Plain English with Derek Thompson - Can a Vaccine Cure the World’s Deadliest Cancer?

Episode Date: March 7, 2025

Cancer is not a singular disease but a category of hundreds, even thousands, of rare diseases with different molecular signatures and genetic roots. Cancer scientists are looking for a thousand perfect keys to pick a thousand stubborn locks. Today's episode is about the hardest lock of them all: pancreatic cancer. Cancer’s power lives in its camouflage. The immune system is often compared to a military search and destroy operation, with our T cells serving as the expert snipers, hunting down antigens and taking them out. But cancer kills so many of us because it looks so much like us. Pancreatic cancer is so deadly in part because it's expert at hiding itself from the immune system. Now, here’s the good news. This might be the brightest moment for progress in  pancreatic cancer research in decades—and possibly ever. In the past few years, scientists have developed new drugs that target the key gene mutation responsible for out of control cell growth. Recently, a team of scientists at Oregon Health and Science University claimed to have developed a blood test that is 85 percent accurate at early-stage detection of pancreatic cancer, which is absolutely critical given how advanced the cancer is by the time it’s typically caught. And last month, a research center at Memorial Sloan Kettering published a truly extraordinary paper. Using mRNA technology similar to the COVID vaccines, a team of scientists designed a personalized therapy to buff up the immune systems of people with pancreatic cancer. Patients who responded to the treatment saw results that boggle the mind: 75 percent were cancer-free three years after their initial treatment. Not just alive, which would be its own minor miracle. But cancer-free. The mRNA vaccine, administered within a regimen of standard drugs, stood up to the deadliest cancer of them all and won. Today’s guest is the head of that research center, the surgical oncologist Vinod Balachandran. The concept of a personalized cancer vaccine is still unproven at scale. But if it works, the potential is enormous. But again: Cancer does not exist, as a singular disease. Cancer is a category of rare diseases, many of which are exquisitely specific to the molecular mosaic of the patient. Cancers are personal. Perhaps in a few years, our cures for cancers will be equally personalized. If you have questions, observations, or ideas for future episodes, email us at [e-mail]. Host: Derek Thompson Guest: Vinod Balachandran Producer: Devon Baroldi Links:  Cancer Vaccine paper: https://www.nature.com/articles/s41586-024-08508-4 P.S. Derek wrote a new book! It’s called 'Abundance,' and it’s about an optimistic vision for politics, science, and technology that gets America building again. Buy it here: https://www.simonandschuster.com/books/Abundance/Ezra-Klein/9781668023488 Plus: If you live in Seattle, Atlanta, or the Raleigh-Durham-Chapel Hill area, Derek is coming your way in March! See him live at book events in your city. Tickets here: The Abundance Book Tour Learn more about your ad choices. Visit podcastchoices.com/adchoices

Hey, it's Bill Simmons letting you know that we are covering the White Lotus on the Prestige TV podcast and the Ringer TV YouTube channel every Sunday night this season with Mallory Rubin and Joanna Robinson. Also, on Wednesdays, Rob Mahoney and I will be sort of diving deep into theories and listener questions. So you can watch that on the Ringer YouTube channel and also on the Spotify app. Subscribe to the Prestige podcast feed. Subscribe to the Ringer TV YouTube channel. And don't forget, you can also watch these podcasts on Spotify. Spotify. White Lotus. Let's go. Hey, folks. First, a programming note. I'm going to be on the road traveling around the country

talking about abundance, the book I co-wrote with Ezra Klein, for much of the month of March and April, will be in New York City, then Cambridge, D.C., L.A., Silicon Valley, San Francisco, Seattle, Chicago, Atlanta, Chapel Hill, and then back to New York with maybe a couple of book events added throughout the spring and early summer. I'm incredibly excited for this book to be live in the world. I'm incredibly excited to talk about this book. We're going to include a link to the Simon Schuster Abundance Tour in the episode notes. What this means, though, for the show is that I'm just going to be really busy for the next five weeks. So we're going to reduce the frequency of plain English episodes to once a week through about the middle of April. I expect that

around then I'll be able to have time to do two shows a week because I love doing the show. So wanted to make sure that you knew we're going down to about one episode a week for the next few weeks as I go around the country to talk about abundance. And if you're in, especially Atlanta, Chapel Hill, Seattle, Chicago, New York, I know that there are a few tickets left in those cities. We would love to see you there. Today, a landmark cancer vaccine and the race to solve one of the hardest problems in science. There is no such thing as a disease called cancer. Because cancer is not a disease, singular.

