Craig Fryer (JP Morgan) 0:02
Thank you for joining us today. My name is Craig fryer and I am a vice president in JP Morgan’s healthcare group. Before I introduce you to our presenter today, I want to call your attention to the blue. Good morning. And thank you for joining us today. My name is Craig fryer and I am a vice president in JP Morgan’s Health Care Group. Before I introduce you to our presenter today, I want to call your attention to the blue button on your screen. This is where you’ll submit questions that will be addressed during q&a. With that I am pleased to introduce you to Andrew Allen, President and CEO of gritstone bio. I know he’s very excited to tell you a little bit about their story. So I’ll turn it over to him, Andrew.
Dr. Andrew Allen (GRTS CEO) 0:41
Very good. Good morning. Thank you, Craig. Well, good morning, everybody. I’m Andrew Allen CEO and one of the cofounders of gritstone. I’ll be giving the presentation this morning and then I’ll be joined by two of my colleagues, Celia economies, who’s our chief financial officer, and Karen Hughes, who is our head of r&d. During this presentation, I’ll be making some forward looking statements. gritstone is a company that’s taking immunotherapy to the next level with a primary focus upon the generation of T cells. To accomplish this, we have two core proprietary technologies. The first is artificial intelligence platform called Edge, which takes sequence data and identifies T cell targets or epitopes within those data. Secondly, we then deliver those selected epitopes to humans in unique vectors, which drive strong T cell responses. And as we’ve learned more recently strong antibody responses as well. We apply these technologies in two different therapeutic areas oncology and infectious disease. And we’ll be walking through both of those programs. today. We have major partners in both of these areas in infectious disease were teamed up with Gilead on an HIV collaboration. And in the field of SARS, cov. Two we have collaborations with the Gates Foundation, with Sepi and with the NIH. And in oncology, we have a collaboration in cell therapy with 270 bio formerly bluebird bio. We have multiple catalysts coming this year, and our unaudited cash position at the end of 2021 was over $220 million. In terms of selecting targets, or epitopes that we put into our vaccines, we have a sophisticated approach that begins by looking at the genes of interest in oncology. These are mutations that are the source of new antigens. In infectious disease, of course, we look at the entire pathogen genome, the viral genome. And we plug the genome into the edge prediction model, which identifies likely regions, which will function as epitopes. For T cells, we then prioritize based upon conservation. And obviously, this is very important and relevant to SARS, cov to where we’re able to select epitopes, which really don’t change from strain to strain to strain. And this enables us to design efficient payloads or immunogens, which we load into our vaccines, with the goal of driving strong immune responses in humans. And of course, we can do this for both surface proteins to ident to drive antibodies, and a broader range of proteins to drive T cell responses. These are the two vectors that we used to deliver the selected antigens. On the left is our self amplifying mRNA or Sam as we refer to it. And this is a little different from simple mRNA because it contains a viral copying enzyme a polymerase wrapped into a lipid nanoparticle together with the antigenic RNA. The consequence of that is that once injected into a human, it enters cells, the polymerase starts making copies of the RNA. And this leads to two different changes compared to mRNA. The first is that we see replication of the RNA that generates longer and more durable antigen expression. And secondly, the double stranded RNA intermediates drive a broader set of innate sensors, motivating a stronger overall immune response. This leads to potential for those sparing and as you’ll see, today, we’re able to achieve a 10 micrograms, what first generation mRNA products typically require up to a log higher dose to to achieve. We have worked on formulation and have good potential for a refrigerator stable product with our Sam RNA. We also have an adenovirus and this remains probably the best vector for driving strong Ciate T cell responses. And this is at the heart of our oncology program, and plays a smaller role in sales co v2.
