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Cleveland Clinic recently opened a clinical trial to determine the maximum tolerated dose of a vaccine in patients with non-metastatic triple-negative breast cancer (TNBC). The breast cancer vaccine was invented and developed by Cleveland Clinic immunologist Vincent Tuohy, PhD, and his research team. Cleveland Clinic medical oncologist and principal investigator, G. Thomas Budd, MD, joins the Cancer Advances podcast to discuss the trial origins and what we are looking to accomplish.

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Triple-Negative Breast Cancer Prevention Vaccine

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today I'm happy to be joined by Dr. Tom Budd, an Oncologist in the Breast and Sarcoma Programs here at the Taussig Cancer Center. He's here today to talk to us about a breast cancer vaccine trial. So welcome, Tom.

G. Thomas Budd, MD: Hi, Dale. Nice to see you.

Dale Shepard, MD, PhD: Good to see you. Tell us a little bit to start out about your role here at Cleveland Clinic.,

G. Thomas Budd, MD: Okay. So I'm a Medical Oncologist at the Cleveland Clinic, with a particularly interest in breast cancer, sarcoma and clinical trials. And I've done some work in the past in chemo prevention. And this study is the first step on the way to an immunoprevention strategy.

Dale Shepard, MD, PhD: Excellent. So let's just launch into that. So we're talking about today about a breast cancer vaccine. Tell us a little bit about this breast cancer vaccine and maybe a little bit about its origin.

G. Thomas Budd, MD: Well, this is all based on the work of a basic scientist colleague of mine and ours, Dr. Vince Tuohy. Vince Tuohy is an immunologist, a PhD immunologist, who did preclinical work in a breast cancer model, showing that a breast cancer vaccine could prevent breast cancer in this animal model. And it's based on what he has termed the retired antigen hypothesis.

So the idea here is that we develop an immune response to an antigen expressed on the cancer cells. The problem is cancer cells are derived from human cells, so a lot of the antigens or proteins on their surface are shared by normal cells. And this has stymied us therapeutically. A retired antigen is one that is expressed conditionally and then it's no longer expressed. And specifically the alpha-lactalbumin protein, which is expressed in normal tissue only in lactating breasts. So it's a milk protein. When a woman is lactating, this protein is expressed in lactating cells. Other than that, it's not expressed.

So the idea is to use this as a target. And the reason that this is a target is that this same protein is expressed on some breast cancer cells, and specifically some so-called triple-negative breast cancer cells. Cells that are negative for estrogen receptor, progesterone receptor and HER2. In the preclinical models it was possible to develop an immune response with a vaccine against this alpha-lactalbumin and prevent breast cancer. Now we're not ready to do that yet in human beings, there are many intermediary and first steps to take.

Dale Shepard, MD, PhD: Since this is going to be primarily targeting initially triple-negative breast cancer, remind us what percentage of patients with breast cancer would have triple-negative breast cancer.

G. Thomas Budd, MD: Triple-negative breast cancer is approximately 15% of all new breast cancer. It is the worst breast cancer to have at the moment because it's triple-negative. And what that triple negative means is that those negatives mean that we don't have targets. In the case of ER-positive breast cancer we can use an estrogen receptor as a therapeutic target. In the case of HER2-positive breast cancer we can use HER2 as a therapeutic target. So we don't have any specific targets for triple-negative breast cancer, and we're stuck with chemotherapy at the moment.

The other thing about triple-negative breast cancer is that it's the most common type of breast cancer in patients who have BRCA1 mutations. And this is a familial tendency to develop breast cancer, so this is a target group. And there are some other inherited breast cancer syndromes that are associated with increased risk of triple-negative breast cancer.

Dale Shepard, MD, PhD: So Dr. Tuohy has done a lot of preclinical work, developed this vaccine, and now it's ready to go into a clinical trial. Is that where we're at, at this point is getting a clinical trial started?

G. Thomas Budd, MD: Yes, we're getting the clinical trial started. The first clinical trial will be done first to show that we can develop an immune response and what the magnitude of that immune response is. And also to make sure that it is safe to administer to patients.

