The a16z Show - Inside Moderna’s Personalized Cancer Vaccine

Episode Date: September 2, 2026

a16z General Partner Jorge Conde sits down with Moderna CEO Stéphane Bancel to discuss a major milestone for mRNA technology: positive Phase 3 results from Moderna and Merck’s individualized treatment for melanoma, after more than a decade of work on personalized cancer vaccines. Stéphane explains how the treatment works by sequencing an individual patient’s tumor and healthy cells, identifying the mutations most relevant to their cancer, and encoding up to 34 of them into an mRNA designed specifically for that patient. Rather than simply unleashing the immune system, the goal is to teach it exactly what to recognize and attack. They also unpack the engineering challenge of manufacturing a different medicine for every patient, how Moderna has brought the process down to roughly 42 days from biopsy to treatment, and what it would take to manufacture personalized medicines at scale. Finally, Stéphane looks beyond melanoma to lung, kidney, bladder, pancreatic, and gastric cancers, as well as Moderna’s longer-term work applying mRNA to rare genetic and autoimmune diseases.   Resources: Follow Stéphane Bancel on LinkedIn: https://www.linkedin.com/in/st%C3%A9phane-bancel-8185251/ Follow Jorge Conde on X: https://x.com/JorgeCondeBio       Stay Updated:Find a16z on YouTube: YouTubeFind a16z on XFind a16z on LinkedInListen to the a16z Show on SpotifyListen to the a16z Show on Apple PodcastsFollow our host: https://twitter.com/eriktorenberg Please note that the content here is for informational purposes only; should NOT be taken as legal, business, tax, or investment advice or be used to evaluate any investment or security; and is not directed at any investors or potential investors in any a16z fund. a16z and its affiliates may maintain investments in the companies discussed. For more details please see a16z.com/disclosures. Hosted by Simplecast, an AdsWizz company. See pcm.adswizz.com for information about our collection and use of personal data for advertising.

It's the first time there is a cancer vaccine working. The field has been doing that for 20 plus years, more than a thousand clinical trials that have all failed. What was different this time? What is it about mRNA technology that enables the immune system to learn in a way that other approaches were enabled? We all have cancer cells all the time in our body. Our immune system is very well trained to basically notice those cancer cells very early and get rid of them. But if your cancer grows, then the question is how can you reteach immune system? We're going to basically take a biopsy of your tumor.

We're going to read all the letters of its DNA. And then we're going to do the same things with the healthy cell of your body. And we're going to literally compare letter by letter nucleotide by nucleotide. And then we're going to use an algorithm to identify which one of those mutations are the most relevant. And so when this is injected in your body, it teaches the immune system the signature of your cancer cell that it missed. What gets regulated here? Because every dose is different, so obviously every dose doesn't get approved. Basically, Jorge, what that FDA wants to know.

Before Moderna's MRNA platform helped produce a COVID vaccine, the company was already working toward another goal, using mRNA to fight cancer. A decade later, that bet has reached a major milestone. A16Z general partner Jorge Condé sits down with Moderna's CEO Stefan Bancel, following positive phase three results from Moderna and Merck's individual. individualized MRNA treatment for melanoma. It's the culmination of a project Moderna has been working on for roughly a decade.

Stefan explains how Moderna takes a patient's tumor, sequences it against their healthy cells, identifies the mutations unique to that cancer, and uses that information to manufacture a personalized MRI designed to teach the immune system what to attack. And because roughly 90% of the selected antigens differ from one patient to another, personalization isn't an edge case. it's fundamental to how the treatment works.