It's not COVID or measles. Cancer is a category, an umbrella term covering hundreds and possibly thousands of what are better thought of as rare diseases. Take, for example, the thing we call lung cancer. lung cancer as a category is very common. But there are at least 100 distinct types of lung cancer, each unique in their molecular identity, proteins, or genetic mutations. It's sometimes said that the world is waiting on the cure for cancer, but this sentiment

is off by one letter. The world is waiting on the cures for cancers. We are waiting on a thousand to present. keys to pick a thousand stubborn locks. And today's episode is about the hardest lock of them all. Pancreatic cancer. I will never forget the sunny Sunday morning in 2012 when I went out to brunch with my parents in Washington, D.C. I was 25 years old, and my mom, who was pretty much the cheeriest person in the world, was in a quiet and concerned mood. She'd been dealing with stomach pains that wouldn't go away.

And her doctor had just run tests for several serious conditions. A few weeks later, she called me to deliver the news. A tumor on her pancreas. Cancer. Not operable. You have to promise me one thing, she said. You will not look up the survival rate for pancreatic cancer. When we hung up the phone, obviously I looked up the survival rate.

Nine and ten people diagnosed with this disease die within the next five years. Most die much sooner. And within 18 months, my mom is gone. Cancer's power lives in its camouflage, its subterfuge. The immune system is often compared to a military search and destroy operation, with our T-cells serving as something like expert snipers, hunting down antigens and seeking them out. But cancer kills so many of us because it looks so much like us.

In his book, The Song of the Cell, Siddhartha Mukherjee says that what makes cancers so hard to treat is their invisibility. Quote, the proteins that cancer cells make are, with a few exceptions, the same ones made by normal cells, except cancer cells distort the function of these proteins and hijack the cells toward malignant growth. this double-headed problem, cancer's kinship to the self and its invisibility is the oncologist's nemesis. To attack a cancer, one has to first make it re-visible, to coin a word, to the immune system.

In this way, pancreatic cancer is the invisible emperor of all maladies. Almost no other disease is so good at hiding itself from the immune system for so long. Now here's the good news. This might be the brightest moment for progress in pancreatic cancer research in decades and possibly ever. In the last few years, scientists have developed new drugs that target the key gene mutation responsible for out-of-control cell growth. Recently, a team of scientists at Oregon Health and Science University claimed to have developed a blood test that is 85% accurate at early stage detection of pancreatic cancer.

This is absolutely critical given how advanced the cancer typically is by the time it's caught. And last month, a research center at Memorial Sloan Kettering published a truly extraordinary paper using MRNA technology similar to the COVID vaccines, a team of scientists designed a personalized therapy to buff up the immune. systems of people with pancreatic cancer. Patients who responded to this treatment, this cancer vaccine, saw results that boggled the mind. 75% of the responders were cancer-free three years after their initial treatment.

Not just alive, mind you, which would be its own minor miracle, but cancer-free. The vaccine administered within a regimen of standard drugs stood up to the deadly cancer of them all and seem to have won. And today's guest is the head of that research center, the surgical oncologist Vinod Balasandran. The concept of a personalized cancer vaccine is still unproven at scale. But if it works, the potential is enormous. Because again, cancer does not exist as a singular disease.

Cancer is a category of rare diseases. many of which are exquisitely specific to the molecular mosaic of the patient. Cancers are personal. And perhaps in a few years, our cures for cancers will be equally personalized. I'm Derek Thompson. This is plain English. Vinod Balasandran, welcome to the show. Thanks for having me, Derek.

