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Dr. Karen Anderson on the Strength of the Immune System

Among the many powerful and intriguing things that Dr. Karen Anderson told me during our terrific conversation: Vaccines have changed the course of human events.

This line – combined with the inspiration Dr. Anderson felt when completing her studies – helped lead her to the important and challenging work she does now: Breast cancer vaccine development, with a long-range goal to deliver vaccines to reduce the risk of breast cancer recurrence after surgery.

Her research focuses on how the immune system can be harnessed to detect and alter cancer development. Dr. Anderson, also, is a current member of the NCI Cancer Biomarker Study section, and has published over 40 peer-reviewed publications. Let's get to the obvious question. What's a translational researcher? That's where our conversation began.

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Chris Riback: I've seen you described as a translational researcher at the Biodesign Institute at Arizona State, as well as a bunch of other titles and affiliations, but, what is a translational researcher? Does that mean that you can make this intense science understandable for the rest of us?

Karen Anderson: Well, I hope so. A translational researcher is someone who focuses on questions about human disease. Where we try to understand what's going on in patients, and take that back to the lab, try to refine it, and then really have an impact in terms of patient care. It is very, we try to translate the science into clinical practice.

Chris Riback: Really putting the patient, it sounds like, at the center of what you're doing. Not so much science for science's sake, but relying on the person and the patient at the center of it. Is that right?

Karen Anderson: Absolutely.

Chris Riback: You focus on how the immune system can be harnessed to detect and alter cancer development. That's one of your areas. Tell me about what that means. How can you harness? How does one harness a person's immune system, not only to detect, but also importantly, to alter cancer development?

Karen Anderson: Well, cancer immunotherapy is a really hot topic right now in cancer research. One thing that we've learned over the years is that cancers don't evolve in a vacuum. They evolve in the setting of people's immune system. They have had to develop ways to evade that. There are whole different sets of mechanisms at how the cancers are trying to evade the immune system. It's like a cat and mouse. As those tumors try to evade the immune system, the immune system is trying to fight them off. Cancer, at the root of it, is an altered cell. It is our cells but we're different. Those cells are different. They have different proteins, they have different mutations, they have alterations in those proteins. The immune system can see that. What we're trying to do is trying to rev that back up. How do you create better T cells, better parts of the immune system that can see the cancer and then can try to help eliminate it.

Chris Riback: Where are the key challenges? Are the key challenges on ... This is going to be overly simplistic, and so correct me on this, but are the challenges of what you just described more on, let's say the tumor side, understanding what's going on there, what changes are taking place? I love that description you just gave that it's our cells, but it's our altered cells, versus challenges in understanding the immune side? What's reactivating that? What needs to be reactivated? How does that get harnessed or amped up? Can the two not be separated? Are they hand in hand, and understanding the challenges on one side fit perfectly, or neatly, or challengingly with the challenges on the other side?

Karen Anderson: It's a great question. It is really both. Fundamentally, the strength of the immune is about the diversity of a response. We have this incredible defense mechanism that we don't know what organisms are going to hit it. What the next plague is going to be. We've evolved this immune system that is incredibly diverse, and it's one of the most genetically diverse part of our genomes. It is also adaptable, and it has memory. Our T cells can see something, so in the same way that vaccines work, we can see an infection, and we can remember. Our immune system remembers that you had this infection so that you can fight it off better, and faster, and stronger the next time you see it. How does this work for cancer? Well, the problem with cancer is that it is also, these are very diverse cells. There's a tremendous amount of heterogeneity, and what I mean by that is that within someone's own tumor, there's a lot of variation. Not all those cells are identical.

There's a lot of genetic variation, a protein variation within those cells. There's heterogeneity within a person, and then there's heterogeneity between people. Not everybody's breast cancer is the same. In fact, they're tremendously different. We have to understand both the differences between people and within people, and then how do we adapt that for an individual person's immune system. Being able to have techniques and tools to be able to get at that tremendous amount of diversity, really helps us understand how we can then harness that in order to fight an individual's own cancer.

