look like that really hard because this may be the greatest way I've ever seen to make antibodies to your tumor and to make even monoclonal antibodies as you could harvest those B cells, something really to do.
So one thing is that the B cells will differentiate towards making antibodies. But some of those B cells are so called professional antigen presentation cells. Dendritic cells, B cells, macrophages, the other thing they do is that they have the antigen on their surface and they present it to T cells. Remember, T cells don't do anything unless they have antigen presented to it in the proper context, which is more complicated than we need to get into now, so activation of T cells. So this is all a concerted process that results in how an immune response occurs.
Immune response is both cellular and numeral usually. And the action really occurs in those lymph nodes. Now although not proven, although there's a lot of preclinical evidence, in fact, one of our collaborators, Jonathan Powell at Johns Hopkins, did this with our drug Ciforaden and showed that in the regional lymph nodes in a mouse tumor, this is published, you got activation of and reduction of what are called suppressor T cells with the treatment with our drug in the regional lymph nodes of a tumor. Regional lymph nodes mean where the antigens from the tumor would be spreading because that's going to be the first site that gets exposed. So what we're seeing here and the reason for our proposed mechanism is all really consistent with what you would expect in normal immunology.
Now we obviously have a lot of work to do. It'd be nice to look and see where what's happening with those T cells. It'd be nice to see are we finding antibodies that are tumor specific. We certainly want to look at that. That's not that easy to look for.
That's challenging exercise. And of course, what we're primarily interested are people's tumors going to go away. And that's, of course, what's driving all of this. But the thing I want to emphasize is that this antibody and if we can go to the next slide, this is a great way to segue into this slide. So there I mentioned there's a lot of CD73 antibodies out there.
And this antibody is unique. Well, why is it unique? Are we just lucky that we just stumble upon that? No, we're not I'm definitely not lucky. I can tell you that.
I've never been that lucky. Actually, you think about most people who've been making CD73 antibodies have been saying, okay, I want to block the conversion of AMP to adenosine. Let me make an antibody that blocks that, okay, because people were thinking adenosine. And that's one of the functions of that protein, so it's not a bad idea. Actually, as I was telling some other people in the room earlier, CD73 was first described had nothing to do with adenosine.
It was first described and was first called lymphocyte vascular adhesion molecule. It was known to be involved in lymphocyte adhesion, and it was called lymphocyte vascular adhesion molecule. Only later did people figure out that it was also an enzyme that convert AMP to adenosine. So actually, this is an antibody that we licensed from a person named Linda Thompson, and I want to give a shout out to her. Linda was at Scripps at the time.
She's now retired. And Linda made this antibody not so much for looking for blocking adenosine, but more about its function. The antibodies you get are a result of what you screen for, what you look for. And she was looking for effects on vascular adhesion and things like that. And of course, we licensed that antibody from scripts and we, of course, did a lot more work on it.
We humanized it. We affinity maturated it. We changed the frameworks. I mean, it's an entirely looking different looking protein now, but it's different. It was made to interfere with a function of that adhesion molecule and it also blocked the conversion of AMP to adenosine.
I was telling somebody before, small molecules to block things have the limitation, who is I talking to about that. You have a geography problem. If you want to block these functional things, you need to cover a bigger surface area. It's hard to block protein protein interactions, easy to block AMP binding, ATP binding. It's easy.
Usually, small molecules can do that, but not these other functional things are much harder. So anyway, how does this result? What's different about our antibody? So in this slide, I've looked at Corvus' antibody, AstraZeneca, that's probably AstraZeneca. Right now, they don't talk.
Their lawyers are very good. AstraZeneca, BMS, Surface Oncology, Innate, a company called Arcus. And I've highlighted in yellow there the key differences. PPI-six inhibits enzymatic activity, no question, very potent at that, kills it dead. You saw the slide that Jason presented at very low concentrations.
But it does it without internalizing the antigen. So a lot of the other antibodies like the BMS antibody, I'm familiar with the AZ antibody, some of the inhibition of enzyme is due to the fact that when the antibody complexes with the antigen, it gets internalized. That happens to a lot of antigens. When you cross link them, they become internalized. Obviously, they become internalized.
There's no enzymatic activity, right, because the antigen is not there. Of course, it comes right back because the cell produces the antigen again. So this does not internalize. We knew that. We can study that in vitro.