This is the pipeline that we have generated off of these technologies. At the top you see the sales COBie two program called coral, and we have four studies which are either ongoing or hopefully about to open enrollment currently under review by regulators. We also have the Gilead collaboration and the IND for that program. The first ind was cleared in December of 2021 by the FDA. And at the bottom, you can see the oncology programs, the personalized individualized Grants Program, which is just completing its first phase one to study in patients with advanced disease, and is now launching trials in earlier stages of disease, where we anticipate even stronger immune responses. And I’ll review those data today. And then there’s the sleep platform, which is an off the shelf product currently focused on K RAS. And we have an optimized second generation K RAS dedicated product. That’s in phase two trials currently, in lung cancer and colorectal cancer. Moving specifically to infectious disease. The current approaches to SARS cov. Two, as we’re all experiencing, have some limitations. And primarily, the limitation arises because the vaccines are very focused on Spike exclusively. And Spike has been mutating much faster than I think most of us had expected, and variance of concern have emerged, which essentially escape immunity elicited by the first generation vaccines, certainly the antibody immunity the couple of approaches that exist to try and deal with these variants. The first is to reboost and drive the neutralizing antibody titers back up again. But this effect is still remain seems transient and protection is often less complete than against the original strain and form of Spike used in the vaccine itself. The second option is to try and play a whack a mole form of game and generate variant specific vaccines as new variants arise. But as we’ve seen with Omicron, the timing potentially doesn’t work. No Macron has really swept the globe. Before we’ve been able to put an Omicron specific product, even into clinical trials, nevermind scale up. A better solution, of course, would provide broader, more durable protection across current and future variants and perhaps even protect against other forms of Coronavirus. The secret to this broader, more durable protection may be T cells and there’s been much interest in the fact that the first generation vaccines do generate CD for T cells and to a smaller extent depending on the platform, some degree of CD8 T cell generation and it’s those CD8 two killer T cells that appear to be key to protect against the virus because they kill virally infected cells complementing neutralizing antibodies. The gritstone call approach potentially begins to open the door to this solution. By including both spike and additional T cell targets from non spike genes. In principle, were able to drive a broad immune response encompassing both neutralizing antibodies to spike. But also CD8 T cells recognizing a broader, more conserved set of epitopes. thus reducing the impact of spiking mutations upon vaccine elicited immunity. And this can potentially all be done at a low dose level.
We recently showed some data off of the first of our trials in humans as an attempt to form prophylaxis against SARS, cov to infection. And this is really the first study off of the SAM RNA platform in infectious disease as a standalone. So an important study from our perspective as a validation of the overall platform. This is a study that was run in the UK where of course, all eligible subjects likely to come into a trial have already received a primary vaccination series. And so this is the coral boosts study. And we’re taking subjects over 60 years old. And in the study, they’re receiving two doses of the AstraZeneca vac Zebadiah vaccine also known as Chad ox one. And then at around 22 to 30 weeks interval, they receive a booster dose of our Sam RNA vaccine containing wild type spike together with a set of selected T cell epitopes. And that’s the TCE five that you see written here. We showed data off of the first cohort 10 subjects those to 10 micrograms. And we demonstrated proof of concept. We demonstrated that we could elicit CD8 T cells, priming these de novo T cells against novel T cell epitopes. From within SAS cov. Two, we also boosted the pre existing T cell response to spike, which of course was induced by the AstraZeneca vaccine. And we showed a strong effect upon the generation of neutralizing antibodies. These data are available on our website, I don’t have time to go into all of them. Today, I’ll just show a couple of highlights. These are the neutralizing antibody data. And on the left you can see our study and on the right is a different study, but highly analogous that was published in December 2021 in The Lancet, and this is the so called cough boost study. So in our study, as I mentioned two doses of chatbox one followed by the sound RNA boost around 22 to 30 weeks later, and in the cough boost study two doses of chatbox one followed by boosts with multiple different vectors including both the biontech product and the Madona product. And you can see on the top the baseline antibody titers are very similar. You can see the median there Is, is around 80 or so the the mean in the gritstone population is artificially inflated by that single outlier, but the median is obviously a highly analogous. And then you can see that with grid stones product, we boost the neutralizing antibody titers against the wild type variant of spike to around 2370 using a standardized assay. And in the comparable study, run by cough boost, you can see that again the Maderna, elicits essentially the same magnitude of response a little lighter for the Pfizer biotech product. And this is consistent with other data that Maderna does appear to be best in class in terms of generating neutralizing antibody titers. And we clearly here match the Maderna profile. But where we differentiate from the first generation products, of course, is that we add in additional T cell epitopes from the virus. And here you can see that we’re generating T cells. And actually, this is an LE spot which doesn’t differentiate between CD fours and CD AIDS. But we’ve gone on to demonstrate that indeed, the majority of these cells are indeed CD eights that we’re measuring here. And importantly, the CDs are recognizing elements from three from all three of the different genes included in our vaccine. So beyond spike, we include nucleo, capsid, membrane, and open reading frame or three, as you can see on the right, the pie chart, demonstrating the breadth of the immunity that we generated.
