Dr. Christine Alewine — Treating Pancreatic Cancer with New Immunotoxin Strategies

Tuesday, January 29, 2019

Pancreatic cancer kills more than 40,000 Americans each year, and just 6% of patients survive five years or more after diagnosis, because the disease metastasizes very early in its development and is resistant to most current treatments. Dr. Christine Alewine is a physician-scientist exploring new treatment strategies for pancreatic cancer. Her lab and clinic are testing and refining two recombinant immunotoxins that target a protein called mesothelin that is present on the surface of several types of cancer tumor cells, including pancreatic, ovarian, and some lung cancers. If clinical trials show that the drug is safe and effective, it could lead to much needed systemic therapies for these cancer patients.

Christine Campo Alewine, M.D., Ph.D., is an NIH Lasker Clinical Research Scholar and a Principal Investigator in the Laboratory of Molecular Biology at the NIH's National Cancer Institute (NCI) Center for Cancer Research (CCR). Learn more about Dr. Alewine and her research at https://irp.nih.gov/pi/christine-alewine

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Transcript

>> Today on Speaking of Science:
>> If ever there is something that needs someone to work on it, it would be this disease. And I, right now, there's between a 7 and a 9% 5-year survival rate, and we need to do better than that.
>> Hello, and welcome to Speaking of Science. I’m your host Ben Chambers of the Intramural Research Program at the National Institutes, also known as the NIH IRP. Today I’m speaking with Dr. Christine Alewine, a physician-scientist exploring new treatment strategies for pancreatic cancer, which kills more than 40,000 Americans each year. Just 6% of patients survive five years or more after diagnosis, because the disease metastasizes very early in its development and is resistant to most current treatments. Dr. Alewine’s lab and clinic are testing and refining two recombinant immunotoxins that target a protein called mesothelin that is present on the surface of several types of cancer tumor cells, including pancreatic, ovarian, and some lung cancers. If clinical trials show that the drug is safe and effective, it could lead to much needed systemic therapies for these cancer patients. We had a great discussion. So please enjoy my conversation with Dr. Christine Alewine.
---
>> So where are you coming from today?
>> This morning, I was in the hospital rounding on some patients, and then I was back in my lab welcoming our new summer students. [laughs]
>> Cool.
>> So that's--
>> You have multiple summer students?
>> I do. I have 2 summer students this year, and our summer students here at NIH, they come to learn about biomedical research because they're thinking that that might be something they want to do in the future, and they want to get a hands-on experience to do that. And it's part of our mission of teaching, and--
>> Are these high-school students or college?
>> I have college students. I have college students, yeah. And so they have an idea that they think that they want to be in science or medicine, and they want to come and see whether it's really for them by working on projects in the lab. Yeah.
>> And so you lead a lab. You also lead clinical studies. And there's another group I'm curious about. So how did you become interested in being a Girl Scout troop leader?
>> [laughs] How did you find out about that?
>> [laughs]
>> So I actually, my older daughter, who's now in high school, she had been part of a Brownie troop that was breaking up, and she was going into fourth grade, and they didn't have another troop that had an open position, but they, the council was like, but look, there's 4 other people on the wait list. If someone volunteers to be the troop leader, we can start a new troop. [laughs] And I was like, well, this could be really awesome because I'm going to be a good troop leader, and we're going to do fun stuff. And my troop has actually stuck together all this time. And there's not that many troops that are still together by the time they get to be freshmen in high school.
>> Oh, really? They just--
>> Yeah.
>> Kind of lose interest or scatter?
>> They do. It's, part of it is a losing interest, and a part of it is they become so busy with every other aspect of their life that it just becomes more and more difficult to--
>> Yeah.
>> Find time. Yeah. We've been really lucky. We've gotten to do a lot of outdoors stuff, and we've also, you know, had 3 girls in my troop who completed Silver Award projects as middle schoolers. So those are big community service award things. And basically, my group now, they don't have as much interest in, let's complete the checklist of things to get a patch, but they're very determined that they want to get a Gold Award by doing a big community service project, and so we've been working towards that. [laughs]
>> Nice.
>> Yeah.
>> Is there anything that informs your work as a troop leader that you bring over from your biomedical research career or vice versa?
>> You know, it's, I think it's one of those things where, you know, there are certain -- we do first aid in Girl Scouts, so it helps to, you know, it helps to kind of know something about that kind of stuff and, you know, it makes it, it makes some of that easier. And there are some girls in my troop that think they're interested in science or medicine, and I know that they like to ask about that kind of thing, especially now as they're getting older and they're closer to making decisions about what they want to do as they get older.
>> So you can practice some of your mentoring skills on the young minds.
>> We try that. We try that. Just trying to keep everybody going in the right direction, and, you know, as they get more and more independent, it's important to encourage that independence, but also, you know, when you ask them to, well, you have to plan a trip for this, and, you know, and they say they want to go to France. And it's like, well, that sounds good. How are you going to get the money to do that? And don't tell me you're going to call your parents and have them write a check. [laughs]
>> Yes.
>> So, you know.
>> That's a lot of Girl Scout Cookies.
>> Yeah, it's a lot of Girl Scout Cookies. And so there's, you know, just helping them get to their goals and realizing what's practical, you know, I think is important. And, you know, I think that if you're thinking about that from a clinical perspective or a medicine perspective, you know, the patients that I treat all have metastatic pancreas cancer that's been previously treated, and we're doing our best to cure the disease or, at the very least, to try and help people to live longer and have good lives. And, you know, cure is something that is not here right now. And, as much as we're trying, you know, we have to understand and be realistic that, about what we can do and where we can go with things. And, you know, but it's important to have hope and to know that we're working very hard to try and help people and that, you know, we hope that we can get there soon.
