Corvus Pharmaceuticals, Inc. (CRVS) Earnings Call Transcript & Summary

I think we should get started. We have a lot to cover today. We're really excited to be back in New York, able to meet all of you and to review all the programs at Corvus. First of all, can everybody hear me? Good. I'm not going to use that podium because I don't know, it's kind of boring and I'm afraid I'll fall off of it. So I think that this enables me to move around and make some eye contact. So my name is Richard Miller. I'm the CEO of Corvus Pharmaceuticals. And we have a really packed agenda today. So I would like to get started. Next slide is our forward-looking statements, which you can review at your leisure. I'm very pleased today to be joined by 3 other speakers. I will be presiding at the meeting. But really, that's -- that's my pleasure to be associated with these 3 individuals. First, we have Dr. Neel Gupta, who's an oncologist from Stanford University. Neel is a clinical assistant professor and is an expert in lymphomas. We're also joined by Erik Verner. Dr. Verner is a chemist, and as the inventor, named inventor on Ibrutinib patent as well as CPI-818, which we're going to talk about today. And then also Suresh Mahabhashyam. Suresh is Corvus' VP of Clinical Development and he'll be reviewing a couple of our programs as well. So let's move to the agenda. What we plan to do today is to move through each of our programs. We'll have some time for Q&A at appropriate spots where we can ask questions to the speakers and also myself. The plan is to review what we've been doing and to also tell you about what our plans are going forward. Now we've not had a lot of interaction with the Street. So I think this is a really great opportunity for us to highlight all the achievements that we've made and where we're going. We have 3 really novel products that are moving nicely through the clinic and through the laboratories. Okay. Let me start with sort of the overall Corvus development strategy. So my team and I have been through this before. We've made immune drugs for cancer namely Rituxan and ibrutinib. And so we like to think of our products as being integrated and connected together. Where when we work on one, we leverage the expertise, the experience, the assays and various other things to help the other products. So this allows us to make progress very efficiently. And I think anybody who is familiar with Corvus knows that we are very efficient. So not only does this allow us to develop our products efficiently, it also gives us deep expertise in the science behind these products. So we think about this in the following way. Our products are designed to modulate tumor immunity. Okay, what does that mean? Well, we have drugs or antibodies that interact with B cells. You're going to hear about that, to interact with T cells. You'll hear about that. And they interact with something you may not have heard much about but is very, very important in what we call the tumor immunity access, and those are lymph nodes. Okay. Those are like the most important part of the whole story. Our drugs target precise molecular targets, you're going to hear about that. We know how our drugs bind to their targets down to an atomic level. You'll see some examples of that. Mupadolimab binds to CD73, our ITK inhibitor. We know exactly where it targets, where it goes, and our A2A receptor antagonist, Ciforadenant. Broad applications, pretty broad. You're going to hear today about solid tumors like kidney cancer, lung cancer, you're going to hear about lymphomas. You're going to hear about autoimmune disorders, you can hear about allergies, and you're even getting hear a little bit about infectious diseases. I don't know what's left in medicine, maybe cardiology, I guess, we have coverage. Okay. So let's talk a little bit about just a very basic science underpinning, integrating and connecting these products together. We call this the tumor immunity access, and Corvus' products are designed to interact at various precise points in this axis. Now I'm going to be describing this a little bit different than maybe you hear from other companies, but I have to admit, I'm a well-trained oncologist and immunologist. So I always back up to the science and think about how do we move these things through the clinic, how do we do our clinical trials, where do we get biopsies, where do we look at biomarkers. So there's 3 players here. The tumor, they lymph nodes, deep down in the right lower corner there, and the vascular system, which is blood vessels or lymphatics. We'll lump blood vessels and lymphatics together as one. So those are the 3 key players that we need to think about. [ Lymph node ] system or the immune system is a little bit different than other organs in the body and that it's really dispersed throughout the entire body as opposed to, let's say, your liver, which is in 1 place. So now tumors, infections, autoimmune diseases, they can release antigens or altered proteins. And these antigens can either remain localized in the tumor, in the tumor microenvironment, they can spread through the bloodstream or lymphatics and go to other lymphoid structures like lymph nodes or more commonly, they're picked up by macrophages, phagocytic cells and they're carried to the regional lymph nodes. Now in those lymph nodes is where we have a lot of things happening, both in the lymph nodes, in the blood and in the tumor. This is where antigens are processed, T and B cells start talking to each other in the lymph node. They mature, they get -- they acquire higher and higher affinity and specificity for the antigen. And these cells, these T cells and B cells then leave the lymph nodes. They go into the bloodstream or the lymphatics and basically, 2 kinds of cells leave. One is called the memory cell, memory B cell, memory T cell. That's the basis of immunologic memory. So the next time you see an infection or the tumor antigen, you're immune to it. That's why you get vaccinated. Okay. You get a shot in your shoulder COVID vaccine and it goes to your lymph nodes. The other thing that leaves the lymph nodes and goes to the tumor are called T effector cells. These are the cells, these are the soldiers. They're armed and ready to go to destroy the tumor or the infection or whatever. So memory B cells, memory T cells, effector T cells effector B cells. Now of course, B cells can differentiate and make antibodies. B cells do a lot of things. They can make antibodies, as you well know. They can present antigen. They're involved in this crosstalk and this refinement of the immune response. Okay. So let's talk about -- where do our drugs interact. So this morning, you're going to hear about CPI-818. That's an ITK inhibitor, and you'll hear from Dr. Verner and others, what is ITK and what's that about? But this drug does some remarkable things. It actually modulates or affects the differentiation of T cells and skews them so that they become or biases them so they become more like effector cells. How do we know that? You're going to see the data for that in animals and in patients. So that CPI-818. Where does it do that? It does it in lymph nodes. It does it in the blood, and it does it in the tumor as well. You're going to hear about mupadolimab, which is an anti-CD73 antibody, but a very unique antibody, and that it's a primary mode. We believe its primary mode of action is stimulating B cells. You're going to hear a lot more about B cells today. So mupadolimab binds to the target in the blood, in the tumor and in the lymph nodes. Same 3 guys, and it activates those cells, stimulating an immune response. And then we're going to talk about our A2A antagonist ciforadenant which blocks the immunosuppressive adenosine from binding to the A2A receptor that can happen in the tumor, which is where it's most likely or most people think it happens, but it also has a big role in the lymph node. And this is something that most people don't appreciate. CD73 and adenosine play very important roles in the function of lymph nodes, specifically germinal centers, which is the main player here. Okay. Just a quick review of where we are with these products, our pipeline. CD73 and mupadolimab -- human anti-CD73, has been examined in well over 100 patients as monotherapy and as combination therapy with standard agents and with other IO agents. We are planning to start a randomized, placebo-controlled Phase II study with mupadolimab, pembrolizumab in chemotherapy in frontline Stage IV lung cancer, all comers of lung cancer, except for the eGFR mutants and [ LPNs ]. So this is a big opportunity, and we are gearing up to start that study in the second half of this year. The A2A receptor antagonist, ciforadenant also been in over 100 patients, both as monotherapy and combinations. You're going to hear about a lot about monotherapy now because it's really important to study a drug carefully as monotherapy. And I don't mean 3 patients. I mean 50 or 100 patients so that you really understand its safety, its efficacy and its biomarkers, its effect on the immune system. Once you put things together in combinations, game over, you can't figure or anything else. And I bring that up because a lot of companies are doing that. So cifo is about to go in a frontline study in renal cell cancer based on some really interesting science that Corvus has uncovered. We're going to go through that a little bit today. I won't be able to discuss all of the scientific basis for it, but it's very interesting. Very interesting new approach to an IO combination. And then our ITK inhibitor. We've not talked much about this drug, deliberately so because nobody else has it. And we want to spend a significant amount of time this morning telling you why we're so excited about CPI-818, our small molecule or ITK inhibitor. Okay. So first, before we roll into ITK and its potential use in T-cell lymphomas, I've asked Dr. Neel Gupta to talk to us a little bit about T-cell lymphomas, the prognosis and management. Now Neel is an expert in lymphoma. I've personally worked in the clinic with Neel, and I can tell you that he is an extraordinarily good doctor. Neel?