Now, this is important because as we think about variants, as we’ve seen with Omicron, there is a particular propensity for variants to arise that have multiple mutations in the spike gene. And this is the challenge of relying exclusively upon spike, and upon neutralizing antibodies to spike as the basis for vaccine listed immunity. By choosing additional genes, you can see that there is greater degrees of evolutionary conscious conservation. And in fact, specifically that we don’t include all of these genes, we don’t have all of all three and all of nucleocapsid we include regions of it, which are selected to be conserved, and at the bottom, you can see that within Omicron, the number of epitopes impacted in our various T cell epitope constructs TC five, which we showed today, TC nine and 11, which are in the next trial that we’re running, you can see up to a maximum of 3% of the epitopes only are effective. In other words, at least 97% of the immunogenic material in the vaccines is unaffected by the Oman variant, and of course that’s likely to lead to durable, across protective immunity against future variants. These are the four trials that we have conceived and designed, called Boost is the one I’ve mentioned that is now expanding in the US and the UK. currently under review by FDA and MHRA, coral Cepi is a study funded by our partners Cepi, the collaboration for epidemic preparedness innovation. And you can see that that study has been run in South Africa with both spike beta and Spike Omicron. And we’re exploring a couple of different T cell epitope constructs to determine which one is the best in humans. We have an ongoing study with the NIH, and all of these three trials are using the same RNA construct as the primary vector. We do have a study the second study here coral immunocompromised, using the chimpanzee adenovirus, selectively in subjects in fact, in patients who have hematologic malignancies, or autoimmune disease and receive therapeutic B cell depleting antibodies. The evidence suggests that of course, those subjects cannot mount a good antibody response because they are functionally B cell deficient, but they have preserved T cells and thus a T cell tropic vaccine in principle should drive protective T cell immunity. And as I mentioned at the outset, the adenovirus is the best driver of CD8 T cell responses in humans, and that’s why we’re using that vector in those subjects. They should be protected against the thrombotic toxicity because that’s mediated by an autoimmune antibody, and of course as a B cell depleted subject. In principle, one’s propensity to develop autoimmune antibodies will also be low, which does may protect these subjects against the rare but significant toxicity seen with adenovirus. Our collaboration with a with Gilead is centered on generating potent vaccines against HIV. As part of their HIV cure program. We received a sizable upfront payment at the beginning of 2021. As I mentioned, this study is about to begin clinical studies imminently. Let’s move to oncology. The premise for our new engine based immunotherapy is that many subjects with solid tumors have cold tumors, meaning that the tumors have successfully evaded immune recognition by the hosts adaptive immune system. Now this means that if you administer a PD one antibody to such a patient, nothing much will happen because they don’t have pre existing new antigen reactive T cells in order to be stimulated by the PD one or PDL one antibody. And that I think explains Why so many subjects with solid tumors have very little response to simple checkpoint administer inhibitor administration. Our hope therapeutic hypothesis is that by restoring or building new antigen specific T cell responses, particularly CDH. In such subjects, we may be able to render them responsive to checkpoint inhibitor therapy. And to do so we administer the patient’s new antigens in our potent T cell vaccines, in combination with checkpoint inhibitors. And we have two programs that seek to exploit this biology. The first is the granite or individualized program. And I’ll show you some data from that today. And this has just entered a phase two three randomized trial that has registrational intent. And then we have the slate off the shelf products currently focused on KRAS, which has just entered phase two studies in colorectal and lung cancer with an optimized product building on the clinical signals we observed through the first iteration of this platform.