>> And so your, would you call yourself a clinician scientist?
>> Yes.
>> Okay, cool. And how long did it take to get a MD and a PhD, both?
>> [laughs] It took 9 years.
>> Wow.
>> So I was in, I did my first 2 years of medical school, and then I was 5 years in graduate school, during which time I had both of my daughters--
>> Oh, wow.
>> And also took a monthlong trip to Thailand. And I started, I didn't choose a lab until after my qualifying exams for various reasons, and so that's part of what took so long. But I obviously wasn't rushing. [laughs] And--
>> Well, that seems like a reasonable amount of time--
>> Yeah.
>> To me.
>> No, it's a while. So when you finally get your first, like, real job, you can be a billion years old. [laughter]
>> Yeah, well, you're much younger than that, so [laughs] I would say you're ahead of the game.
>> Yeah, well. [laughs]
>> And so now, so maybe for nonscientists, what would you tell them that you do? What's your job?
>> So what I do is I do clinical trials for pancreas cancer, and I try and develop new drugs in my lab to treat pancreas cancer.
>> Cool.
>> And that's the 1 liner for what we're working on.
>> Sounds so simple. [laughter] What's your, so do you have maybe an outline of the approaches that you take, or--
>> Yep.
>> How did you get to--
>> Yep.
>> Doing this?
>> So here on campus, we have a group of people that are interested in immunotoxin therapeutics that's led by Ira Pastan. And he's been working on that class of drugs for a long time. I think it's a really interesting class of drugs because it has a very different mechanism of action from the way any other drugs work. And they're very tailorable. So there's a lot of tinkering that can be done to make them work in a better fashion. And so I think that the potential is there to be something really special. And so I started, I was here as, at NCI as a clinical fellow in oncology, and I started working in Dr. Pastan's lab then. And I had the opportunity to stay and to bring the drug that I was working on in the lab to clinical trial, which is a pretty exciting thing for a clinician scientist.
>> Yeah.
>> And so what my lab focuses on is we've been looking at combining our immunotoxin drug with other therapeutics to see how we can get the best effect, and we've also been doing some work recently looking at the biology of the target of our immunotoxin drug, which is mesothelin, which we think may play a role in the metastasis of pancreas cancer.
>> Cool, and I guess before we go too far, could you, so what is an immunotoxin?
>> Yep. So an immunotoxin is what we call an antibody-based therapy, and basically what that means is that it's targeted. When we use antibodies in therapeutics, we're basically using natural developments that the body has made to find something that very specifically binds to a particular target, okay. And the target of the immunotoxin I work with is called mesothelin. And the reason it's special is because it's not made by any important normal cells, but it is made by cancer cells. So if you think about it -- and this is the way I try and explain drug development to my students -- if you're trying to make an antibiotic to kill a bacteria and give it to a person, you need to find something that will kill the bacteria but not the person.
>> Yeah.
^M00:10:09
>> And the difference between bacteria and cells of people are kind of large, and so there's a bigger space in which you can find something like that. When you get to a cancer cell versus a normal cell, these are both cells that came from a human, not just from a human being, but from the same human being, and there's very limited differences between them, and so you have to work very hard to be able to find what those differences are so that you can find a drug that can exploit them because we need to be able to kill the cancer cells without killing important normal cells. And so what the antibodies do is, if we find a target that is specific to cancer cells, we can aim our drug specifically there so that it doesn't kill normal cells. So that's what the antibody portion is. The toxin portion is the payload.
>> Yeah.
>> So there's a targeting portion is the antibody. The toxin is what we call a payload.
>> And so what exactly are you targeting? You mentioned--
>> Yeah.
>> Mesothelin. What is that?
>> So mesothelin is a protein that is expressed on the surface of pancreas cancer and other cancer cells. And so it's hanging there on the outside. And then, what happens is if you give the drug and it comes through, it can bind to the mesothelin that it sees on the surface. Once it binds, that triggers the cell to what we call endocytose, or bring what's on the surface inside the cell. So once it gets in the cell, that's where the payload, the toxin, is active. That toxin actually destroys the activity of something inside your cell that's absolutely important for it to make new building blocks. And it actually--
>> So what does it, what is the target--
>> It targets a protein called elongation factor 2, which is very important for this protein synthesis of cells. So cells make proteins, which is the building block of everything pretty much inside the cell, and this particular enzyme is required to do that. And the toxin actually prevents that enzyme from working, so the cell can't make any new proteins. And that--
>> Oh, okay.
>> Makes the cell get sick and die in most cases. It can't work if it's outside the cell. That's why you need to have that binding portion so it can get inside. But it's extremely toxic to most cells once it's inside.
>> But regular, healthy human cells don't have this mesothelin protein--
>> Yes.
>> On the surface?
>> Exactly. And so if, for instance, we were to put something on the front of it that healthy, normal cells did, people would, could get very sick or even die because the toxin is capable of killing normal cells. Yep. So we have to very, very carefully choose our target, just like people who make cell therapies where the, you're, like the CAR T-cells that everyone's talking about, you have to very carefully choose what target that you're picking because if you choose the wrong target, then there's a lot of normal cells that are put at risk.
>> Yeah. So this seems, well, it all sounds so easy. There's a mesothelin protein on a tumor cell but not on human cells, and you have a drug that targets that and gives a payload. So what's--
>> What's holding things up?
