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Transcript
35 min read · 7,273 words- 0:00 – 0:59
Intro
- SBStéphane Bancel
It's the first time there is a cancer vaccine working. The field has been doing that for 20-plus years, more than 1,000 clinical trials that have all failed.
- JCJorge Conde
What was different this time? What is it about mRNA technology that enables the immune system to learn in a way that other approaches weren't able?
- SBStéphane Bancel
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 your immune system? We're gonna basically take a biopsy of your tumor. We're gonna read all the letters of its DNA, and then we're gonna do the same things with a healthy cell of your body. And we're gonna literally compare letter by letter, nucleotide by nucleotide, and then we're gonna 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.
- JCJorge Conde
What gets regulated here? Because every dose is different, so obviously every dose doesn't get approved.
- SBStéphane Bancel
Basically-
- 0:59 – 2:48
How Moderna Went From COVID to Cancer
- JCJorge Conde
Hi, um, welcome to the a16z podcast. Uh, uh, I'm Jorge Conde, a general partner on the a16z biohealth team. I am thrilled today to welcome back Moderna CEO Stéphane Bancel. Um, for folks that have been longtime listeners may recall, uh, Stéphane joined us on the a16z podcast back in December of 2020, um, when we were talking about all of the work Moderna did to, uh, bring us the, the mRNA COVID vaccine. And at the time, um, if you can go back and listen to that episode, you'll hear, um, how quickly, um, Moderna was able to react to the existence of the virus, to analyze it, uh, to essentially print a vaccine, um, that would protect people against an, uh, against the, the, the COVID-19, uh, vaccine, and hence put us in a much better position, uh, with respect to the, to the COVID pandemic. We titled that, that episode the, "The Machine That Made the Vaccine," and the reason why we're talking again today in August 2026, uh, is because Moderna has, uh, put out news, uh, on a really big advancement on what they can do with mRNA technology when it comes to cancer. And so I wanna hand it over to you, uh, Stéphane. Uh, again, a very big welcome. Thank you for coming back. But maybe the place to start is let's, uh, let's lead with the news. Um, you, uh, Moderna and Merck, uh, announced, uh, earlier this month in August that, uh, you had, uh, uh, conducted a Phase 3 clinical trial in melanoma and have gotten, uh, very encouraging results.
- 2:48 – 5:46
The Phase 3 News: mRNA Cancer Vaccine + Keytruda in Melanoma
- JCJorge Conde
So why don't I hand it over to you, and tell us, uh, what have you announced, what have you seen in this Phase 3 trial? And then I do wanna dig in into what Moderna is doing in cancer.
- SBStéphane Bancel
Wonderful. So Jorge, thank you so much for having us back. We're very happy to be, to be with you. So indeed, uh, last week now, uh, we shared the news with our colleagues at Merck that after working 10 years on a individualized, uh, treatment against cancer using mRNA technology, that the Phase 3 was positive. It's a, it's a first of many. It's the f- first time that there is an agent in melanoma that is better than Keytruda alone, so it's a big deal for patients, of course, with melanoma. Uh, it's the first time there is a cancer vaccine working. Uh, the field, as you know, has been doing that for 20-plus years, I think more than 1,000 clinical trials that have all failed. Um, and, um, if you look at the Phase 2 data, because what we announced last week is that we met the primary endpoint of the study, which was recurrence-free survival, i.e. people having the cancer back or dying, uh, that we met. And then to our own surprise, because this was the first interim analysis, this is not the end of the study, it's the first interim analysis of the study, and what was a surprise even 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 metastasis from your primary tumor. And we also met that, uh, endpoint, which was great. Again, unexpected from our side, but again, means it is very good. Um, we will share the data very soon at a big medical oncology conference, which is, as you know, 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, uh, in the spring of 2026, a few months ago, that our Phase 2 study, which was also randomized against Keytruda alone, so the same type of study, showed that around, uh, 50% of people had recurrence-free survival versus people only getting Keytruda. And this is five years after treatment. And as you know, in oncology, five years is considered by doctor like a cure. Uh, and so it's a big, big deal. And if you look at the data from, again, that Phase 2, you had around 80% of people that were disease-free five years after their treatment and their surgery of melanoma. And so we're very excited at what it means for the field. Uh, we are working very hard already with regulators to file so the drug can be available to patients as soon as possible, and we hope in 2027, and we're gonna try to make it as fast as we can. Uh, the factory is ready in Massachusetts, but we have figured out how to make and scale a product for every human being at the s- at the time.
