Taking CAR T cell Immunotherapy to the Next Level

Chuck: This is the Good News About Cancer. I’m Dr. Chuck Ryan.

Alicia: And I’m Dr. Alicia Morgans. 

Chuck: We're oncologists, and we've spent our careers working to understand cancer. We believe that there's more progress now in research and treatment than ever before, and we're here to share that with you.

Alicia: In each episode of this show, we talk with one of our colleagues about a promising development in oncology. We'll break down what's new, why it matters, and how it points the way forward.

Saul:  We can, in theory, get around all of those barriers to make CAR T cells that are as effective or even more effective than we've seen historically for liquid cancers. 

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Chuck:  You know, Alicia, I think back to my early days in medicine as a medical student, even as a resident in internal medicine and thinking a lot about cancer and deciding I wanted to apply my career to cancer. And I remember there were always a group of people in every cancer center I worked in who really believed that immunotherapy was going to be the direction that we would get. 

And this was back when we had things like, you'll remember this high dose interleukin, maybe interferon, and it made patients tremendously sick, and it maybe worked in five or 10% of patients, but when it worked, it worked really, really well.

But I always thought, you know, that just seemed like it wasn't going to crack through the ceiling, and it just seemed like it wasn't going to be a direction that would be broadly applied. 

But now, a generation later, we've actually gone through this whole revolution in immunotherapy and we're actually moving on to sort of a new generation of immunotherapies.

Alicia: There has definitely been a transformation. Those old treatments that we had to give in the ICU were terrifying.Certainly for the patients and also for the doctors taking care of them. And as you said, they didn't work in most people. 

So now we see that we have treatments that are harnessing the immune system in ways that are safer – for most patients at least – and seem to be much more effective.

One of the biggest advances in immunotherapy is the CAR T approach, where the T cells, the attacking cells of our immune system are trained to attack a specific target, which in this case of course, is cancer.

Chuck: Right. And the cells, the patient's T cells, become the drug. And that's a really cool concept. So CAR T therapy started as a highly experimental treatment for a very refractory leukemia about a decade ago– more than a decade ago, and now it's gradually expanding into other areas, hematologic cancer, and even the solid tumors. 

Alicia: And now beyond those, we're using this type of immunotherapy – or harnessing of an individual's own immune system – to fight more cancers than we even thought possible.

So let's hear from Dr. Saul Priceman, who is an associate professor at the University of Southern California. He works at the Keck School of Medicine and the Norris Comprehensive Cancer Center, where he is the founding director of the Cancer Cell Therapy Research Center.

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Chuck: Saul Priceman of USC. Welcome to the Good News About Cancer.

Saul: Thank you. It's so good to be here.

Chuck: You know, I feel like we're at a bit of an inflection point around immunotherapy. We had a big wave about a decade ago with the checkpoint inhibitors, and those have been wonderful. We've talked about those on the podcast before. 

But there are some gaps that we want to fill and there are some ways that we can take immunotherapy to the next level. And I think it's fairly apparent that CAR T therapy may be one such approach. Could you just kind of walk us through, first of all, what is a CAR T therapy? And then we'll talk about where we use it and what we need to do.

Saul: Yeah, so it's an evolution of our understanding of T cells, which are the major, if you will, fighter cells in our body. They go around the body and they immune-survey, they look for cells that don't belong, and they can kill them. 

And what we've learned to do is we can engineer those T cells outside of the body with a molecule called a chimeric antigen receptor, or CAR, then infuse them back into the patient and they do what they were born to do. Which is to identify a cell specifically, that's a cancer cell or a virally infected cell, and kill that cell very selectively.

Alicia: How does the CAR T really recognize the cancer that we want it to get rid of? Especially since anybody's individual cancer is going to be unique to them also, right, and somewhat similar in some ways, perhaps, to the rest of the cells in their body. So how does that work?

Saul: So, the way that T cells recognize a virally infected cell is because through evolution, our bodies – and don't ask me how – our bodies present bits of a virus on the surface of the virally infected cell, that's how we do it. So that virally infected cell is effectively presenting the virus bits that are inside the cell to the immune system, and a T cell can recognize those viral bits. 