The first trial will not be strictly prevention. This will be done in patients who have a history of high-risk breast cancer, that's triple-negative, and who have completed all standard therapy. These women then, after their informed consent, will receive three vaccinations, two weeks apart and will be monitored for side effects. And to see whether they develop an immune response to the alpha-lactalbumin.

Of course, we'll track them over time. A beneficial response would be an inhibition of the rate of recurrence. This trial really will not be large enough to prove that it works in terms of anticancer effect, it will be designed to look at the toxicity and the immune response.

Dale Shepard, MD, PhD: How many patients are we anticipating will participate in this initial trial?

G. Thomas Budd, MD: Well, it depends a bit, but it'd be probably around 18 patients.

Dale Shepard, MD, PhD: Is this being done as the traditional Phase One with dose escalation in terms of the quantity of vaccine given, or is there a change in how many doses of vaccine are given?

G. Thomas Budd, MD: That's a good question. It's a traditional Phase One trial. So we start at a low dose in three to six patients. If they do okay, we escalate the dose. If they do well, we escalate the dose again. Not with in-patients, but in groups of patients. Because we do several vaccinations and there may be a booster effect with later vaccinations.

So that we will be studying them in terms of side effects. And then every two weeks and later at the end of the follow-up period, we'll be monitoring them for an antibody response, and more importantly, a T-cell response against this antigen.

Dale Shepard, MD, PhD: And so this is ... You did mention about prevention. So some vaccine therapies were giving for treating the underlying tumor. This is being given in patients who have no tumor, trying to ultimately make sure that they have the optimal protection against recurrence, right? Is that-

G. Thomas Budd, MD: Yes, in this setting.

Dale Shepard, MD, PhD: In this setting.

G. Thomas Budd, MD: Where we want to go from here, eventually it would be a true prevention strategy, where we would treat patients who are at risk for breast cancer, who've never developed breast cancer, to see whether this could reduce their risk of developing breast cancer. The next trial that we envisioned would be done in patients who have one of these BRCA1 mutations that puts them at risk to develop breast cancer. They would receive the vaccine informed by the dose studies that we're doing now, and we would look for an immunologic response.

And then unfortunately right now the only preventative strategy is bilateral mastectomy, preventive or prophylactic mastectomy. We would look in the breasts to make sure there's no autoimmune response in the breasts, and we'd look for an immunologic response. Eventually we would hope to get to the point where we would vaccinate patients to prevent their developing breast cancer, and perhaps prevent their having to undergo this mutilating surgery, bilateral mastectomy.

Dale Shepard, MD, PhD: So right now, being treated more from a safety standpoint, next step would be preventing in high-risk patients. Is there a thought of using this as an adjuvant setting as well for those patients who do ultimately get, despite our efforts, triple-negative breast cancer?

G. Thomas Budd, MD: Well, there are thoughts in that direction, yes. In the preclinical models, it's much more effective as a preventative than as a therapeutic, but it may be, it could be incorporated into a therapeutic strategy that would involve other immunologic agents, such as checkpoint inhibitors and so on. That's one potential development strategy. But I think another alternative would be the purely preventive strategy. And we foresee both strategies being pursued.

Dale Shepard, MD, PhD: Has the trial started at this point?

G. Thomas Budd, MD: No, it hasn't started yet. There are a few hurdles to overcome, but we are optimistic. We will be able to start in late July, 2021, perhaps August, 2021.

Dale Shepard, MD, PhD: All right, so well on its way. So something that's going to be starting very, very soon. When this is open, how would patients reach out to us and see about participation?

G. Thomas Budd, MD: Well, the best would be to contact Cancer Answers and that's at eight, eight, six, two, two, three, 8100. And their information will be referred to appropriate study personnel.

Dale Shepard, MD, PhD: Is there work being done on similar vaccines, either by our group or others, to utilize the same strategy?