>> Yeah, what's difficult--
>> Yeah.
>> About that? [laughs]
>> So these are the, the difficult things in general are that, first of all, can we get enough of our drug into the tumor in order to have a high enough dose that we can actually kill cells? So for any drug, there is an amount that you have to get there in order for it to be effective. And before you get to that amount, maybe you'll knock the cells back a little bit. Maybe you'll, you know, make them have to take a little vacation from, for a while, or, you know, in some cases, they're just like, oh, shrug, that's not very much. I'm fine, okay. And so that's 1 thing, and that's, you know, part of doing experiments and that aren't in cells in a dish is trying to figure out whether you can actually get enough of your drug there. The, and there are a lot of aspects of getting drug there. The second thing is toxicity. So are there any toxicities associated with the drug that don't have to do with targeting, right? So for the immunotoxin class of drugs, there is a toxicity that is not related to targeting, so it's specific to the actual payload, that's called vascular leak.
And it basically makes the small blood vessels leaky, and so a little bit of that can cause a really not so much noticeable increase in fluid, maybe a little puffiness. More of it means that patients can gain 10, 15 pounds of fluid weight temporarily. That getting bad means that, you know, people get fluid on their lungs or somewhere else important and have more trouble breathing. And so that's what limits how high a dose we can give of the drug. And so the question is, that we're trying to answer, is, at the doses that we can give before we get to that toxicity, can we kill tumor cells well enough, is really what we're asking. And, you know, as another part of the study, we're trying to have a look at what the mechanism might be that causes this leaking that is what limits how much drug we can give, you know, because it's independent of the targeting.
>> And that's, so that's not something common to all the immunotoxin drugs? It's--
>> It's common to all immunotoxin drugs.
>> Oh, it is? Okay.
>> All immunotoxin drugs cause leaking, regardless of what their target is on the front.
>> Ah.
>> Yep.
>> Why is that? What's doing that?
>> That's the key question there.
>> Oh--
>> That's what we're trying to, that's what we're, part of what we're hoping to find out on, with my current studies. So, you know, like, as we were talking about, with immunotoxins, there's the toxin portion and there's the targeting portion. And they're modular molecules, and so you can change off to a different target. And so I only work with the mesothelin-targeted immunotoxins because that's the target that's relevant to pancreas cancer. But our immunotoxin group here, Dr. Pastan, has other immunotoxin drugs that target other targets, which are intended for other tumor types. And so it's, that's part of the thing that's interesting about that.
And one of those was developed in collaboration with a pharmaceutical company and is now being considered by approval for the, by the FDA after a Phase 3 study. So there's, and we started this with, you know, talking about vascular leak. It's a, what we call class effect of the drug. So it doesn't matter what the target is on front. It's something that we see with all of them. [laughs] Yeah, versus things that are target-specific toxicities, yeah.
>> And so how did you choose to study pancreas cancer?
>> [laughs] I've always been interested in pancreas cancer. I think my best answer for that is simply that, you know, I've wanted to do research for a long time, and I think that pancreas cancer is, in general, a fascinating disease. And if ever there is something that needs someone to work on it, it would be this disease. And I, you know, I want, you know, there's, right now, all comers, there's between a 7 and a 9% 5-year survival rate, and we need to do better than that, and we need research in order to do better than that. And I would like to be a part of that. I mean, it's a very tough tumor type, and if I'm going to spend a lot of time working on a problem, it's a problem where I think we need to make a difference.
>> Yeah. So you're saying only 7 to 9% of people survive for 5 years after--
>> Yep.
>> Diagnosis?
>> Yep, and that includes patients with early-stage disease.
>> Wow, yeah. That's a very aggressive--
>> It's an extremely aggressive cancer. And, you know, so in general, in solid tumors, we have a tendency to do badly when people are diagnosed with late-stage disease. When things have already spread, we usually can't cure them in most cases. There are exceptions. But I think one of the things that's most striking about pancreas cancer is even when we catch people with disease very early where we can go to send them to surgery and we can remove all the tumor that we can see, and even if we give them our most effective chemotherapy regimen that we have, afterwards, the majority of patients will still die of their disease within 5 years. And that's not true of just about any other solid tumor type.
>> Yeah.
>> And I think it just reflects overall that we have a lot of work to do on this disease. I, and I think a lot of people, have a lot of hope that, for early-stage patients, we're going to see some improvements in those survival curves as, you know, there are combination chemotherapy regimens that have been much more effective against the disease that came out early in this decade and are currently being tested in early-stage disease patients. And our hope is that it'll lead to more patients being cured. *** (Editor’s note) — First data on these studies was reported at the American Society of Clinical Oncology 2018 annual meeting. The combination chemotherapy given near the time of surgery in early stage disease is better than some therapies used before, but more than 50% of patients are still dying within five years.
^M00:20:10
But the, those trials are still maturing, and, you know, we'll see where things go. But, you know, even a few years ago, we were talking about 5% of people who were surviving 5 years, and you know, that shift is, even if it's a little shift, is--
>> Almost double.
>> Numerically is nearly double. So, you know, that's the important thing. and, you know, the other, I think that that's, this issue with being able to treat early-stage disease and cure people like we can in many other tumor types is extremely relevant in the survival numbers for pancreas cancer. The second piece that everyone talks about with pancreas cancer is usually the first thing you hear, is that the majority of patients are diagnosed with late-stage disease, and that is true. And that's a much harder ladder to climb and one which, in oncology in general, we've not been dramatically successful across the board. And so there's a lot of work in pancreas cancer trying to figure out how to diagnose people earlier. [laughs] But that's a very, very difficult problem, given what we know about the physiology of the disease, and the numbers of people that get it, and the very difficult location of the pancreas. And there's a lot of things that make that very complicated.
