Enseñarle al sistema inmunitario a luchar contra el cáncer

Welcome to The Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here’s your host, Breastcancer.org Senior Editor, Jamie DePolo .

Jamie DePolo: Hello, thanks for listening.

Antibody-drug conjugates, or ADCs, are a relatively new type of medicine for breast cancer. Enhertu, Dato DXd, Kadcyla, and Trodelvy are all ADCs used to treat breast cancer. Today I'm joined by Dr. Benjamin Schrank, resident physician in radiation oncology at the University of Texas, MD Anderson Cancer Center in Houston. He and his colleagues, Dr. Betty Kim and Dr. Wen Jiang, are working to develop an antibody-toxin conjugate. This new type of drug combines the benefits of ADCs and immunotherapy. He joins us to discuss the research. Dr. Schrank, welcome to the podcast. 

Dr. Benjamin Schrank: Thank you so much. Delighted to be with you.

Jamie DePolo: So, to start, just in case anybody doesn’t know or doesn’t understand, could you give us a little explanation of what ADCs are and how they work? What’s the rationale behind them?

Dr. Benjamin Schrank: Sure. So, you know, antibody-drug conjugates, also known as ADCs, are really special medicines that are designed to deliver powerful treatments directly to cancer cells. So, an ADC combines two parts. There’s an antibody, which, again, is a protein that recognizes and attaches to a specific marker on cancer cells. Then, there’s a drug, also known as a payload, that can be a toxin or a chemotherapeutic agent. The idea is that the antibody guides the drug straight to the cancer cell. And so, once that ADC attaches to the cancer cell it’s basically pulled inside and then the drug is released and kills the cancer cell from within.

So, the goal here really is for the ADC to be more precise than typical chemotherapies, which can circulate around the body and damage healthy cells too. 

Jamie DePolo: Okay. Sometimes when I'm talking about them, I talk about a smart bomb. I know that’s not exactly correct, but it’s almost like the drug that’s going to kill the cancer cells has, like, a homing device on it and it goes directly to the cancer. 

Dr. Benjamin Schrank: That’s exactly right. That’s that antibody that really serves as that homing device because that antibody is unique to the cancer cell. So, that allows it to target the payload directly. 

Jamie DePolo: Okay. And now, your new medicine is an antibody-toxin conjugate. So, what’s the antibody and what’s the toxin, and kind of how did you come up with this idea? What’s the rationale, is it maybe going to have fewer side effects than traditional chemo?

Dr. Benjamin Schrank: Yeah. It really is a new idea because the whole principle behind antibody-toxin conjugate is that it works not just on the cancer cells, but on the immune system, too. So, the protein that it targets on the surface of cancer cells is called CD47. CD47 is known as a “don’t eat me” signal in the cancer world because it helps cancer cells avoid a more specific type of immune cell called a macrophage.

The idea is that CD47 is expressed on lots of different types of breast cancer cells. So, by blocking CD47 we can promote cancer cell phagocytosis, or the process of eating cancer cells by macrophages and other types of dendritic cells.

And then the toxin part of this is called LLO, or listeriolysin O, and that’s a protein that’s found typically in bacteria, called Listeria monocytogenes, and it has a unique ability to work inside immune cells like macrophages and dendritic cells.

Jamie DePolo: Okay. So, let me make sure I understand. So, basically the cancer cells have…I know sometimes people talk about them having an invisibility cloak. This is different. This protein that you're targeting is almost like a big sign that says, do not eat me, I'm not good for you, to the immune system. And then, the toxin of Listeria, now that can cause food poisoning too, so is that okay to get into somebody’s body? I guess if it’s going straight into the cancer cell it’s not a problem?

Dr. Benjamin Schrank: Yeah. Well, this is kind of the magic behind how the drug works because the toxin itself is not acting on the cancer cell directly. It’s actually acting on the macrophage. Let me just take a step back and explain to you how the ADC works. 

Jamie DePolo: Okay.

Dr. Benjamin Schrank: You can imagine that your cancer cell has the CD47 proteins that are expressed on the surface and the antibody basically binds to the surface of the cancer cell and essentially decorates it, kind of like a Christmas tree. And then, the macrophage comes in and eats the cancer cell with the antibody-drug conjugate attached. Inside the macrophage, okay, the listeriolysin O becomes active and what it does is it pokes holes in the phagolysosome membranes. 