What we typically do, and I'm using the royal we, but we identify a cell using what's called antibodies. Those are proteins that can recognize something that's expressed in or on the surface of a cell. We'll call that the target cell, which is a cancer cell for all intent and purposes for us. And those antibodies can recognize and latch on to a specific protein that's expressed on the surface of that cancer cell. And so the chimeric antigen receptor uses that antibody biology, it uses that recognition and binding ability of the antibody. 

Chuck: It’s a way of saying, here's the target, T cell, come and get me.

Saul: The way that I do it is, you know, when I was in jail 10 years ago, I had a number.

Chuck: Mm-hmm.

Saul: Well, I wasn't in jail, but prisoners have a number and it's an identification number. And the warden comes around every night and says, ‘9276463.’ And that prisoner says, ‘That's me.’

Well, a virally infected cell does the same thing, and a cancer cell should do the same thing and it tells the T cell: that's who I am. And if the T cell doesn't like it, it attacks it.

Chuck: Google searches for your name just went up about 20%. Did Saul Priceman really serve time?

Saul: And what was his prisoner number?

Chuck: So, this is different from, if you will, old fashioned immunotherapy. And I think you have clarified that. In that: the standard immunotherapy that we've been using for a while, checkpoint inhibitors, Keytruda being the classic example, activates T cells generally, in a way, in a cancer environment.

Whereas the CAR T dream is sort of – or the scientific goal, shouldn't call it a dream, is that the T cells are going to hit the cancer cell pretty much specifically, and in a very kind of targeted fashion, correct?

Saul: Yes.

Chuck: It's now been, you know, about what, about 14 years or 10 years or something like that since the first CAR Ts kind of hit the news. There's an article in the New York Times in 2012, I found, “A Breakthrough Against Leukemia Using Altered T-Cells” is the title. And that story is sort of part of the oncology, you know, lore and history, now Tell us that story.

Saul: Well, I don't know it as intimately as the folks at the University of Pennsylvania, but this was a young girl, Emily Whitehead, who had a refractory leukemia. And I think she had exhausted all types of therapy. There was nothing left.

Chuck: Yeah. 

Saul:  And she was effectively the Guinea pig for this because she was the first– a young girl who, they had taken her blood out, engineered her T cells with a chimeric antigen receptor, and put it back into her through her veins, and she had a remarkable response.

This was sort of the first example where you could engineer CAR T cells in a very patient-specific manner. You couldn't give Emily's blood or her car T cells to anybody else.

Chuck: Right.

Saul: They were given back to her, and she had a remarkable response. And I think they just presented now – it's a couple years old – but they had presented her 10 years post CAR T cell therapy. She hasn't seen another therapy since. And she's effectively, which I don't like to use the word, but cured of her disease.

Chuck: And she's an ambassador for this approach and this disease, I think, and making national headlines.

One thing you just said I think is really important is: if we were to go and take a tube of blood from her vein today, we would find the engineered T cells still circulating around in her blood. Is that correct?

Saul: You could. I mean, we, we do term this a “living drug.” This is not something that you need more than once. In theory it should be in your body for the rest of your life. And if the cancer comes back, those CAR T cells should wake up again and fight the cancer. We don't see this all the time, but yes, if you looked at her blood, there would be a couple of CAR T cells in her blood still staving off cancer, maybe. 

Alicia: I would love to hear your thoughts on what is different between a cancer that is a bloodborne cancer or something like leukemia or lymphoma. Or something that is what we would call a solid cancer. So something that starts in an organ like a lung cancer or a pancreas cancer.

What makes those different and how does that affect our expectations of how successful these CAR T therapies can be and, and how do we make them perhaps more successful in some of the cancers that are more challenging?

Saul: Yeah, I mean, I'm going to use the word “microenvironment.” But what the biggest difference is, is if you think about leukemia, leukemia is a circulating disease. It's in the blood, all the time, and there's no real home or microenvironment for those cancer cells. 

Whereas if you think about liver cancer or kidney cancer, ovarian cancer, they have a home. There's a microenvironment with which that cancer grows in, and it's a very heterogeneous mixture of cells that encompass that home, that microenvironment, and that can pose a lot of challenges for how those T cells engage the cancer cell, even get into that cancer, to that mass – and how well they function.