Chris Riback: As if the job isn't hard enough, all of that diversity and all the different ... I mean, I'm sure on the one hand, that is at the heart of the challenge and the difficulty. On the other hand, it's probably central to what makes everyday different and really interesting, is that it's probably not one-size-fits-all, which I guess it'd be a lot easier if it were one-size-fits-all, wouldn't it?

Karen Anderson: Well, the good news is that there are some molecules, there are some targets that are in common across different types of cancers and across different breast cancers. Many of those are currently being targeted in immune therapeutics in over a variety of different types of cancers. Some of these are already FDA approved, and are being worked on and studied in great detail in breast cancer as well.

Chris Riback: Yeah. That is excellent. That's a good thing to know. Two things are going through my mind that I'm going to park for a moment. One is the diversity, and there's a question I want to ask you about that in regards to your team, but also, I'm always fascinated by the lessons that get learned. I've heard this over and over again, these conversations with researchers on what one can learn in one area of cancer research, it can sometimes be applied in other areas of research. Maybe we can talk about that as well. First, just finishing up on this idea of immunotherapy, you said earlier, I think you said that immunotherapy is hot right now, something like that. What did you mean by that?

Karen Anderson: Well, there are a number of different immunotherapies that have recently been FDA approved for different cancer types. Not yet for breast cancer but for Melanoma, for lung cancer, head/neck cancers and others. What we're finding is that those immunotherapies either alone or in combination with more standard chemotherapies or possible yet are targeted therapies are starting to show very impressive responses but only in a subset of patients. What we're trying to figure out now is who is responding to these therapies, and why? Why is it that 10% of patients might have a terrific response and have a very long term response in Melanoma, and actually in Melanoma, the numbers are much higher, but why is it only some people that are having those responses and other tumors are not responding as well? That is a lot of what we're trying to figure out now, is who's going to respond to these therapies, and why? Because, that's going to help us make them work better.

Chris Riback: In addition, one of the most interesting things that I've learned in these conversations, which you just mentioned a moment ago, is how leading researchers like you connect work across cancers. It's like being the ultimate investigator. Finding clues in one part of the body or one type of cancer, and defining how they may or may not be applied to other parts. Am I interpreting what you're saying correctly? Is that your approach as well? Are you seeing clues from, maybe say, immunotherapy that's effective in other types of cancers, and really considering how those findings could apply to breast cancer?

Karen Anderson: Absolutely. The entire field learned a tremendous amount from the experience in Melanoma. Melanoma is considered to be one of the most immunogenic tumors. Many of the drugs that have been developed for immunotherapy that activate T cells targets like CTLA-4, and PD-1, PDL-1, those types of targets. Many of those were developed initially for Melanoma, and that's where the initial FDA approvals were for. It's because that is a very immunogenic tumor. Breast cancer in contrast has long been considered not very immunogenic but there are sub-types, and the triple negative sub-type in particular is probably more immunogenic, and so many of these immunotherapies are now being studied actively in triple negative breast cancer. There's some very recent data that suggests that they may also have activity in hormone receptor positive or estrogen receptor positive breast cancers as well. That is also being evaluated quite actively.

Chris Riback: Let's talk, as well, about the diversity that you talked about. That seems to mirror, if I interpreted your lab correctly, your approach to your team, which seems to be very wife-ranging. You're leveraging collective expertise in breast cancer genomics and bioinformatics, mathematical modeling, high throughput protein display, mass spectrometry, and immune monitoring, and who knows, maybe you've even added two or three since then. Is that accurate? Am I interpreting that right? Why the diversity on the team? How do you think about that composition? What does it all add up to for you?

