Immunotherapy and chemotherapy are two powerful tools being used in breast cancer treatment now. The former, a newer approach, harnesses the body’s natural ability to fight disease, and the other, a mainstay in cancer care, uses powerful drugs to kill cancerous cells. But meaningful questions remain: Can these two approaches be used in tandem? What are their particular strengths and weaknesses? And though both deal with combating breast cancer in the present, what tools—if any—exist to help prevent cancer in the first place?
That’s where Dr. Nora Disis comes in. Her research is focused on identifying ways to boost the immune response in breast cancer patients to improve chemotherapy outcomes. She is working to discover new molecular immunologic targets in solid tumors to develop vaccine and cellular therapy for treating and preventing breast cancer.
Dr. Disis, a BCRF investigator since 2016, is the Athena Distinguished Professor of Breast Cancer Research and the associate dean for Translational Health Sciences at the University of Washington School of Medicine. She is also the editor-in-chief of the prestigious JAMA Oncology.
Chris Riback: Dr. Disis, thank you for joining me. I appreciate your time.
Dr. Nora Disis: Great to be here.
Chris Riback: Why don’t we start with some definitions that I think would help many of us, certainly that I think would help many of us. What are immunotherapy and chemotherapy? How do they work and how might they work together?
Dr. Nora Disis: Immunotherapy is a treatment that really harnesses and uses your body’s immune system to fight cancer. There are many, many types of immune therapy. Chemotherapy is a drug or a series of drugs that directly act on rapidly dividing cells, kind of poisoning them. Now, the biggest difference between immune therapy and chemotherapy, you can imagine when you get chemotherapy infused it only stays in your body for a short period of time and then it’s cleared out of your body and it’s not doing any killing. Immune therapy, if the immune system is appropriately stimulated so that it is primed to recognize the tumor, it will keep killing and killing and killing and killing long after you’ve received immunotherapy.
Chris Riback: How might they work together? If you have one in your system, might you also want the other in your system?
Dr. Nora Disis: Well, I kind of liken it to this. If you had an overwhelming pneumonia and you went to the emergency room, you wouldn’t ask the doctor to give you a vaccine. You’d ask the doctor to give you antibiotics, and I kind of look at chemotherapy as antibiotics. Once cancer has gotten out of control or is rapidly growing, you need to cut it back because the immune system doesn’t tackle lots of disease. Well, at one time. In fact, almost everyone who dies of an infection dies with a pretty good immune response against that infection, but the infection was progressing too quickly for the immune response to be able to control it. I look at chemotherapy as a way to kind of stop the cancer in its tracks or slow it down while immune therapy begins to build and build, and then you get that continuous killing. Studies have shown they kind of work hand in hand. I think most of the treatments that you see nowadays use a combination of chemotherapy and immune therapy.
Chris Riback: It’s such a terrific analogy and really does help make it clear in such an everyday way. What is the STEMVAC vaccine? Perhaps as part of that discussion, you might also be able to bring to light the role and importance of type one T-cells.
Dr. Nora Disis: Sure. I think vaccines, which are a form of immunotherapy, are really at a tipping point. The reason why they are is for three major reasons. The first reason is we know the type of immune response you need to kill cancer. Now, if you think about the Covid vaccine, the vaccines that are out there generate antibodies predominantly, and those can bind to the Covid virus and inactivate it. For cancer, you need T lymphocytes and in particular you need type one lymphocytes, type one or a specific type of type one lymphocyte is called the TH-1 lymphocyte. These are highly inflammatory lymphocytes. They cause tissue destruction, which is what we want for cancer. Type two T-cells generally dampen an immune response, and when you have cancer, you don’t want that immune response dampened.
The second tipping point is that we now understand what parts of cancer can be recognized by the immune system. We know a lot of immunogenic proteins, hundreds of immunogenic proteins as a matter of fact. You can almost tailor-make a vaccine for any situation in cancer. Then, the final thing that’s really tipped cancer vaccines over is we now have really effective and safe vaccine technologies, nucleic acid based vaccines, either DNA or RNA are very effective at stimulating and using the patient’s own immune system to get that right type of immune response to attack cancer.
Chris Riback: And in terms of those type one T-cells, and what I’m wondering is do patients who need the vaccine or who use the vaccine have an insufficient amount of those cells? Is the body not making enough? Or is the situation that given they are dealing with breast cancer or something else, they need an extra boost or the ability to manufacture more beyond what the body could create?