So, what are phagolysosomes? Well, these are organelles. These are essentially the workhorses inside the macrophage that degrade material that the macrophage has eaten. And so, what it does is it pokes holes inside the phagolysosome membrane, and it allows cancer peptides and DNA to escape into the cytoplasm of the macrophage and that activates the macrophage and makes it an even more potent driver of cancer immunity. 

Jamie DePolo: I see. So, it’s almost like…this is going to sound a little gross, but it’s like it’s poking holes in it to get the juice out and then that makes the macrophage work harder to chew everything up basically. 

Dr. Benjamin Schrank: Right. So typically, all of that tumor content is degraded. And so, the macrophage doesn’t really know what it’s eaten, but when you poke holes in this little organelle inside the macrophage suddenly the macrophage can say, oh, wow, I had tumor DNA, that’s not normal. Or it will say, oh wow, look, these are tumor peptides. Let me present these on the surface of the cell and try to coordinate an adaptive immune response against cancer. 

So, it’s actually a totally new way of thinking about ADCs or ATCs because, as we mentioned in the beginning, the whole theory behind these drugs is that typically they direct toxins or chemotherapeutic agents towards the cancer cell and in this case what we’re doing is actually taking the active agent, which in this case is LLO and were taking it to the immune cell, not the cancer cell, and having an effect on the immune cell rather than the cancer cell directly.

Jamie DePolo: Oh okay. So, if I'm understanding right, I just want to make sure I've got this, it’s almost sort of a double thing because the macrophage, the immune cell, is eating the cancer cell but then it’s also presenting it to the immune system and saying, hey, this is bad, you better mount a response. So, is the idea then that the immune system starts to recognize these cancer cells and attack them so they can't grow?

Dr. Benjamin Schrank: Correct. And that’s what we think drives a lot of the responses that we’re seeing in our preclinical models. So, when a macrophage is doing a good job, the macrophage is able to recruit lots of different kinds of immune cells into the tumor. Not just other macrophages, but also other T-cells and other B-cells and other important immune cell components that are important for driving anti-tumor immunity. And so, the macrophage, when it’s super charged with our ADC, is able to act almost like a conductor and bring in the different instruments of the orchestra that are needed to attack the cancer. 

Jamie DePolo: I see. And they’re all coming into the cancer cell, is that correct?

Dr. Benjamin Schrank: They’re all going into the tumor. 

Jamie DePolo: Into the tumor, sorry. 

Dr. Benjamin Schrank: Into the tumor. Exactly. 

Jamie DePolo: Okay. Because I have read at least one study that looked at another type of immune cell, a tumor infiltrating lymphocyte. The study found that cancers that had more of these lymphocytes in them were less likely to recur and people had better outcomes. So, it sounds like what you're doing, I mean, it’s kind of all of a piece. 

Dr. Benjamin Schrank: We’re tapping into that mechanism, but it’s a brand-new drug and a brand-new approach to do that. 

Jamie DePolo: Okay.

Dr. Benjamin Schrank: So, when we’re able to activate the macrophage, that macrophage sends signals to the other cell types, those other members of the orchestra, and says, come on in. There’s something unusual going on here. And that drives in all of those important cell types that we know attack and destroy cancer. 

Jamie DePolo: Okay. So, how did you all come up with this idea of attaching, you know, that antibody to a toxin rather than a chemotherapy?

Dr. Benjamin Schrank: Yeah. Well, so we were looking for a way to release these highly stimulatory cancer components inside macrophages. And we were looking for a drug that could do this and there really aren’t a lot of options for this sort of a mechanism where you can increase phagocytosis and then try to spill contents inside the macrophage without damaging the macrophage. At the end of the day, the macrophage is the workhorse of our drug. We need that macrophage to be happy and healthy and coordinating these immune responses. 

And so, we actually turned to nature and that’s where we found listeriolysin O. So, listeriolysin O again, is a peptide or a protein that is produced by Listeria monocytogenes and it essentially allows the bacteria to escape destruction inside the phagolysosome.  So, it forms these little pores, the bacteria basically escapes and then lives inside the macrophage. It takes advantage of the macrophage’s cellular machinery to grow and divide. It doesn’t damage it and that is really the key here, is that we’re not taking the bacteria, we’re taking the protein that the bacteria uses to survive inside the macrophage and coopting that as a cancer immunotherapy. And that’s the rationale. There’s no other drug that I'm aware of that allows us to selectively permeabilize or create little holes in these phagolysosome membranes. It would only be something as amazing and brilliant as nature to come up with these miracles. 