Overall, the study with granite began a couple of years ago in phase one, with dose escalation, we use a standard dose of the chimpanzee adenovirus vector to prime and then we did the dose escalation on the SAM because this has not been in humans before. We combine these with systemic nivolumab and a low dose of subcutaneous ipilimumab aimed at boosting the immune response to the deliver new antigens. And in the phase two studies we expanded in primarily in microsatellite, stable colorectal cancer, and gastro esophageal adenocarcinoma. And I’ll show you data from the phase two today as well as the phase one. We presented these data at ESMO in 2021. In September 26, subjects were treated with the granite immunotherapy. And this was a typical phase one. So these are subjects who have exhausted approved therapies and come into our study at end stage. So end stage metastatic disease. Some of these subjects, of course, are in relatively poor shape. Unfortunately, we do observe fever associated with our vaccines. These are potent vaccines, and we sometimes see injection site reactions, but there were no other important toxicities observed attributed to our vaccines, we do see some adverse events related to the checkpoints Of course. Now this is a very important slide and for the first time, we’re able to show that we consistently elicit strong T cell responses and these are CD aids in patients that we have vaccinated. And these are CD8 responses against their own new antigens. So on the left of the baseline T cell responses, which are below limited detection for nearly all subjects, apart from the one non small cell lung cancer patient, interestingly, who had received prior checkpoint inhibitor, and of course, we know that lung cancer is a relatively hotter tumor than colorectal or gastric. But on the right you can see consistent induction of Neo antigen specific CD8 T cells in all subjects. These lead to apparent clinical benefit observed by reduction in circulating tumor DNA. So, as many of you know, circulating tumor DNA is becoming a now standard approach to assess novel immunotherapy. It appears to be perhaps more reliable than resist radiology, because we’re driving T cells into lesions where we want T cells to expand when they meet their antigen. And thus measuring lesion size may fail to capture clinical benefit if T cell expansion is predominant within the lesion, molecular responses potentially get us around that radiology problem. And that’s why they’re coming into focus. And here you can see that almost half of the subjects that we treated who had colorectal cancer, exhibited in molecular response defined as at least a 50% decrease in CT DNA titer from baseline. Two of these were complete responses. Now, importantly, we showed them molecular response appeared to correlate with extended overall survival. And on the left here is the plot the Kaplan Meier survival plot that we showed in September at ESMO. With an August data cutoff date, we’ve obviously followed these subjects. And I’m thrilled, particularly for these patients to tell you that no further subjects have died since that August cutoff date. And obviously, this is somewhat unexpected in subjects with typically third line colorectal cancer, where the median survival in most phase three trials is between six or seven months. And you can see here that we’ve got extended overall survival, particularly in the group that did experience CtDNA responses. And these are very encouraging data. This is not randomized. Of course, all of the subjects who received granted and some of these sub poor subjects progressed very quickly and died as you can see, and this is the challenge of taking a vaccine into very late stage patients. Nonetheless, you can see the molecular response is clearly correlating with extended overall survival. This is an example of the kind of problems we run into with radiology Gene. This was a patient with metastatic microsatellite stable colorectal cancer, who at baseline had multiple pulmonary nodules, that expanded at week eight. And obviously, we think this is likely due to T cell proliferation. And we’ve shown the D that we do get T cell expansion of new engine reactive T cells in lesions after vaccination. But over subsequent weeks and months, you can see these lesions gradually cavitating and shrinking, leading to almost complete resolution by week 48. And this illustrates some of the challenges particularly with reliance on radiology in early stages, where pseudo progression is a likely problem.
