Brett Hellman: Do you ever wonder what the immune system has to do with cancer? Why are some cancers considered worse than others? And if we can find a way to prevent smallpox and get a man on the moon, why aren’t we closer to finding a cure for cancer? Find out the answers to this and more on Things That Make You Go Huh?
‘THINGS THAT MAKE YOU GO HUH?’ INTRO MUSIC PLAYS
Brett: Hello everyone ... it’s your science-challenged host Brett Hellman, and I’m coming to you live today from sunny California. That’s right – it’s our first podcast road trip, or as I like to refer to it ... “Things That Make You Go Huh” Cali-Style. So we’ve ventured many miles from our Chicago headquarters to spend some time at one of our West Coast labs in AbbVie Redwood City, and we have a very special guest to share with you today ... to be introduced very shortly. But today’s mission impossible: dive head first into a current hot topic of cancer research called immuno-oncology. Immuno-what?! … you might be saying, just as perplexed and confused as I was when I first had heard about this topic. But have no fear, I’m going to try to unearth the many facets of this fascinating area of research today.
Putting on my best Tom Cruise impression by choosing to boldly accept this mission -- minus any dangerous hijinks, of course -- I decided to change things up just a little bit today and bring in some more brain power for our adventure through science. With this in mind, please extend a warm welcome to my colleague, friend and fellow producer extraordinaire, Suzanne Barston ... here to help me get to the bottom of all this! Cause honestly, immuno-oncology is a thing that makes me and Suzanne both go ... HUH?!?! What say you, Suzanne … ?!
Suzanne Barston: I say I am definitely saying huh. But we’re going to get to the bottom of this, Brett.
Brett: Awesome! Okay folks, one last thing before we begin. We didn’t have our normal audio guy with us on our road trip, and so I had to take care of it. And spoiler alert, running an audio board makes me go huh, too … so please excuse any issues in sound quality.
So without further ado, please help me in welcoming our very special guest! We are honored to introduce the amazing Diane Hollenbaugh … Diane, can you tell us who you are and what you do here at AbbVie?
Diane Hollenbaugh: Okay, I’m Diane Hollenbaugh and I lead the immuno-oncology discovery group here in the Redwood City site. So immuno-oncology is a mashup of oncology and immunology. Really we, what we do is we look for ways to manipulative the immune system to treat cancer. So basically get your immune system to recognize a cancer, and reject it. And get rid of it from your body.
Happens all the time that you have cells in your body that get messed up and your immune system clears them out and sometimes there’s mechanisms that happen, that immune system doesn’t recognize it anymore, and then it lets it grow, and that’s what leads to cancer. So we just want to turn that around and use that to treat the cancer.
Brett: Is it kind of the same concept that if you have a cold or you have a sickness that your body is trying to get out of your system?
Diane: That is exactly what it is. That’s exactly … the same exact system.
Suzanne: So if our bodies can fight off something like a cold after a couple of weeks, then why can’t it fight off cancer?
Brett: That’s a good question.
Diane: Well, it does happen all the time. And there are ways and there are some patients that we know how to manipulate their immune system to do that. But before we can really answer it for all of cancer, we have to kind of maybe take a step back and say, “What is cancer?” Because cancer is lots of different diseases. The same underlying, similar mechanisms, but very, very different in different patients and different populations.
Brett: So like there’s breast cancer, there’s pancreatic cancer? Even though they are all labeled cancer, they’re different?
Diane: They’re very different. They can be very different. And all the things that we use to treat them can be different, depending on what they are. So maybe just to take a step back and describe what is cancer.
Brett: That’s a good idea.
Diane: So if you take your hands and you put them across your belly and feel what’s underneath there. For me, I just ate lunch, so my stomach is busily digesting my lunch. But also in there are all the other organs. There’s a pancreas, there’s a spleen, there’s a liver. And so if we think about your liver is, your liver is this little sort of triangular almost shaped organ. Well, it’s made up of lots of cells and all those cells have jobs. They each have a different job to do and they have different functions, and your liver it filters your blood to take out toxins and things out of your blood. And there’s also things in there to help make sure your immune system doesn’t recognize those things. And all that.
