Last Updated on November 15, 2021 by Sultan Beardsley
Hello everyone. My name is Ben Burnett, biotech analyst at Stifle and I’m pleased to be joined by Andrew Allen, CEO of Gritstone Gio. He’s going to give a formal presentation and if there’s time in the end we’ll handle some questions if you have a question submit those through the dashboard as always, and I’ll monitor that. Otherwise, just shoot me an email Burnett be at steeple calm. Andrew, over to you.
Dr. Andrew Allen (GRTS CEO)
Great. Thanks very much, man. Appreciate it. Thanks for inviting us to talk. So my name is Andrew Allen. I’m one of the co-founders and President and CEO of gritstone bio, my pleasure to be with you today I’ll be making some forward-looking statements. This is an overview of what gritstone bio accomplishes these days. As many of you may know, we started as gritstone oncology, built out a couple of core platform technologies. And then as their applicability to other therapeutic areas became of paramount importance, we changed our name to reflect the expanded scope of our platforms and of our products. And so at a very high level, we developed two core platforms, which I’ll describe in a little bit more detail on the next slide. Essentially, one is aimed at finding T cell antigens within targets. Targets can mean either tumor cells or pathogens, infectious pathogens, and obviously identifying the bits of those that are visible to the immune system. And particularly the T cells is not trivial, but it’s very important to potent vaccines. So we built this platform called the edge artificial intelligence discovery platform for finding epitopes. And then, of course, having found epitopes, you need to deliver them to humans to drive strong immune responses, then we have two vectors. That’s the term given to the shell in which you wrap the antigens, and then you deliver them to the immune system. One is a now popular self-amplifying mRNA platform. So that’s one of our vector systems. The other is an adenovirus. And I’ll describe briefly the relative benefits of those two. We’ve applied these platforms, both to oncology and now to infectious diseases. And we’ve signed collaborations and relationships with several different players. In infectious disease, we have an HIV collaboration with Gilead that was launched at the beginning of this year, in COVID-19. We have collaborations with Sepi. That’s the Coalition for epidemic preparedness, innovation, as well as the Gates Foundation, and the NIH, specifically the NIH and division of NIH. And then previously, we’d signed a cancer-based collaboration with bluebird bio. In terms of clinical data, we now have multiple near-term catalysts, we have a slew of data coming off of the COVID platform, which we call coral. Over the next six months or so, we have some phase two data with our off-the-shelf KRAS-directed neoantigen program in the middle of 2022. And then we have important randomized data from colorectal cancer expected in mid-2023. So catalysts come across the different elements of our platform. And we finished the third quarter of this year with around $216 million of cash on the balance sheet.
So these are the two core platforms. As I mentioned, understanding what T cells recognize is critical, but it’s complicated. Antibodies recognize whole proteins. So they’re pretty easy. If you think about identifying antigens within SARS CoV. Two, we all knew that spike was the surface protein on the outside of the virus, which is the target of neutralizing antibodies. So when you make vaccines, you encode a full-length spike in the vaccine, when the cells are transduced. By the vaccine, they then expressed spike that is the antigen of interest to the antibody side of the immune system. T cells are different, they complement antibodies. And as you know, antibodies are designed to try and neutralize the virus before it gets to cells. But if the virus bypasses antibodies and gets through it, then enters cells, and once inside the cell, it’s invisible to the antibodies and to the antibody side of the immune system. And this is where cytotoxic T cells kick in, and they’re designed to recognize virally infected cells and kill them. So you can see these two halves of the immune system do operate in concert. Now interestingly, the way T cells recognize virally infected cells is not through recognition of whole protein, but through recognition of short protein, fragments displayed as peptides on the surface of the cell. By these highly variable HLA molecules act as a platform for peptide presentation. Figuring out which bit of a virus will be displayed by which HLA molecule is not an easy task, but this is where edge or prediction platform helps We’ve developed it as well for oncology, where we tried to predict which of the many mutations in a tumor will function as mutant peptides displayed on the surface of the tumor cell, the so-called famous Neoantigens. So edge helps us with the identification of these T cell epitopes, which is critical when you’re developing vaccines, intending to elicit a T cell response. But as I