>> Yeah, and so I imagine there's probably a lot of people who have a similar question to what I'm about to ask, but, so what exactly is the pancreas? Why do we need it? What does it--
>> Yeah.
>> Do? And how would you even, how would someone even know, like, to ask their doctor to check them for pancreas cancer? Is it, maybe it comes out in the standard blood tests. I don't know.
>> Yeah, so there is no standard blood test to diagnose pancreas cancer. And although it is anticipated to be the second highest cause of cancer death by 2030, it's still a relatively rare tumor. The symptoms that people present with when they have pancreas cancer early are, my belly hurts, or, I feel a little sick, or, doc, I've been losing some weight. [laughs]
>> Yeah, [inaudible].
>> And, you know, and, but, you know, and the thing that people come in with most often, though, are, I'm having pain, or, I just turned yellow. And many times when you get to that point where you just turned yellow or you're having pain, the disease has already grown too much to have surgery. And so that's what we're talking about with options for diagnosing disease early is, is there a blood test that we could use to screen people to say, hey, this is what's going on? And a lot of these other symptoms like, oh, I lost some weight, but, yeah, I've been trying to change my diet, or, maybe I'm not, you know, I don't feel quite as normal, are so nonspecific, and pancreas cancer is so rare by comparison to other conditions that cause that, it's not really something that you can look for immediately. And another of the big problems is even when you have somebody that comes in, and they turn yellow, and you're pretty sure that there's something obstructing things near the pancreas, sometimes we still can't even see it or see it very well on imaging.
And it takes some people a long time to get diagnosed just because of how difficult it is to see things in the pancreas. You ask, what is the pancreas? So it's an organ that sits just behind your stomach, and what it does is it's a gland, actually, so it has an endocrine function. And endocrine function of the pancreas is to make insulin, which I think a lot of people have heard about these days with all the diabetes that's going around. And the pancreas is responsible for making all of your insulin. The pancreas is also responsible for making a lot of digestive enzymes, and that's called the exocrine function of the pancreas. And so, basically, there's a, some plumbing that goes down the middle of the pancreas, and it comes out into the bile duct, and it spills out into your intestine just beyond your stomach so that you can help, that can help with digestion.
And that's, you know, because of those hookups, having surgery to the pancreas, and its location being so far back, and there's some important blood vessels that run very close to it, and the intestine runs right near there, it's difficult to have surgery if, and it's difficult to see things there. It's difficult to get to. It has to be able to diagnose pancreas cancer and get a biopsy. If you're just talking about disease in the pancreas, it takes a special kind of gastroenterologist who has special training to do an endoscopic procedure where they can actually go up the plumbing to see, get to the pancreas. Not everyone can do that.
>> Yeah.
>> And so there's a lot of barriers just from the physical location of the pancreas to getting people diagnosed early.
>> And so you, how are you approaching studying this? So you, right now, you've got 1 open clinical study that's in Phase 1, I believe?
>> Yep. So I have an open clinical study for patients who have advanced disease if, who have previously been treated with chemotherapy. So this can't be their first-line treatment. And we're testing our immunotoxin drug either by itself in a long infusion or in a short infusion in combination with one of the standard of care drugs for pancreas cancer, which is now [nanoparticle albumin-bound (NAB)] paclitaxel. And so we are still accruing to the Phase 1 portion of that trial. And what that means is, when you're talking about a Phase 1 trial, it means that we are looking for the appropriate dose of the drug to give to people. And I think that we're very close at this point to--
>> Oh, cool.
>> Knowing what we think that number should be.
>> And by appropriate, you mean safe and efficacious?
>> So in a Phase 1--
>> Or effective.
>> Trial, the very first thing that you're looking at is safe. You're trying to find the safe dose. Effective is a whole separate question. So to prove something's effective takes a lot of work, okay. And so if you think about this problem, if everybody's tumor grew exactly the same and was in exactly the same space, then the numbers of patients that we bring on to a Phase 1 trial could be enough to tell us that this drug is efficacious, okay. But not everybody's tumor grows at the same rate. One of the things that we talk about all the time is who has good tumor biology and who has bad tumor biology. And so if you have somebody that comes on study, and they're getting your drug for a year, and their tumor never grows, is that because your drug or is that because their tumor just didn't grow over that period of time? And so, in order to absolutely determine efficacy, you need to take a lot of patients on study, and then you need to have a group that doesn't get your drug and a group that does get your drug.
And then, you can say, on average, the patients who did get the drug did better, okay. What we can look at in a small trial like this is we can look and see how many people have responses. So we can usually assume with most tumors -- when people come on study, we require that their tumor be growing -- and we can assume that it will continue to grow if we had done nothing else. So if we make it stop growing or shrink, then, especially if we make it shrink -- that's not something we would expect to see happen -- then we can say, hey, we know that our drug is working for sure. Okay? But one of the tricky parts about a Phase 1 trial is we're not giving everybody the same dose, right. So we're starting at usually what's a lower dose, and then we're going up as we see that that's safe.
And so a lot of times, you don't know, as you're going up on the dose, whether you just need more of it. And so efficacy is a really hard thing to look at. When patients come in, of course that's what they want to know about -- how many people have had, you know, their tumor respond? And I always like to be very honest with people and say, hey, this is what we've seen, but, you know, hey, this is a new dose level or, you know, so it might be, you know, might be better than before. It also could be more toxic than before. And also, that even with the best chemotherapy that we have that's approved by the FDA, the number of people who have their tumor shrink to the point that it's considered an objective response is only 30%.