- 5:46 – 9:23
What Is Keytruda & Why Isn't It Enough Alone?
- JCJorge Conde
Well, there's, I mean, there's so much to, to unpack here, so I, um, this is ex- an extraordinary, uh, advance, uh, for the, the treatment of, in this case, melanoma, and hopefully over time, cancers more broadly. Uh, so let's unpack some of this if we could, Stéphane. Uh, the first one, um, uh- Uh, talk to us, uh, for folks that are less familiar with cancer treatment, uh, why is Keytruda-- what is Keytruda, and why is Keytruda alone not sufficient? Why was Moderna necessary, the, the, uh, the, this particular mRNA cancer vaccine necessary in conjunction with Keytruda?
- SBStéphane Bancel
Sure. So if you look at Keytruda, which is kind of one of the leading, uh, immunotherapy that people might have heard of, it's basically, if I oversimplify for non-biologists, it's basically a molecule that basically open the gates for letting the dogs out that are gonna go and attack your cancer, uh, from your immune system, if you want. Um, the, the thing about checkpoints is when they work, they are fantastic because those people, five years after treatment, are in a, cured in the sense they have no d- uh, remaining disease. Uh, but only 60% of people are disease-free after five years, if you look at the-
- JCJorge Conde
Mm-hmm
- SBStéphane Bancel
... Phase 3 published data of Keytruda. 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 they a lot of time come s-with very serious side effects, very different from chemotherapy or radiotherapy. The side effect of immunotherapy are mostly immune disease.
- JCJorge Conde
Mm-hmm.
- SBStéphane Bancel
So you see people, if you look at the label of the clinical studies, people that get checkpoints, whether it's Keytruda or any other type of checkpoints from other companies, they end up having type 1 diabetes, lupus, Crohn's disease, these type of things. Of course, it's better to have those disease than, of course, being dead from your cancer, which is why th-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 it's really a technology that emerged from Moderna labs back in 2015, uh, 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, uh, a mechanism of action that was totally orthogonal, so very different from immunotherapy, because you will be able to start from a sequence of your, your tumor-
- JCJorge Conde
Mm-hmm
- SBStéphane Bancel
... 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, the beauty of, about our technology is if you think about Keytruda, it basically unleash the dogs, but they go a bit randomly sometime. It's your immune system. Whereas Moderna product is abo- able, 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.
- JCJorge Conde
Okay, so now that, that's where the, the personalized cancer vaccine, um, uh, technology will make a big impact on treatment of melanoma.
- 9:23 – 11:16
Preventing the Return of Cancer: What "Vaccine" Really Means Here
- JCJorge Conde
So let, we'll come back to the personalized piece, 'cause I think that's just fascinating, not only from a technological standpoint, but just from an operational standpoint. Uh, so I do wanna come back to that. But let's focus on the word vaccine. So, you know, you know, typically, when you think of the word vaccine, uh, it is to prevent a disease. Um, here in this context, uh, these patients already have cancer. So what, in a sense, you are preventing something. You're not preventing the cancer. What you're preventing is the return of the cancer, um, which is in and of itself, uh, an extraordinary thing to think about from a, from a therapeutic intervention perspective. Um, so number one, is that, is that a fair characterization of how you-
- SBStéphane Bancel
That's a fair characterization
- JCJorge Conde
... use the word?