We’re taking granite forward into the randomized phase two, three trial, as I mentioned, up to 80 subjects in the phase two randomized component. And this is a maintenance study after induction with FOLFOX Bevacizumab, which is now standard therapy for first line patients newly diagnosed with metastatic colorectal cancer. The endpoint for the phase two is molecular response. And the current endpoints subject to continued FDA review of phase two data is to use IPFS. For a PFS comparison, that’s phase three for the registrational endpoint. We’re also beginning an adjuvant study in earlier stage disease. And finally, on slightly off the shelf product, we focus on K wrasse. And as I mentioned, this is a common mutation in colorectal cancer and lung cancer. And to be eligible for the product, you have to have both the mutation and the relevant HLA allele, which which ends up accounting for about 10 to 15% of subjects with lung cancer and colorectal cancer. We show data off of this program using the first version of V one as we term it of our K RAS product, which had some additional new antigens. 26 subjects again, we see minor transient injection site reactions and fever, but no other major adverse events. And again, in subjects particularly in non small cell lung cancer, and it’s important to note all of these patients had progressed on prior checkpoint inhibitor therapy. Again, we observed about half of them were observing or displaying CT DNA or molecular responses. And we show on the left that genotypes and the baseline CT DNA levels, recognizing some subjects don’t have detectable CT DNA at baseline. But on the right, you can see that if there was detectable CT DNA, around half of them had molecular response. We also observed a recessed response in this program. This is a patient with very aggressive non small cell lung cancer, diagnosed in summer of 2021, who progressed on pemra chemo in three months, came on to our study in January. And as you can see, this sorry, this was January 21. He came in, and you can see that he had a very dramatic response to in multiple lesions. Unfortunately, between five and six months after initiating therapy, he developed breakthrough in a spinal lesion and succumbed to his disease soon thereafter. But you can see the power of the therapy here eliciting an objective response, even in this very aggressive disease. We did learn that the T cell responses we were seeing were not quite as strong as we’d anticipated. And so we went back, we re engineered the vaccine and recognize that an exclusive K wrasse product was going to drive superior immunity. You can see in an HLA transgenic mouse on the left here, there’s a dramatic difference in the strength of the T cell response to G 12 V, for example, here, mg 12, D to a slightly lesser extent, using the version two product compared with version one. And it’s this version two product, of course, that we’ve now taken back into the clinic in colorectal cancer in two contexts, and in non small cell lung cancer. Importantly, we do our manufacturing, both in Cambridge, Massachusetts, where we focus on tumor sequencing, which is part of our manufacturing process. And then the bulk of the additional work is performed at our dedicated facility in Pleasanton, California. As I mentioned, we finished 2021 With over $220 million in cash. And obviously, this sets us up well, for the coming milestones. And to finish, we’ve demonstrated, obviously, rapid execution across our multiple platforms. And we’re excited with the milestones that set lay ahead of us in 2022. Obviously, we’re looking forward to getting those remaining two studies, with our choral program up and running in the first quarter. And then we anticipate having data off of the core program around the mid year phase as well as data off of the slate phase two studies with the K RAS dedicated product, also coming in mid 2022. With that, that completes the prepared remarks and we’ll open up for q&a and I’ll invite my colleagues, Celia, and Karen, to join me.
Craig Fryer (JP Morgan) 24:41
Thank you, Andrew for, for running through that then. And welcome. Silvia and Karen. A couple questions from from the viewers here. Why don’t we start off with the questions around your COVID-19 Coral program? How does gritstone differentiate from First generation vaccines.
Dr. Andrew Allen (GRTS CEO) 25:03
Karin perhaps you want to take that one?
Dr. Karin Jooss (GRTS R&D) 25:06
Yeah, as things enter, as enter mentioned, besides spike, we delivered T cell epitopes that are from genes, viral genes that are outside of Spike. We look for conserved sequences and we look for epitopes hotspots in these sequences are then added to our vaccine cassettes. In addition to spike. Our goal was to try pro T cell responses. And that’s what Andrew has shown today, we are trialing teaser responses against the boost the T cell responses post the approved vaccines against spike in B prime them against these additional viral genes.