They also get into the extraordinary operational challenge behind this. How do you manufacture thousands of different medicines, one patient at a time, quickly and reliably enough to make personalized medicine work at scale? And finally, they look at where the platform could go next, from other cancers to rare genetic and autoimmune diseases. Hi, welcome to the A16D podcast. I'm Jorge Condi, a general partner,

on the A6 and Z Bio Health team. I am thrilled today to welcome back Moderna CEO, Stefan Bancel. For folks that have been longtime listeners, may recall, Stefan joined us on the A6 and Z podcast back in December of 2020 when we were talking about

all of the work Moderna did to bring us the MRNA COVID vaccine. And at the time, if you can go back and listen to that episode, you'll hear how quickly moderna was able to react to the existence of the virus, to analyze it, to essentially print a vaccine that would protect people against the COVID-19 vaccine and hence put us in a much better position with respect to the COVID pandemic. We titled that that episode, the machine

that made the vaccine. And the reason why we're talking again today in August 2026 is because Moderna has put out news on a really big advancement on what they can do with MRNA technology when it comes to cancer. And so I want to hand it over to you, Stefan. Again, a very big welcome. Thank you for coming back. But maybe the place to start is let's lead with the news. Moderna and Merck announced earlier this month in August that you had conducted a phase three

clinical trial in melanoma and have gotten very encouraging results. So why don't I hand it over to you and tell us what have you announced, what have you seen in this phase three trial? And then I do want to dig in into what Moderna is doing in cancer. Wonderful. So Rory, thank you so much for having us back. We're very happy to be with you. So indeed, last week now, we shared the news with our colleagues at Merck that after working 10 years on the individualized treatment against cancer using a Marnet technology, that the phase three was positive. It's a first of the first of the first of, many. It's the first time that there is an agent in melanoma that is better than Ketudra alone. So it's a big deal for patients, of course, with melanoma. Here, it's a first time there is

cancer vaccine working. The field, as you know, has been doing that for 20 plus years, I think more than a thousand clinical trials that have all failed. And if you look at the phase two data, because what we announced last week is that we met the primary endpoint of a study, which was recurrence free survival, i.e. people having the cancer back or dying that we met. And then to our own surprise, because this was the first interim analysis.

This is not the end of a study. It's the first interim analysis of a study. And what was a surprise event to us is we met the secondary endpoint, which was distant metastasis free survival, which is, of course, takes more time to mature because it means that you have

distant metastases from your primary tumor. And we also met that endpoint, which was great, again, unexpected from our side, but again, means it is really good. We will share the data very soon at a big medical oncology conference, which is what the field does. But just to give you a sense, maybe to orient kind of directionally, we showed at ASCO, the big, you know, oncology conference in the spring of 2026 a few months ago, that our phase two study, which was also randomized against K2 alone, so the same type of study showed that around 50% of people had recurrence-free survival versus people only getting

ketudra. And this is five years after treatment. And as you know in oncology, five years is considered by doctor like a cure. And so it's a big, big deal. And if you look at the data from organ that phase two, you had around 80% of people that's where disease is free five years after their treatment and their surgery of melanoma. and so we are very excited of what it means for the field.

We are working very hard already with regulators to file so the drug can be available to patient as soon as possible and we hope in 2027 and then we're going to try to make it as fast as we can. The factory is ready in Massachusetts, but we have figured out how to make and scale a product for every human being at the time. I mean, there's so much to unpack here.

So this is an extraordinary advance for the treatment of, in this case, melanoma and hopefully over time, cancer sport broadly. So let's unpack some of this would be good, Stefan. The first one, for folks that are less familiar with cancer treatment, what is KTRUDA and why is KTRUDA alone not sufficient?

Why was this particular MRNA cancer vaccine necessary in conjunction with KTRUDA? Sure. So if you look at K2DRA, which is kind of one of the leading immunotherapy that people might have heard of, is basically if I oversimplified for non-biologists, it's basically a molecule that basically open the gates for letting the dogs out

that are going to go and attack your cancer from your immune system, if you want. The thing about the checkpoints is when they work, they are fantastic because those people, five years after treatment, are cured in the sense of the remaining disease. But only 60% of people

are disease free after five years. If you look at the phase three published data of Ketudra. So again, for those 60% of people, it's amazing. But it means that there's 40% of people where you go through the treatment, you're fighting for cancer, and the treatment doesn't really work for you.