Dr. Nora Disis: I think it’s a combination of what you just said. We used to think in the past, the problem with cancer patients is that of course they had cancer, their immune system isn’t functional, but that’s absolutely wrong. Patients with cancer have very functional immune systems. That’s part of the issue. It isn’t until you’re in the last stages of cancer and you’re very, very sick, do you have problems mounting an immune response. The key is in what the immune system is seeing. For some tumors like melanoma or kidney cancer, those tumors have a lot of mutations. They’re very aggressive cancers, but those mutations that occur in the cancer appear foreign to the immune system. The immune system has never seen these mutations before. They only occur in cancer. For those patients, they have quite a few type one T-cells because the immune system calls a danger signal. That says these are foreign, we need the tissue destructive immune response.
That’s why some immune therapies, the most common that we use, which are called immune checkpoint inhibitor therapies, they work best in those diseases because you already have a lot of those type one T-cells in the tumor. For most common solid tumors, most colon cancers, most breast cancers, ovarian cancer, prostate cancer, those cancers are not highly mutated. What is the immune system seeing in those cancers? The immune system is seeing abnormally expressed normal proteins. When you have a cancer that’s growing, just think of all the proteins that are involved in driving growth of a cell. Those proteins in cancer become very abnormally upregulated. Now the immune system is very good at telling when something is wrong. It gives the body a signal. Something is not quite right here, but the proteins are not foreign. The signal that the body gets is we have a wound that needs healing and that’s a totally different immune response. It’s an immune response that quenches inflammation, doesn’t start inflammation.
Most cancer patients, the ones with the most common cancers like breast, colon, ovarian cancer, they don’t have a lot of mutations in their tumor. The antigens or immunogenic proteins that are recognized by the tumor are abnormally expressed self proteins. The immune system responds to this because the immune system recognizes they’re abnormal, but the type of immune response that’s generated is an anti-inflammatory immune response. The immune system will not attack itself because we’re built not to develop autoimmunity. What happens is the patients mount an immune response. In most cancer patients, you can find T-cells in the tumor, but the T-cells are the type two T-cells and those suppress inflammation. In fact, they actively work against type one T-cells.
Chris Riback: What a series of challenges that must be overcome. In circling back to part of what we talked about earlier and that you explained so wonderfully about the relationship between immunotherapy and chemotherapy and the ways and timing and efforts that one might want around those, what is the status of using the STEMVAC vaccine alone versus combining it with chemotherapy? I believe, and please correct me if I have this wrong, are you still in preclinical trials on that?
Dr. Nora Disis: We have advanced to phase two clinical trials with STEMVAC.
Chris Riback: Congratulations. I’m very happy to hear it. I’m glad to be behind.
Dr. Nora Disis: STEMVAC is a vaccine that was developed to target cancer stem cells. Cancer stem cells are a very early cell that have the capabilities of being immortal. Cancer stem cells don’t respond well to chemotherapy. They don’t respond well to radiation. After you’re treated, those cells, which have been kind of immortalized, are the ones that have a tendency to come back and start growing again. They’re the ones that have the capability of causing metastases. Our concept was if we could create a vaccine that targeted immunogenic proteins that are found in cancer stem cells, that vaccine might be an excellent vaccine to prevent disease recurrence but it also might be an excellent vaccine to prevent breast cancer, especially in patients who have a genetic predisposition to breast cancer because their tumors tend to have a lot of stem cells. We developed the vaccine, engineering the vaccine specifically to elicit those TH one cells against five different immunogenic proteins that are expressed in cancer stem cells.
Much like getting the flu vaccine, you’re not immunized against one type of flu. That’s important to think about in cancer because cancer isn’t really caused by one individual protein. We focus really on creating multi-antigen vaccines. In preclinical models, in triple-negative breast cancer, which is a very STEM-y type of breast cancer, we were able to show that we could change the T-cell repertoire in the tumor from a type two T-cell to a type one T-cell with lots of killer T-cells that were activated. We performed a phase one clinical trial really looking at doses of STEMVAC in 30 patients with hormone receptor–positive and triple-negative advanced-stage breast cancer. The patients had been treated to a complete response and or had bone-only disease. We chose this patient population because we wanted to look at immunization over a long period of time.