Well, there’s mechanisms in there, so that the cells in your liver know how to be the shape of a liver. They know when to make more cells, if cells die. They divide and make some more, but then they stop. But what happens in cancer is that you get mutations. So those cells, they don’t know when to stop. They just keep growing. And they lose those mechanisms that make them stop, to be the shape of a liver.
Now, when they do that, your immune system could recognize them and get rid of it. But they also develop mechanisms then -- they get selected for mechanisms that trick the immune system. Ways for the immune system to not recognize it. So they set up this kind of complex system where those cells that have those mutations, they have an environment around them that they’ve created, the things that they do create, that creates the tumor. So they have these mutated cells and then all of the stuff around it that helps support it. And that is what really is a tumor.
So depending on what organ and where those cells came from, or what kind of cells they were or what kind of mutations they had — all of those different things that can happen, that can lead to that same uncontrolled growth, make for different kinds of cancers.
So you can have a breast cancer, like you mentioned, the breast cancer, a certain cell within the breast that can become transformed, as they say. And the mechanisms it uses to create its own little environment and to suppress the immune system, might be different than the cell that arose from the liver or from the colon or from the skin. Different places. They all have their different mechanisms for how they do that. And that is what we try to study. In traditional oncology we look for ways to kill that transformed cell. We look for toxins and things that will kill that transformed cell. In immuno-oncology, we look for the ways that that cell is avoiding the immune system, to try to turn that on the other way, so the immune system will recognize it again.
Suzanne: But does that lead to really nasty side effects, I would think? Because if you’re turning your immune system to attack something, I mean, from what I understand about immune systems, like, that’s when -- like a fever for instance. You get a fever because your body is trying to fight off an infection, right? So it seems like the immune system, when it’s turned on, it can do some pretty …
Diane: … bad damage. Absolutely. And so side effects, in the early days when we were working on these things, people were very afraid that if you turned on the immune system you’d get autoimmunity everywhere. And there are, there are definitely toxicities associated with these therapies. It was part of learning to develop -- learning how to manage and recognize those different types of toxicities in the early days, in the clinical development of these agents, for how to manage that. And how to recognize it. Cause it’s very different than chemo, you know. Physicians are very aware and know what the side effects of a chemo might be, but once they started using these kind of agents, they are very different.
Suzanne: So one thing I’m not clear on, sorry Brett, I’m monopolizing.
Brett: No, I’m still trying to absorb all this information so ... this is a lot to take in.
Suzanne: Yeah so, I guess I still don’t understand though, we have so much amazing technology out there. I mean there’s diseases like HIV that in a very short time, we managed to not cure, but essentially manage to the point where people can live long, great lives. So why haven’t we been able to do that after all these years, with cancer?
Diane: I would argue that we have. Some forms of cancer, just like some viral diseases. So yes, HIV, turning it into a chronic disease as opposed to a death sentence, definitely a triumph of drug discovery and development to do that. There’s other viral diseases that we can’t do that with. Smallpox. If you’ve got smallpox, we don’t have therapy for you. Fortunately, we have vaccines to prevent that, but we couldn’t cure it. So just like that, some cancers we’ve been able to figure out, what is it that we can do to manipulate for that particular cancer. And some we haven’t. So the common cold, you can recover from just fine. Your immune system recognizes it. HIV -- we needed to develop the drugs. Some other viral diseases we have vaccines for. We’ve been able to figure out how to have a good vaccine to prevent that. We still don’t have drugs for all of them. So in that sense, saying “cancer” is like saying “virus.”
Brett: There are so many different types of cancer, though. So isn’t that what makes it so difficult? I mean, it’s a lot of different things that you’re looking for, right? To combat each one because they’re not necessarily all the same, so …
Diane: They are not necessarily all the same. The good thing that we do is to try to find the things that are common among them. So for a given set up patients, there may be certain things where there are certain mechanisms that are similar and that we try to target those. We also find that when we look at immuno-oncology, rather than look by the tissue of origin, whether it’s a breast cancer or a prostate cancer or a skin cancer or lung cancer, in some ways there are themes that go across those, where they may have a certain immune phenotype we call it. They may have a certain mechanism of immune, what the immune system looks like, that goes across that. So we try to target -- maybe it’s … maybe it’s not the same definition of a population, maybe different. And we try to figure out who that would be that might benefit from that therapy.
