Breast Cancer Vaccines

Jamie DePolo: Hello. Thanks for listening. I am honored to have two guests on the podcast today. Dr. G. Thomas Budd and Dr. Justin Johnson, both of the Cleveland Clinic.

Dr. Budd is an oncologist and Dr. Johnson is an immunologist, and they have just launched a very early study on a vaccine that aims to prevent triple-negative breast cancer. They join us today to talk about this very exciting research. Dr. Budd and Dr. Johnson, welcome to the podcast. 

Dr. Thomas Budd: Hi. Thank you. 

Jamie DePolo: Now, before we kind of get into the real specifics of your particular study, I’m wondering if you -- Dr. Johnson, since you’re the immunologist I’ll start with you and then I’ll ask Dr. Budd to chime in. Could you tell us sort of how would a cancer vaccine work? What’s the mechanism behind this? 

Dr. Justin Johnson: Okay. So first of all, I’m not clinical, I’m in the research side of this vaccine, so Dr. Budd can answer the more clinical questions, but this is a good technical question. So our vaccine would work in a very similar manner to the vaccines that we’re used to, the ones that you get as an infant. The HPV vaccine as a teenager. Some of the vaccines we get as older adults such as the shingles vaccine and pneumococcus. Basically, a vaccine is training the immune system to recognize these pathogens or invaders in our body and target them and eliminate them. 

Our cancer vaccine is designed along similar lines, so that you are training your immune system to attack cancer cells as they emerge, ideally. So the technology is very similar. The difference is with the traditional vaccine, the vaccine is usually based on or contains all or part of the actual pathogen, which is non-self in the immunologist lingo. We’re trying to create a vaccine that recognizes self, which is cells of your own body, but they are in a sense altered self because they are no longer behaving as a normal cell.

So the trick is to figure out how we target these cells, how we tell the immune system that these cells are no longer normal and are now dangerous. We have, for this vaccine, targeted a protein called alpha-lactalbumin, which is a normal lactation protein that is a component of milk. 

Jamie DePolo: Okay. I want to interrupt you for one second. So if I’m understanding you correctly, because cancer cells start out as normal cells and then they change or mutate and they become cancerous, that’s why the immune system has a problem attacking it. Because the immune system is still seeing these cells as, hey, this is part of my body. I should not attack it. Am I understanding that correctly? 

Dr. Justin Johnson: Yeah. That’s exactly right. It’s very nuanced that these cells are partly self and partly acting like they’re an enemy and that they’re non-self and that they’re dangerous. Tumor cells can even employ tricks to shut the immune system down using the control mechanisms that are naturally part of the way that your immune system operates. So there’s a lot of tricks that the tumor cells use but there’s a lot of tricks that scientists and clinicians can use. Dr. Budd can talk more about the clinical side of things. 

Jamie DePolo: Okay. Thank you. Just to sort of follow-up with that to make sure everybody understands. That’s probably the biggest reason why it’s been so difficult to create a cancer vaccine. I know I’ve seen very early studies for breast cancer vaccines, prostate cancer. I know it would be amazing to come up with one, but it sounds like that’s a big reason why, because these cells start out as part of your body. They’re not a foreign virus that you inhale in like COVID or something. 

Dr. Justin Johnson: Yeah. That’s exactly right. So, with a virus or bacteria, for example, it’s very easy to target that because that organism doesn’t have much in common with your own cells, and it’s very easily recognized as dangerous. But the idea of making a cancer vaccine isn’t new. It’s just very difficult. The research goes back about 100 years when early researchers would take out a tumor, grind it up and inject it into the patient. The problem is you’re injecting self into self, largely, and we needed to find a really good target to target our vaccine against. 

The ideal target would be something that the cancer cell makes that the normal cells do not. That has been the holy grail for 100 years, and it may not be a realistic goal. So what Dr. Tuohy, who spearheaded this research, and sadly, unfortunately passed away last month. He came up with the idea of what he called the retired self, or retired protein hypothesis. Whereby he recognized that later in life, it’s normal for the body to shut down production of proteins that it used to make, that used to be important. For example, the pigment in hair that goes away and our hair turns gray as we age. 

Many of these proteins that are so-called retired, are involved in reproduction. That makes sense because as we reach the age of menopause, we’re no longer having children. We don’t need these proteins, so a lot of the proteins that the ovary makes and the breast makes get shut down and retired. 