Craig Fryer (JP Morgan) 25:54
Thank you. I guess as as we’re looking at the different variants out there, how does right now how does Omicron impact how you think about COVID-19 and the vaccines being used against it?
Dr. Andrew Allen (GRTS CEO) 26:10
I think Omicron has demonstrated the power of this virus and the limitations of the first generation vaccines. The neutralizing potency of antibodies elicited by Spike from the original sequence, the wild type sequence reduces about 30 fold on average against Omicron. And so if you have modest titers of antibody to begin with a 30 fold drop means that effectively you are unprotected. So the response, obviously, that’s rational is to give you another dose of the vaccine. And if I can drive your neutralizing antibody titers up enough, even though the neutralizing potency is low, that may still give a degree of protection. And that’s what we’ve observed the dangerous supporting that thesis. And that’s why boosts at this point make a lot of sense. But obviously, there are concerns about having to give boosts too often, the immune response immune system generally doesn’t like being overstimulated. And of course, what if there’s a variant that really just completely escapes neutralizing antibodies elicited by the first vaccine, then our only solution would be to generate a new variant specific vaccine. However, that takes time. And as we’ve seen with Omicron, we may not have time. And so we need a vaccine that drives a more durable, robust immune response today, using the existing forms of the virus that are available to us. Clearly, our ability to predict the future with Spike is limited. But our ability to predict the future of these other genes seems to be much better based on history, we see regions of the virus that just don’t change over time. And that obviously, is usually evolutionary selection pressure on those gene products because they cannot change because they’re so important to the function of the virus. But most of these live inside the virus, they’re not accessible to neutralizing antibodies, and the only strategy to access them is through developing T cell vaccines. And that’s obviously our secret sauce. So finding the right regions of the of the virus to put in your vaccine, and then delivering it with a potent vaccine that elicits not just antibodies, but also the T cells, particularly the CD8 T cells. That is the core of gritstone. And that’s what we’ve demonstrated we can accomplish. And obviously, that’s a very exciting platform, in principle may be able to drive durable, effective immunity against this and future variants.
Craig Fryer (JP Morgan) 28:26
Thank you. How do you how do you think a pan Coronavirus vaccine? Well, I guess, do you think a pan Corona vaccine is possible?
Dr. Andrew Allen (GRTS CEO) 28:39
Yes, simple answer. It is possible. And I think we’ve taken the first step in that direction. And we’ve shown that those genes that we included, are often conserved in other members of the SARS family. So remember, the Coronavirus overall has a series of sub families, let’s say. And there is a group that are related to SARS. They’re actually called Sopko viruses. And SARS. The original SARS from 2001 is in that family as is SARS cov. Two as the name suggests, and obviously there’s quite a lot of conservation of some genes across those family members. And if we can find conserved regions that act as particularly good T cell epitopes, of course, we can include those in the vaccine. Then there is another family called the Mirbeau virus family, which is where MERS comes from. And that was the very nasty virus that had limited transmissibility happily that arose in around 2012. That has less conservation, so less genes in common between that family and the soccer family as you might expect, but there are there are regions of commonality. And so again, in principle, one can put those into a vaccine to drive the T cell response. And then complementing that there’s obviously interest in trying to find regions of Spike which may be conserved. That’s gonna be very hard for something that crosses South Africa and Morocco because they actually use totally different receptors on the target cells and their spikes are really very different. But if you’re looking for a pan Sopko vaccine, that may be achievable as an antibody level, and there’s work which we’re involved in as well, looking at the generation of broadly potentially broadly neutralizing antibodies. And again, you can then put these together into a single vaccine, the goal of broadly neutralising antibodies and broad T cell immunity against very conserved regions of the virus. That’s the overall strategy for a pan Coronavirus. And our T cell data today demonstrate a meaningful first step.
Craig Fryer (JP Morgan) 30:31
Right. Thank you. And as, as we look at other pathogens out there, how how can your vaccine be applied to to these other pathogens?