I'm going to spend a few minutes reviewing just the basics of T-cell lymphoma to provide a little context for the rest of this morning's discussion. The T-cell lymphomas are a very diverse set of aggressive non-Hodgkin's lymphoma. The WHO in 2016 reclassified them into 4 distinct clinical phenotypes nodal, extranodal, cutaneous and leukemic presentations. So I've highlighted some of the more common T-cell lymphomas, which we'll talk about in a few minutes. And in part, their biologic and clinical diversity can be explained by their cells of origin and the respective cytokines that are elaborated by these cells that contribute to the clonal proliferation of these lymphatic disorders. So in the United States, there are approximately 10,000 new diagnoses of T-cell, [ mantle ] T-cell lymphomas per year. And in the U.S. and in the world in general, peripheral T-cell lymphoma, angioimmunoblastic lymphoma and natural killer T cell lymphoma, make up the majority of lymphoma that we see in clinical practice as demonstrated by the pie chart on the left. It is worth noting that the frequency of certain subtypes varies by geographic region. For example, in North America and Europe, peripheral T cell lymphoma, not otherwise specified and angioimmunoblastic lymphoma are seen most commonly, whereas in Asia, natural killer T-cell lymphoma in adult T-cell leukemia lymphoma are more frequently seen. And it's not that the reason for this increase in prevalence and incidents in Asia for these 2 subtypes is largely due to the endemicity of certain viruses, including Epstein-Barr virus and Human T-lymphotropic virus, which is thought to drive the pathogenesis of these 2 lymphomas. So I think this is a really important slide to give us context for what our patients are facing when they're diagnosed with the T-cell lymphoma. So the bottom line is T-cell lymphoma is having markedly inferior prognosis when compared to B-cell lymphomas. We are able to delineate individual prognosis based on a very simple but powerful prognostic tool called the International Prognostic Index. This index uses very simple data that can be abstracted from the electronic medical record, including a patient's age, their so-called performance status or their ability to be functional with the diagnosis of cancer. The number of extranodal sites, the stage of presentation and whether or not a tumor marker called LDH has elevated that presentation. So using these very simple indices, we can calculate someone's 5-year overall survival. As highlighted here in the red box, you can see that if someone is diagnosed with peripheral T cell lymphoma or angiomunoblastic lymphoma, and they don't have any of these risk factors or maybe 1 risk factor their [indiscernible] survival rates essentially a coin flip. It's about 50%, 56%, depending on the data. Now if they have all of these risk factors or most of these risk factors, you can see their survival at 5 years is pretty dismal. So contrast this with the table on the right and look at -- this is a revised international prognostic index for diffuse large B-cell lymphoma, which is our most common type of aggressive non-Hodgkin B-cell lymphoma that we treat in the United States. If you don't have any of these risk factors for DLBCL, your 4-year survival rate is greater than 90%. We have all of the risk factors, your 4-year survival rate is about 58% or essentially approximating the good risk category for T-cell lymphoma. So a marked difference between the 2 groups. So how do we treat T-cell lymphoma? Is there a standard of care in this country and in the world. And I would say probably most clinicians would argue there isn't a true standard of care. There are some common regimens that we incorporate into practice. I'll list the 2 most common CHOEP is CHOP chemotherapy plus etoposide. And this regimen was devised by the German high-grade non-Hodgkin Study Group. And based on retrospective data, they found a pretty decent signal in terms of 3-year overall survival for various subtypes of PTCL. I will tell you, in clinical practice, this is a difficult regimen to administer. It's very myelosuppressive. People blood counts routinely or low requiring blood transfusion. So it's difficult to get a patient who is older than 60 years of age through this regimen. And also one of the main limitations of this regimen is that all of the data derived for it was retrospective. So the new kid on the block is BV-CHP, Brentuximab Vedotin Plus CHP, CHP is CHOP minus in [indiscernible]. And this data was published in the Lancet in 2019, and this was on the strength of the ECHELON2 study, which is a randomized controlled trial, looking at BV-CHP chip versus CHOP chemotherapy. And obviously, you can see that the progression-free survival favored BV-CHP in this study, but there are some really important caveats with this study. This was a study that mandated that 70% of the patients in the trial had a very specific subtype of PTCL called [indiscernible] which is known to be uniformly CD30 positive. Despite that very significant caveat, the data for this trial has been extrapolated to other T cell lymphoma cell, but we don't know whether or not it's truly effective in the majority of T cell lymphomas. And then the last thing I'll say, the comparator arm was CHOP, and nobody really gets CHOP chemotherapy for T-cell lymphoma. So I would say the deck was back in favor of BV-CHP for this trial. And then a brief word about stem cell transplantation or high-dose chemotherapy with stem cell rescue. Although I wouldn't say it's considered the standard of care, most lymphoma clinicians, if they get a patient in the first remission with 1 of 2 regimens that we just discussed, they will consolidate that induction for the purpose of prolonging their survival. And on the basis of 1 very prominent study published in JCO in 2012 with a [indiscernible] survival rate of 50%, most patients go on to bone marrow transplant in CR1. However, again, important caveats there has not been a randomized study looking at chemo versus chemo plus transplant. And one could argue that the results of bone marrow transplant are fairly midline. And certainly, it is no dispute that a bone marrow transplant is toxic maneuver. And lastly, we really don't know which particular subtypes benefit most from a bone marrow transplant. So some significant caveats to that. This, I think, is the other really important slide. The plight of our patients who have relapsed or refractory disease. It's -- we talked about how poor the prognosis of patients are at initial diagnosis while it's even worse with relapse/refractory disease. So this really terrible looking survival curve was derived from a data set by the Vancouver Group in British Columbia. And it's the largest study of its kind looking at 153 patients who have relapsed refractory PTCL NOS, AITL or anaplastic large cell lymphoma. None of these patients received transplants. 89 of these patients went on to receive chemotherapy as their second line of treatment. So they relapsed or they never responded to their first line, and they went on to receive second-line chemotherapy. And this is the median overall survival. It's absolutely abysmal. So these patients are quite desperate for effective therapy. Now for some patients who do respond, there is the option to go on to an allogeneic stem cell transplant, where another person's immune system is essentially imported in your body, and we rely on the graft versus lymphoma effect. And there is some data to suggest that you can have durable remissions with this maneuver. But as those who practice know, an allogeneic stem cell transplant is a very toxic, very costly maneuver and you're really reliant on the availability of a matched related donor. I think the other main obstacle, frankly, is in order for a transplant like this to work, you have to get the disease back under control again. You need to be able to get them into a second remission if possible. But has demonstrated that's not an easy task. So what are the options? How do we get someone back into remission? What's the current state of things in this space. I'm going to focus mostly on what the FDA-approved indications are currently for relapsed T-cell lymphoma. I do want to point out as maybe have heard that one of the current options being studied with duvelisib, which is a PI3 kinase inhibitor has recently been pulled from the market due to concerns over toxicity. And frankly, it was not all that affected to begin with. But I do want to hone in on what we have. These are the available single-agent therapeutic for the T-cell lymphoma space that have been FDA approved. Pralatrexate is an antimetabolite similar to methotrexate. And romidepsin and belinostat are HDAC inhibitors. And I think this table sort of says it all. The overall response rates are pretty poor, and really maybe only 1 out of 10 patients are going to derive a complete response from these available agents. So we need to do better than this. And so what is better, what's needed in this space. I think we need a therapy with a novel mechanism of action. It has to improve patient outcomes in a clinically, not just statistically meaningful way. I preferably would be single agent while able to be combined with other cytotoxics and other therapies. Obviously, safety is a primary consideration user [indiscernible] patients. They've been pretreated. They have low blood counts. We need a drug that doesn't impair that further. And we got a sense of how diverse T cell lymphomas are. So the ideal therapy should be active against a range of T-cell lymphomas. And then finally, from my perspective and from a patient perspective, remember these folks have gotten multiple lines of treatment and they're not feeling well. So something that's less burdensome, something that comes in a [ to ] form versus something that is a weekly are even more frequent IV therapy would be ideal in this population. So with that, I'd like to close out and looking forward to taking some questions during our Q&A session.

Thank you, Neel. Great. We'll have time to ask Dr. Gupta some questions when we finish the section on 818. I'd like to now ask Dr. Erik Verner. As I mentioned earlier, Erik is a chemist medicinal chemist and really one of the pioneers in kinase discovery and synthesis. Erik?

Yes. So as Richard has mentioned, so I was the VP of Chemistry at Corvus Pharmaceuticals, and I'm currently the Senior VP of Angel Pharmaceuticals. I worked with Richard at Pharmacyclics and Principia, Corvus, and now Angel Pharmaceuticals, where we're focused on developing innovative therapies for primarily oncology. And I'm pretty excited to be here at Angel. I think that these programs are really exciting to me. And to be a part of something like this, an ITK inhibitor, which I'm going to describe to you later, is I think it's pretty innovative and I'm pretty excited about it. So as I mentioned, Corvus was founded by the inventors of ibrutinib. And that, of course, is Richard Miller, Joe Buggy and myself. And with our success in targeting the tyrosine kinase BTK with ibrutinib, we set out to target the T cell homolog that's ITK in T cells. And what we were able to do is make a novel and uniquely selective ITK inhibitor. And this ITK selectivity is very important, and I will describe why we wanted that and the features of ITK. Or the features of CPI-818. And also, it's differences between ibrutinib, which are really critical. So like BTK in B-cells, BTK effects activation, migration and proliferation. ITK and T cells affects the same functions that's also involved in T cell development. as well as differentiation and importantly, for us, immune modulation. So looking at Th1 cells, if you look at the graph on the right-hand side, in Th1 cells, they express ITK and another kinase called RLK, which stands for resting lymphocyte kinase. And these 2 kinases play a supportive and redundant role in Th1 and [ Th8 ] effector cells. And if you look at Th2 cells, they exclusively express ITK. There is no RLK expression. So when you have a selective ITK inhibition, you're able to achieve Th1 cells and effector cells can function normally and you suppress Th2 cells. And Rich is going to describe the clinical features of this later on in the presentation. But this is specifically what we set out to do was to make an ITK selective inhibitor. Now if you compare our 818 to other approved kinase inhibitors, for example. Sunitinib, if you look at the graph on the right-hand side of the screen, that's a kinase tree. It's called a dendrogram, and that particular panel represents over 300 human kinases. And if you look at sunitinib, the red circles represent kinases that it inhibits and the larger the circle, the more -- the tighter the inhibition or the greater the inhibition. So for something like sunitinib, which is used to treat kidney cancer, it's a very nonselective kinase inhibitor. Now if you compare that to ibrutinib, which is the middle panel kinase treat. You see that ibrutinib much more selective than sunitinib. But on the upper part of that tree, it inhibits a family of tyrosine kinases. And some of these are in the TEC families, some of these are in the EGFR family and some other like [indiscernible] and JAK family. And so if you drill down even further and you look at CPI-818, you see that it exclusively inhibits ITK. Now if we look at those panel of tyrosine kinases in -- on the left-hand side of the screen, you can see that ibrutinib is very potent on its intended target. So for BTK, it has a binding inhibition of 0.42 nanomolar. So it's a sub nanomolar inhibitor, which is why we picked that compound. It is a very potent covalent BTK inhibitor. But you can see it also inhibits other kinases in this panel. For example, RLK, 0.52 nanomolar is epo potent on BTK and it's less potent on ITK. So ibrutinib has the opposite selectivity profile of what we wanted to achieve with CPI-818. So if you look at the 818 panel, 2.5 nanomolar on ITK and it's thousands of nanomolar or much less potent on this other panel. So you can see we have over 100 fold or more selectivity over RLK. And this was pretty challenging to achieve because within this tyrosine kinase family, you have a lot of sequence homology amongst all these kinases. So it took us a while to achieve this particular selectivity. But we wanted that ITK selectivity over RLK for the reasons that I described on the previous slide. So for something like CPI-818, you can see that it has good biochemical activity, and it also has a good T cell receptor halfway inhibition in a cellular context. So if you take primary human T cells, treat them with CPI-818 and then activate them, you can measure different functions downstream. But for this particular panel we have, the inhibition of IL-2 expression of these primary human T cells. And you can see that it's about 75 nanomolar -- so it's a very potent inhibitor of the T cell receptor pathway in a cellular context, biochemical and also cellular. And so Richard is going to describe to you why the clinical features of CPI-818.