Dr. Tuohy also recognized that cancerous cells often turn on the expression of these proteins that are shut down. So, he came up with this vision of targeting these proteins that we don’t make anymore in normal cells, but cancer cells do. And alpha-lactalbumin, which is at the core of our breast cancer vaccine, is one of these proteins because once a woman is no longer having children and lactating, that protein shouldn’t be made. But oftentimes breast cancer cells do make it, and in particular triple-negative breast cancer, which is one of the most aggressive and has the fewest treatment options, is very prone to make that protein. So, it’s an excellent target for breast cancer, especially triple-negative. 

Jamie DePolo: Okay. Thank you very much for explaining that. Dr. Budd, we’ll switch over to you to talk a little bit about the clinical side of this vaccine research. 

Dr. Thomas Budd: Well, based on Dr. Tuohy’s work in conjunction with Dr. Johnson, it was clear that in these animal models that this vaccine could, to some extent, treat triple-negative breast cancer in these mice, but more importantly and more potently, it could prevent them from developing breast cancer.

So ultimately, that’s what we want to do is be able to give it to women at risk for developing breast cancer. As a first step, we’re looking at women who have a history of triple-negative breast cancer that was early enough that it could be treated surgically. Also, they usually get chemotherapy, radiation, sometimes immunotherapy. When they’ve completed all the standard treatments but are still at risk to have their cancer come back, at that point we’re giving this vaccination in a series of three injections under the skin, separated every two weeks, and looking at the side effects and the immune response. 

Really what we’re trying to do now is figure out what dose we ought to use going forward. That dose will be based on side effects, of course. We want to have acceptable side effects, but also on the immune response. So, we may not have to give the highest dose. We just want to give the dose that gives us the immune response we’re looking for and has acceptable side effects. So that’s what we’re trying to determine now. 

Jamie DePolo: Okay. That sounds extremely interesting and exciting. I believe, if I read everything correctly, you have two studies going on right now. A phase IA and a phase IB, and I know phase I studies are usually pretty small, like 10 to 20 people. So Dr. Budd, if you could explain perhaps the differences between the two studies and what the aim of each study is. 

Dr. Thomas Budd: Sure. Both of them are phase I trials, which means they’re early studies. First studies in human beings. I have the goal of determining the dose we should use going forward, look at the side effects, look at the immune response in this case. They differ A from B in terms of the population of people who are entering into them. So the IA trial is for this group of patients who have a history of triple negative breast cancer but are at risk for recurrence. So that’s the IA group. And that’s where we started first just to get an idea of the range of doses we should look at. 

The phase IB group is a different group of patients. These are women, basically, who are at risk to develop triple-negative breast cancer because of variant genes that they have, such as BRCA1. That’s the most common one that we think about that puts women at risk for triple-negative breast cancer. As many in your audience know, some women who have this genetic variant know they’re at increased risk and elect to undergo preventive or prophylactic mastectomy on both sides to take away the breast tissue and reduce the risk of developing breast cancer. This is the group of women that we’re targeting in the phase IB study. 

So, these women will undergo the preventive mastectomy, but beforehand we’ll give them the vaccine and we’re going to look at the effects on the immune system and also look for any side effects that would be in the breast tissue after it’s resected. One concern we have is that there could be some areas where there is milk production in these breasts, even though these are women who are not making milk. So just to be on the safe side, we want to look at those breasts very carefully to look for any evidence of that and inflammation that could be a potential side effect from this vaccine. So, we’re trying to be very careful about looking for any anticipated side effects. But of course, we’re also looking at any immune response that we can produce against alpha-lactalbumin and occult tumors that could be there. 

Jamie DePolo: I do want to ask about the protein, the alpha-lactalbumin, if I’m saying that correctly. Do we know why it seems to be found in triple-negative breast cancers, say, more so than a hormone receptive-positive breast cancer? I’ll ask that to whichever one of you would like to respond first. 

Dr. Thomas Budd: Well, I could say I don’t think we know. That’s the bottom line. 

Dr. Justin Johnson: We do have a speculation. We just haven’t researched it directly. But Dr. Tuohy had a suspicion that the hormones, such as progesterone, actually repress it when it’s not needed, and when tumor cells emerge, these control mechanisms break down or are bypassed. That’s how we end up with triple-negative breast cancer, and so that opens up the door for alpha-lactalbumin expression. So, it was speculative based on what’s out in the literature, but we never researched it directly. 

Dr. Thomas Budd: I would say there’s some interesting epidemiologic kind of linkage between breastfeeding and triple-negative breast cancer. So breastfeeding seems to reduce the risk of developing triple-negative breast cancer. So there’s that intriguing link. Now, how that link is formed we can speculate that it has something to do with the development of the breast and involution or the recession of the milk-producing part of the breast after you stop making milk. So there are a lot of hints, but a lot of work left to do to try to figure this out. 