Suzanne: So for instance, if you have breast cancer versus pancreatic cancer. What I don’t understand is I see all these odds for certain treatments that talk about, you know, HER2 negative – I’m not even sure if that’s a real one … but different kind of typing of cancer? So what — I was under the assumption that if you have breast cancer, it’s breast cancer. And one cure for breast cancer would fix everybody who had breast cancer. But that’s not true, right?
Diane: No. And HER2 positive or negative is a marker for certain types of one kind of another. And when you, if you get a diagnosis of cancer, one of the things that your physician would do would be to do that characterization, what kind of markers. And recently now, they may actually sequence your tumor to understand what are the sequences within that. But it is a big thing to be able to understand the differences between them. A long time ago, it was just look in the microscope, but we’re well passed that now.
For immuno-oncology, we’re not there yet to know what are those markers for how we subset our patients. We haven’t -- we don’t have that very well yet. And we only have a few things that have been already been improved. There are only a few pathways that have really shown where we know how they work in the clinic. So the field as a whole is really working towards understanding that.
If you have a patient who has breast cancer, how do I know if I should use this immunotherapy or that immunotherapy? Or this non I-O drug?
Diane: That would be best for that patient. And that in and of itself is a huge field of exploration.
Suzanne: So it’s almost … it’s not even diagnostic, but it’s kind of between diagnosis and treatment, you have to have that middle step of what, what treatment should we even look at first?
Diane: Yeah, it’s really a way — it is sort of a subset of diagnosis. You’re being diagnosed with a certain subset of a certain kind of a cancer that should respond to this treatment, to help guide the physician for what to use.
Suzanne: So why are certain cancers considered so deadly versus others? My grandfather passed away of pancreatic, and I have a friend right now who … who is struggling with the same disease. It seems like there are just some cancers where they are almost considered “better” cancers to get than others. So if each cancer in each individual is a little bit different, why is it just the location of where it is?
Brett: I was going to say, is there certain areas where it’s worse? i.e. the pancreas or...
Diane: It comes down to basically a common theme of how those tumors arise. So pancreatic cancers, there is a large subset of patients that if you could look at their … pancreatic patients, they would look similar across. And that, what that cancer looks like -- and part of the reason that some are better than others, is because those are the ones we haven’t figured out yet what the right therapy is. And I still hold out hope that at some point, we will have a therapy that will treat your friend with pancreatic cancer. That’s why we’re here, that’s what we work on, that’s what we do. Is to make it so that the ones that people say, “Well, there’s nothing I can do for you.” We want to correct that. We want to be able to have a physician have something that they can do for you.
And I think it wasn’t that long ago that certain cancers that people consider treatable now, the reason they are treatable is cause people found ways to treat them. And they are necessarily inherently any different. They are just, we figured out what to do for that particular one.
Brett: So essentially it’s just a matter of time?
Diane: It’s a matter of time and hard work and investment.
Suzanne: So is there such a thing as curing cancer? Cause it seems like it does reoccur a lot even if it’s a different kind.
Diane: Yeah. Yeah. So that is something that … that is why I use that word “cure” cautiously. Because often times if a person has a cancer, has cancer, and you treat that and you get rid of that, where it is initially, there are little seedlings in other places and those little seedlings may have small enough changes that they resist … they don’t, they don’t get hit by whatever that therapy is. And they’ll just sit there. And 10, 20 years later, they’ll grow again.
So, it is, even when we say “cured,” there may still be these little seeds planted that will come back later. So yeah, that definitely happens.
Brett: Does it depend on your body’s environment as well? Like if we both had similar types of cancer and these seedlings came, maybe they would regrow in you, but not necessarily in me, depending on kind of my internal body?
Diane: There’s so many different parameters that we don’t understand. I mean, some of it might be environmental, some of it might be diet and stress, and those sorts of things. There’s definitely correlations. There’s correlations to different generic backgrounds, things like that, for your susceptibility, but no single answer for that.
Brett: Okay, so maybe we can move onto a new topic. One called CAR-Ts. I keep hearing about this around the office and in the news and I have no idea what this is. So hoping, Diane, perhaps maybe you can shed some light on what this topic of CAR-Ts means or what it is?