Thank you, Erik. I'm really glad I got Erik or and that Angel has them now. That's a very tough act to follow, Erik. So I'll try to do my best. The biology never is quite as precise as the chemistry. Okay. I went back to this cartoon. As Erik mentioned, getting selectivity for ITK over RLK is non-used. We're able to do that based on our experience and talent and so forth. As shown in this diagram on the left on the slide, ITK 818 locks ITK, part of the T cell receptor signaling. The main pathway that sends a signal when a T cell binds to an antigen on to the nucleus telling me what to do. But ITK is more complicated. And this is known for mouse and human studies over the past 20 years. ITK is involved in the differentiation of T cells into various subsets. There's all kinds of different T cell subsets. And Erik mentioned that there's 1 subset called Th1 stands for T helper cell 1. That's a critical cell. If you want to kill cancer, it's the most important cell. If you want to kill viral infected cells, it's the most important cell because that is the cell that creates both killer T-cell CD8 cells and killer CD4 cells. You need Th1, okay? Now it's so important that nature had a redundant pathway called RLK, it's run by RLK. So if you just block ITK, the Th1 cell can still form. It's biased. You can drive the cell that way. If you block both ITK and RLK, won't get it because you block both pathways. Now the Th2 cell and Th17 cell, which are also on this diagram, those are T cells on the right-hand side of the screen, those are T cells that play a role in inflammation, autoimmunity, allergy, killing parasitic infections, things like that. ITK is the only way -- is the only pathway to differentiate along that way. So if you block ITK, you block Th2, you block Th17. Good for cancer to block those and skew towards Th1. Bad for autoimmune disease, that is you're going to make autoimmune disease less severe by blocking themselves. So potentially, here's a drug that could be used to SKU Th1 kill cancer and immunotherapy play for cancer or it can be used to block inflammation and autoimmunity. Now there's a cell down at the bottom called a suppressor cell T regulatory cells. That also has ITK, but it goes the opposite direction. If you block that completely, actually, the T-cell suppressor cell goes up. So that's good if you wanted to prevent organ rejection. Good if you wanted to prevent autoimmune disease. Not good if you're trying to treat cancer, okay? So let me just review this. ITK is involved in 2 main functions, the T-cell receptor signaling, which would block all T cells if you give enough of it. Or skewing your biasing the differentiation, in some applications, you want to block inflammation allergy, that you do by blocking ITK, you don't get Th2 or Th17. If you want to treat cancer, you want to bias towards Th1. You want to get the killer cells. Now let's see if we can do this. Okay. So the way we start here is getting pure Th2 cells is not that easy, but mother nature had a way of doing it for us, it's called Sezary syndrome. Sezary syndrome is a kind of leukemia to cutaneous T-cell lymphoma where the cells circulate primarily in the blood. And here's an experiment where we take Sezary cells in the normal T cells from 3 different patients, patient 1, 2 and 3 and a healthy donor, and we look at the antiproliferative effect of CPI-818 in a proliferation assay. And you can see that the Sezary cells are way more sensitive to ITK inhibition. Their Th2 cells were blocking Th2. They can't proliferate, okay? It takes much more drug to block the CD4 and CD8s. Now in normal CD4 and CD8, you have a mixture, you have some Th1s and some Th2. So you're getting some in addition there as well. But what this shows in a pure population of Th2, the Sezary cell. You have very potent inhibition blocks Th2. This experiment from patients with Sezary shows you block Th2. Now by the way, the clinical manifestations of Sezary syndrome. If you don't believe me, go talk to a patient with Sezary syndrome. When the cells move into their skin, they have horrible inflammation redness, itchiness, pruritus, et cetera because the Th2 cells secrete various cytokines. Okay. Let me just touch very briefly on autoimmune disease because it also is instructive in the Th2, Th1, Th17 story. So these are 3 different models. 2 of them have already been presented, 1 in the middle hasn't. So if we look on your left, that's a mouse model of a very bad autoimmune disease, where the mice. It's a genetic disease, a mutation of what's called fast ligand. In that mouse model, the animals get lymphadenopathy, autoantibodies to red cells and white cells, autoantibodies to their kidneys, autoantibodies to their skin, T cell infiltration, et cetera, et cetera. It is a bad autoimmune disease. And if you treat these animals with CPI-818, they're cured, actually even better than cyclophosphamide, which causes profound hematologic and immunosuppression in these animals. That was presented in 2020 at ASH, okay? It's very effective in this autoimmune disease model. As a matter of fact, people at the NIAID, National Institutes of Allergy and Infectious Disease. I want to do a trial with 818 in children with this disease, which, by the way, is called ALPS, A-L-P-S, autoimmune lymphoproliferative syndrome. And we're working on a protocol with them now. It's a disease, you're born with it. You have it into [indiscernible], and these poor children are on immunosuppressive and cyclophosphamide forever. Now in the middle is just a classic psoriasis model, imiquimod model, it on as a chemical causes a lot of inflammation, it's a TLR agonist. And basically, in this model, 818 is as good as Decadron, going on the bottom there. On the right is a recent paper at the ASH meeting just a few months ago from the Sloan Kettering group, and this is an allogeneic bone marrow transplant model in animal, in mice. And basically, with very high doses, 300 milligrams per kilogram, that's a high dose of 818, they basically block graft versus host disease. That's organ rejection. It's the graft rejecting the host. And that happens because as shown in the lower right in the lymph nodes there, the T regulatory cells have gone up. Remember, if you block ITK really, really hard, you get an increase in the Treg cell. Good for treating organ rejection, good for autoimmune disease. You don't want to do that for cancer though. Okay. Now let's return to cancer. I'd like to introduce you to my friends, Chloe and Rudy. Chloe is a 7-year-old boxer dog [ K9 ], who has aggressive peripheral T-cell lymphoma. Rudy is an 11-year-old golden retriever who has cutaneous T-cell lymphoma. Dogs get lymphomas just like people. They get naturally occurring lymphomas. They can get B-cell lymphomas and they can get T-cell lymphomas. And frankly, they're treated with very often, they're treated with the same drugs we give people, except obviously, you can't treat them as aggressively. So these 2 dogs had T-cell lymphomas, and we treated them with 818. This was right out of the ibrutinib playbook. We did this with ibrutinib, obviously, in dogs with B-cell lymphoma. We saw activity, and that was one of the motivators to go into patients with cancer. But as you can see, Chloe had prompt reduction of lymphadenopathy shown in the graph on the upper panel. And Rudy with cutaneous T-cell lymphoma usually involving the smell of these dogs. I don't think it involves the smell of people, that's just more generalized. You can see that Rudy have resolution in 14 days. So we showed monotherapy, single-agent monotherapy in single agent, not combination, was active. That's what this taught us, and it was safe. Okay. So this led to a Phase I/Ib trial in patients with advanced refractory T-cell lymphomas, the kind of lymphomas you just heard Dr. Gupta described. And this was your typical eligibility in your typical 3x3 dose escalation. We gave 100 milligrams BID, 200 BID, 400, et cetera, 600. It's an oral medication, of course. And the objectives were safety, PK, immunologic parameters and, of course, looking for signs of efficacy as well. And based on that, we could expand into the various T cell lymphoma subsets as Dr. Gupta described. For us, the main ones are PTCL NOS that stands for peripheral T cell lymphoma, not otherwise specified or AITL, angioimmunoblastic T-cell lymphoma. Those diseases are very closely related. You have to be a pretty expert pathologist to tease those apart. Okay. So let's look at [indiscernible], this is about 30 patients. Now remember, of course, when you're doing a Phase I trial, you start at the low dose and then you go to next dose, you need to go to next dose, et cetera. So you have longer follow-up on the earlier cohorts, of course. And when you look at this, you see something really interesting. You don't need to be a statistician to look at the winter plot and see that the 200-milligram cohort, the dark blue, so the light blue was 100 dark blue, 200, 400, 600 BID. The dark blue look the best. 200 milligrams BID look the best. Pretty clear. And as a matter of fact, if you go through each of those patients, the CTCL patient had a nodal CR. That means the skin didn't quite make CR, but the nodes went away. It is very hard to interpret in these patients. A PTCL patient had a CR, complete response monotherapy, 19 months. All of this is monotherapy. An AITL patient is -- sorry, another PTCL patient has a PR treatment ongoing, partial response. The fourth patient has -- is responding. There's regression of adenopathy, still on treatment, just started on treatment recently. So nodal CR, CR, PR ongoing, responding ongoing and then 1 patient progressed. Now we see a little whiff of maybe something in the next cohort, but they were all CTCL. So let's talk about now why is this happening? Why did this happen? And think back to that cartoon that Erik showed and that I showed about the effect of ITK on the differentiation of T cells, the different impacts and the different subsets of these cells. Okay. I want to go through now. Case reports are very important in medicine because they can teach you a lot. If you study patients carefully, you can learn a lot. I'd rather study one patient carefully than 100 not carefully. Okay. That was done a long time ago, that led to what was called rituxan. You study 1 or 2 patients really careful, okay? So let's look at these patients now. We're going to talk about patient #1, 2 and 3. All right. This is a lady with PTCL NOS, had multiple nodes throughout her body, pathologic nodes. She was treated with CHOP chemotherapy and got PR, only 5 months, pretty typical. They don't -- these responses don't last very long. And then in relapse, she went on to receive an autologous stem cell transplant, high-dose myeloablative chemotherapy, a bone marrow transplant, she got into remission again, but the remission lasted less than a year. Remember Dr. Gupta's curve. They don't look so good. Okay. And then she came on our study, and she was treated with CPI-818 monotherapy. For you in the audience, that's not a combination, that's monotherapy. Okay. And she went into CR. For lymphos regressing this is a PET scan, very sensitive test, by the way, much more sensitive than a CT scan. So she went into CR, the drug was discontinued at 12 months because she was in complete remission. The question was, do you need to keep needing it. And we wanted to see what would happen if we stopped it. We stopped the drug. She won another 7 months with no other therapy, and CR remains in CR and then finally, the lapse with her tumor coming back, and that's where she is now. Okay. Here's the patient #2. Again, PTCL and NOS. Now this station is interesting because it's EBV positive. Many of these tumors are EBV positive, not all of them, but many. Of course, the question is, it's always been thought that T-cell lymphomas are caused by viruses. Many people believe we just don't know what the viruses are yet. We haven't been able to identify them. That's certainly true in mice. Mice, by the way, get more T-cell lymphomas and B-cell lymphomas and they're all virus, virally related. Okay. So this lady has a football growing on her on the side of her abdomen, subcutaneous large mass in addition to lymphadenopathy, bone marrow infiltration and circulating tumor cells. So this lady has extensive disease. She received CHOEP. You heard about show up from Dr. Gupta. [indiscernible] had a PR short-lived, sailed, and she went on GDP, stands for gemcitabine, Decadron and platinum, very aggressive regimen. Oftentimes using this kind of disease, stable disease, then relapsed. Then on anti-PD-1 azacytidine and an HDAC inhibitor didn't really respond to that. And then she came on our study, and was treated with monotherapy and had a dramatic reduction in this large subcutaneous mass on the abdomen as well as lymphadenopathy seen on CT scan as well as blood as well as bone marrow. Now let's study this a little bit more carefully. Look at the laboratories. They're quite elucidated. Some of the laboratories are shown in the chart at the bottom right. Let's look at the lymphocyte count, first of all. I think that's really interesting. The lymphocyte count was around 6,000. That's a little high. Not terribly high, but a little high because there's tumor cells there, circulating malignant lymphoma cells as well as normal lymphocytes. On day 8, day 15, that count actually went up and then it comes down. Does anybody know what that's reminiscent of? Where you treat somebody with these lymphomas and the accounts go up and then down, that's ibrutinib. That's the ibrutinib effect. First described early on with ibrutinib, but in fact, it was very puzzling because people started stopping the therapy because they thought maybe the tumor was growing, but then they realized the, hey, the lymph nodes are shrinking. And so you get this transient lymphocytosis, what causes that with ibrutinib or 818? Not clear. It's almost as if the lymph nodes as they're shrinking where the tumors are squeezing out those cells and they go into the blood where they [ popped to us ]. That's what's thought to happen with ibrutinib or BTK inhibitors. Look at the eosinophil count. 17,000 is very high eosinophil count at baseline, pretreatment. Drops, days stabilizes at around 1,000, 4,000 back around 1,000 now I heard recently. Eosinophil count is kind of high, that's a telltale sign of a Th2 tumor, by the way. Look at the platelet count. The platelets were low. These people often have splenomegaly and bone marrow infiltration, and they have thrombocytopenia, low platelet count. The platelets were 105, that's low. And within a few weeks, they come up to 150,000, which is normal. You heard from Dr. Group that LDH is a bad sign. When you have a high LDH in a lymphoma patient that's a sign of tumor burden, high-tumor burden. The LDH dropped from 650, down to around 250, 300 is the upper limit of normal in those labs. So okay, let's look a little bit more -- I just did something really bad here. Oh, here we go. Let's look a little more to push on the button. Let's look a little bit more carefully at the immunobiology. Okay. So in this patient because of this large [ NAS ] that was readily accessible, we could get some other information so here, we're looking -- they're very good markers in flow cytometry for Th1 cells and Th2 cells, et cetera. So this is sort of standard immunobiology work. If you look at the panel on the left, we're looking at the Th1 cells in the blood, that's the blue curve and in the tumor, baseline and on day 84. And you can see marked increase in the TH1 cells in the tumor increase in the blood as well. Remember, these cells are probably being made in lymph nodes, and they go into lymphatics in the blood and then they home into the tumors. Okay? That's how the immune system works. Look at the right. The right shows CD4 effector cell. Remember I told you before, you have memory cells that come out of lymphoids and effector cells. The effector cells are armed. They're ready to go. They're ready to pounce on the guy. Look at the blood and look at the tumor, they both increase. Okay. Let's go to the next slide. Now this is looking at CD4 and CD8 cells for the expression of PD-1. When the cells get activated, they often express PD-1. PD-1 can mean other things as well, but most likely, it's a marker of activation. The cells are turned on and look at the 8s and 4s, CD4 and CD8 in the blood on the left and in the tumor on the right, you see they both have increased. So what can we conclude from that? We can conclude that just like that cartoon we showed you, we're skewing towards Th1. We're blocking Th2 because the eosinophil accounts went away in that lady. We've increased the effector cells that has infiltrated the tumor. We've increased the Th1 infiltrated the tumor. They went through the blood, and that's all predictable by the blockade of ITK. Not the general blockade of everything that you would get if you really try to block the T cell receptor, but the selective blockade of the differentiation pathways. Okay? Here's the next patient. Now this is a shorter follow-up. All we have is blood on this patient. But again, if we look at 4s and 8s. Again, another patient with failed multiple chemos on 818 monotherapy responding to treatment, and this again shows activated T effector cells in the blood of CD4 and CD8, all very consistent. Now at the same time that we're generating these key effectors and at the same time, we're seeing these Th1 cells that are infiltrating the tumor, the tumor is going away. I mean that's -- the last sentence I said is the crucial one, right? Because who cares about these [ anti immune] tests. What we care about is that those things are actually having a clinical impact. They are. Okay. So let's get that to this swimmer plot. It's very interesting, a predictable swimmer, her immunology is very predictable. Okay. What is the reason that we see this dose effect, this dose response effect? Well, we have to go back to our [ CAR 2 ], too. So there is a dose, probably around 200 to 400, and we have the PK now in the occupancy and all that stuff, they're well worked out. There is a dose where you block Th2 differentiation, Th17 differentiation and bias towards Th1. And that's now been seen reproducibly. Okay. If you give too much drug, you bought T cell receptor signaling or you increase the Treg to suppress your cells and then you all T cell function. There are applications where you might want to do that. In fact, we have an inflammatory bowel model where you do that and the animals get better. But the explanation for the dose response swimmer plots that we see are based on the feeling or biasing towards Th1 and the inhibition of the other inflammatory cells. Okay. So let's summarize 818. Does it modulate tumor immunity. Remember, this was from our early slide. This is our strategy. Yes, it induces Th1 skewing very selectively and potently and blocks Th2. I've never seen a drug that does that as selectively where you can precisely control an immune response. It increases the effector cells in the tumor. And those T cells are activated. The molecular target, 818 is an oral covalent drug. We know exactly where it hits. We know exactly what it binds to. And it's been very well tolerated. I have not talked about safety, but we've had people on this for many, many months. It's active in PTCL, CTCL, AITL, and the preclinical models I showed you in various autoimmune diseases. So we think that this drug can have a broad range of effects in lymphoma and in autoimmune disease. Now here's the interesting part, okay? We're getting tumor regression here not because we're -- our drug is killing the cancer cell. I going to beat that, we're not killing the cancer cell with our drug. We're activating the immune system, the normal cells to kill the T cell tumors. Maybe we can do that for a colon cancer or lung cancer or kidney cancer. Those experiments are ongoing now. And in fact, there's a paper published last year by at more at Columbia University here in town, we're now collaborating with where he actually shows that there is synergy if you block ITK while you give PD-1. So solid tumors are on the table now. B-cell lymphomas on the table, especially if it's EBV positive. I didn't show you this, but 1 of those patients was EBV positive and [ EBV ] negative, okay, which you would expect if you do Th1 skewing. So the clinical applications are, we think, much, much broader than T cell lymphoma and much more broad than cancer. Okay. Next steps [indiscernible] enrolling patients at the optimal dose. Angel, our Chinese partner has been phenomenally important to us. They're talented, great scientists and clinical researchers. They have been contributing patients and really fundamental scientific discoveries that are incredibly valuable to us. The Angel relationship is really, really important to us. And it is -- and it turns out to be absolutely a great idea for Corvus. Absolutely. So Angel enrolling patients, and we expect to have more data in our T-cell lymphoma, it's open-label trial later this year, perhaps at ASH or some other meeting. We're already planning a Phase II study, global Phase II. We're even thinking about frontline therapy. 818 is so novel mechanism of action so well tolerated. It's easy to envision combining it with other agents, chemotherapy agents or other immuno-oncology agents. So this is a good point to stop. I'd like to ask maybe Dr. Verner and Dr. Gupta to come up here, and we can take some questions from the floor, if there are any. I see one question. Can you identify -- questions on the webcast? Can you identify yourself and [indiscernible] the microphone.