say, of course, the vectors matter, the adenovirus is probably the best vector for generating CDA T cells. Currently, there is no equal very strong priming of a CDA response, self-amplifying RNA, and mRNA. Very good at making antibodies, it seems obviously mRNA has been validated in humans, we’re doing that work right now. But we’ve certainly seen good data in nonhuman primates. But the T-cell effects of the RNA vaccines are not as good as adenovirus and leave something to be desired. And that’s why sometimes you may want to have both of these platforms at your disposal. And I’ll go into that in a little more detail. As we dig into the pipeline. Our pipeline now has four trials against a COVID-19, currently running to about to begin imminently. And I’ll go through the specifics of those shortly. We have obviously collaborated with Gilead in the field of HIV. I won’t speak more about that, because that’s not really our story to tell. And in oncology, we’re wrapping up our phase one to first in human studies. And now launching phase two trials. The personalized granite program is entering these randomized phase two studies in early colorectal cancer, metastatic colorectal cancer first line, and also an adjuvant study. And then with our off-the-shelf slate part platform. We’re currently in phase two studies in patients with mutant K RAS who have colorectal or lung cancers. So more data, as I mentioned, coming soon off of the SLATE platform in particular. Okay, let’s drill a layer down into infectious disease. So as I’ve mentioned, antibodies provide the first layer of defense to neutralize the incoming virus, but often virus will get past and enter cells, and then you rely on your CDA T cells to kill those virally infected cells. And very much you should think of these two as acting as partners. And the natural immune response to a viral infection is to deploy both of these arms of the immune system. The first-generation vaccines are very good at making antibodies against spike. But as we’re seeing the protection doesn’t seem to be terribly durable. And we, unfortunately, are seeing now that something like a quarter of hospitalizations in many places are now in fully vaccinated subjects. So the immune response that’s been generated by the first generation of vaccines, while clearly very good, and we’re all grateful for it is not providing complete protection. It’s not durable, and it is not keeping people out of hospital now as effectively as we would like. And of course, if further spike variants come along, then we’re really going to be concerned that they might change the sequence of Spike reduce the affinity of neutralizing antibodies generated by the first vaccines, and then we might be in a whole different situation. So how can we improve on the first-generation vaccines? The obvious idea is to broaden the antigenic substrate and to provide not just spike but additional antigens, particularly enabling the T cells, the cytotoxic CDA T cells to play a more active role. And the cytotoxic T cells are believed generally to have a longer memory than antibodies. And so their hope is that by broadening the antigenic diversity of the vaccine, and by engaging not just antibodies, but more fully engaging CDA T cells, we may be able to drive to superior, more durable clinical protection that is insensitive or relatively insensitive to spike sequence variation. So that’s the therapeutic hypothesis. And therefore, we’ve designed a vaccine that unlike the first generation doesn’t just have spike, but has spike plus additional regions of other genes from within SARS CoV. Two, particularly nucleocapsid, and all three A and these genes and the regions we pick from are conserved across variants of SARS CoV. Two, and some of these regions are conserved actually across multiple members of the Coronavirus family. So this obviously is starting to give us an angle into the notion of a pan Coronavirus vaccine, which we can maybe talk about later.
We’ve taken these products into nonhuman primates. So we’ve had these data in the public domain for a while. Here we’re using what is referred to as a heterologous prime-boost system. I’m only going to show you primate data mice are really not very meaningful in terms of their immune responses, particularly T cells. So I’m going to show you nonhuman primate data only. So here we’re priming with the adenovirus containing spike, boosting with a self-amplifying product or sound, you can see very nice overall antibody responses to spike on the left. And if you then focus on the important neutralizing antibodies, these are measured using a standard pseudovirus neutralization assay, you can see with we’re getting very nice neutralizing antibody titers, which clearly exceed those observed in convalescent humans. And increasingly, I think the assays are becoming relatively standardized. And generally, folks feel that if your titer is over 100, or 10, to the to, obviously, on this logarithmic assay access, then you’re into the protective zone. So being up at around 1000, or 10 to three is a very good place to be.