- SBStéphane Bancel
And the reason the field has used the word vaccine, it was not us using it, we just followed the field, as I mentioned, there's been 1,000-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.
- JCJorge Conde
Mm-hmm.
- SBStéphane Bancel
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. Uh, 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 system? So I think that's why the field use 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.
- JCJorge Conde
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, um, have, have tested
- 11:16 – 15:09
Why 20 Years and 1,000 Trials Failed Before mRNA Worked
- JCJorge Conde
this theory.
- SBStéphane Bancel
Mm.
- JCJorge Conde
They've all failed. Uh, you and, uh, Moderna and Merck have succeeded here. Um, what was different this time? What is it about mRNA technology that enables the immune system to learn in a way that other approaches, uh, were unable, uh, uh, to be successful?
- SBStéphane Bancel
Yeah. I think there's, there are two components. Uh, one is the mRNA technology, and I think the other one is the 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, uh, actually with Karolinska, as you know, the institute in Sweden that gave the Nobel Prize for Medicine back in 2015, is that with our technology, I cannot speak about other mRNA companies that have different mRNAs, different lipids, and so on, but with our technology, when we inject our mRNA in a muscle Whether it's a COVID shot or flu shot or this cancer treatment, basically the mRNA goes down to your lymph node and enters the APCs, the antigen-presenting cell, which as you know, are key component of your immune cells. And the mRNA gets inside the APCs. This we've demonstrated and proven at the time with Karolinska. And then you basically translate the message contained in the mRNA inside the APCs, inside your immune cells, and present it from within. So we 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, in the, 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 mRNA. So we think that's one very important component of, uh, immune presentation, if that makes sense. The other component is really the individualization. In the past, a lot of time people have tried with non-mRNA, i.e., protein technology or peptide, but also they tried a shared antigen. Whereas here what we said is because DNA is a disea-- sorry, cancer is a disease of DNA.
- JCJorge Conde
Mm-hmm.
- SBStéphane Bancel
What we're gonna do here, because the cost of sequencing is, have dropped so much in the last 20 years, is we're gonna basically take a biopsy of your tumor. We're gonna read all the letters of its DNA, the three gigabyte of, uh, of, of its genes, and then we're gonna do the same things with a healthy cell of your body. And we're gonna literally compare letter by letter, nucleotide by nucleotide, and then we're gonna use an algorithm to identify of your hundreds of thousands of mutation, 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 mRNA molecule, which we make in 30-ish days for you, that is injected then 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 the very specific signature of your cancer cell. And what we, we showed at ASCO and we published from a Phase 2 study, but we believe it's the same thing in the Phase 3 because it's mechanistic, is that around 90, nine zero percent of the antigen are different patient to patient. 'Cause when we started, we had no idea because, again, the field came from shared antigen. So when we started, we're like, "We have no idea. We're gonna get 2%, 5%, 90% of, of same antigen across all the patient." Actually, 90% of the antigen are different from a human to another one.
- JCJorge Conde
Wow. So the only way this can work is through personalization. Just-
- SBStéphane Bancel
We individualize.
- 15:09 – 18:48
Inside the Algorithm: How Moderna Picks the 34 Neoantigens
- SBStéphane Bancel
Exactly.
- JCJorge Conde
You know, assuming that, that carries over. Um, and so in that regard, uh, uh, you know, if you're doing, let's say, this normal to tumor comparison of, of, of, uh, of the genome, you find the differences. I'm curious how you arrive at 34 as, up to 34 as the right number. Um, I'm sure there's a very good reason for that. Um, but what is the algorithm that enables you to do that? Is this something that's proprietary to Moderna? Is this something that is known within the field? Help us understand, like, help us look into that black box.