We know it doesn't cause internalization. We've also made some of those other antibodies from these companies. And in vitro, we show that they don't cross block. If you react with the same epitope, if I treat with 1 antibody and then try to come in with the other, I won't be able to get in there because it's blocked and vice versa. Very straightforward experiments that immunologists do all the time.
So we know we don't cross block. We know we don't internalize. And then there's a third thing. Many of these other antibodies react with human and mouse. We don't react with a mouse because the mouse doesn't have that epitope.
So there's no question that this CPI-six is a unique antibody that has not only the property of inhibiting the catalytic activity, but also has this other property of these immunomodulatory functions, which we've demonstrated in vitro using human cells. We've actually also demonstrated in subhuman primates, we haven't shown you that, monkeys, who also have this antigen and the antibody does cross track with them. And now we've shown it in our human clinical trial. And you see this happen even at the lowest doses. I mean, we're very pleasantly surprised.
At 1 milligram per kilogram, you see these phenomenal changes in blood lymphocytes. Now blood is like shooting ducks in a barrel, right? Because you give the antibody, of course, it's in your bloodstream, it's in a pretty good concentration. And of course, you want the antibody to get into the tissues and the tumor and all those other places, and that's why you need to go up on the dose, and that's what we're doing. So inhibits the enzyme, doesn't cause internalization.
The other antibodies there, they cause internalization. Some of them induce what are called allosteric changes. If something binds to a protein and causes it to bend a different way, you can lose enzymatic activity. This company has a small molecule. Why you would make a small molecule to that is defies my logic.
But I guess if you just wanted to block AMP, that would be fine. But again, you're trying to block proteins that interact with other proteins. I don't see any reason to do that. By the way, it'd be very easy to do that. If I wanted to block AMP binding to CD73, my chemocept, Corvus could do that by next week.
Pretty simple. Small model, it's easy to mimic it. There's already scaffolds out there and such, etcetera. We don't want to do that. Now the most interesting thing, though, is this activation of APCs and lymphocytes.
I don't know, maybe somebody can get me a paper or something. Jason, do you know, I don't know of any Lauren, I don't know of any other CD73 antibody where there has been a description of this effect on immune cells. I just don't know of it, okay? I think this antibody is very, very unique. And I think, therefore, the antibody is unique.
Our combination with it is unique. So this is why we're really excited about this agent because unlike the 12 other guys who have CD73s and A2A antagonists, we can now have something that's really pretty unique and special proprietary to the Corvus and file patents on that and all that other sort of stuff, which, of course, we're doing very aggressively. So very different antibody for the reasons I've mentioned. And so far, appears pretty safe, even at doses of 12 milligrams per kilogram. We're now I just heard last week, we dosed patients at 18 milligrams per kilogram, so we went up on that.
Enrollment in this trial is going very, very quickly. Obviously, there's a lot of interest in prostate cancer, not only because of the what we're seeing, but AstraZeneca, as you know, reported couple of weeks ago or a month ago at AACR with their A2A antagonists, some responses in prostate. We've also seen activity in prostate with our cifiratinib, which we didn't chase because we saw what we thought were better signals in renal and lung. Let me go to the next slide. I guess I can do the next slide.
I'm used to having people working for me. I like doing it myself. So let's just put let me take a moment to put it together. I don't know if this is if I need this, but I'll use it anyway. So cifuradenant, which Jason described, is in the trials that you heard about in combination with 6.
But obviously, we've also been using it as a monotherapy and more recently as a combination with atezolizumab in ongoing renal cell cancer studies that we're doing and also in lung cancer studies that are being conducted by Genentech. And those studies are enrolling nicely. And I think the recent really exciting thing with cifuradenant, and we've now presented this at a couple of meetings, is that we've identified a gene signature called the adenosine gene signature, which we believe predicts response to this treatment. Now everybody says they have a biomarker. Biomarkers are hard.
It's hard to prove this. There's a lot of variables and all that stuff. But what I like about this biomarker is it actually makes sense. Our scientists in our laboratory did some very simple experiments. I can't believe these experiments haven't been done before.