And also what is difficult is those treatments are wonderful, but a lot of times come with very serious side effects. Very different from chemotherapy or radiotherapy. The side effect of immunotherapy are mostly immune disease. So you see people, if you look at the label or the clinical studies, people like get checkpoints, whether it's K2DRA or any other type of checkpoints from other companies. They end up having type one diabetes.

Bates, lupus, Crohn disease, this type of things. Of course, it's better to have those diseases than, of course, being dead from your cancer,

which is why those have become standard of care. But think about those 40% of people who don't respond to checkpoint. They get an autoimmune disease

most of the time and they don't get the benefit of a medicine. And so what we try to do with Merck and is really a technology that emerged from Moderna Labs back in 2015,

2016, when we did a partnership with Merck as we were looking for one of the best company in immunotherapy to partner and to have a complement approach. The idea that we have at the time using our infectious disease learning from our infectious disease vaccine, we learn a lot about the immune system and how MRNA interact with the immune system.

We thought we could develop a mechanism of action that was totally orthogonal, very different from immunotherapy, because he will be able to start from a sequence of your tumor so that we could design a product to basically teach. If I go back to the dog analogy, to teach those dogs what to look for, very specifically. And that's really the beauty about our technology is if you think about K2Dry, basically unleash the dogs, that they go a bit randomly sometimes. It's your immune system. Whereas my product is available at the molecular level inside your immune system

to very specifically teach your T-cell. This is what you need to look for. And that thing is actually on your cancer cell. so that those T cells go and basically attack your cancer cells. Okay, so now that's where the personalized cancer vaccine technology will make a big impact on the treatment of alinoma. We'll come back to the personalized piece because I think that's just fascinating, not only from a technological standpoint, but just from an operational standpoint.

So I do want to come back to that. But let's focus on the word vaccine. So typically when you think of the word vaccine, it is to prevent a disease. here in this context, these patients already have cancer. So in a sense, you are preventing something, and not preventing the cancer. What you're preventing is the return of the cancer, which is in and of itself an extraordinary thing

to think about from a therapeutic intervention perspective. So number one, is that a fair characterization of how you describe it? And the reason the field has used the word vaccine, it was not us using it, we just followed the field, as I mentioned, they've been a thousand plus clinical trial, is because it's about teaching your immune system. If you think about a COVID or a flu shot,

you teach your immune system before you get the virus infecting your body. Here, you teach your immune system, not about the virus, but about basically the cancer signal that your immune system missed. Because what we know today in the field is that we all have cancer cells all the time in our body, whether it's outside factors or just as you have cell replication and you have mistakes that happen that create mutation of DNA

that are cancer cells. Our immune system is very well trained to basically notice those cancer cells very early and get rid of them. But if your cancer grows, then the question is how can you reteach your immune cells? So I think that's why the field uses the word vaccine for that approach as well,

even as you said, it's a therapeutic treatment approach post-cancer. It's about the teaching of the immune system. Okay. And so as you point out, the field has tried this many times before, 1,000, on the order of 1,000 clinical trials have tested this theory. They've all failed. You and Medrenner and Merck have succeeded here.

What was different this time? What is it about MRNA technology that enables the immune system to learn in a way that other approaches were unable to be successful? Yeah, I think there are two components. one is the MRNA technology and I think the other one is individualization by designing a product for one

human at a time. So let me go through those two. On the technology of MRNA side, what we have known and published actually with Kowelinska as you know, the Institute in Sweden that gave the novel Brussels medicine back in 2015 is that with all technology,

I cannot speak about over-MRNA companies that have different amarnes, different lipids and so on. But with all technology, when we inject our MRI in the muscle, whether it's a COVID shot or flu shot or this cancer treatment, basically the MRI goes down

to your lymph node and enters the APCs, the antigen proletic cell, which, as you know, are key component of your immune cells. And the MRNN gets inside the APCs. This we've demonstrated and proven at the time with Karin's car.