I'd love you to help me understand why pancreatic cancer is so low. lethal from the perspective of an oncologist. So we have thrown billions and billions of dollars into cancer research and clinical trials, and pancreatic cancer deaths are just going up. Why has the scientific cavalry fail to make a dent in this cancer? As you know, pancreatic cancer is now the second leading cause of cancer death in the United States. So more cancer deaths from pancreatic cancer than many of the other common cancers, such as breast cancer, prostate cancer, ovarian cancer, melanoma, second only to lung cancer. Their survival rates for pancreatic cancer in 2025 remain only approximately 10% at five years with our best current treatments, which include

surgery, chemotherapy, and radiation. And one of the challenges is that the challenge is that has been that we've had over the past several decades many waves of improvements in oncology with waves of oncology drugs, starting with the chemotherapies and following that, the targeted therapies and more recently the immune therapies. And all of these drugs have had greater impact on many of these other more common cancers leading to improvements in outcome. but I think less so for pancreatic cancer. Let's tell this story then. In oncology, you have these waves of treatment, as you describe them,

chemotherapy, then targeted therapy, then immunotherapy. I think most people know about chemotherapy, but pick up the story there. What is targeted therapy and immunotherapy, and how have those frontiers failed in the quest to take on pancreatic cancer? after chemotherapy is the next wave of therapies that led to improvements in outcomes for cancer patients with targeted therapies. So this idea that cancers arise from a break in the DNA or a mutation, and this mutation causes a normal cell to become cancerous and then start dividing and

replicating uncontrollably. So if you can develop a medicine that selectively blocks the proteins made by this mutation, you can selectively block or kill the cancer cell without affecting the normal cells and thereby having less side effects. And this approach has been very successful in many other cancer types. In pancreatic cancer, when we try to apply this principle. One challenge was the mutation that causes pancreatic cancer to form in the first place is a mutation in this protein gene called K-RAS, which for many years has been among the more challenging genetic mutations to infect block. So when targeted therapies arose, and were making waves of improvement in other cancers,

we had still not discovered yet a way to apply targeted therapy specifically for pancreatic cancer, so we were lagging behind. After targeted therapies, the next wave of cancer treatments were focused on harnessing our own immune systems to fight cancer. And the first way scientists and physicians discovered to do this was through development of a class of drugs called immune checkpoint inhibitors. So these drugs work by boosting immune systems that recognize patients' cancers at baseline. So it's built on the premise that the immune system can recognize cancer enough, but perhaps not strong.

wrong enough in people. And by boosting these immune cells that recognize patients' cancers with drugs, you can further arm and expand the immune system to recognize patients' cancer. So supercharging your body's natural immune recognition of cancer. Now, this class of medicines were very successful in some cancers, for example, melanoma, lung cancer, but have not been successful in pancreatic cancer. Why? What makes pancreatic cancer so resistant to this type of treatment? Part of the reason for this is because some of these other cancers, the immune system is able to recognize cancer much more readily at the outset. So it happens more strongly in patients naturally.

So there are more cells there in cancers. Thus, these cells can be expanded with the drugs. If there are too few cells there to begin with, it is harder to expand them or perhaps not possible to expand them with these drugs. You in fact have to teach the immune system how to recognize the cancer first before you can in fact expand them. And that is one way we could try to do this as with vaccines. As I was reading about immunotherapy and in particular about the child,

challenge of teaching our T cells to recognize antigens, to recognize cancer as an enemy rather than a self. It seemed to me like there's this dance that's going on that I thought of a little bit like red light green light. If there's no infection in our bodies, T cells don't need to attack healthy cells, red light. If we get a virus or a bacteria and our immune system clicks on and mounts a defense, the T cells turn on, like T cells. green light. But cancer's sneaky. It can hide from the immune system, and it sometimes produces proteins that block those T cells, that turn the green light back into a red light. But these checkpoint inhibitors, they remove that block. They flip the green light back on so the T cells

can do their job and fight the cancer. Is that one way to see the game here? It's about how do we use medicine to turn on our T cells when cancer is so good at turning them off? So that analogy is correct. I would add to that by saying that in order for the checkpoint inhibitors to work, you need to have enough T cells that are green lit at the beginning. if you have just one T-cell that is greenlit versus 100,000 T-cells that are green-lit, this will make a big difference in terms of if you remove the red light breaks on 100,000 T-cells versus one T-cell. So what we are slowly learning is that these drugs, seem to have

efficacy in cancers where there is much stronger natural immune recognition of cancer. So these are cancers such as melanoma and cancer others. So for these other cancers where there could be immune recognition, it's just not strong enough at baseline.