So thank you very much for this comprehensive presentation. I guess first one for Dr. Neel. I mean, can you just provide your perspective on the data so far for 818? And then, I guess, how do you think this drug can fit in the current, I guess, the treatment landscape you discussed there's a lot of unmet need here. But then we also said there are approved therapies? So how do you think about potential sequencing there? And I have another one for Rich.

Do you want to have, Dr. Gupta?

Yes.

So let me just repeat the question again for the benefit of the webcast. we wanted to ask, I think, to Dr. Gupta. How do you see this treatment fitting into the therapeutic armamentarium of current T-cell lymphoma therapy? And what about the other approved agents like [indiscernible].

This is Dr. Gupta answering for the webcast crowd. So yes, I appreciate that question. I think the first part of your question was what do I think of 818 so far in terms of the preliminary data. And if you remember my last slide, there's some criteria that I think are necessary for the next great drug in the space. And from what I've seen so far, this checks a lot of the boxes. And I think kind of leading into your second question, the current state of drugs in this space is fairly dismal. And from a clinician's perspective, pralatrexate romidepsin, belinostat. It's not like we are eagerly awaiting to put our patients on these drugs because they really are not that effective truthfully. And also, they're fairly difficult for patients to tolerate. So I view this particular drug as a very exciting opportunity to both improve their disease state, but also make them feel better, most importantly. So I think there's an opportunity here for it to really make inroads in T-cell lymphoma.

So I have another question for Rich. So I have a question about this 200 mg dose that you've picked. I guess you have maybe the theory why this happened. I guess, can you share some, I guess, below marker data maybe at higher doses? Does that support your I guess, the -- is that you actually -- if you go higher dose, you actually see more like Tregs?

Good question. So if you look at the swimmer plot, when you go to 400 a little bit of activity, 600 no activity, very rapid relapses. And we also know from animal models at those doses, you block T cell receptor in. So on the one hand, if you induce a T effector cell, but you block the T cell receptor, it's not going to work, right? It's one thing to get it to differentiate, but you can't block the receptor.

And also on the selection of 200 mg doe, I wonder or you have any discussion with FDA on this already? Or that's your plan to do.

We have not had any discussions with FDA about that. But we are seeing the FDA song here. I mean, think about this. We're going to go in there, not recommending the highest to us, but actually recommending a lower dose, okay? And we've carefully studied these dose levels in over 30 patients now, and we're studying more patients on study now. So I think in terms of dose selection, this is the paradigm of how you do it, okay? So I think we're in great shape there. By the way, the 200-milligram dose because we used to talk about this a lot. And now we realize it's actually not as important as some of the other things you measure. It was important with ibrutinib and not as much here is occupancy. The occupancy of the 200-milligram dose is anywhere from 75% to 90%. Pretty good. Another question?

This is Mara Payne from [indiscernible]. I just wanted to expand on that a little bit or ask you to expand on that a little bit. In the earlier work that was shown, you expressed that you got complete receptor occupancy at the 600 milligram. So I just want to understand the relationship between that receptor occupancy as at the 200-milligram versus the 600 milligram. And if they're within the realm of drug development, where going to that lower receptor occupancy. And then the last question that I had is one on the safety. I mean it's a relatively low numbers anyway. But in the 200-milligram from the 2020 data set, you saw higher incidence of pruritus, and I'm wondering if that's mechanistic.

All right. Okay. So Mara's question has to do with occupancy and dose selection. And second question about pruritus. Let me dispense with the pruritus. First of all, these people all have skin disease that the pruritus is disease related. There's no for they have lymphoma in their skin, most of their skin. So that's a disease associated for sure. Okay. Now the dose. So the occupancy assay, there's a little bit of a ceiling effect here. You can't -- the way the assay is done, you can't be above 100%. So when you start getting to 80%, 90%, 100%, it's really hard to distinguish that. And keep in mind, we're sampling mostly the blood, almost always we're sampling the blood. The blood is only 1 of several compartments. You have the tumor, you have lymph nodes, you have spleen and other things. So with the 200-milligram dose, we're -- we have pretty good occupancy. At the peak levels, you're up around 90% or above 90%. It's only a little bit better when you go to 400 and 600. But occupancy is not the right thing to be looking at. I mean, that's our fault. We were promoting that because that seemed to be very useful in the development of ibrutinib. But BTK doesn't have the myriad of functions that ITK has, at least it's not known. ITK plays a more important role in the differentiation of many different kinds of T cells. And those are more finally controlled, more precisely controlled. So yes, I think you have to have some occupancy. I mean you can't have 0. But we have trough peak with [ 200 ] to 70% to 90%. That's a pretty good occupancy. And even now with ibrutinib due to side effects that I showed, people are backing off on that dose. So now again, it may depend on what you're going after. I think if you're going to go after an organ rejection. You're going to want to like really push the dose. But I don't think I would be looking at occupancy. I'd be looking at more functional.