Karen Anderson: We've been trying to tackle is how do you measure the diversity of that immune response? How do you measure all the different antibodies, and T cells, and what they're recognizing, and what tumor proteins they're seeing, and how that varies between people? To be able to do that, well, T cells have an incredible potential variation. Maybe 10 to the 14th potential different T cell receptors that could be seen. How can we evaluate this? You've got 25, 30,000 different genes encoding proteins that is well within the genomes, and then you have all the mutations. How can we tackle that? To do that requires an ability to measure proteins and to measure T cells in a high throughout way.

What we've done is take an infrastructure for doing ... We can display thousands of different proteins in a variety of different ways to the T cells, so that we can measure those T cells and those antibody levels. We also require the expertise of all those genomicists and bioinformatics, which are people who can interpret all the computational data that comes across from all the millions and millions of sequencing reads from tumor samples. How can we distill that to say, "What is that immune system in that person really seeing?" We have to take people with different amounts of skillsets and different technologies, whether it's proteins, whether it's genomics, whether it's computational abilities, whether it's mathematical abilities of how do you predict what are going to be the immune responses. Then, we try to create this integrated pipeline to say, "Okay, in a given person, what are they reacting to?" If they're getting immunotherapies, what are they reacting to, and why? If they're responding to those therapies, what are they responding to, and how does that tell us to build the next version of those immunotherapies or those vaccine therapies?

Chris Riback: What drew you to this area of research?

Karen Anderson: I started working on immunology back in medical school. I did a PhD in immunology, and I was always been fascinated with vaccines. They've changed the course of human events. Our ability to survive the plague and our ability to survive small pox, and our future ability perhaps to survive Ebola or HIV, or other types of therapies. So much of this have rested on vaccine development, and how are we going to survive the next Influenza. Things like that. I've always been fascinated with how vaccines work and how we can make them better. How the T cells work. Our initial work is really focused on infectious diseases, obviously, because that's where we've learned the most about how T cells work, in particular for chronic viruses where the T cells get what we call exhausted, and I suspect many people can understand that. If the T cells' being stimulated for a long time, it gets tired, literally.

How do you reactivate that? How do you wake that back up? How do you teach it to see the target again, to reactivate it? We've taken a lot of the lessons from infectious diseases and classic vaccine development and then applying that to cancer. Because the system and the problem is very similar. I have been, I can't explain why, but I've been fascinated by this for many, many years, and I've been interested, really in how can we target this for breast cancer.

Chris Riback: I was going to ask to that part. That's a really interesting world life/historical view and you're right. When you phrase it that way, thinking about vaccines and their impact on the course of human history and human events, that's pretty powerful stuff. Did you get to cancer or breast cancer, was it intentional? Was it accidental? Was it that, "Well, okay, if a vaccine took care of small pox and vaccines dealt with polio, well, what's the next big one? Hard to get much bigger than cancer, let's go there." Did that happen intentionally or was it just where you ended up?

Karen Anderson: Well, honestly, it was more directly inspirational. When I was doing my internship and residency in Boston at the Brigham & Women's Hospital, and my fellowship at Dana-Farber, actually early on in my internship, I was originally thinking I would study infectious disease. I was just so inspired both from patients that I had, and also from the oncologist who inspired me in their incredible dedication and understanding of their patients, and the fight that they were in. I just decided that I would really love to study breast cancer, and to study how cancer evolves.

At the time, tumor immunotherapy, it's always sounded like a great idea but in practice, it did not work very well for decades, really. We'd always had these hints that there were some responses in other tumor types like Melanoma or lung cancer, or others, but it's only been really in the last five to eight years where we're starting to see consistent responses in patients, and really starting to understand who might really benefit from targeted immunotherapies. For me though, it was a deeply personal inspiration from the patients that I was seeing through my internship and residency, and I said yes, I would love to have the privilege to be able to take care of breast cancer patients for the rest of my career.

Chris Riback: Does that worry you at all if it doesn't work to the extent that we all hope that it does? I mean, that it doesn't go to the full end that you wanted to, or no, you're not encumbered by thoughts like that?

