Ovarian Cancer: From Research to Treatment and Therapies with Kristin Anderson, Research Associate at the Fred Hutchinson Cancer Research Center: Audio automatically transcribed by Sonix

Ovarian Cancer: From Research to Treatment and Therapies with Kristin Anderson, Research Associate at the Fred Hutchinson Cancer Research Center: this mp3 audio file was automatically transcribed by Sonix with the best speech-to-text algorithms. This transcript may contain errors.

Saul Marquez:
Hey everybody! Saul Marquez here with the Outcomes Rocket, thanks for tuning back in. Today I have the privilege of hosting the amazing Dr. Kristin G. Anderson. She is currently a Research Associate at the Fred Hutchinson Cancer Research Center in Seattle, Washington, in the lab of Dr. Philip D. Greenberg. Dr. Anderson received her Ph.D. in immunology from the University of Minnesota, where she studied T cell responses to lung infection and developed the method that is now widely used in the field of discriminant and isolette intravascular from tissue leukocytes. During her graduate work, she was diagnosed with and underwent treatment for localized breast cancer. Her experience as a patient inspired her to apply her immunology training to the field of cancer biology and translational immunotherapy. Her current research focuses on developing molecular engineering strategies to improve T cell killing and ovarian cancer, with the ultimate goal of translating her findings into treatment protocols for patients, which is obviously where it matters most. She leads a team that uses patient samples to identify immunosuppressive features in the tumor microenvironment, then uses mouse models of cancer that recapitulate these features to evaluate strategies that improve the migration, persistence, and function of genetically engineered antitumor T cells. Just fascinating work that Dr. Anderson leads. And as you heard, having experienced it herself, she brings such a unique empathy to the work that she does. So, Dr. Anderson, thank you so much for joining us today.

Kristin Anderson:
Thank you for having me. I’m really honored to be here.

Saul Marquez:
Yeah, we’re honored to have you here. And one of the things that we really enjoy hearing from our guests is really what inspires us, the work. So we would love to hear from you. What inspires your work in health care?

Kristin Anderson:
Well, I think you covered it in the introduction that you gave. My experience as a patient is truly one of the driving forces that keeps me going and inspires the work that I do. That and I’m really fortunate to get to have conversations with current patients. And that also is a really big reminder of what the goal is and what the real endpoint is that we’re aiming for.

Saul Marquez:
Without a doubt. And so I guess briefly, did your experience as a patient happen before your journey into immunology? Yeah, I would be great to learn more. If you care to share.

Kristin Anderson:
I would be happy to. I started my Ph.D. in immunology, really like you mentioned in the intro, with a focus on wanting to make better vaccines, wanting to understand how we could basically protect people against respiratory viruses, which would have been perfect for the current era that we are in right now. But when I was in the fourth year of my Ph.D. studies, I was diagnosed with a really aggressive triple-negative breast cancer. And that really put a pause on my trajectory. So I did continue to stay in grad school. When I was going through treatment,I would sort of balance treatment for a few days and taking a break from the lab. And then I would go back in for a few days to try to make sure that I didn’t completely stop making progress. And I was very lucky that I had an incredible care team who was really knowledgeable. They were on the cutting edge of understanding all the new drugs and treatment regimens. And when I went through chemo and surgery, I came out the other end of that whole journey and the doctors were able to say when we went in and looked for any tumor, residual disease during surgery, we couldn’t find any. And that moment where they told me that I was no evidence of disease at surgery was really the moment where I said, I want to do that for other people. I want to be able to make therapies that basically melt people’s tumors away and make it so that the surgery piece is really just, hey, we’re checking to make sure we got it all. But I remember the moment of waking up and hearing that we can’t see any cancer left. And that feeling is just so overwhelmingly powerful that that’s really what I wanted to be able to bring forward for other people.

Saul Marquez:
Amazing. Amazing. Thank you so much for sharing that. I’m sure you were relieved when you found out that it was done. And beyond the relief, you said, I want others to feel this, too. That’s amazing. And just incredible that you took this on as a personal mission. And now the work that you do is really changing the way that really these things are, the way that they were handled. So talk to us a little bit about how your research is adding value to the space and health care.