- SBStéphane Bancel
Sure. So I'm gonna share a little bit about the black box. Not too much because there's a lot of know-how and, and things-
- JCJorge Conde
Of course
- SBStéphane Bancel
... that 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 a-and in, in oncology. And then from that starting point, we use a lot of internal data that we've generated over time. We also partner with some companies that, because they are in the diagnostic space or they are, let's say, cell therapy and other space in oncology, had access to a lot of data, a lot of T-cell mapping and so on, that were very useful for the learning. The, the thing that is interesting about the data we shared last week is this is what I consider Intratumoral version 1.0, because the algorithm from the 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 2 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 gonna be doing now that we have access to the Phase 3 patient data and samples, is to go back and mine that data to figure out why some patient responded and why some other patient did not respond, because we have access to all their blood sample, the sequence, everything. And we're gonna try to see can we improve the algorithm, uh, 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, uh, or very obviously. But the way I think about it is a bit like when we talk about AI, it's this, we always joke that the current version of AI is the worst we're gonna see in our lifetime. Well, it's exactly the same for Intratumoral, which is the current version of Intratumoral that Moderna is the worst version of Intras-intratumoral you're gonna see for the rest of medical history. And so that gave me a lot of hope, n-not only in melanoma for those 20% of patients that don't respond, but also for potentially other tumors that have been really hard in the field like, you know, uh, pancreas cancer and others where immunotherapy doesn't work. We want to be able to learn a lot about the technology using also what the field has learned in the last 10 years, 'cause the field has learned a lot, as you know. This is even not in Intratumoral 1.0. So that's why I'm so excited about what's coming next.
- JCJorge Conde
That's fantastic. So, um, looking back, uh, you and I have had-- we've known each other for a very long time. Uh, I won't depress you or me by saying how long, but for a long time.
- SBStéphane Bancel
Oh, but you, you were very young. You were in kindergarten [laughing] .
- JCJorge Conde
[laughing] So I've had the benefit of, of, of seeing the Moderna from the earliest days.
- SBStéphane Bancel
Yes.
- JCJorge Conde
And one thing that is true, that was true then, is true today, is, um, you are-- Well, first of all, you are an engineer at heart. And, um, you have, from the very, very beginning, been obsessed with process, with operations, with being efficient.
- 18:48 – 20:16
The Operational Lift of Making a Vaccine for Every Patient
- JCJorge Conde
Um, 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, a, you know, a medicine for each individual patient, precisely because in 90% of the cases, there's no overlap, uh, uh, uh, in terms of the antigens. Um, can you talk us, uh, talk-- 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, um, this product?
- SBStéphane Bancel
Sure.
- JCJorge Conde
Um, and, and let me-- Maybe, 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 CAR T-cell therapy, right? And in that case, the thing that-- And CAR T-cell therapy, for folks that may not be familiar, is this idea that you take a, you take a patient's tumor, um, and then you take the patient's immune cells, you take them out of the body, and you essentially reprogram the immune cells, um, and, and re-engineer them to be reactive to the tumor and put them back into the patient. I'm oversimplifying, of course, um, but that's, you know, CAR T-cell therapy in a, in a very sort of, uh, in a simple nutshell. In this case, you're doing, in some ways, things that are very similar, right? You're, you're taking a piece of the tumor, and that you have in the form of, of a biopsy, presumably, um, and, and, and you're trying to teach the, um-- uh, you're trying to sequence the tumor to generate a vaccine that is very specific, uh, uh, to that patient's, uh, tumor.
- 20:16 – 24:33
Vein to Vein: How Fast Can You Deliver a Personalized Vaccine?
- JCJorge Conde
How do you think about, um, 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?
- SBStéphane Bancel
Sure. So the time is around 42 days now, needle to needle, so from taking the biopsy to getting the vaccine in the hospital ready for you. I think we're gonna be able to improve that as we still have a lot of efficiencies to work on, and automations, and robotics. Uh, the place where this is very different from CAR T is that we don't have to take your immune cells, reprogram them ex vivo in a reactor in a factory-- in our factory, and send them back to your hospital. The only thing we need is the information. As you and I-
- JCJorge Conde
Yes
- SBStéphane Bancel
... talked about, the beautiful thing about mRNA, 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. Uh, and then we use that information to basically make the DNA, but now we don't make it with plasmid, um, growing E. coli or whatever. We make it all synthetic, so it's all enzymatic in liquid, in water. Then we make the, the RNA from the, 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 CAR T, for me, the analogy is the recombinant world.