Diane: CAR-Ts are, basically it’s a T-cell. So what a T-cell is … it is the component of your immune system, the cell in your immune system, that can specifically recognize a pathogen or a cancer or something. They are the -- T-cell’s are the ones that will go and kill the tumor.
So what a CAR-T is, is take T-cells out of the patient, the patient donates some blood, you know, and they take out the T-cells. And then they genetically add into that T-cell to make it to express a receptor that binds to the tumor. We know what that target might be on the tumor, but we put it into that T-cell to recognize it.
So now we have a T-cell, this whole collection of T-cells and they all think that they bind to that tumor. So you put them back in the patient and the idea is now, you have these T-cells that are all tricked into thinking that the thing they’re supposed to bind to is that tumor. They go there and they eliminate the tumor.
Suzanne: So they are immune cells, did you say?
Diane: Yes. They are the T-cells from the patients. You have to take them from that same patient because otherwise, because we’re all a little bit different, you know, my T-cells would recognize your tissues and your T-cells would recognize mine. So you can’t just transfer mine. It’s the patient’s own, but we’re putting in a receptor so that it binds and thinks that what it’s supposed to kill is the tumor.
Brett: So you are taking it out of the body and genetically modifying it or something?
Brett: And then plopping it back into the body?
Diane: Plopping it back in … a technical term.
Brett: A very scientific term … wow, that’s really interesting.
Suzanne: How the heck do they do that, though? How do they? I can’t even imagine?
Diane: It’s actually a pretty simple process. Like as a process goes. We do it in the lab all the time, for different kinds of experiments. So it’s not that far from what we might do just for trying to understand how a T-cell might work. It’s a kind of experiment we do, it’s really not that far away. So the genetically engineering piece of it is pretty straight forward. The hard part is there’s lots of different subsets of T-cells. There’s different ways to link it into how the T-cell signals. There’s a lot of subtleties and a lot of complexity and a lot of new … new ideas and new engineering and novel approaches using this core technology right now.
The thing is that, in the early versions of it have shown to be incredibly effective. And the reason is because the T-cell is about as powerful a killer as you can get. That … that’s what kills things. They are really powerful little guys. And so they work really well. The problem is they work in a subset of cancers and we don’t know how to get them to the rest yet. People are working on that. And then there’s also a lot of potential for toxicity because now you’re putting them back in the body. And so, like we talked about before, the toxicities, the potential for what those cells can do besides just kill the tumor, is there.
So learning how to control that when you put them back. Learning how to control it once they are back in the body is another area of engineering that’s going on right now.
Brett: That’s crazy. Sounds like science fiction or something.
Diane: Well, it can sound even worse if you … I’ll just tell you that one of the ways that they do the genetic engineering is with a virus. You basically infect them with a virus. That sounds even worse, but it’s all controlled.
Brett: This may sound stupid, but isn’t that like when you get your flu shot? Aren’t they putting the virus into your body to … am I saying that incorrectly?
Diane: You’re saying that right.
Brett: Is it along the same idea, or no?
Diane: Well, in the flu shot, in the flu shot, what you are doing is you’re serving it up … you’re serving a bit of the flu up to your immune system to recognize. And it’ll eat it up and tell all its buddies, “If you see this, get rid of it.” So when you get the flu, “Oh, we’ve already seen you, you’re out of here.” And they’ll kill it.
With the CAR-Ts, what it is, it’s the T-cells themselves. Those cells are … your flu shot is teaching? Instead of putting the flu shot in your body to teach it, we’re taking those T-cells out and we’re changing what they recognize. So instead of recognizing the flu shot you got last week, we’re putting something into them, so that they recognize the tumor, and putting them back.
Brett: But you can’t necessarily control them once they are in there? Is that what you’re saying?
Diane: Uh-huh. So in the earlier versions, in the early versions of it, when you put the cells back in, they recognize it, they expand, they divide, you know, they divide and expand, so there’s a whole bunch of them there, and that’s the potential for side effects. That is where the toxicities can come from. And so some of the newer methodologies are things where once they’re back in there, if they start to misbehave, can we do something that kills them? Can we put something into the cells that makes them sensitive, say, to a simple drug. And we could give the patient that drug and they’d kill them all off and then they’d be done. You know, ways to control them like that.
