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 [email protected]. 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
Chapter 1: What makes pancreatic cancer so deadly?
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 a hundred 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 perfect 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 in 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.
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Chapter 2: How does cancer camouflage itself from the immune system?
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.
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. End quote. 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.
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Chapter 3: What are the recent breakthroughs in pancreatic cancer research?
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 deadliest cancer of them all and seemed to have won. And 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. 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 Balachandran, welcome to the show.
Thanks for having me, Derek.
I'd love you to help me understand why pancreatic cancer is so 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 failed 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. 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 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 cancers.
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?
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Chapter 4: Why has targeted therapy struggled with pancreatic 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, but perhaps not strong 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' cancers. 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... 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 with vaccines.
As I was reading about immunotherapy, and in particular about the 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 cell 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 green-lit versus 100,000 T cells that are green-lit, this will make a big difference in terms of if you...
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Chapter 5: What role do T cells play in fighting cancer?
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 receptors, 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 S4 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 survived 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 group 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?
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Chapter 6: How are RNA vaccines being used in cancer treatment?
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 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 resect 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 virus, by this cancer.
And now you have to develop a vaccine to take on those novel proteins. It sounds like a very complicated process. It 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 countries. 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 scaling individualization
Interesting. So it's sort of like, 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 on 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 Pancreatic cancer type number 19.
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Chapter 7: What were the results of the personalized cancer vaccine trial?
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 returning after removal. In pancreatic cancer, this feature occurs in approximately 20 to 30% of patients. So this vaccination strategy would be applicable
or it 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 the 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 that 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 was SARS-CoV-2 vaccination.
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