>> Oh, wow.
>> Yeah. And so if we treat 3 or 4 people on study and somebody doesn't respond, that doesn't necessarily mean that your tumor won't either.
^M00:30:02
Now, if we're in the [inaudible] position of everyone responding on the study, then that's, you know, that's an easier thing to say, hey, everyone who's gotten these drugs has done great. But, you know, it's hard to know a lot of times whether early-stage studies--
>> Yeah, so how long will the Phase 1 portion of the study go?
>> I think that we should be finished with the Phase 1 portion of the study very soon. I think that we are near to having a dose, and then we can move on to the Phase 2 portion. Yeah.
>> And so is Phase 2 I guess, maybe it's not guaranteed? Only if you have good results, which it sounds like you're probably going to?
>> That's right. So you go to, so if a drug is too toxic, then you can't go to Phase 2.
>> Gotcha.
>> And although it's very difficult to get an idea about efficacy, or we prefer to say activity, with Phase 1, sometimes you treat enough patients on Phase 1, and it's like, I don't really see anything exciting. It's not, doesn't make sense to move onto Phase 2.
>> Yeah.
>> So Phase 2 trials tend to be bigger. In general, the goal of Phase 2 trials is to sort of get a preliminary idea of whether things might be working. So Phase 2 trials usually look at things like, did we make the tumor shrink? And that's a good thing to know, but what you really want to know, ultimately, is, does my treatment make patients live longer? [laughs]
>> Yeah.
>> And--
>> That takes a while to figure out?
>> That -- well, it depends on a lot of things, how long it takes. It really, it takes more people to figure that out because survival is so variable. There's a lot of factors that go into that. So there's some people that are sick with other stuff. And that affects things. There are some people who have this good tumor biology. There are some people, you know, that they got a treatment that made them sick, and they got an infection, and, you know, and they did badly. There's some people that, you know. So survival is a really variable number, and so the more variation there is, the more people you need to treat in order to be able to say, definitively, yeah, the people that got my drug did better. And so that's what Phase 3 studies are all about. And they tend to be much larger because you need these bigger numbers of patients to try the drug to really know whether it's going to improve something like survival. Yeah.
>> That's kind of the way clinical trials progress is we want to find the safe dose, we want to get a preliminary idea of activity without treating hundreds of patients, and then, in Phase 3, we want to definitively prove that this is something that will help people to live longer. And that's the trajectory of how they go.
>> So you have both a lab and a clinic here at the--
>> Yes.
>> Intramural program of the NIH? How do you characterize your time that you spend--
>> Yeah.
>> Or how's that work?
>> So it depends on how many patients we're seeing at the time because patient care always comes first. And in general, though, I spend at least 50% of my time in the lab, and what we're doing is we're trying to work on combinations of our immunotoxin drug with other things that could be efficacious and also to look at the basic biology of mesothelin, which is the target of our drug, to see whether we can do a better job of targeting mesothelin protein because, you know, we were talking before about targets. It's very, very difficult to find something that's expressed in reasonable amounts on the surface of a cell in tumor cell that isn't made by important normal cells like the liver, the heart, the lungs.
>> Yeah. [laughs]
>> And so there's a limited number of choices in general when you're looking at targets. And so this is one that's clinically been proven to not come with a huge amount of toxicity, and the drugs targeting mesothelin have been in clinic so far. And so to understand more about how it works so that we can be more precise in the way that we target it and design better drugs I think is important.
>> Does the mesothelin protein appear on other types of tumor cells?
>> It does. So mesothelin itself is what we call a differentiation marker for mesothelial cells, and now I'm speaking like scientists.
>> That's all right. [laughs]
>> So basically, there's a lot of different, like, different blood cells in your body. They express different things on their surface that say, hey, I am a lymphocyte, or, hey, I am this kind of cell. And this particular mesothelin protein, it's made by, there's a fibrous surface lining on the outside of the heart, on the outside of the lungs, on the outside of the abdominal organs, and it's made of these things called mesothelial cells. Just a thin, little layer. And you don't actually need that fibrous lining. In fact, for some other medical reasons, sometimes people need to have surgery and have that stripped off the outside of the heart or stripped off the lung. So that's when I say that there is no important normal cells that make it because those cells you don't need to survive, okay. And those cells make mesothelin, and that's what the mesothelin's named for is those, because it's made by mesothelial cells. For reasons that we don't understand, there are some tumor types that turn on expression of mesothelin, like pancreas cancer. There's no cells in the normal pancreas that make mesothelin.
>> Interesting.
>> Gastric cancer turns on mesothelin. Some of the biliary cancers do. Some colon cancers do. Some lung tumors do. Some thymic cancers do. As well as some gynecologic tumors like, especially ovarian cancer, and there's a type of endometrial cancer that does as well. And, but the poster child for mesothelin expression, besides ovarian and pancreas cancer, is actually a cancer called mesothelioma. It's caused by asbestos, usually, and it's a tumor of the lining, those lining cells of the lung. And I usually think of that as a little bit differently because that cell type is supposed to make mesothelin, whereas--
>> Yeah.
>> These others somehow turned it on special.
>> Yeah.
>> So, but those, but the biggest ones are mesothelioma, pancreas cancer, and ovarian cancer, but there are a lot of other solid tumors that make it.