Kristin Anderson:
Yeah, sure. So when I started working for my current advisor and mentor, Dr. Greenberg, he actually pitched this idea that he needed someone who was going to work on ovarian cancer. And I was just thrilled when he offered me that project because there was such a huge area of opportunity in ovarian cancer research, there are some really wonderful people who have done some really incredible work in terms of chemotherapies and surgical techniques. And lots of people have been really working hard to try to understand if immunotherapy can work for ovarian cancer patients. But to date, lots of the strategies that we’ve been trying in the clinic haven’t really moved the needle very much for ovarian cancer patients, especially those that present with late-stage or advanced disease. And so that to me, was a great area to jump into to try to bring about some new therapy that might really be able to offer patients another option. So really what we do is we take T cells out of someone’s blood and we engineer them to have a new receptor that recognizes tumor antigens, things that make tumors look distinct or different from healthy tissue. And so there’s a couple of different ways of doing that. Some people listening to this might be familiar with chimeric antigen receptors or car t cells. That’s one strategy that’s worked really well in liquid tumors like leukemias, in solid tumors. It hasn’t had as much success. And so we’re still trying to understand exactly why that is. Now, in Dr. Greenberg’s lab, we work with a different kind of receptor. We actually engineered T cells to have a T cell receptor that recognizes the tumor antigen that’s processed and presented in a special presentation molecule called a molecule. And so the two different receptors recognize different things on Tumor cells, but they’re both strategies that are actively being researched to try to bring new tools into the clinic.

Saul Marquez:
Fascinating. And so this approach is really unique. How exactly is it offering different data or how exactly is it bringing about better outcomes? Can you share some of the findings?

Kristin Anderson:
Yeah. So in ovarian cancer, one of the things that make this disease particularly tricky and is true for many types of solid tumors, but one issue is that these tumors are very heterogeneous. So it’s not like this tumor is one ball of cells that are all identical. The different tumor cells in that solid tumor have different gene expressions. There are immune cells that infiltrate into the tumor that will actually suppress an immune response and turn it off. So there’s a whole bunch of other things going on in these tumors besides just can a T cell, you engineer, recognize the tumor? So my work really is looking at these tumors from patients and trying to ask that question. What are the different obstacles within these tumors that are going to prevent engineered t cell therapies from functioning or being effective? And how can we overcome that in advance? So if we know something is going to be a problem and we’re already going to be engineering cells in the lab before we put them into a patient, why don’t we preemptively engineer them to avoid certain off signals or stop signs that they might encounter in the tumor?

Saul Marquez:
Fascinating. So you’re doing the work to find out the defensive strategies of these tumors and engineering it into the therapies?

Kristin Anderson:
Exactly. Yes. Some of the issues that have really been problematic in using engineered T cells or adaptive cell therapy is another way we refer to this type of therapy. Some of the real hurdles have been just in getting the T cells we engineer to persist in tumors. And there are, again, a whole list of things that could be causing that in various tumors in ovarian cancer. One that we know of in particular is that these tumors actually have a protein both on the tumor cell as well as the blood vessels that immune cells used to get into the tumor that actually that receptor or that protein will cause t cells to die. So effectively, what we’re doing is engineering a cell that can recognize and kill cancer. But the moment that it arrives at the tumor, it’s triggered to undergo death. So it’s a really, really important evasion mechanism we have to get around. So in our lab, one of the things that we worked on, so I worked in conjunction with a woman who is a fellow postdoc at the time and now has her own lab at Children’s in Seattle. So, Dr. Shannon Otha, we engineered this fusion protein that basically has the heart of the receptor that recognizes that protein. But instead of sending a signal, we actually made this fusion send proliferative like a survival signal to the trash. So we engineered these cells to actually use the tumor evasion mechanism against itself.

Saul Marquez:
Wow, that is fascinating. So what exactly did you guys do to make that happen? That’s interesting.

Kristin Anderson:
Yeah, it’s a lot of molecular biology and in all honesty, Shannon was the brains behind putting together all of those fusions, what we did was we did a lot of the validation to see in this huge panel of constructs that she made, how many of them work and which ones work the best. And so we teamed up to cover more ground really quickly. And she basically tested lots of these in leukemia models and in pancreas cancer models. And then we drove in deeply on trying to figure out if this could also help in ovarian cancer. And so actually, we published the preclinical work for this last year in the journal Experimental Medicine. We’re working on the follow-up paper on ovarian cancer that will hopefully be out this year.