I told my guys, it's the dumbest experiment I've ever seen, but it was like, it's the dumbest experiment that had to be done. He just took white blood cells, stimulated them, throws adenosine in, suppresses them. What genes are associated with that suppression? And it turns out, shockingly, it's a set of just go to the next slide. Let me just shockingly, it's a bunch of myeloid associated genes, which we've presented at meetings.
Now so adenosine, the presence of adenosine is associated with these myeloid genes. And then, of course, we did the obvious thing. Let's look in the tumors, and we find that from these waterfall plots, again, this is old data. We've presented this. Patients who respond have this adenosine gene signature.
Makes sense. Now things got really interesting and even more exciting. Right around this time, a paper by McDermott et al. Was published in November Nature Medicine in 2018, 400 and something patient frontline renal, okay? And Genentech, of course, does very nice biomarker work and genetic analysis, and they described what they called a myeloid gene signature, which was associated with lack of response to atezolizumab, a PD L1.
Let me repeat that. Myeloid gene signature, they found. They're not looking at adenosine. Adenosine wasn't in the picture. There was no adenosine in the treatment.
No CD73, A2A, nothing like that. It was just a study looking at Sutent, Atezolizumab alone versus Atezolizumab plus adastin. And a myeloid gene signature was found to predict no response to or lack of response to atezo. We look at their genes, they're virtually identical to our genes. I think of 12 or 13, like 90% of them are the same 95% are the same.
So putting this together, what does this mean? It makes very good sense. This adenosine signature, which is indicative of the presence of adenosine, appears to be a resistance mechanism to anti PD-one or PD L1 therapy. So that makes perfect sense then to combine a PD-one or anti PD L1 with an adenosine antagonist. That would make perfect sense.
And that's what we're going to test in the clinic. Now and I won't go through this. Again, this has all been presented. By the way, I mean, we looked at, of course, the obvious things. CD73 expression, does that correlate?
No, it does not, okay? We've looked at 100 of people. There's no CD73 in tumor, CD73 in the serum doesn't seem to predict anything, okay? So I know a lot of people are talking about that. We don't find it, and we've got the most data.
But I hope they keep working on it. So this adenosine gene signature appears to make biological sense. By the way, the biomarker game is never that easy. So it's but it's good to find this connection. Now you might ask, why don't we just measure adenosine in the tumor?
That's hard to do. Adenosine is a very short lived molecule metabolite. It's used to Adenosine is actually a drug. It's used to treat supraventricular tachycardia. You give it IV.
If you got a rapid heart rate, it will slow your heart rate. And it has a half life of 10 seconds because there's a lot of enzymes that metabolize it. Now in a tumor, what some people have reported, and they know better than this, they do know better than this, they take a tumor and they crush it. And they say, oh, it's got a lot of and they put enzyme inhibitors in there and they say, oh, there's a lot of adenosine in the tumor. Well, yes, because you've crushed the tumor and all the adenosine from the inside the cells leaks out and all that other stuff.
What you really care about is the adenosine in the extracellular space. By the way, that was measured 20 years ago. We've measured it. Charles River Labs will measure it for you if you can buy the test from them. It uses and employs a cool technique called microdialysis, a little tiny microdialysis tube hooked up to a mass spec that's made for measuring these wrapped short lived metabolites.
And when you do that and you do it right, the level of adenosine, at least in mouse tumors, several that we've measured and was found again 20 years ago is around 100 nanomolar, 100 to 200 nanomolar, not micromolar. So the levels of cifuradenant that we achieve easily, easily outcompete the adenosine in the tumor, easily. And I'm only bringing that up because some of our competitors make a big deal about that. Now some people might ask about A2B. What about A2B?
The role of A2B receptor is unknown. We actually have an A2B selective drug that we made in Corvus. It's really selective for A2B, and we're having a hard time figuring out what it does. So the role of A2B is not yet clear. Actually, I'm being a little flippant.
It actually is believed to be important in fibrosis and diseases like that. But most people who have an A2A antagonist are also blocking A2B because A2B is also known as a low affinity look it up, low affinity adenosine receptor. The affinity of adenosine for A2B is like 25 micromolar. So I would say pretty much anybody's A2A receptor antagonist is also substantially blocking A2B. So if people are telling you that they've got A2A, A2B is important and they can differentiate it, it's hard to believe that.