Brett: That’s interesting.
Suzanne: Is that? I’ve been hearing around, too, this concept of a bi-specific or an anti-drug conjugate -- is that something to do with this? Is there a way to attach something to the CAR-T that has a different kind of mechanism of action?
Diane: So an antibody drug conjugate is that, it’s an antibody, which is just a protein that has a known specificity. We know what it’s going to bind to. And we’ve chemically attached a drug to it, a small molecule drug. And that — what that does is the antibody finds the tumor and takes in that drug into the tumor, and kills it.
In some sense, with the CAR-T what we’re doing is we’re taking that same kind of specificity, but we’re giving it expressed in a T-cell, so we’re bringing the T-cell to the tumor and now the T-cell kills the tumor.
Suzanne: So the T-cell is sort of being the medicine in that case?
Diane: In that case. Uh-huh. And then for the bi-specifics. We have bi-specifics as well, it binds to the tumor. The other side binds to the T-cells. So instead of taking the cells out and giving them a specificity, we’re going to take those bi-specifics, stick it to the tumor, and then that other side of it binds to the T-cells, and says, “Hey T-cells, these are the cells you want to kill.” And draws them in that way.
Suzanne: So does that make it hard then to use CAR-T on someone who has just had chemo?
Diane: In that case, yeah, that’s an important point is that they do need to have T-cells that you can use. So if they’ve just had something that … and even the cancer itself, that’s one of the limitations of it. From the beginning, when we were talking about is this at the beginning, one thing that cancer does is suppress the immune system. So depending on the mechanisms of that, that patient may not have very good T-cells to use anyway. So that is also one of the challenges, that the patient has to have cells that you can use that way.
Brett: And like you said, you can’t use somebody else’s T-cells, you have to use T-cells from your own body.
Brett: Gold star for me? That,I actually understood that.
Suzanne: Could there ever be a situation where you could synthetically create T-cells that the body would recognize?
Diane: So that … it is part of a … it is one goal to be able to have what they call off the shelf CAR-T. Where you wouldn’t have to do it from the patient’s own cells, you could just have cells that you could just use. But what you have to be able to do is you have to make it so that the patient doesn’t recognize … the patient’s immune system doesn’t recognize those cells, and those cells don’t recognize the patient, for other reasons. And that’s actually not as easy as it might sound.
Suzanne: It doesn’t sound easy at all.
Brett: That doesn’t sound easy, it sounds confusing.
Diane: It’s just like if you needed a kidney, not anybody could just give you a kidney because your body would recognize it. So you have to make sure that it’s the right match. So the key in trying to have an off the shelf CAR-T is getting rid of all those things that would give you that reactivity that you don’t want. Both directions.
Brett: You’ve got a lot on your plate to think about this. This sounds like a hard problem to solve.
Diane: It is, but the way I look at it is that, we have lots of opportunities. It gives us lots of different ways. There are different cells in the immune system that can kill tumors, we have different ways to stimulate them. We have different ways to manipulate them. We just have to figure out the right way for certain cancer types.
Brett: It’s so fascinating. It’s really cool.
Suzanne: It is really cool. But I would think too, working in this field, if you … I’m sure you have friends and family who have been affected by cancer and how do you explain to people, when they … I’m sure they come to you with questions on okay, hurry up! You know, why can’t this be done sooner? Do you have any response to … what do you tell them?
Diane: I agree. Why can’t we do it sooner? More, faster. Sometimes at work when things are kind of crazy and things are going back and forth, we just stop and say, “We just have to stop. Patients are waiting. We really can’t mess around with this. We’ve got to figure this out. There’s gotta be a way.” It’s incredibly motivating. And you’re right. Most people, if you’re on the planet long enough, you’ve been affected by cancer. Someone you know, someone you love, or even yourself, unfortunately. And it is, it’s just a powerful motivator every day.
Brett: Do you love coming to work every day? Do you love what you do?