Okay. And then if I could just ask the clinical treatment landscape question, and there are a handful of experimental treatments that we're looking at T-cell lymphoma, more from the cellular therapy side. And I'm curious from a cellular therapy perspective, so I'm just curious about how this will exist with the potential for those experimental therapy?

Okay. I think the question was there's growing interest in CAR-T for T cells. Good luck on that one. I wish you well, and we can come back in 10 years and you can tell me how that's going. But there's just a small amount of data. It's hard because you have the problem of suicide, right? If you make a CAR T to a T cell, it kills itself. So you have that problem. It's extremely expensive talk. I mean you know this, Mara. It's even in the B-cell lymphomas, where I would it CAR-T, CAR-Ts are pretty effective. But I mean that's a last resort, okay? And now, of course, the landscape with bispecific antibodies and other things. I mean I would not that optimistic that, that's going to be a growing area. An opportunity for CAR-T is really going to be in solid tumors if anybody can get that to work. But in T-cell lymphoma, I don't view that as a threat. PD-1's been another: anti-PD-1. That's been mixed. I mean, we would know if it were working. It's been going on for 4 or 5 years now. So many people are concerned about anti-PD-1s and T-cell lymphomas because there are some papers that claim that it stimulates the tumor. So I mean right now, especially with the removal of duvelisib from the market, the PI3K, and that happened because people were dying in the B-cell lymphomas. With longer follow-up, it was worse. That's a very toxic drug, even though PFS looked good early on in response rate, I think, right, with longer follow up, they actually have a worse survival. So that drug is gone now. There is no PI3K on the market now. And all you have is pralatrexate, belinostatin (sic) [belinostat]. But as Neel said, those drugs are just -- I've actually never seen them used. Do you actually use that?

It's rare. I mean, there've been difficulties that we mentioned: toxicity.

And I think it's also -- he has a slide on the response rate with those drugs, belinostat, [pralatrexate]. It was [up] 25%, 30%. That's very generous because if you look at those patients, they were very favorable patients to begin to go on that study. So I think that's a pretty generous number to begin with. Anyway, I think we should probably, any other questions, I think we -- Mara, does that answer your question?

Yes. Thanks a lot.

Okay. Thank you for that. All right. I think then we can move on. We can move on to the next speaker, which unfortunately is me. So I'm actually earning my wage today. Okay. So let's move now to mupadolimab, okay? So we were talking about T cells, how we're going to control T cells. Now we're going to talk about B cells because mupadolimab is a very, very unique anti-CD73 antibody and Corvus and our team of scientists have really been pioneers in this area. I would say along with AstraZeneca. So let's talk about this antibody further. A little background for those who are new to this subject. CD73 is an ectoenzyme. It's present on the outside of cells, T cells, B cells, other tissues. It's pretty highly expressed in B cells. It can be the majority of B cells: 70%, 80% in the blood, depending on who you look at. CD73 is known to catalyze the conversion of AMP to adenosine, clips off the phosphate. Less well-appreciated, although we've been talking about it now for a couple of years, is that its main function, for which it was originally described, is it's an adhesion molecule. It has the structure of an adhesion molecule. It's involved in lymphocyte migration and activation, homing. That's really one of its main functions. Mupadolimab is a humanized IgG1 antibody that's been engineered to be Fc-receptor deficient. So this antibody does not fix complement. It does not mediate cellular cytotoxicity. That's by design. It's very good at blocking the catalytic activity of CD73. It pretty much totally blocks adenosine production in vivo and in [indiscernible] [animals] when we can measure it. Most importantly, we believe most importantly is that mupadolimab emulates -- it's an agonist, stimulates B cells and T cells, but mostly B cells to divide and differentiate or to differentiate and mature. Okay. So we see the strategy here for Mupa to be -- okay, we have an IO agent that stimulates T cells, that stimulates immunity. Wouldn't that be nice to combine with an anti-PD-1 or agents that release the brakes, release the negative signal. So it's a complementary mechanism. You want to remove the negative signal. You want to add the positive signal. So that's been our strategy. Now there's a lot of companies and people working on CD73s. This is a very short list. It's not everyone. I think there are like 40 companies working on this now. We were one of the first along with AstraZeneca. I believe we're the only company that's actually published any papers on this. AstraZeneca has as well. So our antibody fully blocks adenosine, strongly activates B cells. I'll show you the data for that basically in Phase II now. Oleclumab blocks adenosine pretty well. Very weak in terms of B cell activation. None of the other antibodies that we've gotten our hands on, none of the other anti-CD73s have we been able to show B-cell activation. Now some people are claiming that, but then they never show you any data to support that. So I don't know if it's sure or not. So why is this happening? Why is mupadolimab unique? We know exactly why it's unique. And that's shown in this very elegant study that we did. This is using cryo-EM, cryo-electron microscopy, where we took the CD73 homodimer and incubated it with mupadolimab. And we know exactly based on the cryo-EM studies, where mupa binds in terms of CD73. And it binds on the amino-terminal amino acids 205 to 300 in case you're interested. We know every salt bridge. We know every [indiscernible]. We know every other interaction. Now also shown there are oleclumab. There's a published EM structure of that. [indiscernible]. There's a published EM structure of that. And some of the others, I don't know if they've actually been -- if they've done EM, but those are proported regions of the molecule. And so mupadolimab binds to a very unique epitope and we know precisely what that is. Now this diagram, by the way, just shows an Fab, a 1 arm of the antibody just for clarity. Of course, there's really 2 arms of the antibody. What you actually have formed, interestingly, is a tetramer. You have 2 antibodies and 2 homodimers of CD73. So you have like this green-shaped complex that forms. Very interesting. So we know it's different than the others, than everybody else's. By the way, we already knew that because I told you previously at some other meetings we had, they don't cross block. So none of this was a surprise, but now we know exactly the determinant. Now the real question is, how does that activate a B cell? How does that signal get from the outside from that region into the B cell? We'll talk a little bit about that. But first, let's compare mupa and Oleclumab. Oleclumab Is AstraZeneca's CD73. They have become the leader in the field, of course. So both antibodies are humanized IgG1s. Theirs is [Olanda]. Ours is [Kappa]. As far as I can tell, that would make no difference. Both are engineered to be deficient Fc gamma receptor binding. Both are very good antibodies. What we -- anybody would call high-affinity antibodies. Those are antibodies with low hundred picomolar KDs. So these are good antibodies, very tight binding antibodies. What about antigen internalization? We never see internalization of the antigen. When we bind to the surface of the cell, we don't see the antigen go inside. Oleclumab does that. It's reported in the literature. That has to do with how the complex is formed on the surface of the cell. Now whether that's good or bad clinically, I don't think anybody knows. I don't think it really matters. Hook effect. Hook effect is something that a lot of people are talking about. That means when you get really high with the antibody concentration relative to the antigen, you lose binding. You lose affinity. We never see that. They do see it and they've published that and some of the other antibodies have that. Again, what is the significance of a hook effect? Does it matter clinically? I really don't think so because in order to get to that hook effect, you got to go pretty high. So I don't know if it's clinically relevant. And then some of these other things you can see there: T-cell restoration, dosing. We actually use a lower dose: 1200 milligrams Q3 weeks. Oleclumab is given in a loading dose, 3,000 milligrams in the first couple of cycles and then 3,000 milligrams every month. It's a little bit more antibody actually, but not grossly more. Okay. Let's look at some of the science behind this very quickly. What the panel in the upper left shows you, and I won't go through the details, is that if you take a human CD73 positive tumor, we grow it in an immunodeficient mouse, and give either control or mupadolimab. Panel on the left shows that you don't lose the antigen. I just told you that. It's not internalized. This is proof of that. In the middle panel, it shows that the Mupa is there. The Mupa got to the tumor because when they come back and stain that or try to react it with a labeled mupadolimab, it doesn't react because there's a Mupa already sitting there. So the antibody got there. The antigen is still there. And the antibody's there. It's fully saturated. And then the third panel is the enzyme. If we take the tumor out of the mouse and assay it for adenosine, there is no adenosine. It's blank. It's a completely blocked adenosine formation. So this antibody is reacting with an epitope that's involved in signaling the B-cell, but it also is blocking the enzymatic activity of that protein. Okay. The more interesting thing is at the bottom. And this is dramatic. If you take B cells, [human] B cells and incubate that with mupadolimab, within hours, you see stuff happen, actually within minutes. And you can see over a couple of days, these cells transform into what's shown in the middle there: these large plasmablasts. Plasmablasts are the cells that become plasma cells. Plasma cells, of course, make antibodies. Plasma cells also can be memory cells. They can go to the bone marrow and [the long-lived] cells. They can go other ways and make antibody and then do their job and go away. Now interestingly, if you look at the lower-left, we've look at a marker called CD69. That's been the workhorse in our labs. CD69 goes up when cells are activated, lymphocytes are activated. CD69 goes up very robustly with oleclumab, just a tiny bit with -- sorry, it goes up very high with mupadolimab, goes up a little bit with oleclumab, the bar, the black bar on the lower-left. But what is CD69? Why am I even talking about that? CD69 is a protein that's expressed on lymphocytes that keeps it in the lymph nodes. So the B cells or T cells are circulating around the lymphatics, the bloodstream, the tissues, the lymph nodes. And when they encounter antigen, whoop! CD69 appears. They're trapped there. They're stuck in the lymph node because they want to process that antigen. They want to have a tighter fit. They want to get better. It's called affinity maturation. And then they eventually go out as memory B or T effector cell -- memory cells or effector cells. So CD69 means activation and homing to the lymph nodes. Okay. Very quickly, there's a bunch of other markers that change. CD27, CD38, CD138, CD69, I mentioned, 83 Class II, 86. These are markers that tell you that the B cell is differentiating into a plasma cell and it's differentiating into an antigen presenting cell, okay? Antigen presenting means they pick up an antigen on the cell surface, and then they present it to T cells [and they] [indiscernible]. These cells do that very well, and they do it differently than macrophages because they don't do it with peptides. They do [indiscernible] They're very different. Okay. Let's look at the CD69 blow-up on the right. You see mupa causes the expression of CD69, the blue curve. Oleclumab just a little bit. In fact, maybe that's your hook effect there, if you go really high, you start to lose it a little bit. The other, clone AD2, is another CD73 antibody, which doesn't do it. So CD69 goes up in vitro and plateaus at around a microgram per mil of antibody in vitro. Okay. Now what about adenosine? We know this blocks adenosine, but is adenosine involved in the activation of the B cell? The answer is clearly and emphatically no. It is not. And on the left, and I won't go through every detail of this experiment. But if you look at all these activation markers 69 to 83 and you throw in [tons] of adenosine in the form of NECA, which is a potent analog and agonist, you don't affect it. You don't block it. It does not -- it is not involved in this property. The middle panel shows -- gets to the question of, well, how is this activation occurring? So again, looking at CD69 expression, mupa causes CD69 expression. Ibrutinib blocks it almost completely. Now we've done this experiment with other agents that block the B-cell receptor signaling pathway. So we are sure now. We are certain that mupa is causing activation of B cells through the B-cell receptor pathway, okay? It's almost a costimulatory molecule. Now details I won't go into today, we know exactly the complex that's formed in the cell membrane. Those are going to be really great drugable targets, by the way. So we understand that now. And the final [evidence], which I won't dwell on, is you get phosphor ERK when you stimulate with mupa and [indiscernible] again. B-cell receptors sitting on pathways involved. Okay. Let's get down to the third player [indiscernible] that's the most important. Talking about the tumors, [indiscernible] but let's get back to our [indiscernible]. This -- a lymph node, obviously, lymph nodes are all over your body, thousands of them and they're connected and they eventually feed into the bloodstream. These are 2 lymph node specimens, 2 individuals stained with CD20, which is a B-cell marker and CD73, which we've been talking about. And these are the germinal centers. Some people refer to them as the follicles of a lymph node. Again, this is where the action takes place. You'll notice there's a clear zone and a dark zone. In fact, some people call it clear zone and dark zone. Some pathologists refer to it as that. We more recently called it the germinal center and the mantle. Mantle cell lymphoma comes from that area. That's why you've heard about mantle cell lymphoma. So you can see that CD73 is pretty extensively expressed in this normal lymph node, okay? It's in the germinal center. It's in the mantle and it's out into what we call perifollicular areas. Those are mostly T cell areas. Okay. What's CD73 doing there? Good question. Okay. So lymph nodes are so important. They're so important that tumors said, "You know what, I got to make some of my own lymph nodes." Infections, tuberculosis, chronic infections. They sometimes say, "Hey, I got to fight this infection. I better make my own lymphoid structures." Those are called tertiary lymphoid structures. So what are we talking about here? On the left are the follicles in a normal lymph node, low magnification. That's normal. In the middle there, the upper middle, you have a tumor. And you can see, if you look carefully, there's these darker areas. There are 2 of them, those are lymphoid structures, germinal centers that are forming within the tumor. Sometimes they're in the tumor. Sometimes they're around the tumor. Those have been known for 100 years as being associated with a good prognosis. One hundred years ago, pathologists saw those things and said, "Hey, these little dark blue things mean you're going to do well." They've made those -- of course, they didn't know what they were looking at. Now what are those tertiary lymphoid structures? Well, very quickly on the far-right, they're germinal centers. They have CD20 in the middle of B cells. They have CD4 helper cells in the mantle zone. They have CD8. So they're little lymph node structures. What are they doing? They're making immune cells. They're making T cells and B cells trying to fight the cancer, trying to fight the infection. But the cancers are smart and they outsmart them. Okay. So back to these cells. There's intense interest now in tertiary lymphoid structures. How do you control them? What reduces them? What are they doing, et cetera, et cetera? What are the ligands? What if CD73 is an actual ligand? Not known, okay? CD73 wasn't made for Corvus to make mupadolimab. It has some other function. So B cells are now a hot topic in immuno-oncology. What are they doing? What is their role? And there's already tons of papers on what the B cells -- they're making antibodies to viruses. They're making it to HPV. They're making -- some slightly recent study on immunity showed the B cells that are actually following up the fibroblasts into the tumor turning into plasma cells as they do that. Really interesting. So now let's turn to what are we seeing on patients? You've heard about ITK. We've studied the immunology and [used it on] our patients and stuff. Well, does that -- does that happen to patients when we treat patients. And now I'd like to ask Suresh, Dr. Mahabhashyam, to give us an update on our clinical trials.