Saul Marquez:
Wow. And so what were the findings? Is it applicable thus far?

Kristin Anderson:
Yeah, it’s really exciting, actually. So the most important experiments that we did that I think are probably the most encouraging for translating this into the clinic are the experiments that we did in the animal models where the animals had a tumor. And in our ovarian cancer studies, we actually wait until the animals have a late stage of disease because we really want to simulate the patient population that we’re actually going to be bringing this treatment to in the clinic first. And so we wait until the animals have advanced-stage disease and then we treat them with these engineered T cells, either cells that just have the new receptor that allows the T cells to recognize cancer or T cells that have both the receptor and this fusion protein. And what’s really exciting is T cells alone that recognize the cancer can prolong survival of the animal. So we know that T cells are doing something. They are an active and effective strategy. But when the T cells also have that fusion protein, the cells themselves not only persist longer, but they improve survival of the animal even more than just T cells alone. So it’s really exciting that we can take a finding from the clinic. So here is an issue in a patient sample or many patient samples that seems like it’s going to be a problem. We can go into the mouse models, make sure the mouse system matches what we see in the patient. We can do lots of molecular biology and engineering techniques to try to figure out a way to overcome that obstacle. And then we can actually validate that some of these tools we’re building can be effective in an immune, competent setting where there are a whole bunch of off signals that are still at play. So we are actually currently gearing up to do the clinical trial in patients with the T cell receptor itself, those engineered cells. And we’re hoping that over the next year or so we can accumulate all the preclinical data that we would need in order to bring this additional fusion protein to the clinic as well.

Saul Marquez:
Amazing. And so does the T cell actually destroy the tumor?

Kristin Anderson:
Yeah, so that’s a really good question. So the mouse models that we use are actually incredibly aggressive. And one of the benefits to that model is that we can actually learn to study mechanisms that the tumor might use to evade our T cell therapies. So even though in our settings we’re improving survival, these mice are always going to die from the cancer that’s developing just because that’s the way the models are engineered to work. OK, but our goal is we want to make sure that we are continually making iterative improvements in these technologies or these tools that we want to bring to the clinic that consistently are improving survival in that really aggressive, really high bar setting.

Saul Marquez:
Got it. So just given the nature of the model, the animal will die. But you guys are working to find ways to really improve survival now.

Kristin Anderson:
Exactly. So, in short, yes, our therapies are killing cancer cells, but the cancer is always going to come back.

Saul Marquez:
And this is more just kind of looking to learn here, I guess. When does the model change or does that fall on somebody else’s research where you say, let’s kill this thing all the way?

Kristin Anderson:
We would love to be able to kill this thing all the way. So one of the hurdles comes from the fact that in ovarian cancer specifically, there are not very many animals that naturally develop ovarian cancer. So if you had to take a guess, do you know, other than humans, the one other animal that naturally gets ovarian cancer?

Saul Marquez:
Oh, my gosh, I don’t know. I mean, a chimpanzee maybe.

Kristin Anderson:
It’s actually chickens, chickens, chickens will get ovarian cancer, but they’re not really one of the only other animals that consistently will develop tumors on the ovary that look like ovarian cancer.

Saul Marquez:
So I guess I have to ask, though, like, so why? Is there any knowledge around why?

Kristin Anderson:
You know, I saw a seminar many years ago and there are definitely some experts in this area. I do not pretend to be one of them. I think it has to do with the number of violations that the animals go through.

Saul Marquez:
Fascinating.

Kristin Anderson:
I think that is the current working hypothesis.

Saul Marquez:
Ok, all right, so I don’t want to derail this, but I was just curious.

Kristin Anderson:
Yeah, but mice don’t naturally develop ovarian cancer, so we have to make these genetically engineered and transplantable models to do our best to simulate human disease. And so the more we push them to be like human disease, sometimes the more aggressive we have to make them, which again, is really good in that we’re setting a bar really high. We’re not trying to clear something from an animal that we could have done in a dish in the lab. We’re actually making a model that looks as much like a human disease as we can get. And right now, lots of patients, especially ovarian cancer patients, have disease recurrence. So if we’re studying models where recurrence is an ongoing problem, then that in my mind is actually a really good thing because we are continuously working on trying to understand what’s going on in patients. We have mouse models that simulate that so we can continue pushing the technology to build better and better therapies as the tumors learn to evade what we build.