Jamie DePolo: Right. Right. Okay. Well, that’s pretty amazing. So, your study, it was preclinical, and if I read everything correctly it means it was done in cells, not even mice, am I right or you did do it in mice?

Dr. Benjamin Schrank: Yeah, it’s done in mice, which was important for us to see because we needed to have mouse models of breast cancer that were metastatic so we could see the effects of the drug not just on the tumors that we were treating, but also on the tumors that were growing throughout the body and it was really important for us to see that the immune response inside the tumor that we were treating was having an effect on untreated tumors. 

So, essentially meaning that concerted effort inside the tumor by the macrophage to recruit all these immune cells inside was leading to an overall body response inside the animal. So that way, the animal was able to fight off the cancer cells that didn’t directly see the drug, which is sort of the whole premise behind anti-tumor immunity; that you are developing an immune reaction against the tumor that then educates the immune system and allows it to go off and fight cancer in other parts of the body. 

Jamie DePolo: Right. That’s amazing. So, where do you go from here? I know with most things like this at this point that it could be 10, 15, 20 years. What are the next steps for your research now?

Dr. Benjamin Schrank: Yeah. So, we have different versions of this drug to try to increase its specificity for the cancer cell. So, one thing that we notice in our study is that when we target with CD47 we see some off-target effects because CD47 is also expressed on some healthy cells in the body, like platelets and red blood cells. 

And so, what we’re doing is we are taking this drug and we’re changing it just slightly to create something called a bispecific antibody, which basically recognizes two components of the tumor. One of them is CD47 and another is a tumor antigen that’s specific to cancer cells. And the idea here is to try to decrease some of the potential side effects related to this medicine; we’re creating this iteration of the ADC, which we think will have equally if not greater efficacy and much less risk of side effects to patients. 

Jamie DePolo: Okay. And when you talk about platelets, that could potentially be some sort of blood side effects, I don’t know, leukemia or anything like that? Or just different types of autoimmune disorders?

Dr. Benjamin Schrank: Thankfully, no risk of leukemia that we’re aware of with this drug. No risk of autoimmunity with this drug. More, it’s that the CD47 antibody itself can bind to platelets and when it binds to platelets it can decrease their number in the body and so it can cause patients to have low platelet numbers. So, what we’re trying to do is increase the specificity of the antibody, so that way it doesn’t affect platelet numbers, and it only affects the tumor cell. 

Jamie DePolo: Okay. Okay. Well, that all sounds very exciting. I do have to ask in today’s cancer research climate, are you funded by the NIH and is the research going to go forward?

Dr. Benjamin Schrank: Oh, yes. So, absolutely. I mean, I think this new therapy shows so much promise and there’s so much excitement. And quite frankly, there’s so much need that we’re really fortunate here at MD Anderson to have institutional investment in this idea and a commitment to see this move forward in the translational pipeline. You know, it’s our goal to get this therapy in the best possible shape so that way it can help patients who desperately need it. Although I will say that, you know, across the country it’s a challenging time for many researchers with some uncertainty as to whether or not certain projects are going to be funded. And so, my heart goes out to a lot of my fellow scientists and physician scientists who are struggling right now and not knowing whether or not their projects will be carried forward. 

Jamie DePolo: Okay. And then finally, I believe, again if I'm remembering correctly, you tested this in breast cancer and I think melanoma, is that right?

Dr. Benjamin Schrank: That’s correct. 

Jamie DePolo: And so, would this have the possibility to work in other cancers as well? Or is there something specific to those two types that this drug is targeting?

Dr. Benjamin Schrank: That’s the beauty behind using CD47 as an antibody, it’s highly expressed in multiple kinds of solid tumors, including breast, including melanoma, including pancreatic cancer, including head and neck cancers, including hematological malignancies in which you just mentioned. So, we think that while we’re most excited by the results that we’re seeing in breast cancer, we think that this has potential avenues forward in terms of treating multiple kinds of cancer. And so, for that we’re really excited. 

Jamie DePolo: All right. Dr. Schrank, thank you so much. I appreciate your insights. I'm going to keep you in my folder and I'm going to check back with you in about five years. We’ll look for papers and I can't wait until I see more research on this particular drug. Thank you so much. 

Dr. Benjamin Schrank: Thank you.

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