Like I said, it’s not like chemotherapy. If you think about the COVID-19 vaccine, we had to get vaccinated to be able to achieve the level of neutralizing antibodies that would protect us. We did something very similar. We immunized patients once a month for three months, and then we gave booster shots three months after the last vaccine. Then again, nine months after that vaccine, the antigens or immunogenic proteins we were immunizing against were not mutated. They were some of those non-mutated proteins. There was a lot of concern that maybe we would precipitate autoimmune disease, but the vaccine was safe. It was very similar to the Covid vaccine. People got redness and swelling in their arm. They felt sick for a few days, but we didn’t see any evidence of autoimmunity. We found the most immunogenic dose.
What was important was the boosters. More people converted to a positive response when we gave the boosters. You might say at the end of the initial series of vaccines, those three vaccines, we had 60 percent of the patients having a high level of immunity. But after the two boosters, 90 percent of patients had very high levels of immunity, and they responded to almost all of the STEMVAC antigens. Now we have two clinical trials ongoing. One of them is a phase two study in triple-negative breast cancer—we’re almost done enrolling it—where we looked at patients who had finished their adjuvant chemotherapy and we added STEMVAC as a continuation of therapy once they were done with their chemotherapy and immune therapy after surgery. Our goal is to get more data on the safety and the immunogenicity of the vaccine, but we are going to look to see whether the vaccine can prevent disease recurrence, which is a major problem for triple-negative breast cancer.
The second study that we have is a randomized phase two study in non-small cell lung cancer, which is also a very STEM-y tumor. In this case, we’re enrolling patients who have received immunotherapy and chemotherapy. They have not achieved a complete response, but they have disease stabilization, which is about 40 percent of patients. At that time, when they go off one of the chemotherapies, a platinum drug, and they’re on maintenance immunotherapy and a chemotherapy called pemetrexed alone, we’re adding the vaccine. We hope that what the vaccine will do is to stimulate those type one T-cells while they’re still getting an immune checkpoint inhibitor, which kind of takes the breaks off the immune system. It would really let those type one T-cells flourish and hopefully push more patients into a better remission and hopefully extend their lives.
Chris Riback: Wow. Well, two studies going on, I guess it sounds like going on simultaneously addressing different types of cancers, but also at the stage that you’re at enrolling patients, it sounds like you maybe are just a little bit closer to having a fulfilled roster on the first one than on the second one, but that is a lot of juggling. Is the difference between the phase two and the phase one that you already discussed with the 30 patients, is it that the N is greater, it’s a greater number of patients, or did you do something else to increase the degree of difficulty?
Dr. Nora Disis: Yes, that’s an excellent question. We generally talk about clinical trials in terms of three phases, phase one, phase two, and phase three. Phase one is the earliest study. For us, it’s the first in-human study. The way the study is designed is really to emphasize safety, safety, safety, safety. Most phase one studies also are looking at finding the best dose to move forward into a phase two study. The phase two study is a larger study, and it’s generally designed to try to get some data on whether the drug, or in our case the vaccine, is doing what we think it should be doing. In this case, we think it should prevent disease recurrence. It will not be a definitive answer, but if the answer is encouraging, then we would move on to the final study, which would be the phase three study.
Now, those studies are big, they’re expensive, they enroll hundreds of patients, and they’re powered to give a definitive answer. In that case, a phase three study compares the new approach, in our case vaccines, with the standard of care. In the case of triple-negative breast cancer, people would get their neoadjuvant chemoimmunotherapy, their surgery, their adjuvant chemoimmunotherapy, or the exact same treatment with STEMVAC added. The question would be, do we truly prevent more recurrences in the [clinical trial] arm that got the vaccine?
Chris Riback: It sounds like I need to get on your calendar for another conversation around phase three.
Dr. Nora Disis: Hopefully in a couple of years. That’s how long it’s going to take to get, once we enroll the patients, then we have to watch them and see how they do.
Chris Riback: Okay, well, I want to reserve my spot on your schedule. I should ask you as well, if I could quickly, about another vaccine you have developed, ADVac.
Dr. Nora Disis: Yes.
Chris Riback: What is it and what does it do?
Dr. Nora Disis: Well, ADVac is a different approach. I told you that we create vaccines that engineer a type one immune response, but to create those vaccines, to engineer that type one immune response, we have to identify within a protein, all those type two fragments or epitopes that stimulate a type two response. Because what we do is we remove those epitopes from the vaccine, so we get an unfettered type one immune response. As we did this for dozens and dozens of antigens, we also validated that these type two T-cells for some of these proteins were anti-inflammatory. We started thinking about how could we use these epitopes to create a vaccine to fight chronic inflammation, because chronic inflammation is one of the things that can lead to cancer. We started thinking about a cancer prevention vaccine.