And then he basically translates the message contained in the MRI inside the APCs, inside your immune cells, and present it from within. So I think it's a very important differentiation from most of the previous vaccine in cancer in the field that were made by protein or peptide that basically are made in reactors,

are injected in the patient, but they basically turn into the blood because as you know, recombinant or protein when you inject them, they just go into your blood and they turn around. So your immune system sees them, but not in the same manner from within as it's done with the MRI. So we think that's one very important component

of immune presentation, if that makes sense. The other component is really the individualization. In the past, a lot of times people have tried with non-MRNA, i.e. protein technology or peptide. But also we tried shared antigen. Whereas here what we said is because cancer is a disease of DNA. What we're going to do here because the cost of sequencing is,

have dropped so much in the last 20 years, is we're going to basically take a biopsy of your tumor. We're going to read all the letters of its DNA, the 3 gigabyte of these genes, and then we're going to do the same things with the healthy cell of your body, and we're going to literally compare letter by letter nucleotide by nucleotide, and then we're going to use an algorithm

to identify over your hundreds or thousands of mutations, which one, based on the current knowledge of the field of immunology and cancer, which one of those mutations are the most relevant. We select the 34 that we believe are the most relevant, and we stitch them together into one big amount in molecule, which we make in 30-ish days for you that is injected than in a hospital intramuscularly. And so when this is injected in your body,

basically it teaches the immune system the signature of your cancer cell that it missed, not the signature of every other patient with a shared antigen, but a very specific signature of your cancer. And so, and what we showed at ASCO and we published from our phase two study,

but we believe it's the same thing in the phase three because it's mechanistic, is that around 90, 90% of the antigen are different patient to patient. Because when we started, we had no idea because,

again, the field came from shared antigen. So when we started, we have no idea if we're going to get 2%, 5%, 90% of the same antigen across all the patient, actually, 90% of the intigen are different from a human

to another one. Wow. So the only way this can work is through personalization. We can individualize, exactly. You know, assuming that carries over. And so in that regard, you know, if you're doing, let's say, this normal to tumor comparison of the genome, you find the differences. I'm curious how you arrive at 34 as up to 34 as the right number. I'm sure there's a very good reason for that.

But what is the algorithm that enables you to do that? Is this something of proprietary to modernized, is this something that? something that is known within the field. Help us understand, help us look into that black box. Sure. So I want to share a little bit of the black box, not too much because there's a lot of know-how

and things are very confidential to us. But basically we started with, of course, what is known in the field. And so we basically use a lot of database and publication and a lot of scientists and doctors kind of best in class in immunology and in oncology. And then from that starting point, we use a lot of internal data.

that's who generated over time will also partner some companies that because they are in the diagnostic space or they are, let's say, cell therapy and other space in oncology, add access to a lot of data, a lot of T-cell mapping and so on. That's where they're very useful for the learning.

The thing that is interesting about the data we shared last week is this is what I consider in Tismaran version 1.0 because the algorithm from a phase 3 was the same from the phase 2 was the same from phase 1. But because we've been doing this for 10 years, it's a 10-year-old algorithm. So as you look at the data, it works pretty well, right? As we said about the phase two data, 80% of people are disease-free after five years.

It's amazing for those patients. But there's still 20% of patients that don't respond. And so one other thing we're going to be doing now that we have access to a phase-free patient data and samples is to go back and mine that data to figure out why some patient responded and why some of our patients did not respond because we have access to all their blood sample, the sequence, everything. And when I try to see, can we improve the algorithm?

And we will go to CFDA if we find scientific reason why we should change the algorithm to go from, let's say, 1.0 to a 2.0 algorithm and then change it. Of course, we have to do that in a very controlled way to ensure we don't lose efficacy, very obviously. But the way I think about it is when we talk about AI,

we always joke that the current version of AI is the worst we're going to see in our lifetime. Well, it's exactly the same for Intismaran, which is the current version of Intismaran that's modern. It's the worst version of Intimismerin you're going to see for the rest of medical history. And so that gave me a lot of hope, not only in melanoma for those 20% of patients that don't respond,

but also for potentially over tumors that have been really hard in the field like, you know, pancreas cancer and others where immunotherapy doesn't work. We want to be able to learn a lot about the technology. using or so what the field has learned in the last 10 years because the field has learned a lot, as you know. This is even not in Interimperon 1.0. So, so I'm so excited about what's coming next.