Now, T cells that do matter, you can’t interrogate monkeys quite as well, because we design the epitopes with the human HLA in mind, again, remember, T cells recognize peptides presented by these HLA molecules, monkeys have a whole different system, they don’t have human HLA. So you can’t really interrogate the nuances of T cell responses. But at a crude level, just looking at Spike, you can see we get nice T cell responses to multiple regions of the spike protein in these monkeys. And these are obviously good strong responses, up over 1000 in a very standard ex vivo ELISpot assay. Now, these are data from a manuscript that we pre-published on Bio Archive just last week. And these data come from an NIH-funded challenge study again, in rhesus macaques, very similar to the studies published by Maderna, and BioNTech. So you can look at these four drive comparisons. These are not direct head-to-head studies, but the assays and the experimental systems are very, very analogous. And what you can see just here is that whether we’re giving a single dose of the adenovirus that’s shown on the left, a heterologous, prime and boost with Chad followed by the sound that’s in the green, or just the SAML, learn in a homologous prime-boost, at three different dose levels, 3010 and three micrograms, you can see that we’re generating very nice neutralizing antibody titers. And that’s true whether you measure using pseudovirus or actually a live virus neutralization assay, which is shown on the right, the live virus assays have to be run in high biosafety level four facilities, which are few and far between and very expensive. So a lot of folks these days use the pseudovirus assays for day-to-day work, it’s important to show that these assays do correlate very closely. And that correlation is tight. And as shown in the manuscript. I’m not showing the slide here, because it’s a bit complex to kind of see in a brief visual form that the challenge of with viruses done. And then we showed that our vaccinated monkeys recover more rapidly from viral infection than the control animals and the overall magnitude of antibody response. And the recovery looks very analogous to what was observed by Maderna and BioNTech. And importantly, we see this at 10 microgram level. And it’s worth comparing that with the Maderna work, where they looked at 10 micrograms and 100 micrograms. And our 10 microgram data looks pretty analogous to the 100 microgram data, which of course, is what Maderna then took into the clinic. And so we’re getting a suggestion here that dose sparing with self-amplifying RNA may be possible when we maybe can achieve with 1/10 of the dose, the same degree of least antibody generation as seen with the first-generation products. So we’ve got four trials running as I mentioned, the first one to produce human data will be a gritstone sponsored study, which is running currently in the UK. And this is a boost in elderly subjects who have received an adenovirus prime. So primary series adenovirus with AstraZeneca. And then after a minimum of four months, we’re giving a single boost with our Sam and we’ll be looking at antibody and T cell responses. And we’ll have early data from the first dose cohort at the beginning of next year. The NIH study is ongoing, we have less control over that and it’s taken a bit of time with some protocol amendments, as it converted from a naive study to a booster study where we anticipate data in the first half of 22. And then we’re beginning another gritstone pair of studies, one in immunocompromised subjects. This is the interesting and important group of patients who are B cell-depleted often with CD 20 antibodies who mount very poor responses to first-generation vaccines. So those patients have been given our adenovirus with the goal of driving a strong protective T cell immune response. There’s an unmet need there, there may be an accelerated approval. strategy. We’ve not yet discussed this with regulators. But clearly, there’s an unmet need, and generating a strong T cell response may be perceived to be addressing that. And then we’ve got an important study going in South Africa starting early next year. This is Sepi supported. And this will be in people who are vaccination naive. Either they’re fully naive to viruses or they’re naturally convalescent. And we’ll be exploring the benefit of our vaccine in those subjects. So lots of data coming over the next six months off of this platform. And as I said, as we look to the future, particularly thinking about T cell epitopes, many of which are highly conserved between members of the Coronavirus family. We of course are generating data that will be informative to the notion of Pam Corona vaccines.