Thank you, Richard. So Richard just talked about some of the preclinical data, the mechanism of mupadolimab, the B-cell activation, the adenosine blockade. I'm going to walk you through the Mupa clinical program and how this mechanism of action could translate into clinical activity. The Phase I study for mupadolimab is a comprehensive study. We evaluated mupa as a monotherapy and in combination with pembrolizumab and ciforadenant. The primary objective of this study being a Phase 1/1b is safety and tolerability, but based on the PK/PD data and safety, we were also able to pick an optimal dose for mupa for expansion and for other studies. So this is a classic dose escalation followed by dose expansion design in dose escalation. We studied multiple ascending doses of mupa in monotherapy and in the combination arms. Now currently, we are enrolling squamous cell, head and neck and non-small cell lung cancer patients in the mupa plus pembro expansion arm. This study has enrolled over 100 patients. I think Richard mentioned that before. I talked about dose escalation, those expansions. The dose escalation part of the study is done for both monotherapy and for combination. Now for monotherapy, we went up to doses of 24-milligram per kilogram of mupa given every 3 weeks, once every 3 weeks. And in combination, we went up to the dose of 18 milligrams per kilogram given every 3 weeks in the combination arm. The MTD or the maximum tolerated dose was not reached for either the monotherapy or combination. If you look at the table on the right, the characteristics of these patients who are enrolled in this study, these are patients with advanced cancers and have received multiple prior lines of therapy if you look at the median number of prior therapies, 3 to 4 prior therapies. We also enrolled different tumor types. It's a Phase I study. So colorectal, pancreatic, renal, head and neck and of course, lung cancer. So earlier, Richard mentioned the data about B-cell activation, the mechanism of action of mupa. So we looked at the peripheral blood of our Phase I patients, and we looked to see what were the changes in the B and T cells in the peripheral blood. Now if you look at the panel on the left that shows the B cell dynamics and we see the B cell dynamic at a dose as low as 1 milligram per kilogram. But this is data in patients who got a dose of 12 milligrams per kilogram or above, and it shows the full change in circulating B cells compared to baseline. Now if you look at the panel on the left, within 30 minutes, after mupadolimab infusion, you see this rapid decrease in the B cells. And this reduction is actually correlated with CD73 expression. So you see those 2 red dots, those are patients who have low baseline CD73 expression. So you don't see appreciable, immediate drop in B cells for those patients, although you see some at 24 hours. So this reduction is dependent on the CD73 expression on B cells. And these B cells, they partially return to baseline levels. And when they return to baseline levels at day 21, they are CD73-negative B cells. We see a similar dynamic with the T cells. You -- within 30 minutes of infusion, you see this -- you see the decrease in circulating T cells. The T cells return to -- return to baseline levels by day 21. So as a note, over 60% of these patients at baseline, the B cells are CD73 positive. So moving on to clinical activity. This was data that was presented at [indiscernible]. It shows a waterfall plot that compares the percentage change in the target lesions from baseline to the time in study. And this is in 25 squamous head and neck cancer patients and non-small cell lung cancer patients who got a dose of mupa of 12 milligrams per kilogram and above. If you look at the table on the top, these patients, if you look, almost all of them had prior PD-1 or PD-L1 therapy before starting on this trial. And again, the median number of prior therapies was 3. So heavily pretreated advanced cancers. And if you look -- and in these patients we did observe some tumor regression in these patients, as noted on the right side of the waterfall plot. You see, you see patients with tumor regression. The one thing we did was we saw tumor regression with mupa. How did that compare with their experience on their most recent prior therapy before starting on mupa? So if you look at the table on the bottom, that shows the best response these patients had on their most recent prior therapy before mupadolimab. You look at -- again, you look at those patients on the right that had tumor regression. Most of them had a PD-1 or a PD-L1 as an immediate prior therapy, and their best response to that therapy was progressive disease. So they failed at PD-1 or PD-L1, and then they came on the study and got mupa, either as monotherapy or with cifo in some of these patients, and we saw tumor regression. And the time on treatment for these patients who had tumor regression was anywhere between 4.5 to 12.5 months. So we do see clinical activity in these advanced cancer patients with mupa. CD73 as a target has been validated. AstraZeneca presented some data on oleclumab in COAST and NeoCOAST studies in the recent months. In both these studies in earlier stage lung cancer patients, the combination of oleclumab and durvalumab, the anti-PD-1, showed improvement in clinical outcomes. In the NeoCOAST study, they also showed up regulation of genes involved in B-cell activation. And as a result of this data, the next step -- the next studies have been initiated: a Phase 2 NeoCOAST 2 and a Phase 3 study in Stage III, frontline, non-small cell lung cancer. So what does all this mean for mupa, what are the next steps. We have seen clinical activity in advanced cancers in non-small cell lung cancer patients, we have the validation of CD73 as a target in earlier stage lung cancer patients. So we are planning on a randomized placebo-controlled Phase II study. It's -- the plan starts for this in the second half of this year. This is in frontline Stage 4, or metastatic non-small cell lung cancer patients regardless of PD-1 expression. These patients -- and in patients who don't have eGFR or out mutation. So this is a fairly, fairly large population in the frontline metastatic setting. These patients will be randomized 1:1 to 1 of the 2 treatment arms, 1 of the arms being mupadolimab plus standard of care pembrolizumab and chemotherapy. Pembro and the chemotherapy is considered standard of care in this setting. And in one of the arms, patients get mupa in addition to standard of care. In the other arm, patients get placebo in combination with standard of care pembrolizumab and chemotherapy. So there is a comparator there. Primary endpoints are progression-free survival, secondary endpoints are ORR, DOR overall survival and safety. This is a blinded study. So the site and the patient -- the investigating sites, the investigator and the patient are blinded to the study treatment assignment. Corvus will remain unblinded. We have multiple -- we have interim analysis both in into this study. So at the time of these interim analysis, we will be monitoring the clinical data, safety and efficacy. And our goal is, if we see a positive or an encouraging signal, we are priced to do a Phase III study. Moving on to summary of mupadolimab. We talked about Harvest's development philosophy, our strategy this fits in -- right in there, modulating tumor immunity. We see evidence of B-cell activation with mupa, the B-cell redistribution to lymphoid tissues, evidence of antitumor antibodies, precision molecular targets, earlier talked about the Cryo-EM data, where we know the epitope that mupa binds to complete adenosine blockade. And the Phase I study with mupa has shown favorable safety in monotherapy and in combination with pembrolizumab and ciforadenant. From a clinical applications perspective, the antitumor activity in those advanced cancers is encouraging, and hence, our next steps in non-small cell lung cancer. And there's also the potential application in infectious diseases. From a next-steps perspective, we are initiating the randomized, placebo-controlled Phase II trial in frontline non-small cell lung cancer in combination with pembro and chemo in the second half of 2022. Well, I want to thank you for your time, and I'll hand this off to the next presenter, happens to be, Richard.

