Immunotherapy for Breast Cancer: Part 2
Listen to the podcast to hear Dr. Litton discuss:
how immunotherapy medicines work
why immunotherapy medicines haven’t seemed to work as well in breast cancer as they have in other cancers
the direction of immunotherapy research for breast cancer
Dr. Jennifer Litton is a board-certified medical oncologist and professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, where she is also vice president of clinical research. She also is a member of the Breast Immuno-Oncology Task Force of the National Cancer Institute.
— Last updated on May 3, 2022, 2:05 PM
Jamie DePolo: Hello everyone, welcome to this edition of the Breastcancer.org podcast. I’m Jamie DePolo, the senior editor at Breastcancer.org. Our guest today is Dr. Jennifer Litton, board-certified medical oncologist and associate professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. She’s also chief of the Section of Clinical Research and Drug Development for Breast Cancer and a member of the Breast Immuno-Oncology Task Force of the National Cancer Institute. Today, she’s going to talk to us about immunotherapy for breast cancer.
Dr. Litton, welcome to the podcast.
Jennifer Litton: Thank you very much for the invitation to talk about immunotherapy and breast cancer today.
Jamie DePolo: To start, we get a lot of questions about immunotherapy to our website. I think a lot of people are seeing the news stories. They’re seeing all the commercials, especially for Keytruda, and how amazing these things work. And there’s a lot of questions about immunotherapy to treat breast cancer. So to start, can you just talk to us generally about how does immunotherapy work and why is this such a big deal?
Jennifer Litton: Sure. So I think immunotherapy, right now, is a very broad term for just using the immune system to find and attack and battle the cancer. And I certainly understand, we see those commercials all the time, and these drugs that are out there and are FDA approved for several cancers, I really do believe have been absolutely game-changing for a lot of cancer patients. One of the things you’ll notice is that the cancers that they’re actually approved for are ones that have a lot of differences than breast cancer. I mean, they’ve been absolutely game-changing for things like melanoma and lung cancers and other cancers that are coming forward, even some of the colon cancers and kidney cancers.
If we take melanoma, for example. So melanoma is, when we look at the scale of how much DNA damage is in different tumors, melanoma’s really at one of the top of the scales. It has such a high burden of mutations within each and every tumor. But if you look at those tumors, they tend to have a lot of immune cells that are really just kind of sitting in the middle of the tumors.
And now what these drugs — and I’m going to really say these are some of the first generation, because what’s coming through I think I equally have a lot of enthusiasm and excitement about — but these drugs, the ones you’re seeing on TV, what they do is… if you can imagine, these tumors have found a way to live with immune cells just sitting in them but not eating the tumor cells. And what these new drugs do is all of a sudden kind of take off the mask of the tumor cells, and those immune cells, those T-cells that are just sitting in the tumor, just start to attack the tumor that it’s sitting in. These tumors get really smart. They find different ways to blockade. I do have a young son, and when I’m talking about them to patients I kind of talk about Harry Potter, and I talk about the cloak of invisibility, and these tumors find a way to do that, and this is really ripping them off. And I think patients get that when we kind of talk about that. So, those tumors tend to have, already in them, a ton of immune cells.
Now, the problem with breast cancer, when we look at the whole list of how much DNA damage, breast cancer is not at that top tier. It’s really kind of in the bottom half of tumors. And a lot of breast cancers are very… when you look at the tumors, they don’t have a lot of immune cells that are just sitting there ready to be affected. If you give those immunotherapies and there’s no T cells or immune cells just sitting in the tumor ready to attack, then giving the immunotherapies really don’t make a difference. It takes the attack signal off, but there’s nothing there to do anything about it.
Now, we also know that breast cancer is not a disease in and of itself. It’s so many different subtypes and subtypes of subtypes, and we are noticing that some of the tumors such as some of the triple-negative breast cancers, some of the HER2-positive tumors tend to have a higher percentage, although we’re talking still low numbers, of having immune cells just sitting in the tumor. And that’s why a lot of the early trials in breast cancer using those similar drugs are really focusing on using those in those subtypes of breast cancer. And the early studies show, not surprisingly, that for the vast majority of patients the immunotherapy really didn’t have a huge impact. But why do people start to get a hint of excitement? Because in some of the early trials for those patients who did have a response, they had what we saw in melanoma as a very durable response, a very long response, still going response, and so that’s absolutely what we’re going for.
So I will say in breast cancer right now, the use of single agent of these immunotherapies that are currently FDA approved, I don’t think has as much excitement as they would for other types of tumors. So how do we augment that? How do we bring more of the immune cells sitting into the tumor so that they can really start to attack the tumors where they are in the body? And that’s where all the new clinical trials’ research in new agents are going. And you’re going to see things like the addition of radiation or combining immuno-oncology agents, one that kind of brings those immune cells in and then allows them to attack the tumor. Or, can we use things like vaccines? Can we use other ways of trying to spur the tumor into becoming its own almost beginning of the immune response and then letting it go to the other sites within the body?