That's fantastic. So looking back, you and I have had, we've known each other for a very long time. I won't depress you or me by saying how long. But you were very young. You were in kindergarten. So I've had the benefit of seeing the Moderna from the earliest days. And one thing that is true, that was true then, is true today, is you are, well, first of all, you are an engineer at heart.

And you have, from the very, very beginning, been obsessed with process, with operations, with being efficient. And those things need to be absolutely true if you're going to attempt to do what you're trying to do here with personalized cancer vaccines and make a, you know, a medicine for each individual patient, precisely because in 90% of the cases, there's no overlap in terms of the antigens. Can you talk us, walk us through a bit the operational lift that is required here that you've already had to do to even run the trial, but that you would have to do

if you eventually commercialize this product. Sure. And let me, maybe one way to frame it is, I think a lot of people think about the other big personalized therapy that exists in cancer is Carty cell therapy. And in that case, the thing that in carty cell therapy for folks that may not be familiar is this idea that you take a patient's tumor and then you take the patient's immune cells,

you take them out of the body, and you essentially reprogram the immune cells and re-engineer them to be reactive to the tumor and put them back into the patient. And we're simplifying, of course, but that's, you know, cartis cell therapy in a very sort of in a simple nutshell. In this case, you're doing, in some ways, things that are very similar, right? You're taking a piece of the tumor and that you have in the form of a biopsy, presumably, and you're trying to sequence the tumor to generate a vaccine that is very specific to that patient's tumor. How do you think about essentially the vein to vein time? Like, what needs to be true from the moment you, you know, sort of see a patient and get access

to the tumor to the moment that patient receives their personalized vaccine. Sure. So the time is around 42 days now, needle to needles, from taking the biopsy to getting the vaccine in the hospital ready for you. I think we're going to be able to improve that, as we still have a lot of efficiencies to work on in automations and robotics. The place where this is very different from Carty is that we don't have to take your immune cells. we program them

in a reactor in our factory and send them back to your hospital. The only thing we need is the information. As you and I talked about the beautiful thing of our RNA it's an information molecule. And so basically what we get from the lab is the sequence of your healthy cells

and the sequence of your cancer cells. So we just get a file. And then we use that information to basically make the DNA but now we don't make it with plasmid growing e-coli or whatever, we make it all synthetic. So it's all enzymatic in liquid, in water.

Then we make the RNA from the template. Then we put the lipid around it. And because of that, and that it's a synthetic process, it's much more like small molecule than a large molecule. If you think about Carty, for me the analogy, is the recombinant world. Where you have cells and big reactors

and you have big volumes. Because as you know, the reason you have big volumes in biotech industry is if you compress the cells too much, they die. You have the same issue with CARTI. So everything is big. Whereas here, because it's all in water and it's all enzymatic, meaning it's very catalytic, the reactors are very, very time.

And so what we've been doing since before the clinic, because as you said, we had to start developing the technology to individualize it one human at the time to even do a phase one study, right? Is we shrunk everything down. So the first version of a machine that looks like a bit of, big American fridge was a big, big and cranky because we told the team, make it good enough so you have good quality, but we're not serving for efficiencies yet because if it doesn't work in a clinic, what's the point of wasting five years making a beautiful, amazing,

optimized robot, even bad science doesn't work, right? So we told the team, make it good so that we have no quality issue and we don't have a false experiment, a false negative in the clinic, because it would be terrible for patients if you build a robot kind of working but not working, you run the study and it tells you the science doesn't work and you don't if it should have worked, right? That would be a disaster for humanity, obviously. And so the team did exactly that. They developed a robot that was good in terms of quality, but it was not very efficient. And when we got the phase two data that this was working, the first in term of phase two data at only two years.