>> So is it on your mind that this drug you're working with might have applications to these other tumor types?
>> So Dr. Raffit Hassan here at NCI, he does studies with these immunotoxin drugs in thoracic malignancies, especially mesothelioma. And we, my study, although it focuses on patients with pancreas cancer, for the arm of my study, where we're giving the LMB-100 as a continuous infusion, we'll accept patients with any mesothelin-positive malignancy. And we've had patients with biliary cancer, with rectal cancer, with mesothelioma who have been on that portion of the study. Yeah.
>> And so, in the lab, what is your approach? What kind of tools do you use to study this?
>> So we use human cell lines and mouse cell lines from special mouse models, where the mice developed tumors that are similar to the kind that patients get. And when we're testing drug combinations, we test them first in cells. And then, if we think that they might be promising, we test them in mice because there can be a big difference between what we see in cells growing in culture versus what we see inside of a living system. That's especially true of drugs that may or may not activate the immune system because, obviously, if you're talking about just having tumor cells in a dish, that component of things isn't there. And like I was talking about before, actually being able to get a drug through the circulation, into a tumor is an important aspect of drug development.
And once again, that's not something that we can test just having cells in a dish, and it takes a living organism to be able to see that. We do molecular biology to change the, make mutations, and so little changes in the structure of mesothelin to see how that affects its ability to cause tumors.
^M00:40:00
And we, that's basically the idea. [laughs] Yeah. And then, we have to evaluate that in some way to see what effect that we've had.
>> And so you're using immunotoxins. Does that mean that it actually uses the immune system and its cells or not really? It's sort of its own immune thing?
>> Yeah. So the immune part of immunotoxin comes from it being an antibody-based molecule. So antibodies are something that are made by immune systems, by the B-cells in the immune system. And we have coopted them in order to use them as a targeting agent.
>> Gotcha.
>> And so even 10 years ago and before that, when we said immunotherapy, we meant that we were giving an antibody. Since, if a [inaudible] came out when people say immunotherapy, a lot of times, they specifically mean not just something that's an antibody, but something that's directed to make the immune system attack a tumor or to give a cellular immune therapy, where you're giving immune cells to attack a tumor. And so that word has become a little bit ambiguous. If you ask, so that's why it was originally called immunotoxins because there's a portion of the molecule that comes from an antibody, which is an immune component. We have datas that suggest that not only is an immunotoxin something that can just kill cancer cells like a chemotherapy, but that the way it kills cancer cells may actually provoke the immune system to notice the tumor. And so Dr. Pastan, who's the head of our group, has published data about that, and we're looking to see whether that actually happens in patients.
And we're developing some mouse models in my lab where we can evaluate that specifically in pancreas cancer because pancreas cancer's been a little bit different, once again, than other tumor types. It's not been one of the tumors where these new immunotherapy drugs, these immune checkpoint blockade drugs have not really had much efficacy in pancreas cancers, single agents. There's almost nobody that responds to them, just people that have a particular mutation that's, that results in something called microsatellite instability, which is less than 2% of patients. Other patients with pancreas cancer, they get these immune checkpoint inhibitor drugs that have been revolutionary in other tumor types, have not had responses. And it's one of the biggest questions in the field is, why is that?
>> Yeah.
>> And how can we bring pancreas cancer patients in with the rest of the group that's benefitting from this new class of therapeutics? And we're looking to see whether, you know, whether there's, we can generate an immune response with our immunotoxin drugs.
>> Cool. Let's see here. What would you say is something that your lab, or clinic, or your group does exceptionally well?
>> [laughs] So I think that, you know, I think that I'm a young investigator, and we're still in the process of learning how the best way is to do a lot of things, and I think that that's a good thing in that it gives us a chance to be open and to listen very carefully about everything that's going on. And from a clinical side, I would say that listening to patients, and what they need, and what they want, and what their goals are, and what they're hoping to get out of this is a really important part of things. Everybody coming here to be on my trial knows that they're in a tough spot in general.
>> Yeah.
>> And some people in tougher spots than others. And just being able to individually look after everybody the way they need to be looked after and to make sure that we're doing for them what we need to do for the things that are important to them I think is a big deal. And, you know, one of the things that I tell my patients is, you know, my particular trial is an investment of time. You have to -- it's not a drug where you come and you get an infusion and go home today. You have to stay here with us for a while, but one of the things is that, you know, I like to make sure that symptoms that you're having from the tumor making [inaudible], we have, we also have that time when you're here under our very careful attention to try and help get those things better. And, you know, I think that that's important, and I think it's important that, you know, that people get that kind of care that they need to sort of get every aspect of their disease on track.
You know, in the lab, we're building a program, and I've had my lab for almost 4 years now. And I think that we have some exciting data that I hope the rest of the world thinks is exciting too so that we can publish nice papers this year. [laughs]
>> [laughs] I hope so.
>> And, but that's kind of where things are.
>> Are you counting your time as a assistant clinical investigator?
>> Yes.
>> Okay, cool.
>> Yep, yep.
>> And now, you're--
>> So.
>> So now, you're a Lasker Clinical Research Scholar.
>> Yep, so that has been, it'll be a couple years probably now. Right now, it's been a couple years since I've been a Lasker Clinical Scholar, which means that I'm a tenure-track investigator here. And so I think we have things rolling along pretty well now, and I'm hoping that we have a lot to tell the science world this year.
>> So what happens when a patient comes here to the NIH? Do they meet with you? Do they meet with other doctors first? And what's their kind of--
>> Yep.
>> Overall experience like?