This strategy to remove this red light break it's not really effective if there's not just enough cells there to begin with. I think this sets up our challenge nicely. Cancer is often immunologically invisible. It grows by evading the immune system, by disguising itself. And pancreatic cancer is particularly good at this disguise. So the challenge for cancer scientists here, I think, is made quite clear.

How do we make pancreatic cancer visible to the immune system? system? How do we turn on enough T cells that our bodies can mount a sustained attack in the tumors? So this brings us to cancer vaccines. What's a cancer vaccine? So cancer vaccines, as you know, have been perhaps one of the most sought-after challenges in medicine, namely, can you teach the immune system to recognize cancer? And part of the motivation for this has been because vaccines against infectious diseases, viruses, bacteria, have been perhaps the most arguably successful medicine to improve health in human history.

We also know now that the way the immune system recognizes viruses and bacteria is quite similar to how the immune system recognizes cancer. We use the same cells, the same receptor. the same molecules. So if you can do this against a virus or a bacteria, why could this not

be possible against cancer and that it theoretically should be feasible, but perhaps we just don't know how to do it yet. The central challenge here, I think, has been the

difference between teaching the immune system to recognize something that is intrinsically foreign, a virus or a bacteria, that the immune system is hardwired to recognize as foreign versus teaching the immune system to recognize something that is self-cancer, or cancer arises from our own tissues. The immune system is, in fact, hardwired to recognize, to not recognize ourselves as foreign. So to teach, the immune system to recognize cancer

as for and requires us to identify the specific proteins that are found in cancers, but not in normal tissues. And to deliver these tumor specific proteins

as antigens, or these are the key critical components that you put in vaccines to make T cells. So let's talk about your discovery, and I want to build up to last month's breakthrough slowly. Your lab studies rare survivors of pancreatic cancer. It studies them to understand how these survivors' immune systems are different. What have you found? We had found now about eight years ago by studying rare

survivors of pancreatic cancer. So these are approximately 10% of pancreatic cancer patients that received similar treatments as other pancreatic cancer patients but survive long term. What we had found in them through deep scientific analysis is that these patients are able to mount natural T-cell responses against their cancers spontaneously, and that these T-cells were contrary to the thinking at the time recognizing mutated proteins in pancreatic cancers, despite pancreatic cancers having very few mutations, which is a common feature of essentially all cancers. So this led to this idea that if natural immune responses against a mutation, a ubiquitous byproduct of cancer in pancreatic cancer could somehow impact

outcome, could you then replicate this through vaccination in other pancreatic cancer patients? If we teach their immune systems to recognize their cancers in a way similar to what's happening spontaneously in the survivors, could you generate a similar outcome? So you find these groups of super survivors, and your goal is to replicate their immune system response for other patients. Why did you try to do this through RNA vaccines? The reason why we had chosen RNA, this is actually back in 2017,

was because these antigens that these T cells were recognizing in the survivors were mutated antigens that were individual to a patient's cancer. So to vaccinate, pancreatic cancer patients and teach their immune systems to recognize their own cancers, what this meant was that vaccine would be, need to be created through individual genetic analysis and bespoke vaccine design. And we had felt the best technology for rapid custom cancer vaccination in 2017 was RNA.

All right, you build these RNA vaccines with your colleagues in biopharma. You conduct your first cancer vaccine clinical trial. Tell us what you did. Tell us what you found. In this trial, we did surgery here on patients at Sloan Kettering in New York. Within 72 hours, we ship the tumors to colleagues in Germany who then do genetic analysis of the tumor, create a bespoke vaccine, ship it back to us. And then we treat patients here in New York and then watch how the patients do and perform deep scientific analysis in them.