Now we have five years of data maturing beautifully for duration of efficacy. we told the team, okay, now we are behind and knew this was going to happen in case of success, which is a happy problem. And so we dedicated a lot of very smart engineers to think about, okay, now how do you make a very efficient machine that you can compress even the volume of a machine

because one of the important vector, of course, is time, as you mentioned, cycle time from needle to needle, but also cost. And so one way to reduce the cost is reduce the footprint on the floor. Because if you have a fixed envelope of a clean room facility and you can put

as a 2x or 10x more machines in that surface area. Of course you're going to get a bigger throughput and a much lower price on your fixed cost. And so we are obsessed about cycle time because the more, you mean more you can reduce cycle time,

the more you can get a turnaround in a year on your asset. And the second vector I'm obsessed about is square inches. Literally, I'm always a pain about when I go to the factory to look at all the space we can save, how we can be creative,

how even we can move some compute out of the clean rooms, just to shrink things as much as you can because there's a huge impact on cost of the product at the end of the day. And at scale, roughly, how many, roughly, how many, let's just focus on melanoma,

how many doses would you need to produce in a given year? So, if we've already got thousands of doses because of the nine clinical studies that are ongoing. The facility will be able to make the one in Marlboro Mass at tens of thousands of doses. And then as we keep improving the technology, that number is going to grow up in the same facility. And then we might need to build several over facilities.

But if you look at the incidence of melanoma, if you're in a tens of thousands of doses, you're going to cover easily the melanoma market. Yeah, I can believe that. Have you disclosed how you think about cogs and price, or is that something that? We have not disclosed yet. We need first to disclose the data.

We want more colleagues. We need to engage with the payers. Once we can share the data with them in terms of what is the value being driven there and so on. But this has not been discussed yet. So maybe one place to focus is on this concept of personalization. I'm sure you've seen the story of the GitLab founder who went founder mode on his own osteosarcoma.

Number one, do the future sits of the world come to Moderna? Or is this end-of-one phenomenon something that you think will just happen and exist in parallel? So I think there will come most of them to Moderna because he will just be easier and safer. Because as you know, making an injectable product always carry risk of contamination of a product.

If you inject to somebody a product that has even one copier bacteria, you might give the patient sepsis. Then you always have a question of quality because when you have a multi-step process, a mistake can happen. And of course, if it's industrialized and has been validated

in terms of good manufacturing practice, kind of FD standard, you have much less chance of this happening. So it's a bit like every tools in life, which is, you know, do you make your first knife because there's no knife store and you are in a cave and you need to feed your family. Yes, of course you make your first knife

because you have to feed your family, right? But when you have a store making high-quality knives down the street, you're going to use your time to do something else. So I think it's a bit of the same phenomenon, which is like in any technology, which is when you have industrial scale of high-quality product, you use your time as a human to do something else with your time, right? And in that world, how does the regulatory environment,

the regulatory apparatus function here. So in other words, you mentioned earlier, you along with Merck will prepare a regulatory filing soon. What gets regulated here? Because every dose is different. So obviously every dose doesn't get approved. Is it obviously the process for synthesizing MRNA? Is it the algorithm?

Is it a combination of the entire system? Help us understand that and build intuition around how we think that these kinds of persons, personalized medicines will be regulated in the future. Yes. So the good news is there are precedents. As you mentioned, Carty. Carty was also approved in the same way as we believe in this one will be, which is as a process BLA, not a product BLA. So as you know, Mondana's five product approved.

So that's really product approval. On this one, the whole process since we started in the clinic, the I&D was a process IND because we had to ask the FDA, can we go to the clinic? Do you think it's safe and do you think we have a good conference? control of a process so we can do safely a phase one study. So we already had that discussion just to go into the clinic years ago. And then before we started every phase three, we need to have end of phase two meeting and agree with a design of a study, the manufacturing protocol with the FDA.

