Inside Moderna’s Personalized Cancer Vaccine

0:00Jorge Conde: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.

0:08Stephane Bancel: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?

0:18Jorge Conde: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 a 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.

0:49Jorge Conde: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?

0:57Stephane Bancel:Because every dose is different, so obviously every dose doesn't get approved.

1:00Jorge Conde:Basically, Jorge, what the FDA wants to know?

1:04Stephane Bancel: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 Conde sits down with Moderna CEO Stefan Bancel following positive phase 3 results from Moderna and Merck's 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 mRNA designed to teach the immune system what to attack.

1:47Stephane Bancel: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 A6NZ podcast. I'm Jorge Conde, a general partner on the A6NZ Bio and Health team.

2:27Stephane Bancel:I am thrilled today to welcome back Moderna CEO, Stéphane Bancel. For folks that have been long-time listeners may recall, Stéphane joined us on the A6NZ 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.

3:12Stephane Bancel:We titled 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.

4:03Jorge Conde:Wonderful, Soror. 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 an individualized treatment against cancer using mRNA technology, that the phase 3 was positive. It's 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. It's the first time there is a 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.

4:42Jorge Conde: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 metastasis 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 oncology conference in the spring of 2026, a few months ago, that our phase two study, which was also randomized against ketudra alone, so the same type of study, showed that around 50 % of people had recurrence-free survival versus people only getting ketudra.

5:58Jorge Conde:And this is five years after treatment. and as you know in oncology five years is considered by a doctor like a cure and so it's a big big deal and if you look at the data from again that phase two you have around 80 % of people that were disease free five years after their treatment and their surgery of melanoma and so we're very excited about what it means for the field 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 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.

6:38Stephane Bancel: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 support broadly. So let's unpack some of this if we could, Stefan. The first one, for folks that are less familiar with cancer treatment, what is Keytruda and why is Keytruda alone not sufficient? Why was this particular mRNA cancer vaccine necessary in conjunction with Keytruda?

7:02Jorge Conde:Sure. So if you look at Keytruda, which is kind of one of the leading immunotherapy that people might have heard of, is basically, if I oversimplify for non-biologists, it's basically a molecule that basically opens 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 checkpoints is when they work, they are fantastic because those people, five years after treatment are cured in the sense of not remaining disease. But only 60 % of people are disease-free after five years. If you look at the phase three published data of Ketudra.

7:40Jorge Conde: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 it comes with very serious side effects. Very different from chemotherapy or radiotherapy. The side effects of immunotherapy are mostly immune disease. So you see people, if you look at the label or the clinical studies, people that get checkpoints, whether it's Ketudra or any other type of checkpoints from other companies, they end up having type 1 diabetes, lupus, Crohn disease, these type of things.

8:18Jorge Conde: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 it's 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 companies 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.

8:55Jorge Conde:We learned a lot about the immune system and how mRNA interacts with the immune system. We thought we could develop 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 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 KT-dride, basically unleash the dogs, that they go a bit randomly sometimes, it's your immune system, whereas MOLA product is 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.

9:48Stephane Bancel:Okay, so now that's where the personalized cancer vaccine technology will make a big impact on treatment of melanoma. 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. You're 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.

10:28Stephane Bancel:So number one, is that a fair characterization? That's a fair characterization.

10:31Jorge Conde:And the reason the field has used the word vaccine, it was not us using it, we just followed the field, as I mentioned, in 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 the 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.

11:11Jorge Conde: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.

11:35Stephane Bancel:Okay, and so as you point out, the field has tried this many times before. 4 ,000, on the order of 1 ,000 clinical trials, have tested this theory. They've all failed. You and Moderna 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?

12:02Jorge Conde:Yeah, I think there are two components. 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, actually with Karolinska, as you know, the institute in Sweden that gave the Nobel Prize for Medicine back in 2015, is that with all technology, I cannot speak about other mRNA companies that have different mRNAs, different lipids, and so on. But with all technology, when we inject our mRNA in the 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-proxetic cell, which, as you know, are key components of your immune cells.

12:53Jorge Conde:And the mRNA gets inside the APCs. This we've demonstrated and proven at the time of Karolinska. and then it basically translates the message contained in the mRNA inside the APCs, inside your immune cells, and presented 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 that 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.

13:27Jorge Conde:So your immune system sees them, but not in the same manner from within as it's done with mRNA. 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 a 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 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 its 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.

14:22Jorge Conde: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 a field of immunology in 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.

15:02Jorge Conde:And what we showed at ASCO and we published from a 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 were like, we have no idea if we're going to get 2%, 5%, 90 % of the same antigen across all the patients. Actually, 90 % of the antigen are different from a human to another one. Wow.

15:33Stephane Bancel:So the only way this can work is through personalization.

15:35Jorge Conde:We can individualize, exactly.

15:37Stephane Bancel:Assuming that carries over. And so in that regard, 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, up to 34 is 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 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.

16:07Jorge Conde:Sure. So I want to share a little bit about 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 we 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.

16:45Jorge Conde:that were very useful for the learning. The thing that is interesting about the data we shared last week is this is what I consider Intis Moran version 1.0. Because the algorithm from a phase three was the same from a phase two, was the same from a phase one. 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 three 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 samples, the sequence, everything.

17:36Jorge Conde:And we're going to try to see can we improve the algorithm and we will go to see FDA 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 a bit like 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 Intis Moran, which is the current version of Intis Moran that Moderna is the worst version of Intis Moran you're going to see for the rest of medical history.

18:11Jorge Conde: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 also 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 Intisperine 1.0. So that's why I'm so excited about what's coming next. That's fantastic.

18:40Stephane Bancel: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. Yes. 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 medicine for each individual patient precisely because in 90 % of the cases, there's no overlap in terms of the antigens.

19:34Stephane Bancel: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 CAR T cell therapy right and in that case the thing that in CAR T 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.

20:18Stephane Bancel:I'm oversimplifying, of course, but that's CAR T 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 sort of see a patient and get access to the tumor to the moment that patient receives their personalized vaccine?

20:57Jorge Conde: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 going to be able to improve that as we still have a lot of efficiencies to work on and automations and robotics. The place where this is very different from CAR-T is that we don't have to take your immune cells. we program them ex vivo 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 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 and then we use that information to basically make the DNA but now we don't make it with plasmid growing E.

21:52Jorge Conde: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. I think with CAR-T, 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 CAR T. 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 tiny.