So we had vaccinated 16 patients in this trial. In eight of the 16 patients, these vaccines made lots of T cells. We called these eight patients responders. and in 2003, when we had looked at on average a year and a half follow-up,

we had reported that among the eight responders, none of the responders had seen their pancreatic cancers return after surgery. And in contrast, eight of the non-responders, six of eight

of these non-responders had seen their cancer's return after surgery. So at the highest level, it seems like you've proved that a cancer vaccine, a personalized cancer vaccine, can teach certain patients' immune systems to recognize a previously unrecognizable cancer. That sounds exciting to me. What's most exciting about this result to you? Yeah.

So I think the exciting part of this result is that prior to this, we were still searching for ways to teach the immune system to recognize pancreatic cancer. And there perhaps was a belief that maybe this was not even possible to teach the immune system to recognize pancreatic cancer because it was too immunologically. invisible. So the proof of principle that this is not correct and that you can in fact teach the immune system to recognize pancreatic cancer. And this is one way to do this, I think is exciting, not only for pancreatic cancer, but also for other cancers because the manner in which we achieved this in pancreatic cancer, we think can be applied to other cancers. All this good news, and we still haven't covered the breakthrough that you reported in nature last month. What did you discover in the last two years that demanded yet another positive update

on these cancer vaccines? So here, what we examined is whether these T cells made by the vaccine had the ability to persist in patients and retain function in patients. And if they stuck around, do these patients continue to do better? And what we found was that these T cells made by these vaccines appear to have really quite exquisite potential to stick around in patients, which addresses a really fundamental challenge, I think, for cancer vaccines. The average estimated lifespan of these T cells after their vaccination crime and boost was approximately seven years. And not only do they seem to have the potential to stick around, they seem to also continue to work. So people are

familiar with RNA vaccines for COVID, how is this class of therapies that you're developing similar or different to the mRNA therapies that we know from Pfizer and Medina? One critical difference here is vaccines against infectious diseases. You have a single pathogen, a virus or a bacteria that infects an entire population. Usually these pathogens are genomically much simpler. You can identify the antigen and then you can make one vaccine to then administer the entire population to then protect the entire population from exposure. In cancer, number one, we know that each person's cancer is individual. So their immune system recognize their individual cancer in a unique way. Although the same cancer may be shared in different

patients, meaning one individual might recognize their pancreatic cancer in a different way compared to another individual recognizing their pancreatic cancer. So a vaccine wouldn't have to be individualized. And the individualization process at the current moment cannot actually be initiated until patients have the cancer. So at the moment, we would not be able to know how to make, we think, a vaccine to prevent cancer before it in fact occurs because we actually have to perform genetic analysis of the cancer to understand, oh, this is how this patient's immune system would recognize this individual cancer. Thus, we would have to make the vaccine as such. It's a fabulous answer. And it raises a question that with the COVID vaccines,

we could scale them immensely with the understanding that you got the same. same COVID vaccine that I got, that my wife got, that my friend got, all the same shot, and it could be batched in one place and just mass manufactured. You cannot do that, by definition, with a personalized cancer vaccine. What is the hope in terms of scaling up these kinds of therapies? Because I can imagine someone listening to this and thinking, this is incredibly exciting, but if we have to re-sect a tumor and then send the genetic material to Germany, and then in a few days or weeks, Germany sends back to the doctor's office the recipe for the novel proteins that are being spit out by this cancer, and now you have to develop a vaccine

to take on those novel proteins, it sounds like a very complicated process that will be difficult to scale for a patient population that counts in the hundreds of millions. What is the hope on scaling? The strategy through which we did cancer vaccination, which required real-time cross-atlantic transfer of genetic material and drug, does not have to be done this way. This was because this was a foundational effort to do this.