Whereas in a leukemia patient where we infuse the CAR T cells, those T cells are engaging cancer almost immediately, and they're circulating in the blood as the cancer is doing, which in some cases makes it a lot easier for those CAR T cells to do what they are supposed to do.

Chuck: I remember early in my career I was at a conference and somebody talked about: a tumor is really not just cancer cells, it's really an organ by itself. It's got its own blood supply, it's got its own immune defenses, it's got its own sort of extracellular matrix, you know, sort of the stuff that keeps it all stuck together.

And the sooner we begin to think about a tumor like that, the sooner we'll realize, A, the complexity of what treating cancer is, and B, how we can figure out ways to get our treatments, whether it's a drug or a cell, to the cancer cell itself. 

And I think to some degree, the work you've done and the work that's been done with CAR Ts more generally has attempted to do that, right? You can engineer into the cells ways to combat, to, to defeat the defenses that the tumor organ, if you will, is putting up against the T-cell penetrating.

Saul: Yeah, I remember being utterly shocked when I learned that if you took a breast cancer mass and you cut it in half and looked at the cells that are in there. About 50%, half of the cells that are in breast cancer and a lot of other cancers are not the cancer cell. It's as you said, Chuck, it's the blood supply. It's the stromal cells that keep an organ intact, and actually 30 to 50% of that mass can be immune cells. 

So the first question that I wanted to answer as a new scientist was like, what are those immune cells doing? And if they are so abundant in the cancer, shouldn't they be getting rid of the cancer?

And so we do spend a lot of time understanding what those cells are doing in the cancer. And are they benefiting or disrupting an effective CAR T cell response. And again, very distinct from leukemia – not that it's an easy disease to eradicate – but there's no microenvironment.

Alicia: Chuck and I treat prostate cancer. This is what many people have referred to as an “immunologically cold” tumor. And in English, I think that means just that the immune system is not able to penetrate those cancers very well. We don't expect that CAR Ts can get in there and really root out the cancer cells and kill them as they're supposed to. 

And I know that prostate cancer cannot be the only cancer that behaves that way, but I also know that I would love to have this kind of technology target and attack those cancer cells just as they can in other settings. 

So what are the next steps, and how do you see this kind of a treatment moving forward for solid cancers to try to allow them to be sensitive? And where do you see this going in the future to expand our opportunities for other people?

Saul: The Royal “we” were investigating how to use CAR T cell therapies and other immunotherapies to treat cancer, whether it was a blood cancer or a solid tumor. And for many reasons, we applied CAR T cells to liquid cancers for reasons that maybe we talked about, lack of microenvironment, maybe somewhat easier to treat at least, transiently, temporarily, and could identify whether there was a there there with CAR T cells for cancer in general. 

And it was striking in the early 2000s, 2010, and, and the few years after that, where we knew there was a there there and how best to apply it. And it was probably one of the shortest development programs that I've seen in terms of gaining FDA approval for a CAR T cell – I think it was six years or seven years – 2017 was the first FDA approval. And there have been like eight to ten FDA approvals over the last eight or nine years. All for liquid cancers, leukemia, lymphoma, or myeloma. 

But now we know it's not a one trick pony. When we started, it was CD 19, which is the protein that's expressed on most all B cells, which is where leukemia, lymphomas, and myelomas arrive from. And now we've shown that BCMA, which is another target that we've gone after for myeloma. So we have two different targets and we know we can make them a bunch of different ways. 

And we know we have different patient populations – at least three, leukemia, lymphoma, myeloma – where we can see tremendous responses. So when I started this, now 13 years ago, I was like, ah, should be really easy. We're going to develop CAR T cells for solid tumors and it'll work as well as for liquid cancer. And we soon found out that's not the case for many reasons. 

But one of the beauties of CAR T cells is that you can make them so many different ways, and because we're engineering them with genes that make the CAR protein, we can, in theory, engineer a T cell to express anything we want them to. 

So the barriers that we've identified in solid tumors, being the microenvironment and immunologically cold, as you mentioned, we can in theory get around all of those barriers to make CAR T cells that are as effective or even more effective than we've seen historically for liquid cancers. 