As I mentioned, our collaboration with Gilead is in the field of HIV. There are exclusive partners there. And hopefully, we’ll be starting phase one studies soon, with the platform as part of their HIV cure program. We received $60 million at the beginning of this year associated with the launch of this collaboration. And obviously, there are further milestones down the road. But we will not speak about this further. This is Gilead, sir partnership to speak publicly. Okay, let’s change gears and think about taking these technologies into the field of cancer, actually, where we began and new antigens are now very well-validated as being the best targets for a generation of strong adaptive immune responses because of course, they are regarded as foreign by your immune system. They are mutation-derived peptides, the sequence is different from your normal proteins, and therefore your immune system regards them as foreign. And so the therapeutic hypothesis here is that, of course, we’ve seen really wonderful immune responses and clinical benefit from checkpoint inhibitors in patients who have hot tumors at baseline, often manifest by high mutational burden, infiltrating CDA T cells, high PDL one, there’s a high overlap between those three different metrics. And these are the patients who tend to do well, just from receiving checkpoint inhibitors. But sadly, the majority of patients with solid tumors do not respond just to checkpoint inhibitors. And the thesis is that the reason they don’t respond is that their immune system is ignorant of the existence of their tumor, the tumor has successfully hidden from the adaptive immune system. And these patients perhaps just don’t have T cells that recognize the Neoantigens, their immune system has not been primed. And so if you give them a nonspecific T cells stimulant, there are no T cells to stimulate, to make grow. And therefore the worst you can do is just generate autoimmunity. So our thesis is to engage in these patients with Neoantigens in a vaccine, priming an immune response in a lymph node far from the immunosuppressive tumor microenvironment generate the foot soldiers of the immune system in that lymph node, where we hope they will then leave traffic through the blood into the tumor and start killing tumor cells enabled and amplified, perhaps by the addition of concomitant checkpoint inhibitors. So that’s the hypothesis we’re pursuing. We use that adenovirus to prime this very strong CDA response, which is probably critical here. And then we boost with self-amplifying RNA. We have two product classes, granites, which is the personalized product. This really is a flagship product, it’s obviously a little harder to make. But each patient then receives multiple candidate Neo antigens specific to them, because most Neoantigens are unique to the individual patient. And we’ve got some data that we just showed at ESMO, which I’ll share with you in a moment. Very exciting data suggesting that indeed, we’re doing exactly what we intended driving a strong CDA response to personalized Neoantigens, and those then kill tumor cells and drive long-term clinical benefit for those patients. I’ll show you some data highlights in a second. Of course, there’s interest in an off-the-shelf product, and we’re pioneering this in the field of K RAS mutations, which are common, about 10 to 15% of lung or colon cancer patients possess a shared Neo antigen of K RAS mutant form. And these are patients at the center of the slate program. I’ll show you their data in a second.