Chemistry doesn't work that way. Okay. So let me okay. So getting back to the Adenosine Signature, we've looked at TCGA and we asked the question, well, are there other tumors besides renal cancer? Because what I showed you was elucidated on renal cancer biopsies.
What about other tumors? So we go to TCGA where we have sequences on lots of tumors, and we find that it's possible to use this adenosine gene signature for a lot of tumors. And there's some really interesting things here. Some tumors are low and some are really high. Like one thing that one that I like, I don't like it, but it's interesting as a target, colorectal cancer is really high.
Lung cancer is high. Renal cancer, half the patients are high. And you can go through the list. Pancreatic cancer is high. So there may be some targets there where we can use our adenosine gene signature and our drugs for what are now I O recalcitrant tumors.
These tumors that have been I O resistant, colon, prostate, pancreas, gastric, the list is pretty serious, maybe recalcitrant because they have another mechanism of resistance. There's multiple checkpoints, and you have to hit the right ones. So this is precision medicine at its best. So that's our plan to use this adenosine signature both for A2A and for CD73. Now will the adenosine signature predict CD73 response?
That's a question. I don't think that we know the answer to that. It may not. It's a different agent working by a different mechanism. Now just to go back to this slide.
So you heard about cifiradmins, you've heard about CD73. I want to mention our ITK inhibitor because we announced, I think, a week ago or so that our ITK inhibitor so this is a drug that has nothing to do with adenosine. It's as you may know, our team at Corvus are the developers of a drug called Ibrutinib, which is a very successful drug for lymphoma, for many lymphomas now. But more than that, it was a paradigm shift in how you make a drug. It was a covalent drug, which most people say, you should never make a covalent drug, but it was covalent.
We ignored those people, and we made it anyway, and it's a great drug. So Ibrutinib hits a target called BTK, which is in lymphomas. There's a homologous target called ITK that's in T cells. We've now made a covalent inhibitor of ITK that's extraordinarily selective. And our clinical trial has recently been initiated.
Initially, we'll be treating patients with a variety of T cell lymphomas and that so that drug is in the clinic now. And we're doing a lot of cool biomarker work associated with that. What we're really interested in the T cell lymphoma patients, of course, we're interested to see if their T cell lymphomas go away. That's what we're primarily interested in. But T cell lymphoma patients have normal T cells, so we can also interrogate and evaluate what's happening to the normal T cells.
And it turns out that when you hit ITK selectively, you affect lymphocyte differentiation, and that's what we're going to be looking at. So did Jason get bored? He left me. Sorry. Okay.
So just to finish off, what we have to look forward to. Again, I mentioned this on our conference call last week. Corvus presents data at every almost every major meeting, AACR, CTC, ASCO. We get all presentations and stuff like that. Usually, it hurts us.
People say, Oh, it's too early. It's this and that and the other thing. But I've learned from my experience at IDAC and Pharmacyclics that ultimately you win that way. And we're going to continue to do that. Of course, it represents good science and good drug development and allows us to work with the great people like Doctor.
Harshman and Luke and many others. I mean, we are well wired in the medical community. But here's what you can expect. I think we'll see more data on cifiratininat SITC. I expect to see more clinical data on CD73 at SITC, which is in November.
We should have more follow-up and more patients treated by then. We'll be trying to get abstracts accepted there. And I'm hoping that we can have some clinical data, although it's going to be very early for ASH meeting in December of this year. More likely, that would be in some meetings early in 2020. So 3 products in the clinic, generating clinical data.
We communicate that to The Street. We're pioneers in each of this field. Everybody is talking about they have better A2As and A2Bs and CD73s, but we're still the pioneers, and we can continue to do that. I'm still waiting for people to come up with better rituximabs and ibrutinib. It's 20 years later now and they haven't.
So it's good to be a leader. All right. Let's I guess I started by answering a question that I asked. So Great. Nice to meet you.
All right. So Michael, you have a question. Yes, you can use this.
So that's great because Doctor. Luke left to add a question. The prostate cancer patients, I was wondering if you could just elaborate a little bit more about the type of tumor reduction, tumor volume reduction that you've seen in that patient because the last scan on the swimmer's plot shows progressive disease, not stable disease. And I was just wondering if you could elaborate on that.
Yes, yes. So that's a good question. So I can answer that since he's not here. So this patient has some lymph nodes regressing, about 20% regression of some of these periortic lymph nodes. He has one lymph node in the pelvis that's actually a little larger.