Dr. Andrew Allen (GRTS CEO) 30:44
Karin, perhaps you take that one?
Dr. Karin Jooss (GRTS R&D) 30:47
Yes. Intro has shown today, we have demonstrated with our CO program that our vaccine platforms in vaccine immunogen designs are able to try high neutralizing antibodies and product T cell responses. And therefore, when you look across other pathogens you go after we we can move into pathogens that for for prophylaxis, for example, that are neutralized by neutralizing antibodies, the incoming virus as well as requiring T cell responses if the virus infects cells. So I think it’s probably applicable because it tribes immunity to both arms within the immune system, which is quite helpful in selecting a path forward in infectious disease.
Craig Fryer (JP Morgan) 31:39
Thank you. And I guess B. Before we we move on to a question about your oncology program. Can you just talk about your r&d engine across granite, slate and coral and how it spans across all of your programs and one program helps inform the other?
Dr. Andrew Allen (GRTS CEO) 32:01
Yeah, that’s a perceptive question. Thank you, Craig. We began life as an oncology company. And our primary focus was on that problem that I illuminated today, which is the identification of new engines as critical targets in humans with cancer. And the fact that they function as the critical targets when you’re responding to a checkpoint inhibitor was a seminal moment in the field of tumor immunology. And it was pretty obvious early on that there were many patients with the common solid tumors, the tumors that kill the majority of people from cancer, such as lung cancer, and colorectal, ovarian, breast and prostate, that most of those subjects don’t respond to checkpoint inhibitors. And the the hypothesis that stood up to time is that the really the primary reason they don’t respond is that they just have immunological ignorance of their tumors. In other words, the quote, successful tumor in a human is one that’s frankly learned to avoid the immune system, because our immune system is actually pretty good at finding abnormal cells with these mutated Neo antigens and getting rid of them. And the only tumor that will grow successfully over time, if I can use that word is a tumor that actually is good at evading the immune system. And one of the mechanisms is upregulation of PDL one, and that obviously is operating in melanoma to a very clear extent such that just blocking that one pathway reactivates those new antigen specific T cells and really good clinical benefit can ensue. And that’s just obviously a magical phenomenon. However, most patients aren’t that lucky. And when you look in their tumors, they don’t have any evidence of pre existing new antigen specific T cells, in particular, the CD8 T cells. And so when you give them checkpoints, there is no substrate that there’s nothing for those checkpoints to reactivate, perhaps apart from autoimmune T cells, which of course, is not what we want. And so the question becomes, how can I help this huge number of subjects for whom checkpoints are just irrelevant today checkpoint inhibitors. And the the obvious hypothesis is I’ve got to generate those new engine reactive CD8 T cells. That’s really what we said about doing. And so to do that, we realized there were two core challenges. Number one, predicting what the CDH we’re going to recognize, and that’s a hard biology problem. And then number two developing vaccine platforms that generate strong CDH in humans, recognizing that most vaccines traditionally don’t, they’re very good at making CD CD for antibodies, and neutralize certain T for T cells and neutralizing antibodies. They’re not very good at driving CDH, particularly priming a new CD8 response. So those were the challenges we had to overcome. And we did that by developing the Edge platform training on huge amounts of human tumor surface antigen data, derived from our own experiments, and then combining those two training data and then educating and training a machine learning model off of those data. And that’s the Edge platform and then we develop the antivirus and and self amplifying RNA as the vectors to deliver strong CD8 responses in humans. And of course, as COVID came along, our thesis right at the beginning was that there would be mutation, and that escaped from neutralizing antibodies was likely. And that a path to durable immunity would involve CDH T cell generation. And so we apply started applying the Edge platform to the viral pathogenic genes to the Syntha viral sequence. And we predicted a whole bunch of T cell epitopes. And we teamed up with Alex SETI and his team at the La Jolla Institute criminology who are analyzing blood from convalescence subjects. And so they actually validate epitopes, and many of our predictions validated out. So now we had knowledge, right, these are targets for T cells in humans, within SARS, cov. Two, let’s select them, can put them together efficiently into the finite payload of a vaccine. Let’s select them carefully to try and generate a globally relevant vaccine because different people with different ethnic backgrounds often react to different bits of viruses. So you have to bear that in mind. And this is all comprehensive within our machine learning model. And thus, you can design a very elegant pathogen specific vaccine. And of course, then you can generate strong CTAs. What we didn’t know as much about was whether we can make good neutralizing antibodies. And obviously, Sam has surprised us with these very, very strong neutralizing antibody titers that we show today. So it’s a natural extension of our oncology platform into infectious disease, using the same tools, the same manufacturing importantly, and obviously, that’s very valuable to us as a company trying to innovate and develop improved therapeutics and prophylactic vaccines.