- JCJorge Conde
Mm-hmm.
- SBStéphane Bancel
Where you have, you know, cells and big reactors, and you have big volumes. Because as you know, the, 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 CAR T. So it's all-- everything is big. Whereas here, because it's all in water and it's all enzymatic, meaning it just, it's very catalytic, the reactors are very, very tiny. 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 a time to even do a Phase 1 study, right? Is we shrunk everything down. So the first version of a machine that looks like a big American fridge was big, big and clunky because we told the team, "Make it good enough so you have good quality, but we're not solving 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 if the ba-- 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." 'Cause 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're done, uh, 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 term of quality, but it was not very efficient. Uh, and when we got the Phase 2 data that this was working, the first interim of Phase 2 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." I knew this was gonna 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, let's say, 2X or 10X more machines in that surface area, of course you're gonna get a bigger throughput and a much lower price on your fixed cost. And so we are obsessed about cycle time 'Cause the more, I mean, the more you can reduce cycle time, the more you can get a turnaround, let's say, in a year on your assets. And the second vector I'm obsessed about is square inches. [chuckles] Uh, literally, I'm always a pain in the butt, sorry, uh, when I go to the factory to look, you know, 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 sh-shrink things as much as you can, because it has a huge impact on cost of the product at the end of the day.
- 24:33 – 27:08
Manufacturing at Scale & the COGS Question
- JCJorge Conde
And at, um, at scale, um, how many, roughly how many, for let's say, let's just focus on melanoma.
- SBStéphane Bancel
Yeah.
- JCJorge Conde
How many doses would you need to produce in a given year to come up with-
- SBStéphane Bancel
So if you look at it, we've already got thousands of doses because of, uh, nine clinical studies that are ongoing. Uh, the facility will be able to make, the one in Marlborough, Mass, uh, tens of thousands of doses. Uh, and then as we keep improving the technology, that number is gonna go up in the same facility, and then we might need to build several other facilities. But if you look at the incidence of melanoma, if you're in the tens of thousands of doses, you're gonna cover, you're gonna f-easily the melanoma market.
- JCJorge Conde
Yeah, I, I can believe that. Um, ha-have you disclosed how you think about COGS and price, or is that something that-
- SBStéphane Bancel
We have not disclosed yet. Uh, we need first to disclose the data with our Merck colleagues. We need to engage with the payers once we can share the data with them in term of w-what is the value being driven there, and so on. Um, but this has not been discussed yet.
- JCJorge Conde
So maybe one place to focus is, uh, on this concept of personalization. Uh, I'm sure you've seen, uh, the story of the, of the GitLab founder, uh, who went founder mode on his, on his own, uh, osteosarcoma. Um, uh, number one, uh, do the future Sids of the world, um, come to Moderna, or is, is this N-of-one phenomena something that you think will just happen and exist in parallel?
- SBStéphane Bancel
So I think they will come most of them to Moderna because it will just gonna be easier and safer. Because as you know, uh, making an injectable product always carry risk of contamination of a product. If you inject to somebody a product that has even one copy of 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 term of good manufacturing practice, kind of FDA 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, a store making high quality knives down the street, you're gonna use your time to do something else. So I think it's a bit of the same phenomena, which is like in any technology, which is when you have industrial scale, uh, of high quality product, you use your time as a human to do something else with your time, right?
- 27:08 – 29:37
How Do You Regulate a Medicine That's Different Every Time?
- JCJorge Conde
And in that world, um, how does the, how does the regulatory envir- uh, the regulatory apparatus function here? So in other words, you, you mentioned earlier, uh, you along with Merck will prepare, um, uh, a regulatory filing soon. Um, what gets regulated here? Because every dose is different, so obviously every dose doesn't get approved. Is it, is it obviously the, the, the process for synthesizing mRNA? Is it the algorithm? Is it a combination of the, the entire system? Help us, uh, understand that and build intuition around how we'd think that these kinds of personalized medicines will be regulated in the future.