Jamie DePolo: I’m curious, too, what happens if a woman never had children or had children but didn’t breastfeed. Does that affect the level of this alpha-lactalbumin? I mean I know we don’t know if that would directly affect breast cancer risk, but it sounds like there could be some linkages in there somewhere. 

Dr. Justin Johnson: Well, one of the concerns that we had before launching this trial, was we had tested this vaccine in a mouse model. It was very effective. It was 100% effective in prevention and also very effective in treatment. But one of the critiques we got was when we go into the human populations what’s going to happen if women have had children and lactated or if they haven’t. Is that going to affect how the breast cancer vaccine works? So this is a great question. We addressed that question in our mouse model with mice that either had lactated or hadn’t, and we found that immunologically and the effect on the tumors wasn’t altered at all whether the mice had a history of lactation or not.

So, it’s a question that remains to be answered in the human population, and our trial may help answer that question. But as far as we know it shouldn’t make a difference either way. 

Jamie DePolo: Okay. Thank you, Dr. Johnson. That sort of leads me to another question. I know this is a very early study and you can’t answer all the questions or have all the different types of people that you might like in the study. But are you looking at all by, say, a woman’s age? So are you looking at somebody who maybe is done having children but hasn’t gone through menopause yet versus somebody who has gone through menopause? Or is everyone in the study post-menopausal? 

Dr. Thomas Budd: Well, we have pre- and post-menopausal women on, but all women are cautioned that they should not become pregnant and breastfeed afterwards. Many of these women, because they’ve had chemotherapy for instance, sometimes are pushed into menopause by chemotherapy, but we are just cautioning women that we do not want them to breastfeed after this. 

Jamie DePolo: And this is probably a question further down the road, but I’m wondering if this vaccine is successful and say I’m a younger woman, I’m 25, I don’t know whether I want to have children yet or not, but I do know I have a genetic mutation, say a BRCA1 or BRCA2 mutation, so I know I’m at higher risk of breast cancer. Is this vaccine a possibility for a younger person like that, potentially? Or is it really for somebody who is finished having children, is say, they’re heading toward menopause?

Dr. Thomas Budd: Well, it’s for women who are finished having children. That’s what we would say at the present time. But in the mean time they can do, and many women do this now because they’re waiting to have children, is they are screened. So MRI screening is done and hopefully we’ll have better screening methods going forward. 

Jamie DePolo: Okay. And then I do want to ask a little bit about side effects. I’ve read some of the side effects with the immunotherapies, where perhaps you have thyroid issues after that, you have other sorts of autoimmune disorders that come up because of the immunotherapy. It sounds like the vaccine works a little differently, so I’m wondering if the side effects you’re anticipating or have seen, say, in the mouse models. Are they similar to that or are they different? Do you have any idea what the side effects might be? 

Dr. Justin Johnson: So pre-clinically in the mouse models, this vaccine was tolerated very well. We did extensive toxicology testing on these mice. The main issue that we saw in these mice was that there was irritation at the sites of injection. To get a good immune response, we’re injecting an emulsion under the skin. So that’s kind of like mayonnaise. It’s kind of creamy. 

Jamie DePolo: So it’s very thick. 

Dr. Justin Johnson: Yes. Exactly. And it’s meant to be that way. It’s meant to remain under the skin in a small blister for a couple of weeks and that activates the immune response. Because that’s one of the clues the immune system gets that there is something there that shouldn’t be. So this is necessary. Unfortunately, there’s a side effect of causing some irritation there, that eventually resolves on its own in our mouse models. So it wasn’t considered serious but it was something that we noted. I believe that Dr. Budd can confirm that the human trials are sort of mirroring what we saw in the mice. 

Dr. Thomas Budd: Yes. So we are seeing essentially what Dr. Johnson told us about. There’s a lump, it’s itchy, it turns red, sometimes tender and we’ve raised the doses. If you go too high on the dose it takes longer to resolve and sometimes it even weeps. We consider that unacceptable, so we’re looking at lower doses than the doses that cause that. We’re exploring all of the dose ranges. We haven’t seen a lot of fever, that kind of thing, but I would point out this is different than some of the immune therapies you’re talking about here. We’re trying to focus the immune system on this one protein. 

