One key goal in developing precision vaccines and immune therapies is straightforward and imperative: to reduce the risk of breast cancer recurrence. Yet currently, there is only one FDA-approved immunotherapy drug for breast cancer, and it benefits just a small subset of women.
That’s among the reasons that Dr. Karen Anderson is studying the proteins in breast cancers that can be recognized by specialized immune cells, called T cells. These efforts could lead to the creation of vaccines and additional targeted therapies that treat a broader range of patients.
And of course, we’d all like to know: What’s the progress? And how has COVID-19 impacted this progress?
Dr. Anderson, a BCRF investigator since 2015, is a translational researcher at the Biodesign Institute at Arizona State University. She also works as a breast cancer medical oncologist at Mayo Clinic Arizona. Her research focuses on how the immune system can be harnessed to detect and alter cancer development.
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Chris Riback: Dr. Anderson, thanks for joining me. I appreciate your time.
Chris Riback: Perhaps we could start with a brief coronavirus update [for] breast cancer patients and their families. What are you hearing from the breast cancer community? What are you hearing from patients?
Dr. Karen Anderson: Oh, it is so important to our patients right now. In the time of coronavirus, it has really changed how clinics are working. It impacts everything that they’re going through. As you know, cancer patients in particular, patients that are undergoing active chemotherapy and immune suppressive therapy are at particular and potential for risk because they’re immune suppressed. And it is so important and challenging for them to actively undergo care, to work out the logistics of going into the clinic, how to get tested, how to isolate effectively.
Dr. Karen Anderson: Also, in how we deliver care obviously, there’s been a lot more rapid and necessary development in videoconferencing, in tele-health and tele-medicine and trying to limit contacts and exposures for our patients so that we can focus on the care that they need.
Dr. Karen Anderson: It’s been incredible how the community has come around to help facilitate the care of our patients and being able to provide cancer care and top-flight cancer care in this time. And help protect them as well during coronavirus.
Chris Riback: We are already in a high-stress level of the situation. It seems like it’s just another real degree of difficulty.
Dr. Karen Anderson: Oh, absolutely. They have enough to worry about but I will tell you, my patients are extraordinary with their families taking this in stride. They’ve just made the adjustments that they need to do. And clinically, also with adjusting prior to chemotherapies, with adjusting treatment regimens and being able to really take it in stride and move forward with it.
Dr. Karen Anderson: I mean all of us know people who have been dealing with it. It changes the way that we’re able to communicate with people. It’s tough on our patients. There’s no question.
Chris Riback: Now, you work at Arizona State Biodesign Institute. I understand you do your clinical work at the Mayo Clinic in Arizona but in reading and researching for this, I saw where the Biodesign Institute has been converted into a fully FDA-approved and clinically certified lab capable of performing thousands of COVID-19 tests per day. Have you been involved in that at all?
Dr. Karen Anderson: Well, when coronavirus was starting in our community, it was recognized by the leadership in our institution that we were going to need to be able to do more testing. We had the fortune really to have high-throughput robotic systems that were capable of doing these kinds of tests, not for COVID-19 specifically, but those types of quantitative PCR tests already here for really another project. And so that work was pivoted over to developing a sort of a high-level clinical lab type of a setting for coronavirus.
Dr. Karen Anderson: Several of the members of my laboratory have been working in the corona viral testing facility, including my lab manager. We’ve been able to shift some of the work so that they can ramp up and be able to do this testing. It’s been really important for the university and for Arizona to be able to provide more testing facilities and capabilities for identification of people, to be able to screen people and emergency workers as well, and to start thinking about what it’s going to take to return, and the return to work components of this.
Dr. Karen Anderson: So, they were able to ramp up for testing and I think that that’s been critical here at the university. And we’re just now starting from a laboratory standpoint to think about reopening laboratories for other types of research.
Chris Riback: Talk about translational medicine and taking learnings from one area of science and applying them to others. I’ve heard that part of cancer research so much. And you’re just describing a whole other level of that kind of taking of skills from one part of science and applying them to another. And it just sounds like all hands on deck.
Dr. Karen Anderson: Absolutely, but I think that there have been a lot of advances in nucleic acid sensing and testing that is coming out from the COVID-19 epidemic that I predict and in turn, will end up impacting breast cancer diagnostics and care as we learn better how to sense nucleic acid in this case for corona viral nucleic acid. But I think that many of those systems and approaches are going to start to be applicable for other things, whether it’s in infectious diseases for our patients or whether it’s actually genotyping identification of high-risk individuals processes like that. I suspect there’s going to be a collateral benefit, I would say.