- SBStéphane Bancel
Yes. So the good news is there are precedents. As you mentioned, CAR T. CAR T was also, uh, approved in the same way as we believe intysmeron will be, which is as a process BLA, uh, not a product BLA. So as you know, Moderna has five product approved, so, uh, that's really product approval. On this one, the whole process since we started in the clinic, the IND was a process IND.
- JCJorge Conde
Uh-huh.
- SBStéphane Bancel
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 control of a process so we can do safely a Phase 1 study?" So we already had that discussion just to go into the clinic years ago. And then before we started every Phase 3, we need to have a end of Phase 2 meeting and agree the design of a study, the s- 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, and we're gonna show up at their, you know, front door [chuckles] you know, in a week or two and tell them, "This is a new product." And they're gonna like, "What is this?" Uh, there's been a lot of discussion, a lot of engagement. Several time we've had technical question on the manufacturing front, uh, where we basically requested additional meetings to ask their 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 term 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 give-- If we get the same sample at the beginning, the tumor and the blood, do you get the same product make at the end of a big black box?
- JCJorge Conde
Right.
- SBStéphane Bancel
And that's what we have to demonstrate first to ourself, and then with the data to the FDA, so that we have really robustness of the whole process. So if we have the same input, we're gonna get the same output going to patient as an individualized medicine.
- 29:37 – 35:58
Beyond Melanoma: Which Cancers Are Next?
- JCJorge Conde
How do we think about, uh, moving beyond, or how do you all think about moving beyond melanoma? Uh, is this an approach that's going to be, uh, applicable to a broad range of cancers? Are there cancers that are much more likely where this is going to be a viable, uh, option versus others? Uh, and sort of what's your, uh, I'll use the word, what's the ambition here for where, uh, cancer vaccines can, can have an impact?
- SBStéphane Bancel
So the ambition is pretty big because we believe we have demonstrated, at least to ourselves and we hope to the world, there's always will be skeptics, but that's, that's always true, um, that We are able to create an edu-- a de novo education of T-cell. And this, we showed it even at ASCO this year, where we took the blood before treatment, after treatment of cancer patients, melanoma with our technology, and we showed that don't think we have an expansion of the T-cells, but we have de novos and new T-cells being created that recognize what we code in the mRNA 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 Moderna's mRNA 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 are going after in term 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 three study. So what we are doing is we are going first everywhere where Keytruda works because, as I told you, we believe the mechanism of action of a PD-1 and Moderna's Intratumoral 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. Uh, we are in phase two for kidney cancer, bladder cancer. So we have a whole slew of studies ongoing where the world knows that Keytruda works because Keytruda has been approved there. And we believe you're gonna see a material improvement versus Keytruda alone. Before you run the clinical experiment, it's impossible to know are you gonna get fifty percent like we saw in the phase two of melanoma, or you're gonna get thirty percent or forty percent 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 three study for patients with stage one lung cancer. But as Intratumoral, so Moderna's product, as a monotherapy without checkpoint.
- JCJorge Conde
Wow.
- SBStéphane Bancel
And we are doing that because we believe when you go early in disease, checkpoints are not used because of the side effect that they bring.
- JCJorge Conde
Mm-hmm.
- SBStéphane Bancel
'Cause if you have stage one cancer, the medical field thinks it's worth monitoring your cancer versus giving you a checkpoint because not everybody's gonna respond, but everybody's gonna get pretty serious lifelong side effects like autoimmune disease. But what if you could have an mRNA made for cancer patient that has lung disease stage one, y- 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 gonna go from not seeing the cancer to seeing the cancer. Uh, and then the idea is do you do a surgery, which is to the side of care, and you give Intratumoral monotherapy, which the side effect is similar to a vaccine. You know, you might, you might be feel tired for a day, but that's it. So in cancer, it's a pretty cool type of side effect, right? Uh, and that's another approach we have in term of clinical studies, uh, 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.