Chris Riback: Wow.
Dr. Nora Disis: One of the biggest things that we’ve come to know is that obesity causes cancer, and it’s responsible for some breast cancers, some prostate cancer, some colon cancers. What happens when people become obese is not that they develop more fat cells, it’s that the fat cells or adipocytes expand. They balloon up and they stress the system. These expanded adipocytes cause the blood vessels to be pinched and the tissue becomes hypoxic. They utilize a lot of the nutrients in the fat. Metabolic dysfunction occurs and the tissue in obese fat, these adipocytes, begin to upregulate proteins that stimulate the immune system. But in the face of all this inflammation going on, what happens is that the immune response that’s stimulated is a type one immune response. CD8 T-cells are drawn to the fat and CD4 T-cells as well. They begin to compete with these ballooned adipocytes for the nutrients, and they become extremely dysfunctional. It’s thought that over time, as this stress and inflammatory immune response continues, it causes changes in the cells that can lead to the development of cancer.
Unfortunately, the T-cells that are already there are dysfunctional due to the fact that they’ve been living in this environment without the appropriate nutrients. We asked the question whether we could develop an adipocyte-directed vaccine, and that’s called ADVac. We identified proteins that were highly upregulated in inflammatory fat, and we created a five antigen vaccine this time using the type two inducing epitopes from those proteins so that the vaccine generates high levels of cytokines, which are substances that help feed the immune response like IL-10 and those cytokines dampen immunity, like I told you before.
We hope to continue working on ADVac and bringing it to the clinic as the first vaccine approach to reduce your risk of breast cancer when you have a very high BMI so that we can buy people time to be able to correct that metabolic disorder without continuing to increase their risk of progressing to an invasive breast cancer.
Chris Riback: How extraordinary that would be.
Dr. Nora Disis: It would be. Wouldn’t it?
Chris Riback: Yes. Yes. Given what we all read about, you certainly have the data on, but the role, just as one example, the negative role that obesity plays in so many health aspects, not just cancer, but including cancer, to be able to, if I’m understanding you correctly, help create the environment where the obesity can be disaggregated a little bit from the effect, that would certainly, that would be a big deal for sure. Along with all of the other big deals that you are working on and have accomplished throughout your career, which makes me want to ask you briefly as we close the conversation, how did you get into this all of it? Going back, where did you grow up? Was it always science for you? Did we all ever almost lose you to a career in poetry or creative writing or anything else?
Dr. Nora Disis: Yes, that’s funny. I was drawn to an English major. My mom was heavily into English literature, but I was a geek. Science was always it for me, kind of wonky. I went to college and medical school, and I loved being in the laboratory. I always found opportunities where I could work in a lab. When I was in medical school, I had a very excellent mentor who was an immunologist and really turned me on to immunology. I thought cancer was a fascinating and scary disease. I ended up marrying the two, my love for trying to figure out how to harness the immune system to combat cancer. When I went on to my fellowship in oncology, I was lucky enough to be able to go to one of the places that was the top place for immunology and cancer, which at the time I started was a long time ago. People didn’t even understand whether the immune system had anything to do with cancer. I had another wonderful mentor who really influenced my path to attack solid tumors like breast cancer. It’s been a wild ride, and I’ve loved every minute of it.
Chris Riback: It sounds like you have, it’s totally evident in the way that you talk about your work and with the very, very, very accessible comparisons as well as the wonderful detail you give around the process and shout out to mentors. They are so powerful in so many of our lives. Lastly, I would be remiss if I didn’t ask you, I know mentors have played a big role, it sounds like. What role has BCRF played in your research?
Dr. Nora Disis: BCRF has played a tremendous role. I’ve been able to launch really crazy ideas with funding from BCRF. Oftentimes, when you’re applying to the government, they practically want you to be done with the project. People are not risk averse, but BCRF, if they see an idea or something that is a spark, they encourage you to generate that data so you’re able to go on and get the bigger awards. I can tell you, our work in ADVac would not be advancing without BCRF, and it’s a crazy idea and it’s a wonderful thing to think about. It’s a project that’s going to keep us busy for a long time to come, and BCRF will be instrumental in us being able to get that vaccine to the clinic.
Chris Riback: Dr. Disis, thank you. Thank you for this conversation. Thank you for the work that you do every day.
Dr. Nora Disis: Thanks for talking with me.
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