Chris Riback: Well, that would be fascinating. It’d be kind of nice for something positive like that to come out of this challenge that everyone is facing. If we could, let’s talk a little bit about your work. And broadly speaking, you are in the vaccine business and we hear a lot about vaccines these days, of course, with the search for the coronavirus vaccine.
Chris Riback: At the highest level, now that many of us are getting kind of a 101 on how to create a vaccine from people like Dr. Anthony Fauci. How does your process compare to what we all hear about on television nearly every day?
Dr. Karen Anderson: What we do in our laboratory has been identifying neoantigens or neoepitopes. And what that means is trying to find out what’s different about the cancer cell compared to a healthy cell and use that for the vaccine.
Dr. Karen Anderson: So, in coronavirus, it’s relatively straightforward. The virus is different and so you can take pieces of the virus and then you can generate vaccines to those pieces of the virus. And most vaccines that are being developed for coronavirus are trying to target antibody immunity, just like most of your usual vaccines for pathogens and infectious disease. But for cancer, the types of vaccines that we’re looking at developing are really designed to create T cell responses. It’s the other sort of half of the immune system and how it will react against cancer.
Dr. Karen Anderson: So we’re trying to create strong T cell responses but they have to be specific to the cancer and not to healthy tissue. And so a lot of what we try to develop is what is different about a cancer compared to a healthy person. And it’s different for everybody’s breast cancer. They mutate and they alter in different ways. And so, you have to do it in the context of those tumors.
Dr. Karen Anderson: So what we’re doing is trying to identify what those targets are for each individual person. And then to think about how to design those next generation vaccines. Along the similar kinds of lines that people are doing for coronavirus, there’s a lot that overlaps in strategy. And then eventually try to get those into clinical trials.
Chris Riback: It’s a very different process that you’re undergoing than what we all might be becoming used to and hearing about every day. Is that correct?
Dr. Karen Anderson: Yes. I mean it’s the types of targets and how to build them are much more complicated because you’re not just looking at a spike protein or a piece of the virus. You have to go after the tiny little pieces that the T cells see and they’re much smaller little fragments. And you got to kind of rebuild them into a new version of a vaccine. It’s like putting a bunch of a little jigsaw puzzle pieces back together.
Chris Riback: Your research is described as focusing on how the immune system can be harnessed to detect and alter cancer development. I love that description. What does it mean to harness one’s immune system?
Dr. Karen Anderson: Well, I think what the field of cancer immunology has realized over the last decade is that for a lot of cancers in particular in breast cancer, triple-negative breast cancer and HER2 breast cancers have pre-existing immune responses. So, it’s not that the immune system hasn’t been involved and it doesn’t already recognize that cancer, but the cancer turns it off.
Dr. Karen Anderson: And so, part of what your main therapy does is just reactivate what’s already there. And then part of what vaccines are designed to do is to try to retrain it to recognize even more strongly and more robustly. But what we have learned is that across the board in cancers, whether it’s lung cancer or bladder cancer or breast cancer, a lot of these cancers have some amount of what we call pre-existing immunity and they’re what we call hot tumors. In other words, there’s an inflammation that is already occurring at the cancer and part of the strategy is just to wake that back up.
Dr. Karen Anderson: And then there’s a subset of breast cancers that are cold, that don’t have a lot of pre-existing immune response. And there you really have to get it reactivated. You have to try to drive it to new responses and try to make them more immune active.
Chris Riback: And what’s the why? Why are some hot and some cold? Why do you need to reactivate? Why is the reactivation process so challenging? Talk to me about the discovery process that someone like you has to go through.
Dr. Karen Anderson: Yes, it’s a great question. I’m not sure that we know why some are hot and some are cold. What we do know is that the more mutated, the more altered that tumor is, the more sensitive it is for immune therapy. So in other words, the immune system has more things it can see that are different. You’re looking for differences between tumor and normal tissue, the more changed that tumor is, the more things we can see as different. And that is certainly related in part to a tumor being hot versus cold is how different is it. And then it’s also in part how the tumor itself has evolved to evade the immune system. It does it in different ways.
Dr. Karen Anderson: And so scientists like myself are trying to look at what are the different ways because I suspect we’re going to be designing vaccines that are going to be different depending on how those tumors are immune silenced, how they’re evaded the immune system, how they’re cloaked really from the immune system. And that’s going to be different for different types of breast cancers.