Thank you, Suresh. So we'll take questions for -- on the mupa and cifo after I talk about ciforadenant, which is our adenosine A2A receptor inhibitor. And I will show some new clinical data here. All right. So just by way of background, I know you're all familiar with this, so I won't dwell on it. Extracellular adenosine is produced in the tumor microenvironment, and it can interact with the A2A receptor, which is present on T cells and certain other immune cells and suppress an immune response. That's the dogma. Ciforadenant is an oral small molecule antagonist of the A2A receptor which has been shown. We've published this now to be active in animal models and in some of our early clinical results. And you can see in the cartoon on the right, adenosine is made really by several different pathways, probably dozens of different pathways and it interacts with A2A. There's another receptor called A2B, that it can interact with, and we'll come back to that in one moment. So adenosine is immunosuppressive. Here are the biochemical features of ciforadenant. It's a very good A2A inhibitor, low nanomolar KI. 3.5 nanomolar, pretty good selectivity over A1. You don't want to hit A1 because A1 is in the heart and other places. And A2B 1500, let's talk about A2B because I've just been hearing about this a lot recently that, oh, my inhibitor hits A2B or so here's the fact you need to know. So A2B and you can Google this and look it up. A2B has another name. It's called the low-affinity adenosine receptor, low affinity. The KI to block A2B adenosine blocking -- binding to A2B, I should say, not blocking -- binding is over 20,000 nanomolar, okay? Let me tell you what that means. That means that ciforadenant blocks A2B. So does everybody elses. Pretty much every A2A antagonist I've seen. If you're at the 1,000 -- a couple of 1,000 nanomolar KI, you're going to block adenosine binding to the low-affinity A2B receptor. Moreover, what the function of A2B is a sort of unknown. As a general rule, I can tell you that most pharmaceutical people like to make drugs as selective as possible. So anyway, we're primarily interested in A2A, but just keep in mind that the adenosine binding to A2B is so weak that pretty much everybody blocks it. On the right side of this slide shows just a signaling pathway. Cifo completely blocks the A2AR signaling pathway. Okay. So this is data that was published by Stephen Willingham in Cancer Immunology Research in 2018. This paper has got lots of data on the biochemistry and preclinical, et cetera. But what was a little noticed back in 2018, but what now that is getting increasing attention and we're working on it a lot now in the laboratory is the information in these preclinical animal models. In MC38 and CT26 and other models, the best combination with ciforadenant is not a PD-1, but an anti-CTLA-4. In fact, in a combination of cifo and anti-CTLA-4 and MC38 which is very immunogenic tumor, 100% cures in animals who are -- who have established disease. They're all cured with the combination. CT26, they're not all cured. It's much less immunogenic tumor, but still most you can see in the green curve, there in the lower right, there's a march regression when you use the combination of CTLA-4 and cifo. In fact, also in that paper, if you reduce the dose of PD-1 and CTLA-4, use a 1/4 of what usually used in the mouse, you can still show really good efficacy in this model in the CT26 model, a very poorly immunogenic tumor where most of the animal, 60% or so are cured. So it turns out that CTLA-4 is the best thing to partner with cifo with A2A. It's not going to be specific to cifo, it's going to be any A2A. That's going to be your best partner. Now why is that? Okay. Before we get to that question, now we've published our data on cifo pretty extensively, and I'm going to show you some more of an update on it now. We published a clinical trial in cancer discovery in 2020, Larry Fong was the first author. We reported on 68 patients with advanced metastatic renal cell cancer. The details are on this table, median prior therapies is 3, 92% were PD-L1 negative in the tumor, most but not all had prior PD-1. And in this study, patients were assigned to either get the combination with atezolizumab, cifo plus atezo or monotherapy with cifo. That's the way the trial was set up. And again, this has been published and what you see from the waterfall and spider plots here in this patient population. First thing you see is you -- and this is the only thing I actually ever look at is the blue. There are some blue bars there. There are some patients actually who responded to monotherapy. We like to see that, okay. Now there are also some red bars, there is more red bars. Several of those red bars are people who didn't get a prior PD-1. So it's possible that, that would have occurred anyway, even if you didn't give cifo. That cannot be ruled out. But the monotherapy activity gives you some extra belief that the cifo is doing something in the system. Okay. Also in this paper, very careful analysis of biopsies and some very fine laboratory work showed that when you take peripheral blood immune cells and you add adenosine you ask, well, what genes, what happens when immune cells are exposed to adenosine. And what we found and the details are in the paper are that there's 8 genes that get expressed by adenosine. It's the immunosuppressive effect of adenosine are mediated through these 8 genes: CXCL1, 2, 3, 5, 6, IL1B -- IL1 Beta PTGS2. And if you express those genes in near tumor biopsy, which was expressed by 59% of the patients, 40% didn't express those genes. You were more likely to have tumor regression. That's shown by the yellow heat map on the lower left. So adenosine signature expression meant you were more likely to respond to adenosine blockade. That's pretty -- it sounds all pretty obvious, but it wasn't always backed in. Those are adenosine-induced things. And if you block it, of course, you're more likely to respond. Right around this time and independent of us, McDermott, reference is down there at the bottom. McDermott et al published in Nature Medicine, genetic study in 400 patients with frontline renal cell cancer treated with atezo versus [indiscernible] versus atezo-avastin. And in that study, they described a myeloid signature. And if you had that myeloid signature, you did not respond to atezo. The response rate was low single digits, terrible. Okay. So putting all that together, if you're tracking with me, it means that the adenosine signature or the presence of adenosine works against an anti-PD-1 or anti-PD-L1. And so you want to block the adenosine related proteins that are expressed. Now more recently, the Sloan Kettering group, and I believe their paper has now been accepted and that's coming out in Nature Medicine also has shown same thing, same genes. They added a couple of genes. They call it the Sloan Kettering signature now, I think. But basically, the same thing. These genes are predicting resistance to PD-1s. Okay. And in fact, if you looked at the clinical data, and again, this is from our publication. If you were adenosine signature positive, you had a 17% ORR by RECIST confirmed versus 0%. Okay. That's pretty good, 17% versus 0% in a heavily pretreated population. Okay. So now we've updated this. These are more patients include the patients I just described, but these are patients who have all failed PD-1s. We wanted to look at PD-1 refractory patients, okay? So on the top, you see the waterfall and the swimmers for renal cell cancer, median, 3 priors or more failed a prior anti-PD-1 or PD-L1. And again, you can see the blue, there's some blues and there's some reds. Now these are all different refractors. So it's a little different than the waterfall I showed before, okay? And you can see the swimmer lanes. Some of those people are out there pretty long time. 2 years. Okay, metastatic renal cell cancer. That's a long time. So the response rate to monotherapy, by the way, by RECIST, it is about RECIST is 11%. Not bad in 3 or 4 prior therapies, PD-1 failures, okay? Okay. Now below its monotherapy. Monotherapy is great because it tells you more about what you're doing. And this is 80-something patients, I think. At the bottom is lung cancer, same story, PD-L1 failures. Now lung cancer -- multiply recurrent lung cancer is a bad disease. And renal cell cancer [indiscernible] people, but lung cancer is a different beast. I mean, second, third, relapse is a reasonably bad disease. Anyway, you can see again in the waterfall, there are some blue bars. There are some red bars. Again, these are PD-L1 failures. I think the response rate by RECIST here is -- for the combo is 7%. Again, 11.5%, 7% heavily pretreated population, we think that's pretty good. It's certainly as good or better than what any other company has reported that I'm aware of. Okay. So let's get back to what we're doing with cifo. So we were barreling down the track of late-line renal cell cancer. That's become a very difficult space. There are several agents approved how you do a registration trial in late-line renal cell cancer has become complicated. And frankly, I'm not sure there's a need for it. But here's what's interesting. What really changed the thinking of people in this field and why they're coming to us is the Motzer presentation, Dr. Motzer from Sloan Kettering presented in ASCO 2020. The updated data on CheckMate 214, which was the registration trial for frontline renal with IPI/NIVO, anti-CTLA-4 anti-PD-1. And what this progression-free survival curve shows is there's a plateau. Plateaus are great in oncology because that means you have the opportunity of curing those patients. They might be cured. And in fact, similar plateaus has now been seen in lung cancer, IPI/NIVO is approved for frontline lung, you see in melanoma, of course, as well. So the Kidney Cancer Consortium led by Eric Jonasch, who's the Head of GU Oncology at MD Anderson. So wait a second, you guys showed in 2018 that CTLA-4 is really good to combine, why don't we add cifo to IPI/NIVO with the idea that we can maybe raise the PFS plateau. There are more people. That's the idea. And that's what we're doing. Now this study has been slow to get going because it's a multicenter study involving 8 different academic centers, very good centers. We're now targeting July to start this. Here's the protocol design, newly diagnosed advanced renal cell cancer, frontline therapy little run-in phase, IPI/NIVO and the usual doses, the IPI is 1 milligram per kilogram every 3 weeks for 4 doses, that's a relatively lower dose plus cifo continuously around 50, 60 patients enrolled. It's an open-label trial. And what we're looking for, the endpoint, which we'll be able to read very quickly is what's called deep response rate. Those are CRs and deep PRs. The MD Anderson Group had shown that if you use criteria of 50% or more tumor reduction rather than the typical 30%, that correlates best with PFS, with prolonged PFS. So the endpoint is deep PR/CR. That's about 30% historically. So with maybe 10%, 20% CR. So we'll be looking for CRs in this, so really good responses. Okay. All right. Now just one more thing. Now why is CTLA-4 synergistic. So we're beginning to understand that and it makes perfect sense. When you know the biology of CTLA-4 and you think about that adenosine signature a little bit, and that's a clue, it starts to make really perfect sense. Okay. So for ciforadenant summary, modulate tumor immunity, enhanced T cell infiltration in tumors, that's been published, new T cell clones in blood, that's been published, augment efficacy to PD-1 and CTLA-4, precise molecular target, of course, which binds the receptor selectively. It's been very well tolerated. We've identified this very relevant and reasonable biomarker, broad clinical applications. Obviously, we've shown the data in renal cell cancer, lung cancer, other cancers potentially. And the next steps are this upfront trial in renal cell cancer with the kidney cancer consortium. So before I open it up to questions, let me just kind of give you what we think are the 3 takeaways from this symposium. Number one, 3 clinical programs with significant anticipated near-term milestones. Second, a unique pipeline focused on the tumor immunity axis, we've been the leaders in this field, okay, other companies are working on this. ITK, we're the only company, although I think tomorrow, there'll be several others. Robust preclinical and clinical data with -- particularly paying attention to monotherapy and identification of the biological features. So 818 data later this year, cifo in the clinic, data will be coming on that as we enroll it. Mupa frontline together with pembro and chemo, randomized placebo-controlled trial. Just a word about that. As you well know, in addition to dose, the front-runner program at FDA now is asking companies, "Hey, you do all these combination trials and you now have a control arm, I don't know what you're doing." So we've been hearing that. We've been saying that for a few years now. So we're going to be doing that in our Phase II lung cancer trial, and we'll have interim data. And we'll know, we'll have a control arm that tells us whether we're having an effect. The pipeline very well defined targets, unique targets. Mupa is unique in its characteristics, even though there's other CD73s, ITK is certainly unique. And the A2A, I think we have more data and the use of our signature than anyone. And I think the preclinical data and the clinical data we've generated, we have experience in a large number of patients. We've been a pioneer in the adenosine pathway. In fact, I'm giving a lecture up at adenosine meeting Thursday in Boston. And I think we've been the first to show clinical activity of an ITK inhibitor in lymphoma and immune diseases. I don't know if any companies actually put an ITK inhibitor into the human. So I don't think that's been done actually. If so, I think some people were interested in looking at it for autoimmunity or allergy. And finally, we've identified this marker. Okay. First of all, I want to thank everybody for hanging in there. Your patience has been extraordinary. And maybe I can ask the other speakers to come up, and we can open it up for questions about cifo or any other thing that's on your mind.