So by resist criteria, not IR resist, but strict resist criteria, any progression is a PD. However, remember what I told you about regional lymph nodes, right? There's a lymph node in the pelvis near the prostate. And I'm not convinced I mean, I don't know what that is. So he has scored a PD now, but the guy is feeling great.
His pain is better, bone pain. He's having a regression of lymph nodes, and he's got maybe some slight enlargement, tiny enlargement in a regional lymph node. So we'll have to continue to treat and see what that looks like. He's been a few I don't remember exactly when that scan was. Yes, I think it's a yes, yes.
So resist criteria is pretty tough. I mean one of the things it's interesting and a lot of people are having so imaging techniques are so much better now. Getting I mean, it's getting really harder to call PRs and CRs because the imaging techniques are so good. And they took a millimeter differences, which we never really saw before. But anyway, he scored a PD now, but clinically, he's not a PD, And I don't know what that lymph node is.
Now what I would like to do is biopsy that lymph node, but that's going to be not trivial. But maybe in a dark alley some night, I could no. In New York, we would do that, all right, Mario? All right. Any other questions?
There's got to be some Tony? But I think it's webcast that you need to.
Thank you. So 2 other papers that I would love for you to help rectify for me the notion of what's going on in the Adenosine Signature. One is, Maryanthesin in Nature in January last year in 2018, let me just explain in Vicar, just like McDermott, right? Atezo is used, they get a 50% response rate. What happens in the patients that don't respond?
They have elevated TGF beta by the way. And I'm curious how that relates here because likewise in McChord blood advances in May, This was again in a blood tumor. Looking back at NHL, they demonstrated that patients that responded also had that myeloid signature as well. So it seems to be a common theme as you alluded to, but I'm trying to also just justify what happened in InVigor with the elevated TGF and if in fact that's what you see with that adenosine signature as well.
So first of all, you're right, the myeloid signature is being a repeated theme now, and myeloid cell biology is a hot thing in immunology. We only recently started studying that because it's not been easy study myeloid cells. They're difficult to work with in lab, and we don't have good markers for them. But that's really the hot area now. We've looked at other genes, TGF data, probably I can't remember specifically if we've looked at it, but we've looked at a lot of things.
For example, we've looked at the T Effector signature, which by the way is up on the slide. So the T effector signature, which is a good biomarker for some tumors and tumors may be different, Tony, also. Basically, this up here, if I were to follow-up, this is your T Effector signature. And it looks like with our myeloid signature, about half of them express the T Effector signature and about half don't. I mix it up, half of them express and half don't.
I only say this because IMVIGR was in bladder cancer. If you go to your slide, which had the it actually showed if you look over here
at the
far left, way over here far left, right? Yes. It looks like
you get some Yes. So I mean different tumors might be different and the cutoff the other thing to think about is the cutoff. What's your cut point for calling high or low? I mean, that's a struggle. So that may not be the same in all tumors.
Just like for PD L1, I mean PD L1 is a great biomarker, but it's not true in every cancer. I mean, it's probably a great biomarker in melanoma for sure, lung cancer probably. But other tumors, kidney cancer, that's not a great biomarker in kidney cancer. So the biomarker game is tough. But again, what's nice about PD L1 is it makes sense, the target of your antibody.
What's not what I like about the adenosine signature is the target of your drug. So that makes good sense. All right. Any other questions? Michael?
I've captured this before. Michael Morabito, Credit Suisse. If you're getting target saturation of 12 mgs per kg and it's 100% or near 100%, do you anticipate any efficacy benefit from raising the dose beyond that?
Great question. So first of all, the occupancy data that was shown was in the blood. That 100% occupancy is on blood cells, not in the tumor. So I don't know what the percent occupancy is in the tumor, and we don't have that much data on that. That was one biopsy specimen, and it's a core biopsy.
So I think we're pretty close to full occupancy, but I think we should go higher and get some more data and figure it out. Blood is going to be different because blood is, as I said, really easy. So it's going to and in terms of the immune function, I mean, really, there's CD73 is expressed on a lot of tissues. And I'm not sure exactly what the right occupancy is going to be. So we're going to have to be a little empiric and go until do it the old fashioned way, go until we think we're pretty high, go until we see an MTD or maybe not.