And with advances in next generation sequencing, genetic sequencing can be done on site or locally. and we also know, and we had always suspected this, which is one of the reasons why we had selected RNA technology for our cancer vaccination platform, RNA can be made extremely rapidly. And this can be done locally, even in local academic or centers of excellence, for instance. So you could envision a scenario where you would not have to send the tumor to location X for genetic analysis. Genetic analysis and custom vaccine design and manufacture could all be done on site in a very rapid manner compatible with rapid treatment that is required for cancer patients. And I think this is a real realistic. possibility for a scaling individualization.

Interesting. So it's sort of like, you know, let's say that at a molecular level, we discover that there are basically, let's say, 30 types of pancreatic cancer. And you can just have those cancer vaccines all in a shelf. And I can have some genetic test that's done that gives my doctor a good sense that if I have this type of cancer, it's likely to be, you know, pancreatic cancer type number 19. And so you can dose me even before you've resected anything because you have a good enough idea that I'm likely to be a good candidate

for that particular rare disease vaccine. That's correct. And that would be one potential application where you could have ready-to-go vaccines for rapid deployment after initial genetic analysis of a tumor, that's one application. You could also envision another application where perhaps there is a library of genetic changes that is particular to a cancer type because these genetic changes that occur in cancer

that the immune system can recognize, the space is not infinite. And it is a finite space. So over time, as we learn about, for example, oh, pancreatic cancer has these particular types of genetic changes. Could we create then a library that incorporates these genetic changes into a vaccine that you might perhaps deploy for high-risk individuals for pancreatic cancer, even before they have any signs of cancers occurring? This is, of course, future-looking.

But I think the learnings that we will now have in secondary prevention will really position us to understand whether such primary prevention efforts, which is really a sort of a holy grail for cancer vaccines, whether we in fact have a path towards that goal. Let's talk about some caveats here. First, to pick up on something you've said a few times, these vaccines are for secondary prevention. Can you spell that out? We typically think of vaccines and infectious diseases in primary prevention. you vaccinate so that you don't get the disease related to the pathogen. In cancer, here we are testing these vaccines for secondary prevention,

namely patients have a cancer, the cancer is removed, and then we try to use a vaccine to either prevent or delay the cancers from return, after removal. In pancreatic cancer, this feature occurs in approximately 20 to 30% of patients. So this vaccination strategy would be applicable or was tested in that patient population. The second caveat that I want us to hang with for a second is that you've alluded to the fact that this is not a randomized trial. This is a study that split patients into two groups, those who had a powerful immune response to the vaccine, and those who didn't have a powerful response. And the patients with these stronger immune response tended to stay cancer-free for longer, which suggests that something is working. But maybe that something is the vaccine, and maybe that something is.

not the vaccine. We don't know for sure without an RCT. How in your research did you attempt to control for the possibility that the signal you were picking up on wasn't the effectiveness of the cancer vaccine at all, but rather just an underlying fact of the responder group having much stronger immune systems? Yeah. This is an important point to address. And when we look to see, are there other reasons that might explain why the responders are doing better than the non-responders? It's not related to vaccination. We did not find any such differences that could account for the big difference in magnitude that we were seeing in the recurrence rates between the two groups. in terms of the immunological differences that you brought up, this was also an important

confounder that we addressed, namely, is it possible that the non-responders just had a weaker immune system at baseline? So interestingly, both responders and non-responders also received, concurrent vaccination with an unrelated mRNA vaccine, which is SARS-CoV-2 vaccination. And turns out that the responders and the non-responders had equivalent immune responses to an unrelated MRI vaccine. So there was no evidence to suggest that the non-responders just had general, weaker immune systems across the board,

because they were able to make a equivalent immune response as the responders to SARS-CoF-2. Vaccines are an ancient technology. Edward Jenner invented, so to speak, discovered the first vaccine in the 1790s against smallpox. Cancer is very old, hundreds, thousands of years old. What makes this moment in personalized cancer vaccines so exciting for you.