Diane: I love what I do. I love the … even if there’s something that I don’t like doing. You know, dealing with the budget or whatever. But even that stuff, the end goal. So the end goal is seeing patients being treated by therapies we can create. Therapies that … we have to do a good job of it. And I’ll tell you, there’s nothing, no bigger thrill than knowing that -- you know, you hear back from the clinicians, you know, that there’s a patient in the study that’s responding. Oh my gosh, that … that’ll cure any amount of bad days that you have.
Suzanne: So you talked about all the good things that kind of erase the bad days. But I’m curious about the frustration that I feel like must be so prevalent in your field. I mean, just all the dead ends and the failures. And how do you get through that?
Diane: There’s definitely more failures that successes, that’s just the nature of science. And when I was in grad school we used to always joke that 10 percent of science works. And so you’d go for weeks and say, “I’m waiting for my 10 percent. It’s gotta be coming soon, because I’m stuck in the 90.” And it’s just the nature of it. Is just kind of what we do.
This business is incredibly high risk. It just is. It’s just the nature of it. And if you, you know, if you’re not able to tolerate that, you go do something different, because it is what it is. But for me, it’s also that every time something fails, if it fails because I did the right experiment, it’s not a failure. We did the right experiment, we generated good data, it just wasn’t what we wanted it to be. That’s not a failure. Anytime -- what’s really a failure if you didn’t design your experiment well, you didn’t have the right controls, or you know, you dropped the sample on the way to the plate reader. Not that that’s ever happened.
But when it’s a good experiment, when it’s good data, it’s still good. It’s not really a failure. You can’t look at it that way. It’s something that, you know, it’s never a straight line. And you have to weave and turn and back track, and you have to be open minded and look for those things. If you think it’s linear, it means that you’re … you’ve turned off your peripheral vision and you are probably chasing wild geese. And not seeing that what you’re really looking for is somewhere else.
So, it’s just the nature of it. And to me, also, I do go back to thinking about the patients who are out there waiting. And if you get frustrated and let that set you back, you’re not doing them any good. You’re not doing anybody any good. You’re not going to get something better that they need.
So, it’s just part of what we do. And there’s definitely more frustration. I mean, I … I’m talking about it like I deal with it easily. But it’s there. You know. There’s a lot of days I drive home with the windows up and the radio cranked, cause you’ve got to sing really loud to something. That happens. But then the next day you come back and you’re at it again. It’s just what we do.
Suzanne: Okay so, Diane, thank you so much.
Brett: Thank you so much. I’m like in awe of our conversation today. We’ve been … we’ve been wanting to have this conversation with you for a long time. So we’ll have to get your autograph after we’re done with it … for a keepsake.
Suzanne: Before we go, there’s a little something fun that I try to torture Brett with at the end of these podcasts, where I make him basically regurgitate the information in a way that …
Brett: … to ensure that I actually learned something.
Suzanne: … to ensure he digested it. So I’m going to quiz him right now and you’re going to be our judge. Let us know if he learned what he was supposed to learn.
Brett: Okay so, I think I’m going to fail, but let’s see. Let’s see what happens. Okay, so what is immuno-oncology? Um, okay, this is going to sound like a really easy response, is it using the immune system to treat oncology? Something like that?
Brett: Niiicee. Pshewww.
Suzanne: Diane gives you a B+.
Brett: That was an easy one. Now give me the next one.
Suzanne: Okay, what do CAR-T cells have to do with immuno-oncology?
Brett: They are a way of … well, something about taking T-cells out of your body, genetically modifying them, like many of the science fiction movies I see, and then putting it back in the body to fight off immune cells in your body … the cancers in your body? Something like that. Close enough? A-?
Diane: Yes, that exactly right.
Suzanne: And lastly, why is it so difficult to cure cancer?
Brett: I think because so many cancers are different in their genetic make-up. And also they present themselves differently in different people, depending on the person’s biological make-up, environment, diet, stuff like that. Exercise. Stuff like that. I mean I know that’s not the perfect answer, but … do I pass? Diane: That’s pretty good. You pass.
Suzanne: You pass.
Brett: Good enough to make me pass. Awesome! Cool, psshhew … that stress is over with. Thank you so much, Diane. Thank you for having us out here in Redwood City. We had fun visiting your place of work and testing your brain this afternoon, so thank you so much!
Suzanne: Yeah, we appreciate it.
Diane: Thank you. This was very fun!