Li Wang Watsek from Cantor. I got a 2 questions on mupa. Can you expand a little bit more on the clinical relevance of activating these cells, especially in lungs and you show this B cell dynamics and T cell dynamics? Can you just put into perspective for us, what does that mean? Like why is that relevant, and how does that tie up with the tumor reduction used on the clinic.

So the question was what is the relevance of activating B cells and expanding them in terms of clinical benefit and what's going to happen to the patient. I think that -- we know that tertiary lymphoid structures are important in cancer. Pathologist would tell you that for 100 years. The predicaments. We more recently know that B cell infiltration in tumors, and again, you can look up these papers. There's dozens of papers now showing that B cell infiltration in the tumor is an important prognostic factor, both for how they do the standard therapy, how patients do and how they respond to IO therapies. So -- and of course, we know that antibodies to tumors, I think it goes without saying, have been an effective -- somewhat effective way to treat cancers. And so I think that our part of the puzzle here is that we have the way driving -- through CD69 in B cell activation driving these B cells into tumors and into lymph nodes where they're going to play a bigger role in antigen presentation and antibody formation. Now we have been able -- this is hard to do because you don't know what the antigen is in the cancer patient, but we have looked for antibodies to tumor antigens in some of our patients, and we have found them, for example, anti-CEA. Okay. Or anti-PMSA, prostate membrane specific antigen. So we think we're doing that. Now a lot of times, you don't know what the antigen does, it's really hard to look for antibodies. We've not been able to do this in people because it's hard. You have to do really multiple biopsies to show that the B cells are getting driven in there. But we have a humanized mouse model where you can cut off a lymph nodes and stuff. We give mupa because mupa reacts with these cells in this mice. And you can see we're driving it in there. So that's it, direct evidence is lacking. But I would say that direct evidence is lacking that adenosine is important in cancer response as well.

I have another question on the interim analysis of Phase II. You mentioned you wanted to see a positive signal. Can you just sort of expand on that a little bit what that signal might look like for you?

If you look at KEYNOTE 18. So you want to know what a positive signal could be, right? So these interim analysis are based on events PFS. So let's look at KEYNOTE-189, the pembro pivotal trial in non-squamous the PFS, median PFS was 8.8 months in the pembro plus chemo arm versus 5 months. So there's room for improvement there. So we're going to use that as a benchmark. And in addition, we have a control group with pembro. So as this data matures, we're going to use those benchmarks to guide us on whether it's a positive data, encouraging data.

Any other questions?

First, this is Ted Wang, Co-Founder of Angel Pharmaceuticals. First, I just want to say that it has been a great, from Angel's perspective, a great proof for collaboration between Corvus and Angel. And those top of joint venture companies very, very rarely work out just because of the complications in the alignment of interest and the cultural differences and the personality is involved, but in this case, it can be happier. And the -- I think the resources of the 2 companies pulling together and working in a very synergistic manner on clinical programs and explore solutions in some of the most difficult to treat patients. And this is what Angel and Corvus is all about. So it's been benefiting greatly under Richard's leadership for Angel. So thank you, Richard and the Corvus team. This is really -- was fantastic. And my question really is more about Richard, you and to Dr. Gupta, which one of the things we're mentioning here is the for T-cell lymphoma, it was a very devastating chart you showed about the survival rates. The median survival rate is 5.6 months. And not only that, but also that the toxicity of those treatment is very hard to take for patients. And what we have found so far is that 818 has been very mild, I would say, in its side effects. And so the question is, from a clinician's perspective, and you talking about treating a patient that is the survival is not so rate. So I would -- how would the quality of life for those type of patients that has refractory and relapsed T-cell lymphoma and the kind of the quality of life type of decisions coming into your treatment options. And how would that guide into the direct development and potential implications for the regulatory path in 818. And Dr. Gupta, Richard, you can add comments.

Sure. No, I really appreciate the question because this is always on our minds as clinicians. The quality of the question is what role quality of life play in the decisions about your therapeutic options for these patients? And I think what's not fully captured in the slide is I alluded to this a little bit. These are sick patients. They do not feel well. They've been heavily pretreated plus their disease itself is quite debilitating. And so this does always enter our thought process. When we're thinking about romidepsin, belinostat or pralatrexate, we do it with a little bit of fear because we know they're already feeling poorly. When we give them these drugs with kind of a crossing of our fingers hoping it's going to work, we understand that we're probably going to make them feel even worse. And to your point, these unfortunate patients don't have too much longer to live. So we're -- it's actually a very challenging thing for us as a clinicians to put our patients through that. So when you have the potential for something, let's remove for just a moment, the efficacy argument. But if you have the potential to give something that's not going to make these patients still worse. This is a huge deal, it's not accurately captured by any sort of paper or data that we can readily have for you. But it makes all the difference in the world for the clinician and of course, our patients.

I just want to ask on the cifo study. I thought the primary endpoint there is the percent of patients who end up with a greater than 50% tumor reduction. That's in the Phase II study that was from [indiscernible]. So I'm hoping maybe we could just spend a moment on that, on that hurdle rate of greater than 50% tumor reduction, both from a trial perspective, but also clinically, is there meaning in less than a 50% reduction on top of what we already see.

I think the question is basically why are we picking the so-called deep response rate criteria and what's behind that. So the Sloan Kettering -- sorry, the MT Anderson Group had published papers that so-called Deep Response, which was CR plus greater than 50% shrinkage of tumor by RECIST, that was the best predictor of PFS. So they like that endpoint because it's quicker. It's a lower number, and you can get a feel faster for whether your drug is doing something. And in their hands, I think best results are like 30%, okay? CR and 50% greater reduction. So I think in our study, we're hoping to see like [indiscernible] that. But really, it's even easier than that. Really look at CRs. One of the disappointing things in immuno-oncology, frankly, with the agents we have so far is that even though PFS curves are improved, no question, CR rates have improved, no question. CR rates have not improved that much, okay. Now I'm a lymphoma doc, Neel is a lymphoma doc. He'll tell you that at least at Stanford when you don't want to say you got a PR you're attending throws you out, so I don't want our PRs. I want CRs because CRs are potentially curers. PRs are not going to be curers. The goal is cure. And so from my standpoint, I'll be looking -- if we're making an impact on CR, the [indiscernible] for example, if we treat the first patient -- first 10 patients, and we get a couple of CRs, I'd be very excited. Now of course, we're going to look at overall response rate by the usual criteria, right? You're not going to ignore the 30% criteria. That's important, too. And 30%, 50%, sometimes these measurements are not as precise as we like in some patients, yes, it's pretty precise, other patients, it's more difficult. And as you know, I -- it drives me crazy when people get so hung up on this because it's one thing to have a 2-centimeter tumor shrink by 30%. That's really hard to even see on a CT as opposed to a 10-centimeter tumor shrinks to 6 centimeters. That's a big difference. Okay. That's a lot of cell kill. So the details on all this stuff is important. That's why I did those case report -- case histories for you. okay? And usually, if the tumor like it's go away in 15 days. I don't need a stats issue to tell. I mean it seems like gone. [indiscernible] Nothing's ever would. [indiscernible] chemotherapy and suddenly it's gone. So that's why I'm here stressing the monotherapy, monotherapy because I am really, really somewhat discouraged by all the R&D going on in the biotech industry where people go right to combinations. I feel they're not going to learn anything. I feel it's actually [indiscernible] patients. Because the bargain we make when we put a patient on a study is that you're going -- you're being kind enough to donate yourself for the betterment of knowledge. And so therefore, it burdens on us to do a study that answers the question, so that even if our drug doesn't work, you can at least say, okay, well, you contributed to knowledge. That's the bargain we make when we put a patient on a clinical trial, not to put them on the study that might not be needed. Okay. Now I know at Stanford, we have scientific review, not just the IRB, the IRB is the easy part. Scientific review committee, it has to be scientifically meritorious, right? It has to be a good question, a good study that's going to give an answer to a question [indiscernible]. But just doing the study in putting patients with chemotherapy and PD-1 [indiscernible]. Okay. That's not fair to the patient. It's not going to contribute, it's not going to get a drug approved. And frankly, I think the FDA is now reacting to that with these new initiatives. The dosing 1 and the Dr. Pastore's admonishment. Now, hey, let's move this up earlier. It's ethical. It's okay. Lung cancer frontline most of those patients still die, okay. It's okay to give them standard treatment and add something to it. And you need to know a little bit about the safety of your agent before you do that. But it's okay to add something to standard therapy in frontline. It's in fact more ethical because you're going to get an answer that's going to move the field and it's going to be better for the next group of patients. So I think, frankly, I think it's incumbent on us as [indiscernible] I think that you need to be say, you guys, what's this going to do for us? How are you going to know, and I know the answer you'll get is, there's this paper published in 1858 that showed standard treatment with leeches didn't work or something like that. Obviously, I'm exaggerating, but boy, I have to be very careful if you're going to use literature controls and stuff like that, as you all -- you know that. Anyway, it's a very interesting time we're in now because we have a lot of cancer agents now. And a lot of agents in development and how that's all going to be sorted out is going to be complicated. But rest assured, it will be sorted out. And one of the reasons -- I mean, we're taking some bold moves, frontline lung cancer, combination with chemo, randomized trial placebo control, okay? We'll know after 50 or 100 patients, whether on margin or whatever detail for cifo. We're looking for CRs basically. Okay. ITK, nobody's done that. Now rest assured, next week, they'll be doing it. I have no doubt. And one of the reasons that we haven't been talking much about that. So anyway, so we're sticking to our strategy, developing novel agents, being careful on the science, being careful on the -- what we get out of our monotherapy, putting together in intelligent ways and doing the laboratory work to justify and to give us the ideas and also uncover new targets. All right. That's my sandbox speech today. Any other questions? Again, I want to thank -- if not, any other comments from the speakers. First of all, I want to thank you all for your attention and hanging in there for this long to our session almost. Appreciate it if you have any follow-up questions, let me or any of the speakers know or anyone else at Corvus. We do want to keep the street more informed about what we're doing because we're really excited about what we're doing. And I want to thank Dr. Wang for coming and appreciate that. And if any of our Angel friends are listening in at this late hour, we appreciate them as well. Thanks, everyone.