So we presented the edge as I mentioned it ESMO from phase one to study in advanced disease. So these are tough patients with very advanced disease progressed on chemotherapy, really running out of options. So these are not great patients for vaccines because of course, healthy patients with good immune systems are what we ideally would like. But nonetheless, this is where you begin. Everybody gets prime with the adenovirus everybody gets monthly boosts with the self-amplifying arms We did a dose escalation of the self-amplifying RNA because this was first inhuman. And then everybody gets systemic nivolumab. And we introduced subcutaneous low dose ipilimumab at the vaccination site to try and drive CTLA four blockade in the vaccine draining lymph node, which is probably where you want the CTLA four blockade rather than systemically. So that was phase one. And we expanded in a small number of cohorts, going to focus on colorectal where we saw the clear signal. And it’s clear because checkpoints really don’t do anything in microsatellite stable colorectal cancer. So any signal there can reasonably be attributed to the vaccine. We treated a bunch of patients, roughly half of them were MSS, microsatellite, stable, colorectal, and some gastric cancers. We saw no dis dose-limiting toxicities. The common adverse events were injection site reactions, and low-grade fever, all transient as you would expect with potent vaccines. The patients we’re treating clearly have cold tumors, they’re TMB low, they’re PDL one low, they’re interferon-gamma expression low. And so these are the patients that you least expect to respond to checkpoint inhibitors. Nonetheless, we see very nice Neo antigen-specific T cell responses. So on the left for the baseline blood draws, you find very little in the blood in terms of CDH recognizing those new antigens, and we then see strong and consistent induction on the right, I will make a parenthetical note, we now have moved to use the lower doses of Sam, we think we were probably overdoing the SAM, which appears to have a bell-shaped dose-response curve. So as we move forward, we’re actually giving lower doses of Sam interestingly,
but you can see his strong and consistent neoantigen-specific CDH induction. And in the patients with microsatellite stable colorectal cancer, nearly half of those retreated. And of course, these are small numbers. And this is not a randomized study. But nonetheless, half of the patients we’re treating are having molecular responses, meaning their CT DNA declined by at least 50%. And that correlated with the prolonged stable disease per resist, or I resist, I should say. And interestingly, it looks like that’s correlating with extended overall survival. These third-line colorectal patients typically die at around six months. It’s reproducibly, grim, and expected that that survival is so very short. And indeed, our patients who did not have molecular responses progressed and died at the expected six or seven-month time point. The patients who did have molecular responses are all doing very well apart from one patient, who continued to receive irinotecan and sadly died from neutropenic sepsis. So that was not a cancer death in the dotted lines on the right there that was related to continued irinotecan. So we’re seeing this very early suggestion, the molecular response is associated with very good clinical outcome, as manifested by the endpoint that matters survival. So again, very early signals, but obviously very interesting, particularly to these patients. Here’s just a quick example. One of these patients with a very typical color of actual cancer presents with detectable mutant tumor DNA. So circulating tumor DNA that we’re tracking on the left, these are all the mutations followed over time, in the middle of the 20 that we put into the new antigen vaccine. And you can see that she has this initial blip, which we see reproducibly now and looks to be a wave of tumor lysis tumor cells releasing their CT DNA, or releasing their DNA that’s then measured, and then it goes down and this patient had a complete molecular response that lasted for nearly a year. And then very interestingly, she developed new mutations in tap one, this is a protein that traffics peptides from the cytosol into the endoplasmic reticulum where it’s loaded onto HLA molecules. So this apparent resistance mechanism, this acquired resistance mechanism would explain the apparent emergence of acquired resistance. At around a year, this patient developed a new radiologic lesion at around 15 months. Although you can see that from the blood, unfortunately, we were expecting that at around the from a year onwards. This is the radiology of that patient. She had multiple lung nodules and you can see they expanded that week eight. This looks like the now well-described pseudoprogression, presumably T cells coming into the lesion, meeting antigen and proliferating. And then very slowly over the course of that year, these lung lesions then disappeared. She had a couple of liver lesions, one of which didn’t really change the size, which is why she was not a recessed responder, but we’re really defocusing from recessed it’s hard To interpret resist when you’re trying to make cells proliferate in lesions, so survival and the molecular response I think are going to be much more informative. We’ve now begun this randomized Phase Two in the setting of newly diagnosed metastatic disease, where patients get FOLFOX Bev induction chemo and then randomization they receive either just five FQ Bev which is standard maintenance therapy from four to six months onwards or they get five a few Bev plus immunotherapy. The randomized phase two is the open-label primary endpoint is the molecular response. We anticipate data in mid 23. We also have a study in the adjuvant setting in patients with even earlier stage two-three disease who are undergoing attempted curative surgery but have measurable CT DNA, which means you know, they’re going to recur, and those are patients obviously, who have a high need of additional therapy.