Craig Fryer (JP Morgan) 36:47
Great, thank you need, tell me why you’re, why your molecular response is superior to a radiological response.
Dr. Andrew Allen (GRTS CEO) 36:58
Yeah, so radiology is served as well for chemotherapy. And for targeted therapies, the idea that when I treat a tumor with a drug that kills the tumor cells, I can get a pretty good proxy for whether outcomes are good just based on whether the lesion shrinks, and obviously, measuring the size of the lesion is what we do. And that’s how recess was developed is to standardize the way in which we measure lesion size. When checkpoint inhibitors came along, the relationship between lesion size and overall survival, however, began to fray and of course, recognize its overall survival that we care about. No one actually cares about the size of the lesions in their tumors, they can’t experience lesion size, all they know is how do I feel and am I alive. And so we measure resist purely as a surrogate for overall survival. And we’ve seen this repeatedly with checkpoint inhibitors that resist response is sometimes very low. PFS trials are sometimes negative, but overall survival is often benefited. And this has led to some regulatory meetings, as you know, assessing drugs that we all believe are helpful for subjects, but that have actually failed some of their pivotal trials using some of these radiology based endpoints. And AstraZeneca. She had some very nice data Desmo, showing that it primarily had stable disease, as its termed in resistance lost its utility. Stable disease used to be a sort of a bad outcome because it wasn’t as good as response and it meant that you were going to progress pretty soon. But with immunotherapy doesn’t actually seem to mean that stable disease can mean two very different things, it can mean your diseases slowly progressing and you’re going to do badly, or it can mean your disease has been completely arrested. And you’re actually going to do extremely well. And you cannot tell those apart just using radiology. Measuring CT DNA appears to be able to differentiate those two states. And that’s what AstraZeneca showed was one of their big lung cancer trials it as mode. And then the poster child has probably become immuno core, who have a effectively a bi specific against a subtype of melanoma that really had de minimis effects on recessed response. It was 9%, with sorry, 5% with Pembury versus 9%, with their therapeutic in their pivotal trial, but the hazard ratio for survival was 0.5 and profound effect. And you just can’t see that in using the radiology assessments, but it’s visible when you use CT DNA. And so the thesis in the field, I think, is that radiology response is still good, don’t get me wrong, but lack of response doesn’t necessarily mean I’m not getting real clinical benefit. And CtDNA potentially gives us a better tool. So I think you’re going to see a migration where people will start measuring both radiology and CT DNA. And I suspect they’ll show that CT DNA pretty consistently is actually better. And as we get more and more validation data, I think then we’ll start to see regulatory acceptance of CT DNA as a surrogate for efficacy and the basis for approval. We’re not there yet. FDA obviously Eazy E is accepting CtDNA for patient selection, but not yet there’s a basis for approval. I do believe that’s a matter of time however.
Craig Fryer (JP Morgan) 40:08
Right, thank you, Andrew. And unfortunately that is is all the time that we have for for this morning. So I want to thank Andrew, you, Karen and Celia, for for joining us today and spending time with us and I want to wish the the viewers joining us to that they have a great rest of their day and and thank you very much.
Dr. Andrew Allen (GRTS CEO) 40:31
Thank you, Craig. Thank you