- JCJorge Conde
Mm-hmm.
- SBStéphane Bancel
Uh, but because the mechanism of action is different from a checkpoint, we and Merck, uh, 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 Keytruda 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 a proof 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, uh, Revolution Medicines had a wonderful new medicine approved, uh, for pancreas cancer using the KRAS mutation. What if you could combine that medicine and Intratumoral? Those are very orthogonal mechanism of action. For me, it makes no scientific sense that if Intratumoral work, and we should know soon in, in pediatric, sorry, in, in, in pancreas cancer, uh, by itself, and of course, the Revolution Medicine, uh, does great improvement of survival, uh, 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 gonna want to do. So if you think about Intratumoral, the Moderna medicine is gonna be used with Keytruda, is gonna be used early in disease with Keytruda, and it might be used in places where Keytruda does not work, uh, but with other agents.
- JCJorge Conde
Well, that, that gives a lot of, uh, reason for, I think, uh, cancer patients and their families to have a lot of hope-
- SBStéphane Bancel
Yes
- JCJorge Conde
... for the future of, of, of, of, of novel therapies in, in this field.
- SBStéphane Bancel
Yes. And, and on top of, of what we just said, remember this is Intratumoral one point zero. So what I saw is very powerful, and I'm really pushing our team, uh, to think really outside the box and to do a lot of analysis and to use AI to look at that gigantic set of data that we have, which is what are the things we can learn from the clinical studies to understand about the people that did not respond? 'Cause I think you always learn more from things that don't work than things that work. So I want to obsess about the twenty percent 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?
- 35:58 – 38:38
The Full Arc: From COVID to Cancer to Autoimmune Disease
- JCJorge Conde
Well, that's remarkable. And I, just to, just to wrap, I think, uh, it's remarkable to see how you were able to take a technology platform that originally wasn't built for a, uh, you know, a, a pandemic, uh, pointed at a pandemic- create a vaccine for millions and millions and millions of people, and essentially point it back towards, uh, treating some of the diseases that you had originally intended, uh, 10 years later, as, as you described it.
- SBStéphane Bancel
Yes, that's very remarkable. And the piece that's gonna be exciting, Jorge, maybe to close, is before the end of the year, we should have our pivotal study, so late-stage study for rare genetic disease for kids that have rare genetic disease of the liver. So it's another vertical at which we're pointing the technology. The Phase 1/2 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're pointing our M- mRNA platform is autoimmune disease. 'Cause 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 patient to treat the symptoms so they can have a higher quality of life, but it doesn't treat the root cause, and we think we might have found ways to use the immune system to treat the root cause of autoimmune disease. So there's a, still a lot of ways to point the platform, so we're quite exciting about what's, what's to come.
- JCJorge Conde
Would the theory there be that you'd have, uh, personalized autoimmune modulators? Or would this-
- SBStéphane Bancel
Yeah
- JCJorge Conde
... be more product or more process?
- SBStéphane Bancel
So we, we're doing both. So what we presented in the, in the spring was a product that would be the same for everybody. But what I'm the most excited about, which is in the lab still, is the ability to do individualized autoimmune treatment where you target directly to the immune cells that are attacking your body as self when you have an autoimmune disease, and to have 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 immune disease out. Again, it's still early days, but that's what I'm excited about today.
- JCJorge Conde
Well, going from infectious disease to cancer to eventually autoimmune disease, we would love to have you back on the podcast to film episode three and complete the trilogy when you're ready.
- SBStéphane Bancel
Wonderful.
- JCJorge Conde
Stéphane, thank you so much for joining us on the a16z podcast. It's always-- As always, it's great to see you.
- SBStéphane Bancel
Thanks for inviting us today.
Episode duration: 38:53
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