Now, very briefly, on the sleep program, you have to have the right mutation and the right HLA allele. As I said, that’s around 10 to 15% of lung and colon cancer. We’ve done phase one work with the first version of this product, half the patients who had lung cancer had progressed on prior checkpoints. The toxicities were again as seen within Granite, largely injection site reactions and transient fever. And again, in lung cancer patients, we see around half of them have molecular responses that then correlate with radiologic benefit and stable disease. And here is a nice example actually of a patient who blew through Pembo chemo. So this is a KRAS mutant patient g 12. C, who progressed on Pember chemo in three months, came on to our study at the beginning of this year and had a very nice, molecular and radiologic response. But sadly, at around five months, his very aggressive disease recurred in the spine, where he already had some baseline disease. And so this response was not confirmed at a radiologic level. But nonetheless, I think clear evidence here that even in this very aggressive form of the disease, we’re impacting his disease beneficially, as you can see here, both molecularly and radiologically. So we’ve improved the product, we’ve removed some non-KRAS Neo antigens that we think we’re actually immunodominant. And you can see on the left that in transgenic mice, this modified form version two, as we call it, is driving a dramatically stronger T cell response to some of these key K wrasse, Neoantigens. And this has gone back into humans with lung and colorectal cancer. And these are the patients will have data on in the middle of next year. Importantly, we make all of our own products, manufacturing has become a strategic asset in this field. So we make our own. And as I say, We’re well set now with cash will comfortably through towards the end of 2023. With a lot of catalysts coming up both from the infectious disease and from the oncology programs. With that, let me hand it back to you, Ben. Thank
you. Fantastic, great presentation. Again, if anyone has any questions, submit those to the dashboard or email me. Quick question for you. While we wait. You mentioned that there was a bell-shaped curve in response to this, Sam, I think you’re talking about this thing the Greystone College,
Dr. Andrew Allen (GRTS CEO)
self, I’m flying RNA. That’s right.
What if you could offer more color on that? Like, why is that the case?
Dr. Andrew Allen (GRTS CEO)
Isn’t that interesting. So too little, of course, will be will have lower activity, that’s no surprise to much seems to activate the innate immune system too strongly. And in particular, we get a lot of interferon-alpha. And that seems to shut down RNA translation, which is a natural physiological response. If your cells are threatened by what they perceive to be viral RNA, foreign, double-stranded RNA, they will shut down the translation because they don’t want to make protein on the assumption that there is a virus in the media. And of course, no translation, then the RNA doesn’t turn into protein, and then there’s less immune response. And so this is where the innate immune response shuts down and attenuates the adaptive immune response. But of course, from our perspective, we want adaptive here, we’re trying to generate B and T cell responses. In the case of infectious diseases B and T for cancer, it’s really just CDA T cell responses. And that’s why if you go too high, you probably actually hurt the immune response. And so you got to kind of find the sweet spot, maybe a little bit different between young and old, because generally younger people, they’re more reactor genic, and they have a good immune response at potentially a lower dose, older people may need a little bit more. So we’re very open to the notion of different doses for the young versus the older. And we’re exploring that very actively in the clean context of COVID-19 where of course, you’ve got healthy patients with a nice vaccine. So lots of exciting and important data really informative to the whole platform coming over the next few months.
So interesting. Okay, one other quick question in the last like 30 seconds we have. I guess just how much is vaccine durability like the vaccines that are approved now? Yeah. mRNA vaccine, how much is durability a function of new variants or like poor T cell immunological memory?
Dr. Andrew Allen (GRTS CEO)
I think simplistically, I think more of the latter. I think the current were wave we’re seeing where, you know, now I’m seeing that unfortunately, up to 25% of people in hospital with COVID-19 are fully vaccinated, people. That probably speaks more to the lower durability of the immune response. And that’s probably because they don’t have much of us have a CDA T cell response. Generally, antibody titers wane and if you’re relying on that, you got to have a boost. If you’ve got a strong CDA response, you probably don’t need the antibodies as much you can stay healthy, even if the title is diminished. And the current first-generation vaccines the CDA responses are modest at best. That’s really the opportunity for improvement.
Okay, fantastic. I think we’re out of time. Andrew, thank you so much.
Dr. Andrew Allen (GRTS CEO)
Great. Thanks, Ben. Cheers.