Chris Riback: Yes and the good news in your work as I understand it is that targeted immunotherapy with checkpoint inhibitors has been effective in some patients with solid tumors, including triple-negative breast cancer. The challenging aspect, of course, is that only a subset of patients respond. Is that accurate? Is that the status of some of the work to this point?
Dr. Karen Anderson: Absolutely. We now have the FDA approval of Sacituzumab chemotherapy for women with stage four breast cancers. It clearly has a benefit in a subset of patients and it’s those tumors that rely on that PPD-1/PD-L1 pathway to turn off the immune system. So that was really the first evidence that a sort of a T cell-targeted type of approach can have an impact for patients with breast cancer. But that’s only a subset of women with triple-negative breast cancers. So what about the rest? And how can we make that work better?
Dr. Karen Anderson: So, some of the work obviously that a lot of people are doing and trying to identify, which cancers are going to be sensitive to immune therapies with the ones that we already have available. And then the next step is what new immune therapies can we use for breast cancer to try to make them be seen by the immune system, to turn those cold tumors hot, to try to create vaccines that might reduce recurrence rate, which is really what we’re focusing on.
Chris Riback: In terms of your focus, you use as I understand it computational programs as well as proteomics.
Chris Riback: The large-scale study of proteins made throughout the body. How do those approaches work together?
Dr. Karen Anderson: So, we rely on computational systems to help us see what is different between the tumor and normal breast tissue. And what we’ve been looking at up until this past year has been well what’s mutated. One thing is mutated. One thing isn’t. Is there something in those mutations that we might be able to see? Like mutations and genes like PIK3CA or P53, driver mutations that are found throughout breast cancer. So unfortunately, that’s only a small subset of the differences that are in tumors between healthy and tumor. And so we’ve started to develop new or broader scale prediction programs to be able to mine the huge amount of differences that are hidden.
Dr. Karen Anderson: And I would say that the mutations are just sort of the tip of the iceberg of about what is different in a tumor versus normal tissue. And so, we’ve now developed some newer computational programs to look at the broad array of genes that are expressed, are unique, and it might be highly immunogenic.
Dr. Karen Anderson: A new one that we just developed recently looks is a program called Ensembl MHC. And what that does is it helps improve our prediction efficiency. So, we combine proteomics and what proteomics is, is it’s a broad study of all the proteins in the cell.
Chris Riback: Are the computational programs, the work that your colleagues are adding to the proteomics and to the ability to kind of analyze or make predictions about thousands of proteins at a given time? Is that computational work almost reinventing the approach?
Dr. Karen Anderson: It’s been changing my mindset. And if you think about targets that you can drive an immune response to; and if you think well maybe there’s a couple of targets in that tumor, you build your vaccines in one way. You approach it in another way. If this combination of computational systems and proteomics tells you, “All right, there’s actually these 250 targets.” Then it might be very good and there might be another thousand underneath that, that might be there but maybe it changes the way we do science. It changes the way we prioritize these. It changes the way we think about our vaccine strategy, about what we might need to do to create an effective immune response because the one thing we know about cancer is it’s very good at changing.
Dr. Karen Anderson: It’ll mutate, it’ll alter. If we create a vaccine to one thing, it’s going to try to lose that thing. It’s going to change it. It’s going to mutate it. It’s going to evolve some other cancer that maybe doesn’t rely on that. It’ll find ways around that immune response. So, you need to target multiple things. You need to go after multiple targets and you need to do it early. And you need to do it effectively early on. That’s the best way to reduce recurrence of cancers.
Dr. Karen Anderson: We know this. We’ve learned this from chemotherapies and from hormone therapies and others.
Chris Riback: Is it accurate to describe one of your goals is to determine what proteins and breast cancers can be recognized by the T cells of the immune system? Is that an accurate characterization of one of your goals?
Dr. Karen Anderson: Yes, absolutely.
Chris Riback: Okay. So then here’s my dumb question to follow up on the goal. For all of us, would our T cells recognize different proteins?
Chris Riback: Okay, for patient A, which proteins do his or her T cells actually recognize?
Dr. Karen Anderson: I think that as with all things, it’s a combination. There are common targets that the immune system can see, something like HER2/neu is a common target for 25 percent of breast cancers. But what we’re going after is actually going to lead to more precision medicine. It’s going to be different for every single tumor because we know that they mutate and they alter differently. And the immune system and how T cells see things is you have different HLA. You have different genetics on how your immune system sees a tumor or sees a virus or sees a coronavirus on how your immune system sees it compared to somebody else.