So those discussions have happened for years. And so it's not like we have not talked to FDA for the last 10 years. I'm going to show up at their, you know, front door in a week or two and tell them this is a new product. And they're going to like, why is this? there's been a lot of discussion, a lot of engagement. Several times we've had technical question on the manufacturing front where we basically requested additional meetings to ask the guidance, to also educate them on the technology, what we've learned and so on.

So there's already been a lot of discussions, and there's a very clear regulatory pathway in terms of approving the entire process. Basically, Jorge, what the FDA wants to know, which is very legitimate, which I would want for my own family's sake, obviously, which is if you get the same sample at the beginning, the tumor and the blood, do you get the same product made at the end of a big black box? And that's what we have to demonstrate first to ourselves,

and then with the data to VFDA, so that we have really robustness of the whole process. So if we have the same input, we're going to get the same output going to patient as an individualized medicine. How do we think about moving beyond, or how do you all think about moving beyond melanoma. Is this an approach that's going to be applicable to a broad range of cancers?

Are there cancers that are much more likely where this is going to be a viable option versus others? And sort of what's your, I'll use the word, what's the ambition here for where cancer vaccines can have an impact? So the issue is pretty big because we believe we have demonstrated at least to ourselves and we hope to the world. There's always, we'll be skeptics, but that's that's always true, that we are able to create a de novo education of T-cell. And this we showed it even at ASCO this year, we took the blood before treatment,

after treatment of cancer patient, melanoma, we were technology, and we showed that I don't think we have an expansion of the T cells, but we have de novo, some new T-cells being created, that recognized what we code in the MRA that was not in the patient's body before the treatment. So we already, in my book, have proven to ourselves and to the clinical community that modern Alzheimer's technology can develop, teach the immune system to develop new T-cell

to go attack your cancer. So based on that, there are basically, I would say, three different vectors we're going after in terms of expansion from melanoma. So this study, to remind people, was a cancer patient in stage two, stage three, and stage four. that were enrolled in that phase-free study. So what we are doing is we are going first everywhere where K2DRA works. Because as I told you, we believe

the mechanism of action of a PD-1 and modern-a-intis maran are totally orthogonal. So we think these allow to have synergistic element and performance of efficacy for the patients. And so we are in phase three for lung. We are in phase two for kidney cancer, bladder cancer. So we have a whole slew of studies ongoing.

where the world knows that K2DRA works because the K2 has been approved there. And we believe you're going to see a matter of improvement versus Ketudra alone. Before you run the clinical experiment, it's impossible to know how you're going to get 50% like we saw in a phase 2 of melanoma, or you're going to get 30% or 40% or another number.

We have to run the study. So these are a lot ongoing. The second vector is to go early in disease where checkpoint work. And the best example is we announced in the spring of 2026, starting a phase-free study for patients with stage one

lung cancer. But as intismaran, so modernized product, as a monotherapy without checkpoint. And we are doing that because we believe when you go early in disease,

checkpoints are not used because of a side effect that they bring. Because if you have stage one cancer, the medical field thinks it's worth monitoring your cancer versus giving you a checkpoint

because not everybody is going to respond, but everybody is going to get pretty serious lifelong side effects, like autoimmune disease. But what if you could have an MRI made for cancer patient that has lung disease, stage one, which you can find easily with x-ray, let's say, in former smokers is the easiest target population, just screen regularly with x-ray your former smokers.

And if you do it regularly, you're going to go from not seeing the cancer to seeing the cancer. and then the idea is do you do a surgery, which is to the cell of care, and you give in Tismaran monotherapy, which the side effect is similar to a vaccine. You might feel tired for a day, but that's it. So in cancer it's a pretty cool type of side effect, right? And that's another approach we have in terms of clinical studies, where checkpoints are not available today.