Saul Marquez:
Amazing. Wow. Well, thank you for that, Kristen. So I’m curious what you believe is maybe one of the biggest setbacks you’ve experienced in your research or the work that you do or the way that cancer responds? And what was a key learning that came out of it?

Kristin Anderson:
That is a great question. You know, I think one of the biggest setbacks I had was when I was first learning how to mentor others. One of the things I had a really hard time doing was letting go. I don’t know how many of your listeners will relate to this with me, but when I was in school and when I was in training, I’m a type-A person who’s very detail-oriented, very organized, very meticulous about when I do experiments because I want to understand if things didn’t work, why not? And I want to make sure that there’s not alternate explanation for why something didn’t work or the outcome that I got from my experiment. And so when I actually joined this lab that I’m in right now, I was given the opportunity to mentor full-time research technicians who have an undergrad degree and are really excited and engaged in science, which was a wonderful opportunity for someone like me who wants to run a lab someday because I got a chance to actually challenge myself to let go and cede control to other people. And it was obviously a setback in a way of I have less control. I can’t necessarily get things as quickly as I want. And that can be super frustrating when you’re first learning how that feels. But I think I spoke with a mentor who gave me some really great advice. And one of the things that I think really helped to reframe was the idea that I was helping to train the next generation of scientists.

Kristin Anderson:
And I had benefited from really great mentors who came before me. And so if I could learn how to take that energy and discipline and dedication that I put into my experiments and put that into mentoring other people how to do really great science, that it was just going to expand and grow. And there were that many more people who could do really great science. So that setback actually caused me to miss a few grant deadlines and it delayed some papers getting submitted because rather than doing all the work myself and just getting it done, I took the time to teach people and to really let them learn. If they made a mistake. That was not a big deal. It was OK. What did you learn from this mistake? And how can we move to the next step? How can we make sure that we plan better or that we fix it for next time? And in doing that, actually, we found that some of the things that I would have assumed, just looking at the data where mistakes were actually not mistakes, sometimes they were findings that I never would have expected that led us down really cool research paths. So what initially felt like a setback actually has opened doors to several different projects that we’re working on.

Saul Marquez:
Wow, that’s awesome. That’s really great. And congratulations, Dr. Anderson, on and sort of being able to let go because it’s not easy right., especially when the science you’re working on requires that control to explain why something happened and why it didn’t work versus why it did. So the beauty of leadership and welcoming this kind of diverse perspectives to the work could be surprising what you could get at the end of it.

Kristin Anderson:
Yes, and I think in the past four years that I’ve had this excellent and amazing team of people working with me. I have learned so much from them, probably more from them in some ways than they have learned from me even so, yes, one hundred percent. I agree that there’s so much value in ceding control sometimes and letting the people that you trust and you have put the effort into training really fine.

Saul Marquez:
Amazing, great message. Great message. What are you most excited about today?

Kristin Anderson:
Oh, I guess it depends on if you’re asking personally or professionally or just in the field in general.

Saul Marquez:
What comes to mind?

Kristin Anderson:
Well, I’m really excited about this clinical trial that I mentioned in the last several decades. The survival for patients with ovarian cancer has been the needle hasn’t moved very much at all. And we’re really excited because this new T cell receptor that we developed in the lab and are bringing to patients is finally after a very long delay due to the pandemic, finally going to get started this year. So I’m really excited that we have a tool that we feel so strongly has the potential to really make a difference, really excited that that’s making it to the clinic. Personally, I’m actually finishing up my time in the Greenberg lab and I’m doing my faculty search right now. And that’s really exciting because everything I get to talk about on these interviews is all about the lab that I’m going to start in my research program. And so I’m really excited about that next step. And right now, I’m looking out the window at the Pacific Ocean, just really enjoying this incredible view that is really exciting for me right now in the moment.

Saul Marquez:
I love it. Thank you so much for that. And so do you already have that mapped out? Dr. Anderson, where your lab will be and all that stuff or is what you mentioned was that you’re searching for it.