>> So here at the NCI, almost everybody that we see is here coming to screen for clinical trial to see if they're eligible. We don't have an emergency room where people show up with any old disease and want to be treated. So what happens is is patients or their physicians contact us. Either they find us on the web or the physician had somebody that came here before. And then, come through our referral office. We get their records, and we bring them in to come to see us in clinic. And depending on a patient's situation, they might be multiple clinical trials that they could potentially fit into. And then, we work with other groups to see what makes the most sense for that patient based on eligibility requirements, and where they are, and their convenience, and, you know, and what makes sense in their life.
>> Oh, so they're not necessarily coming just to see you.
>> So there are some people that come just to see me because we know from the records we have before they get here that I might have the only trial that they're eligible for.
>> Yeah.
>> There are other patients that come, and they're potentially eligible for some other trial that, and then we can sort of look into what would make the most sense.
>> And if people ask you how to get involved as a study participant, where do you point them to?
>> Oh, I point them, I let them know to call our referral office or to call my research nurse.
>> Oh, okay.
>> We have a medical oncology referral office, and if you're going to ask me the phone number, I'm not going to be able to help you with that.
>> Oh, no, that's all right. They could potentially find it by going to your profile--
>> Yep.
>> Page on the website or--
>> So usually, it's posted on clinicaltrials.gov.
>> Gotcha.
>> You can find that information for a study coordinator contact. Yep.
>> Just search for "pancreas cancer"?
>> Yep. You can search for "pancreas cancer," and our name of our drug is LMB-100. And that makes it easy to find.
>> Yep, or they could also search by your name as well, right?
>> I don't know whether that will help you.
>> Okay.
>> No, I don't know that that will help you. Yes.
>> I'll test it out after this.
>> You should test it out.
>> And see if it works.
>> And, yeah.
>> Okay, and so now that you're a Lasker Clinical Research Scholar, what does that entail? What's involved with--
>> Yep.
>> That?
>> So what's involved with that is that I was lucky enough to be given funding to continue my lab for an additional period of time and to fund my clinical study. And it's up to me to invest that money wisely into making advances in pancreas cancer. And, you know, it's one of those things that, by making the right choices and doing things well, that hopefully we can have some advances in pancreas cancer and that, as a side effect, leads to me having a job. [laughs]
>> Yeah. [laughs]
^M00:50:20
>> You know, I think it's been a wonderful program that's given me the opportunity to pursue my research interests and hopefully be able to have something good come out of this for patients with pancreas cancer. Yeah.
>> And so the Lasker Program, you have, is it 5 or 7 years?
>> So it's guaranteed for 5, and then there's the possibility of 3 additional years after that, as long as things are going well.
>> And that could either be here at the IRP or at another institution?
>> Yes, that's correct.
>> Okay, cool.
>> Yep.
>> Can you, so I've got a tricky question for you. [laughs] Can you, are there any mistakes that you've made in the past over the course of your research that seemed like a mistake at the time but then maybe turned out to lead you in a better direction that you might not have found?
>> I have to say that those kinds of serendipitous things happen occasionally in the lab, and there's one of those that we're working on now. You know, from a mistake standpoint, you know, I have to say that, you know, with running clinical trials, we have a huge emphasis on safety. And the entire system is geared to making sure that patients are safe and are not injured from a drug.
>> Yeah.
>> And what I hear from my patients who are in some pretty dire straits sometimes is, who is paying attention to what the risk of doing nothing is in me? And, you know, I have patients that come in, and they have no treatments that are available to them anywhere, and they don't want to go to hospice right now.
>> Yeah.
>> They're still feeling well, but, for one reason or another -- either they've had too many treatments before or there is 1 number in their labs that's too high -- they're not allowed to come on clinical trial. And we have a, there's only a small percentage of the patients in this country with cancer actually get onto clinical trial, either because it's a lot of effort and it wasn't something that was on their radar or because they didn't qualify for some reason or another. And I think that, in a way, you know, I've done my best to try and include who we can very safely put on clinical trial, but it's still one of those things that's a bit heartbreaking at times when you have somebody who, they are not ready to stop, and there's, you know, with this disease, there's not a lot of consideration given to, you know, what the alternative is.
And I say plenty of, I have plenty of patients that say to me, hey, okay, that's great, doc. You don't want to give me this drug because you're worried it'll kill me. Well, if you don't give me this drug, I know what's happen. I'm going to be dead--
>> [laughter] Yeah.
>> Very soon. So that's really a nonstarter from my perspective as a patient that you're worried you're going to kill me because [laughs] that's where I'm headed anyway unless you do something now. And I think that that's something that, as physicians taking care of patients with a terminal disease that has such a short survival in general as pancreas cancer, that maybe we need to think very carefully about what we can do.
>> Yeah.
>> Yeah.
>> Sounds like a challenging way to consider, is it the Hippocratic Oath that you--
>> We do no harm.
>> First, do no harm.
>> That's right. And so we talk about doing no harm. There's a "do" portion of that. But there's not as much of a "not do" portion of that. And I think it's a very interesting philosophical question because, when patients are coming in and they're asking for these treatments, we don't know whether they work. [laughs]
>> Yeah. [laughs]
>> We just, you know, we, you know, and that's the other side of the equation that we were talking about. We're testing these drugs in clinic because we don't know whether they work. And so we have to make a decision as physicians about whether we think that this is a patient who could potentially benefit from this drug, or this is a patient we could potentially harm with this drug and actually keep them from living as long as they could have otherwise. And it's a really, really difficult question. Yeah.