Karen Anderson: Well, I've been in practice long enough that I recognize that many exciting new developments take time to mature. When we find some evidence of responses, that tells us a direction that we can go in and we can chip away at to make them better, to improve them. Then, periodically, we get the larger breakthroughs, the Trastuzumab, which is Herceptin, that reduces recurrence rates, and we use routinely in clinical practice the hormonal therapies, the endocrine therapies that we use to reduce recurrences. We see the more major breakthroughs in breast cancer care. I think that we're on the cost of this for immunotherapies. We're going to find more response rates perhaps than we want to see, initially, but then that'll point us in the directions at how to improve it and how to make it better.

I recognize that these are really hard problems. If they were simple, we would have figured them out already. They take time, and they take persistence to chip away at them, but the fact that we're seeing responses now, really, I think is very encouraging to tell us the directions we need to go.

Chris Riback: Yeah. That is the inspiring part, no doubt. In terms of where to go, what is next? Looking at the research specifically, what are your next steps, or what are the upcoming milestones that you would highlight, and say, "Okay, check back in around this time, because these are the upcoming milestone that we really are tracking, and we'll understand whether to make a right turn or a left turn?"

Karen Anderson: I think probably the first immunotherapy that we're going to get mature data on is the use of checkpoint blockade therapies, which are these targeted therapies that activate T cells. We're going to start to see the more mature data coming out from triple negative breast cancer trials, the keynote trials, and other trials of looking at these targeted agents in triple negative breast cancers. Both as single agent therapies where the response has actually been low, but measurable. Some people do respond very well. We're not starting to look at the combination with different types of chemotherapies and others.

After that, I think we're going to start seeing these agents looked at and evaluated in detail, and hormone receptor positive breast cancers as well. There is exciting data from the I-SPY Clinical Studies looking at improvements in response rates before surgery of different immunotherapies. Both for triple negative breast cancer, and also for hormone receptor positive breast cancer. We will start to see those. I think that coming down the line will be T cell targeted therapies. Whether they target individual mutations and alterations in individual patients' tumors or more broadly across multiple different targets across different breast cancers, both of those are being evaluated, and I think that both adoptive T cell therapies where they take T cells from people, make them better, stronger, more effective, and then give them back, or vaccine targets trying to create the T cell responses within a person, rather than trying to do it in the test tube and then giving them back.

I think we're going to start to see those trials coming forward, those early phase trials in breast cancer, across a number of different breast cancers [cells 00:22:44]. I think that where a lot of the excitement is, can we really reduce recurrence rates with these? Can we improve response rates both before surgery and after surgery to reduce recurrence, and reduce the chance of these cancers coming back? Many of these therapies are obviously being evaluated in women with more advanced disease, initially. We may see some of these clinical trial data coming out before surgery, and also in women with early stage breast cancers after surgery and immunotherapies, to reduce the risk of recurrence. As well as in women with stage four or more advanced breast cancers as well.

What we've been working on has been trying to identify what are those targets. What are really good targets that we can think about for vaccine development? When I talk abut vaccines, I'm talking about therapeutic vaccines, so to treat patients who already have breast cancer. Although, certainly there is this potential down the line to try to prevent breast cancers, but I think our first goals are going to try to reduce the recurrence rates of breast cancer. Whether we use that for vaccines, or whether we use that to stimulate T cells and try to give activate T cells as infusions, for example, to reduce the risk of disease recurrences is what we've been working on developing.

Chris Riback: Two thoughts are going through my mind. One is what you just described at the end there, and the researchers and scientists who, there's such a wide spectrum. There are the scientists and researchers who are working to try to prevent breast cancer in the first place, and that's an incredible work, obviously. Then, maybe on the other side, there are folks like you who are trying to help with how do we stop reoccurrence and how do we address patients when they have breast cancer, or when they have had it, and that's got its own set of challenges. Anywhere on that spectrum, there's a ton of work, which brought me to my second thought. I now understand why you would be in Arizona working in the dead heat of Arizona summer. You got a lot of work to do. You've got a lot on your plate.