Jamie DePolo: So it’s the amount of DNA damage in a cancer that makes the…
Jennifer Litton: Yeah, I think that’s part of it.
Jamie DePolo: I just wondered, why don’t all cancers have high levels of immune cells in them? Do we know?
Jennifer Litton: I think it’s a lot of complicated of how the cells talk to the non-tumor cells that we’re still really trying to learn. It’s not just all about the tumor cells, but it’s also, I’d say, the tumor bed and all the other cells and how they talk to the tumor cells. And there’s so much research going on right now to understand the whole conversation that the tumor cells are having with the rest of the body either locally and distant. And so unfortunately, it’s not a very clear-cut “we can just shove a T-cell in there and it will work” because we would do that and we would try that, but are we also bringing in the right ones? Are we bringing in the right ones that when we give the attack signal they actually do what we want them to do, and do they spare the other cells around it we need to keep healthy?
It’s a very complicated question on how to get that done. And I think the next round of trials, if people want to participate, I think it’s going to be very important that these trials not only have the new agents or the new interventions but also have associated biopsy and blood that we can make sure we’re doing what we hope we’re doing in those tumors.
Jamie DePolo: Okay. Thank you. That’s a helpful explanation. And one thing I’ve always wondered, too, I understand that it’s better if the immune cells are in the tumor and then when they’re activated they’re already there and they can attack, but I guess I’ve always wondered if an immunotherapy is going to rev up the immune system and rev up these cells, there are immune cells in other places in the body. How come, then, they don’t go and attack the tumor? Is that not the way immunotherapy works? I don’t know.
Jennifer Litton: No, it does. I mean, if you look at the side effects, those are the biggest side effects, is that you start to get inflammation in other parts of the body where you’re not wanting to get inflammation: the lungs, the thyroid, the liver, skin, the gut. So that is always — we could just rev up the immune system and let it go, but that would be a horrible thing. There has to be checks and balances all across there, and there has to be, or certainly what we’re searching for, is to try to get it targeted for the tumor and not for the rest of the body. And it’s a balance, and that’s why you can’t just rev up the immune system without having the appropriate stops. So how do you take the stops off just with the tumor cells and keep the stops on with good and healthy tissue? That’s a bit of the yin and the yang, I suppose.
Jamie DePolo: Thank you. That’s helpful. Speaking of being very targeted, some researchers have explained to me that targeted therapy medicines like Herceptin, Perjeta, Kadcyla, those are also considered immunotherapies. Can you help me understand why that is?
Jennifer Litton: I like to say in breast cancer, I know that in the last decade everyone’s been talking about targeted therapy and immunotherapy, you know in breast cancer, targeted therapy such as the estrogen receptor and immunotherapy — we’ve been doing it for decades. I think that when we look at things like Herceptin, specifically, because the rest are really based on that, it was always meant to be the vehicle to get us to the targeted area and that’s why something like Kadcyla, where you actually use the vehicle and then deliver the very toxic chemical directly inside of the HER2-positive cell, is exciting. But we’re really realizing that the Herceptin itself also had immunotherapy properties.
I think one of the best ways to explain it, or maybe not even explain it but that you can really kind of see that, is if we look at the CLEOPATRA data, which was [docetaxel], trastuzumab, and pertuzumab, and we saw the progression-free survival that was clearly better with the addition of the triplet. But we look at the overall survival data and it so far surpassed what you would expect from just the progression-free survival. I think we underestimate how much of the antibody-directed attack that these monoclonal antibodies can have. So although they do have some direct signaling I think that we’re also seeing the antibody do its immunotherapy killing on the backside as well.
Jamie DePolo: Immunotherapy isn’t quite ready for prime time for breast cancer yet. The studies are ongoing. Can you kind of give us a sense of where we are now and kind of where it’s headed? I know you mentioned maybe using some combinations either with radiation or with a vaccine? Where are we going with all this?
Jennifer Litton: So, I think you’re going to see several trials coming forward where they’re adding chemotherapy to try to also, if you have cell death that releases antigens, with the immune therapy and I think that’s something very promising to look at. The use of radiation has been especially interesting in other tumor types and evaluating in breast as well, and I think many trials are going to be looking at how best to do that, and not only just the combination but how should the radiation be given? Should it be a more directed dose, the scattered dose, the lower? And there’ll be a lot of ways to be asking that question. You might see things that are directly injected into the tumor. You may see different ways of trying to get the immune response started and then taking advantage of it with some of these immune checkpoint inhibitors.
Jamie DePolo: The immune checkpoint inhibitors, that’s something like a Keytruda where they’re actually taking the breaks off the immune cells that are in the tumor. Is that right?
Jennifer Litton: Exactly.
Jamie DePolo: Dr. Litton, thank you so much. This has been very helpful. We are going to keep checking in with immunotherapy and keep everybody updated on the latest and greatest. Thank you so much.
Jennifer Litton: Please do. I expect that with every year we’re going to see new studies trying to enhance its use in breast cancer.