The third vector is where checkpoint don't work. So, of course, it's where you have the highest risk. but because the mechanism of action is different from a checkpoint, we and Merck believe that there's a very good scientific rationale to go try. So two places we're trying right now is pancreas cancer and also gastric cancer. Those two cancer type checkpoints and catruria do not work. The clinical studies have been run in the past and they were negative.

But we think because, again, the mechanism of action is different from checkpoint. and we know now that we have approved that we can create de novo T-cell. We think it's an experiment worth running. If we have good signal, we'll think about combination, as you know, literally yesterday, you know, Revolution Medicine

had a wonderful new medicine approved for Pecklas Cancer using the Keras mutation. What if you could combine that medicine and Intismaran? Those are very orthogonal mechanism of action. For me, it makes no scientific sense that if in this man work, and we should know soon in pediatric,

sorry, in the pancreas cancer by itself, and of course the revolution medicine does great improvement of survival in pancreas cancer. If you combine those two things, we believe it should have benefit. Again, you need to run the clinical experiment to see how much. But that's the type of things we're going to want to do. So if you think about in Tismeran, the modern medicine is going to be used with a ketri-dra. It's going to be used early in disease work. cathedral and you might be used in places where cathedral doesn't work, but with overageants.

Well, that gives a lot of reason for, I think, cancer patients and their families to have a lot of hope for the future of novel therapies in this field. Yes. And on top of what we just said, remember, this is in this around 1.0. So what I saw is very powerful and I'm really pushing our team to think really outside the box and to do a lot of analysis and to use AI to look at that. Chagantic set of data that we are, which is what are the things we can learn from the clinical studies to understand about the people that did not respond? Because I think you always learn more from things that don't work and things that work. So I want to obsess about the 20% of patients that do not respond five years out.

So we can understand why they did not respond? And can we tweak anything in the algorithm or in the technology to be able to help them? Well, that's remarkable. And I, just to wrap, I think, it's remarkable to see how you were able to take a technology platform that originally wasn't built for a, you know, a pandemic, pointed at a pandemic, create a vaccine for millions and millions and millions of people, and essentially pointed back towards treating some of the diseases that you had originally intended.

Ten years later, as you described. Yeah, it's very remarkable. And the piece is going to be exciting already, maybe to close, is before the end of a year, we should have our pivotal studies or late stage study for rare genetic disease, for kids that have rare genetic disease of a liver. So it's another vertical at which we're pointing the technology. The phase one, two, have shown kids three years on drugs doing fantastic.

So we'll see when we get that data. And in June, we had our annual science day and we announced that the next mountain where we are pointing on MR-on-a platform is autoimmune disease. Because if you think about it, we've learned a lot for infectious disease which are, you know, mediated by the immune system. Cancer, we've just been talking a lot about immune system.

So we learned so much about the immune system that we think we have some very novel approach on how to treat the root cause of autoimmune disease, not the symptoms, which is what the pharma industry has been doing. It's, of course, very helpful to patients to treat the symptoms so we can have a higher quality of life, but it doesn't treat the root cause. And we think we might have find ways

to use the immune system to treat the symptoms, to treat the root cause of autoimmune disease. So there's still a lot of ways to point a platform. So we're quite exciting about what's to come. Would the theory there be that you'd have personalized autoimmune modulators? Or would this be more product or more process? So we're doing both. So what we presented in the spring was a product that would be the same for everybody.

But what I'm the most excited about, which is in a lab still, is the ability to do individualize autoimmune treatment where you target directly to the immune cells that are attacking your body as self when you have an autoimmune disease and who are basically part of your immune system going attacking those immune cells that are out of order so that you are able to take the symptom of the immune disease out. Again, it's still early days, but that's what I'm excited about today. Well, going from infectious disease to cancer to eventually autoimmune disease, we would love to have you back on the podcast to fill.

episode three and complete the trilogy when you're ready. Stefan, thank you so much for joining us on the A16C podcast. It's always as always, it's great to see you. And congratulations. Thanks for listening to this episode of the A16Z podcast.

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