G. Thomas Budd, MD: Not that I'm really aware of. People have thought about HER2-directed vaccines. Again, these are primarily therapeutic, and right now there's no known familial predisposition, and there are other therapeutic vaccines. A truly preventive vaccine is unique. There are investigators who have talked about vaccines against the mutated BRCA1 mutation, but these are not nearly ready for human clinical trials.

Dale Shepard, MD, PhD: And are there other cancer types that there are similar vaccine strategies for prevention?

G. Thomas Budd, MD: Well, I think there could be vaccine strategies. Other so-called retiring antigens of the particular alpha-lactalbumin vaccine would not be effective against other cancers, it would be specific. It could be that with a similar immunologic adjuvant and a similar antigen, which is retired or which is unique to a protein, that a vaccine strategy could be developed against other cancers using a similar strategy.

It would be important to have a group of patients who are at sufficient risk to develop a specific cancer that in effect could be seen. And that the potential, any potential side effects would be worth it.

Dale Shepard, MD, PhD: Excellent. So we don't really know for sure what this side effects are going to be, since this hasn't been given in people, but-

G. Thomas Budd, MD: Well, it hasn't been given to people, it has been given to mice. And the side effects are primarily local reactions. As you might expect, any injection that induces an immune response may cause a local reaction. Fortunately, the clinical vaccine seems to produce a less of a local reaction that was used in the earlier studies, because the clinically-used vaccine is a much cleaner preparation, frankly, because it's GMP ready for human use.

So it's a much cleaner vaccine preparation than was used in the preclinical studies and seems to produce less of a local reaction, but still the immunologic effects are preserved when it's given to mice. In mice, given the preclinical vaccine, there were some abnormal liver findings, but we do not anticipate that this will be a problem with this cleaner vaccine.

Dale Shepard, MD, PhD: Just going back to the trial in terms of the patients that are going to be enrolled. So clearly has to be a patient with triple-negative breast cancer. When we think about clinical trials, Phase One trials that involve other types of therapies like chemotherapies, we think about liver function, kidney function, bone marrow function.

Are there any particular characteristics for this particular trial that would keep people out of the trial? What patient population are you going to be looking for?

G. Thomas Budd, MD: Well, of course we don't know all of the side effects. And we are looking for patients at sufficient risk of recurrence, that some attempt at additional treatment is reasonable. We are requiring basic normal liver function, kidney function, hematologic function. But it's not an exhaustive list, just generally healthy people.

Dale Shepard, MD, PhD: What do you see as being the other big gaps in developing a therapy like this? We have to have patients with the right characteristics, the right risk. So are there any other gaps that we're trying to fill?

G. Thomas Budd, MD: Well, I think the real difficulty will come when we try to do a prevention trial, because these are very difficult to do. There are very few drugs that are actually approved to prevent cancer, because they require very large patient populations. The patient populations have to be at sufficient risk, and the treatment has to be sufficiently safe because you're treating healthy people.

So these are very difficult trials to do. There's a long payoff, so to have a pharmaceutical company do this is a big gamble. And I think will probably have to come through some public resources to do this kind of a trial.

Dale Shepard, MD, PhD: I suspect that given the severity of this disease and the lack of treatment options when this disease recurs, that you're probably getting a lot of interest from patients that would like to take part in this trial?

G. Thomas Budd, MD: Yes, there is tremendous patient interest. We have patient advocates, of course, who are associated with our program. There has been a lot of interest from the patient community. The breast cancer patient community is one that is very involved and has been very supportive.

Dale Shepard, MD, PhD: Well, thank you for your insight on this really novel approach to treating breast cancer. And thank you for joining us.

G. Thomas Budd, MD: Thanks, Dale. Nice to talk with you and hope to talk with you again.

Dale Shepard, MD, PhD: Dr. Tuohy is named as inventor on the technology, which Cleveland Clinic licensed to Anixa Biosciences, Inc. He will receive a portion of commercialization revenues received by Cleveland Clinic for this technology and also holds personal equity in the company.

This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget, you can access real-time updates from Cleveland Clinic's Cancer Center experts on our Consult QD website consultqd.clevelandclinic.org/cancer. Thank you for listening, please join us again soon.

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