>> Yeah, and I imagine you've probably known some patients who've probably passed away when you, while you knew them.
>> Yes.
>> So that's probably--
>> That's an epidemic of taking care of this population of patients, yes.
>> Yeah. Do you have any, I don't know, recommendations for other people who might be in a similar situation for how you best deal with whatever emotions or whatever experiences come up?
>> So, you know, I think it's one of those things where we all need to understand that we're in a difficult place, you know, both the patient and as a physician when you're treating patients with this disease, that we're in a difficult place. And we're doing the best we can to help people either live as long as they can or as well as they can. And we just, we have to keep sight of what our goals are and to understand that, as good as medicine is these days, there are times when there is nothing we can do to change the course of things. And, you know, that's the best that we can do. I had a patient last week who said to me, you know, they were getting sick because of their tumor before they came on study, and I took them on study, and they said to me, "Doc, I'm so sorry. I'm messing up your study because I'm sick." And I said, "No, that's not the way it works. You're not messing up my study because you're sick. Our job with our drug is supposed to make you better. If you're not getting better, then our drug is not working for you. Our study is not working for you. It's not that"--
>> Yeah.
>> "You messed up my study." [laughs] And, you know, it's just one of those things where, a lot of times, we have to take things 1 day at a time and see how we're doing today. [laughs] And, you know, and that's the thing to keep in mind, you know.
>> And the, there's probably also, hopefully there's some patients that you've seen improvement with as well.
>> Absolutely, and it's very exciting.
>> Yeah. [laughs]
>> It's very exciting, and, you know, and we all get very excited about that when people are doing well, and they have good numbers, and they're feeling well. And, you know, and that's, it's a great feeling. That's a really great feeling. Yeah.
>> Cool. So is there anything in particular that you're looking forward to? Any next goals that you might have? Would you potentially envision yourself working on any other major problems, or--
>> Yeah. So, you know, I, I've only gotten started in the last couple years with my lab and with our clinical program, and, you know, we're looking to expand our clinical program over the next few years, but it's a slow process. It's one of those things that takes--
>> Yeah.
>> That takes time to do. And, you know, we, the up and coming, you know, we're thinking of some studies that will follow up our current study on pancreas and biliary cancers to see if we can make a dent there, yeah. I really, you know, I think that pancreas cancer has been really tough for a long time, and we just need more people focusing to try and get through that. Our patients need that. [laughs]
>> Yeah, definitely. Do you have any other thoughts about life at the NIH?
>> We can do some really wonderful things here that are, you know, I think is can be a really good respite for patients to come here and not have to deal with all of the other overarching issues with the health-care system, like insurance approvals and the--
>> Yeah.
>> Financial burden of figuring out how to pay for all these things. And we have a tendency to have more time here than we do in other places in order to, you know, to help patients out with symptoms that they're having and that kind of thing. And I think it's a wonderful place to practice medicine in that regard. And I think there's a really unique opportunity here to be able to translate things from the lab to the clinic just because of the way we're structured that makes it so much easier than anywhere else. It's, more or less, a seamless transition here because, you know, our funding is not necessarily earmarked for 1 particular, little thing. And, you know, we have that ability to move things to the clinic. And I think that's been really a dream for me.
^M01:00:00
I think I was saying earlier, you know, I worked on the drug that I have in clinic now as a fellow in the lab, and that's extremely exciting to be able to see it come to clinic. And that's what all us nerdy clinician scientist types, you know, that's the dream right there. And to be able to do our work in the lab and then have it come to patients is just incredible, and, yeah, our infrastructure here is really well set up for that.
>> Do you think there's any people that you've spoken to that have misconceptions about what your life is like as a researcher here at the NIH or as a researcher in general?
>> I don't think most people have much of an idea about how the clinical aspects of things at NIH work because it really is so different than medicine everywhere else. And--
>> Why is that, or what is it about--
>> Because we're not accountable to payers like insurance companies. Because we can bring things to trial, by comparison, relatively easily compared to outside, and we can do those correlative studies in our labs that go with it to have the science that goes behind it with, you know, without having to apply frequently for 17 more new grants--
>> Yep.
>> Because we can shift, you know, the way we can shift our budgets to do what we think is most important. And I think it gives us a freedom in that regard. And also, because, you know, the clinical burden, as in the number of patients that we need to see, we're not seeing patients with every single person that walks into oncology clinic, like we were talking about, with every kind of disease. We are seeing patients in our clinics that are specifically screening for our clinical trials. And so, overall, our clinical load is not the same as somebody who's in an academic position somewhere else who has, is not, is seeing many, many, many more patients besides any patients that might come on trial with them.
>> Yeah, and you're like, you're hyper focused in comparison.
>> We're hyper focused on, you know, on our own clinical trials and our own laboratory research. And so when we're able to do that and not have all of that other work that's not associated with our research program, it gives us a chance to be more productive in our research program. One of the things that I've had to learn with becoming an investigator is that there really are only so many hours in the day, and each one of them needs to mean something. [laughter] Yeah.
>> Yeah, and so I really appreciate you giving us an hour of your time. Otherwise, people can just go to your profile page if they want to learn more about your research and recent papers that you might have published. And it'll be cool to follow this and hopefully, I mean, it sounds like such a promising treatment.
>> We're hoping. We're hoping. We'll see where things go.
>> Thank you for listening. That was Dr. Christine Alewine. To learn more about IRP research and the work of Dr. Alewine, please visit irp.nih.gov. And make sure to subscribe to our weekly newsletter for the latest updates. Have a great one. Bye.