So in the lab now we are at work a lot, learning how to engineer the T cells, and how to test them in the lab so we can better predict what might happen in our clinical trials.

Chuck: But Saul, you may get to a point where you don't even need to take the  T cells out, right? There's work being done on what are called in vivo CAR T. Tell us about that.

Saul: Yeah, so there's a couple ways to get around having to take the T cells out of the body, do stuff to them and put them back into the body. One is: you know, Emily's blood gave Emily's CAR T cells, which were infused back into Emily. That's what's called autologous. Is Patient A provides Patient A with their therapy. 

But now we have what's called allogeneic, which in theory, you can take healthy donor A blood and provide CAR T-cells to patients A through Z. Through allogeneic CAR T cell therapy. And now, because we've learned so much about how to engineer cells in general, we are right now, as we speak, gaining clinical experience – without FDA approvals, but early clinical experience – that maybe we don't need to take out the T-cell from the body, we can just engineer them inside the body, which saves time and also becomes more of a typical drug.

Chuck: It is one of those amazing points about technologies. The more sophisticated it gets, the simpler it gets in a way. It’s a paradox, right?

Saul: Totally.

Chuck: You know, it's interesting also, I've heard recently that outside of the world of cancer, the world of rheumatology, or autoimmune disease, is seeing some progress with regards to the use of CAR T therapies. 

Which, if you think about it, makes sense because an autoimmune disease is cells and T cells may be, you know, overactive, attacking normal tissues. Is that something that you work in or is that something you're following closely? What, what do you know about that?

Saul: You know, I'm following closely for many reasons. Autoimmune diseases are, very prevalent as we know, and it's a very exciting field, and it’s really new, but I actually think in the next, couple of years, maybe even sooner, we will start to see FDA approvals using CAR T cells that we've used for liquid cancers to treat very durably, sclerosis and lupus and maybe type one diabetes.

Chuck: Wouldn't that be amazing? Type one diabetes.

Saul: Totally. I think the field is burgeoning. I know the field is burgeoning and there are a number of academic lab and programs and industry, which is always beautiful to see, that are expanding this field. 

So I think we're in early days of changing clinical practice for a number of solid tumors. We're obviously in trial for various cancers – ovarian cancer, breast cancers, prostate cancers, soon to be pancreatic cancer. I think we'll have great progress using CAR T cells for a number of cancers and autoimmune diseases in the very near future. 

Alicia: It is truly exciting and, thank you for your time and for sharing your enthusiasm and your expertise.

Saul: My pleasure. 

Chuck: To be, witness to some of the great developments that you and your lab and your colleagues are doing, and I look forward to more. So stay tuned,

Saul: Thank you both.

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Alicia:  Wow, what an exciting conversation. 

Chuck: I really like talking to Saul. I've gotten to know him a little bit over the years and he's a great ambassador for this technology and you know, it's about programming the patient's T cells and so it sort of turns the concept of a drug on its head a little bit. And that I think is really exciting because if we can program it to do this thing or to hit that target, there's, I don't wanna say no end, but there's a pretty bright future for all of the different areas that we can program T cells against various different targets, combinations of targets, et cetera, et cetera. So very exciting times.

Alicia: And the idea of a living therapy that continues to work over time. Yeah. Even as the patient is exposed to the rest of his or her life is pretty incredible.

Chuck: I love that. I love that idea of the living drug that's with us forever. 

CREDITS:

Alica: Thank you for listening to the Good News about Cancer.  I'm Dr. Alicia Morgans at Dana-Farber Cancer Institute in Boston.

Chuck: And  I'm Dr. Chuck Ryan at Memorial Sloan Kettering Cancer Center in New York. The views we express on this show are our own and do not represent the views or opinions of the institutions where we work. 

Alicia: Thanks to Lilly for support of the show. Our production partner for this series is CitizenRacecar. This episode was produced by Anna Van Dine with post-production by Alex Brouwer. 

Chuck: And there's a whole lot more good news to talk about. So make sure you subscribe to this wherever you listen to your podcasts. And if you like the show, share it with someone you think might find it interesting. 

Alicia: And we'll be back again soon with some more good news about cancer.