We may never see an MTD. If you take a drug like Rituxan, we went up and up and up and up and never had an MTD, right? And then finally, we said, wait a second, there's only so much antibody you can give, right? So but we're at 18 millig in our monotherapy now, we're at 18 mgs per kg. We just started that.
That's pretty high dose. Now in monkeys, we've gone to 100 mgs per kg, and we didn't see any significant toxicity. I think we went over 100. But we're not going to do that in people. I mean that's an enormous amount of antibody.
We would need swimming pools full of antibodies to do that. I think it's going to be somewhere between 12 24, maybe 12, but we don't know yet.
I just wondered when you're going to start dosing the cohort with pembro and then wanted to know, are you going to have to start with 1 milligram as well or can you start higher?
Great question. We can start higher. The protocols are written so that we can start 2 dose levels below where we have where we are with the monotherapy. We wanted to get we wanted to fill up our monotherapy and our safradenin data first because we're most interested in that. I'm not that interested in making pembro work better.
Having said that, mechanistically, there's a beautiful story emerging here, and I'm hoping that you guys came to that conclusion yourself. The thing that makes the most sense here is the for admin, CD73 and PD-one, a triplet. Because then when you think about it, you're removing immunosuppressive adenosine, you're unleashing your T cells with PD-one and you're stimulating your APCs with CPI-six. I mean, that's a triple threat. What do they call that in stock or the hat trick or something like that?
Yes. So I mean that's really what makes the most sense. We didn't want to go start with in our protocol with a triplet. We thought a lot about that. But we thought that was a little too rigorous to go to the FDA with a protocol that had singletoublet triplet in the first protocol, first in man study was a little aggressive.
But now we have safety data. So now I think we can go to that. But we want to do the pembro, but we've been the protocol is written so that we can fill up the others first. And I wanted to get more data on that because those are our products. All right.
Any other questions? Yes, Mara.
Properties of CD73 and whether looking at that in a combination with an antiogenesis strategy makes any sense?
Yes. Mera is you're too smart for me, Mera. So CD73 is on some vascular endothelium, but it's very complicated. It's on some vascular endothelium, but not others and what all that means. And it is involved in angiogenesis.
Does it make sense? I mean, I don't know. I think we have enough things to do right now. I'm not sure that would be the top of my list, but it is an interesting thought. You like it?
You like?
Investigator initiated clinical trials. So you guys were talking about with cabozantinib. So any of the TKIs, but right now in kidney cancer, you have to think about what's going to be used upfront, and then what's going to be used second, third line. We're kind of in an embarrassment of riches in kidney cancer with a lot of different therapies. However, we're still not getting enough cures.
So I do think we got to go to things like triple threats and thinking about how to take advantage of potential combinations and synergies with anti angiogenesis. And so I do think what you're you actually set my trial really well. Yes.
But I haven't agreed to do your study.
I know. Not yet, Richard.
So speaking of new studies, I should mention that we're very close to opening a study at Johns Hopkins in myeloma. Now why myeloma? And that's because CD38 is see, I still think the best way to block adenosine is to hit the A2A receptor because adenosine comes from a lot of places. And I'm not sure you can get them all. And one of the places that comes from the CD38, CD73, CD39, but CD38 is another source through what's called NAD cofactor.
So there's very good paper several months ago in cancer discovery in mouse models showing that anti CD38 and A2A blockade work spectacularly in cancer. And of course, what is it, daratumumab, I always forget the name of that antibody. J and J's daratumumab is an anti CD38 that's approved for multiple myeloma. Patients fail it. I mean, it's a very good antibody and it has a response rate.
And of course, people ultimately fail it. So we have a study we're going to do with the Hopkins guys, adding our A2A antagonist to daratumumab failures. We're going to give our drug alone, and we've looked at the adenosine signature in myeloma. It's expressed there. We see it in the bone marrow cells and so forth.
So that's going to be interesting study. That's just going to be open at their center and maybe one other's. So I don't know how we got yes, so we're interested in these other things, and I forgot about your study. All right. Any other questions?
I think it's getting late. Again, I want to thank everyone for coming. Great turnout. Appreciate your time on this Sunday evening, and we'll be hanging around for answering any other questions you have. Thanks