Dr. Karen Anderson: And that’s based a lot on your genetics. And in the same way that that your transplantation proteins, you can’t just transplant a kidney from one person to another. It needs to be a match. It’s the same kind of idea. So we have the tumors that are unique and then your immune system that’s unique. And so both of those lead to what will probably end up being precision based immune therapies.
Dr. Karen Anderson: Now there are a lot of people, ourselves included, who are trying to find some parts of that, that are in common between people. So we can start with the simpler ones that are in common. And like PIK3CA mutations or P53 mutations where you’ve got common targets that might be present in 2 percent of breast cancer patients or some number. And those might be a place to start but I think ultimately, I predict we’re going to have to have precision vaccines that are unique for each individual patient.
Chris Riback: What are you most excited about regarding your work right now?
Dr. Karen Anderson: I am most excited right now with when we integrate the proteomic work, when we integrate that type of biochemistry with the power of computational structure work. Then I think what we can start to do is to bypass a lot of the really slow biochemical work that gets us there. And what am I trying to explain? So let’s say your tumor has 100 or 1,000 targets. Okay, I can go test those in the laboratory but it’s very hard to design a vaccine with a thousand targets. Maybe we can do it to 100 or something but we need to know which hundred we want to go after, which 50 we want to go after.
Dr. Karen Anderson: So, to narrow that down has actually been hard and we’re starting to develop structure-based modeling systems to be able to tell us, “Well, these are ones we really need to go after.” And so we can speed up the process because for me, taking months in the laboratory to narrow that down, we’re now learning, “Okay, well maybe this computer can tell me which 50 to go after and it only has to run an hour to be able to tell me that.” And the better we get at that, the more efficient we get at this, then we can really start the efficiency of trying to design the best possible vaccines to reduce your current rates. And do that in a timely fashion and efficient fashion, that’ll make it feasible to manufacture these things, and to be able to deliver them.
Chris Riback: And it’s so straightforward to understand how that can directly impact people’s lives and quality of life. And we started out this conversation talking about the amount of stress that a person and her family is under when going through breast cancer, and other diseases and situations as well. But that back-of-the-mind worry about recurrence has got to be ongoing, one of the great stress components. And what you’re talking about, heightening the ability to potentially work on and reduce recurrence and do it in an exponentially faster time, that the line that from your work to potentially improving one’s lifestyle at the least. If not, one’s potential life expectancy that’s got to feel pretty good.
Dr. Karen Anderson: We will see what role things like vaccines have in the armamentarium that we have for cancer care. The more ways we can go at this, the better we can do to reduce recurrence and also reduce toxicity. That we can go at cancer multiple different ways. And I certainly envision a time where part of our adjuvant therapy, maybe you get your surgery, maybe you get your treatment before surgery, maybe you get radiation. But part of this is also going to be immune therapy to reduce recurrence, immune therapy of some form.
Dr. Karen Anderson: And I am hopeful that that will start to have an effect and a benefit for patients with cancer. I think that remains to be seen. There are a lot of clinical trials ongoing right now already with vaccines, targeting for triple-negative breast cancers for HER2 type vaccines for others but I think you’re going to start to see a lot more of those clinical trials coming forward as we learn who might benefit from them and which one’s work and which ones don’t.
Chris Riback: And as we talk about those clinical trials and to start to close out our conversation, what role has BCRF played in your research?
Dr. Karen Anderson: They’ve been absolutely integral for everything that we’ve been doing for the vaccine development. They have funded some of the very early research that we need, the pilot research, sometimes the crazy research where it’s early and it’s developmental. And you have to do that in order to get it to a point where you can compete for regular grants or do other projects. And it has really allowed me and my laboratory to do a lot of focus on breast cancer, and on this particular question in breast cancer.
Dr. Karen Anderson: I think BCRF is an incredible organization. It allows us to come together as researchers and as clinicians. We talk about our work. We collaborate. We have one mission and one mission only and to prevent and treat and help our patients with breast cancer. And that guides everything that we do on this project and BCRF reminds us of that. The support is absolutely undeniable in terms of the impact it has on the breast cancer community, breast cancer care.
Chris Riback: Dr. Anderson, thank you. It’s always a treat to get to talk with you. Thank you for the work that you do and thank you for taking the time with me today.
Dr. Karen Anderson: Well, thank you so much. This has been great, Chris. Thank you.
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