Kristin Anderson:
Actively in the search process? I was one of those. I am one of those individuals who was just starting my faculty job search right at the beginning when the pandemic hit. So I probably had the worst timing for starting my faculty, unbeknownst to me, obviously in the different institutions that I’ve been working with have been really wonderful. Lots of institutions had to go on a hiring freeze. I’m sure as far as the audience probably recognizes, when the pandemic hit, everything was sort of thrown into disarray and no one really knew what was going to happen. And everyone had to be really, really cautious about hiring and all of those pieces. So we were sort of in limbo for several months where I had interviews lined up and then they all got postponed or converted into virtual interviews. So really navigating that, doing virtual interviews was a big hurdle to overcome. One of the pieces that researchers will do in a faculty interview that’s sort of the make or break part of the interview is called the Chalk Talk. And it’s basically where you get up in front of your potential future colleagues and you share your ideas for your research plan where you want to take your lab. What do you think the first grant is that you’re going to write? Where do you see projects that graduate students can work on? Things like that? It’s a really in-depth discussion where you don’t preplan slides or anything. You just stand at a chalkboard and map things out and you go back and forth. And it’s a really amazing opportunity, not only for the institution and the department and your future colleagues to evaluate you and your scientific thought process and your planning. But for you to evaluate your future colleagues. Do these people give me good feedback? Are they asking questions in a way that stimulates really exciting thoughts for me? Are these the people that are going to help me make my grants and my research program even stronger? And when we switched to the virtual environment, all of that was lost. Really hard to do a dynamic discussion like that virtually, but it is. So that was a hurdle that we had to sort of navigate through. All the institutions that have been doing this have been trying to figure it out. And we’re at the other end of this now where I’m actually finally able to travel and see people in person. And some of those meetings are happening again face to face, which is great. But yeah, that was definitely a challenge in the process.

Saul Marquez:
Definitely sounds like it. And I’m so glad that things are starting to pick up again, you know, and things like finding that right fit for yourself and your new lab and working with others across the health care continuum. It’s critical. And so big kudos to the people working on the vaccine for COVID and I mean, just the amazing work that they’ve done to help us get to that right?

Kristin Anderson:
Yes, I second that completely. I am so grateful, really, really grateful for all that hard work. I know the scientists who worked on these vaccines pulled late nights, long weekends, and even now they’re still doing it because they’re working on boosters. And do we need additional vaccines to address some of these variants that are now out in the population? So they are still working incredibly hard and my hat is off to them for all that they are doing.

Saul Marquez:
Kudos. Kudos to all of you out there that did your part on this. And kudos to Dr. Anderson and her colleagues and this tribe of just amazing people that are doing all this behind-the-scenes work to help us find ways to live longer and healthier lives with some of the diseases and things that could allow us, this has been so much fun. I’ve really enjoyed our discussion. I love it if you could just give us a closing thought, what should we be thinking about and what’s the best place that the listeners could reach out to you and learn more about your work?

Kristin Anderson:
Yeah, of course. I think a closing thought would be that I am a living, breathing example of what happens when the system works. I mean, quality research that received sufficient funding, early detection and screening, access to health care, medical care, knowledgeable and experienced care team. All of these things came together to help me have the outcome that I did from my cancer journey. And I am incredibly fortunate that that was true in my case. But there are so many people out there for whom that’s not true. And so for everybody who’s working on any aspect of this system to try to make it better to try to improve outcomes for patients. Thank you. Thank you. Thank you for everything you’re doing. We have a long way to go, but there is a light at the end of the tunnel and I think we will get there.

Saul Marquez:
I love that. Thank you for those thoughts. And how about anybody that wants to explore your work or learn more about what you’re doing? Where can they visit or find out more?

Kristin Anderson:
Yeah, of course. So my email, if people have questions, is ande8527@gmail.com. And I’m also on Twitter. I’m @ImmuneGirl.

Saul Marquez:
Nice. Love it. There you have it, folks. If you have any questions around the T cells and ovarian cancer, Dr. Anderson is your expert. So we really appreciate all that you do. Dr. Anderson, thank you for being amazing and thank you for jumping on here and sharing your insights with us. It’s been a lot of fun.

Kristin Anderson:
Thank you so much for the invitation. This is really fun. I really appreciate the opportunity.

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