Yeah. As you mentioned, vaccines have been the most successful medicine in history to improve human health. And I think a hope of the community and a goal of the community has been to try to follow in the footsteps of the successes of our colleagues in developing successful infectious disease vaccines and be able to deploy that against cancer. But we have been challenged by four critical barriers. What is the optimal antigen for a cancer vaccine? Namely, how do you teach the immune system to recognize something that is self as foreign? What is an optimal antigen for a cancer vaccine? What is an optimal delivery platform to be able to make very strong T cells, namely if a patient's immune

system has to be taught to recognize each individual cancer individually, meaning you would have to do a bespoke vaccination. Well, what's a platform that could make a bespoke vaccine quickly and strongly, which would be needed for cancer treatment. Number three, what patients could you vaccinate who would have the suitable characteristics to make a lot of immune cells? Unlike prior generations of cancer therapies, which directly kill the cancer cell, chemotherapy or a targeted therapy, vaccines are in fact pro-drugs, if you will.

They have to activate cells in the host to generate the response and then fight the cancer. So what optimal hosts would be able to make the cells? And then what are the optimal cells that would then be able to find the cancers and kill them? And I think we are in a unique moment, a vaccine moment, where scientific work by the entire community has led to advances where we have potential solutions for all four of these pillars, namely optimal antigens. We now know that mutations in cancer cells are a highly potent class of clinically relevant antigens. you can also identify them very quickly through advances in next generation sequencing. We now have an extremely versatile and safe and potent delivery platform through RNA.

So you can find the antigens in the genetic material and you can make the vaccine very quickly with the RNA. So I think that's sort of the moment where we are right now, exciting moment where we have some initial ideas of all of these critical components of an effective vaccine for cancer. Thank you for that breakdown. So what you've described are four pillars that in a way are four barriers to building a cancer vaccine. One, make the cancer visible to the immune system.

Two, a vaccine platform, in this case, RNA. Three, target the right T cells. And finally, figure out the patients who can mount an effective response. What does the frontier here look like? What's the next challenge that you're trying to solve for? So I think right now it's also exciting that there are several clinical trials that are currently ongoing that are testing RNA vaccines against patient-specific mutated antigens across a range of cancers, including cancers with very few medicines. mutations such as pancreatic cancer, as well as cancers with many mutations, such as melanoma. So essentially spanning the mutational spectrum, which I think will provide the community with a lot of

important information on the principles and practice of cancer vaccines across human cancers. But I think as a field, we are still in the first generation of cancer vaccines, and there are advances that can be made in terms of vaccine selection accuracy, delivery potency, patient populations that might be more suited, also suited for cancer vaccines, but perhaps yet undiscovered, as well as other ways to be able to make the cells last for very long periods of time. So I think these are all very interesting scientific areas of exploration that the field will be embarking on in the years to come, I'm sure. And you, Vinod, what are you personally most excited for in the world of cancer vaccines? Well, I think we're extremely excited about what we've been observing here in pancreatic cancer, namely that this particular strategy of vaccination is one way to teach the immune system to recognize pancreatic cancer. cancer, one of the most challenging cancers in oncology and a cancer that has been historically considered immunologically invisible and vaccine unsuited. So I think we are excited that this approach can, in fact, teach the immune system to recognize pancreatic cancer and can do so, we think,

at least at this point in time, quite well. So this can now provide directions on how to apply and test these concepts and extend these concepts for vaccines for other cancer types as well as other pancreatic cancer patients. So we're very excited to really work hard on all those efforts. Vinod Balasandran, thank you so much. Thank you so much, Derek. Really appreciate the time. Many thanks to Vinod Balasandran. One thing I'm taking away from this episode is this concept of immunological invisibility, this idea that cancer is so deadly in part because of how it disguises itself from our immune system. And therefore, one job of cancer vaccines is to make cancer's proteins revisible to the immune system, to teach our T cells and our bodies to recognize

antigens that they would otherwise be blind to. It's such an interesting challenge to try to solve for, and I'm very excited to do more shows on the frontier of immunotherapy, checkpoint inhibitors, and all the various ways that we're trying to teach our immune systems to be not just human but superhuman, to see cancers, even where cancers try to be invisible from us. We'll talk to you next week.