Karen Anderson: Well, I work at the Biodesign Institute here at Arizona State University, and it is a research institute with an incredible diverse array of scientists with different expertise. I have physicist, and I have chemist, and engineers, and biologist, and immunologists, and the idea is if you put people with this type of diverse research approaches and background, and you put them together in a building, what happens? What I've been able to do is have people who know a tremendous amount of filtering genomic data using high throughput computational methods, and mathematical modeling, and engineers who can try to engineer robots that can try to understand this diversity, so that we can express the proteins that we want and do the protein [arrays 00:26:10] that we need to be able to measure those T cells, and measure those antibodies.

Yes, we're in the absolute heat of summer right now, but the rest of the year, Arizona is a terrific place to be, and to work. It is very exciting. It's very technology-driven institution, I would say. We have a lot of exposure to latest technologies to be able to do some of these analysis. It is a very exciting place to work.

Chris Riback: It sounds like it. In fact the thought that's going through my mind is if this science thing doesn't work out for you, or you get tired of it at some point, maybe we just set up live webcams in the faculty dining room. I can only imagine what those conversations are like among physicist, and biologists, and chemist, and everyone discussing and arguing. We've got a great reality show there, I think at the very least.

Karen Anderson: Perhaps. Although, there might be more talk about baseball than you think.

Chris Riback: Good. Well, that's because the Diamondbacks are having a great year, come on.

Karen Anderson: Yeah. There is that. Although, I'm a Red Sox fan. One other thing I want to mention is that I also have a joint appointment with the Mayo Clinic here in Arizona, and I am a practicing breast cancer medical oncologist, and that gives us the opportunity to do that translational bridge that we talked about. How do you bring these latest technologies that people are developing in the lab, and how do we actually try to bring this into patient care? I think it's been very important for me, and my career, in my path, to have an active clinical practice. This is really important. I learned so much from my patients about what works and what doesn't, and what are really the concerns that they're seeing. To really understand how the cancer behaves and how the immune system is behaving, and what are the primary concerns that my patients have for treating breast cancers.

That has been really, really important for me in my practice and in my research practice. How could I bring that into the laboratory and try to understand this. Here, I have that opportunity to do that translational bridge and make it work.

Chris Riback: With the work that you're doing at ASU, and with the Mayo Clinic, tell me as well, what role does BCRF play in your work?

Karen Anderson: I think one of the important things that BCRF has done for many investigators, myself included, has been to help us study the hard problems. Many of the grants and the federals grants that we have, and that we get extend work that we've already done. But if you really want to branch in new directions, if you want to try something challenging, if you want to high risk, more high reward type of research, it really does require funding support from an organization such as BCRF that recognizes that we need to have that kind of pilot funding to be able to go off into a riskier direction to try to get the more innovative therapies out there for patients. For me, that has been really critical. The support from BCRF has been critical for us to be able to evaluate different targets for breast cancer and in breast cancer immunotherapies, and be able to support some of the more innovative research, I would say, in the laboratory.

Chris Riback: That's terrific. It's terrific that their efforts are so actionable, I guess, or you're putting them into action in such a directed way that's very meaningful. Thank you. Thank you for the work that you do, and thank you for your time today. I really enjoyed the conversation.

Karen Anderson: All right. Well, thank you so much. This was great.

Chris Riback: That was my conversation with Dr. Karen Anderson. What a key point that was about vaccines and human events. I totally felt how that simple idea could inspire a lifetime of work. My thanks to Dr. Anderson for joining, and you for listening. To learn more about breast cancer research, or to subscribe to our podcast, go to bcrfcure.org/podcasts.

 

 

 

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