In these other checkpoint inhibitors, so called, such as the PD1, PD-L1 inhibitors, they’re kind of taking off the brakes. Your immune system has brakes because your immune system is active all the time. It’s responding to infections and other inflammation, that sort of thing. It has ways to turn itself off. Essentially, what we’re doing is turning it off when it attacks the cancer but we’re turning it off in other situations as well. So, you can get these immune side effects, which are really autoimmune side effects. So, we’re trying to produce autoimmunity but autoimmunity that’s just very focused on these alpha-lactalbumin producing cancer cells. So far, we’ve not seen any of those kind of side effects on the thyroid or colitis, or on the colon, that sort of thing. 

Jamie DePolo: That’s great. I do want to ask Dr. Budd, where does a woman get the injections? Is it in the arm? 

Dr. Thomas Budd: We tested a group of patients and we’ve been treating many of them in the phase IA, many of them have undergone bilateral mastectomy. They elect to do that or else just one side, but they have some procedure done under their arms, to the lymph nodes there, removing a few or many lymph nodes under the arm. So, we wanted to avoid the arms for that reason. So we went to the legs and then a third injection on the stomach, on the belly but it was really for that practical reason. 

Jamie DePolo: I’m assuming that’s for lymphedema reasons, needle sticks, those kinds of things. 

Dr. Thomas Budd: Yes. We didn’t want to cause lymphedema in women who had had surgery under their arms. 

Jamie DePolo: Okay. I’m curious, I’m not sure which one of you, Dr. Budd or Dr. Johnson should answer, are either of these trials still recruiting? Say, if there’s someone listening who thinks she might be a good candidate, is that possible? Or are they closed and you’re pretty much just now going through the trial and then analyzing? 

Dr. Thomas Budd: Well, they’re both recruiting, actually. Because the phase IA, we kind of figured out the ceiling on the dose and we’re still continuing to study below that ceiling. So we are accruing patients. I will say we have a long waiting list because women are very interested in this approach. I don’t want to promise or mislead any of your listeners to thinking it’s likely that they’ll get the treatment, but we’re certainly open to putting people on a list.

This IB trial we’ve just opened, so yes, we are looking for participants. I should point out though, because we’re looking at this breast tissue, all of the surgery has to be done at the Cleveland Clinic and the injections have to be at the Cleveland Clinic. So that does limit to people who are able to do that. To have the surgery here because of geographic or insurance reasons. 

Jamie DePolo: Sure. So it would have to be people listening in the Cleveland area. 

Dr. Thomas Budd: Basically. 

Jamie DePolo: And then finally, I’m wondering, what are the next steps? So if these two trials look successful, what happens then? I don’t want to ask this question but I do want to ask this question, as far as a timeline. When might we see something if the results are successful? I’m assuming you would have to go…I don't know if the phase II trial is necessary, but definitely a phase III trial would be necessary before you could get approval for it. So what are the next steps and what sort of timeline are you looking at? 

Dr. Thomas Budd: Well, it would be a long timeline, unfortunately, especially for the prevention group. We would do a phase II trial to get a better idea of the side effects, immune response to allow us to calculate how many people we have to enter on a phase III trial. In a randomized phase III trial, these are generally fairly large studies and really we’d be waiting for cancer to develop or not develop. Now, whether we can find a shortcut around that is another question. So, we’ve been thinking of ways to try to shorten the timeline, but I think it’s going to be a decade or decades before we get a final answer. 

In this other group of patients who are at risk to have recurrence, that also is a long timeline. Because treatments are getting better, fewer people have the cancer come back, which is a good thing, but it makes it harder to find a difference, and it always takes years for such trials. So to show that it has a clinical effect that’s important to patients, not just test results, then it’s going to take years and I think decades. 

Jamie DePolo: Thank you. Yes, I guess I was assuming because, as you said, the goal is after somebody gets the vaccine you have to see whether cancer develops or not. I would assume you’d want at least five years of follow-up and ideally 10 to 20. 

Dr. Thomas Budd: Yeah. 

Jamie DePolo: That’s what I thought because sometimes cancers develop very slowly and you need to…you know, sometimes the results at five years are good but then 25 years out they may be very different. 

Dr. Thomas Budd: So we would start with patients at high risk to develop these cancers. This is where we would see an effect that’s most obvious. 

Jamie DePolo: All right. Thank you very much. Is there anything else either of you would like to add? This has been very fascinating. 

Dr. Thomas Budd: I’d just like to note this is all based on the work, as Dr. Johnson said, of Dr. Vince Tuohy, who came up with this retired protein hypothesis. He did see this study get started, so he saw his work get into human beings, but we’re all sad that he’s not here today with us. 

Jamie DePolo: Yes. I’m very sorry about that. But thank you, both, for your time. I appreciate it. This is very exciting and we’ll definitely keep tabs on your results as you publish them. Thank you so much. 

Dr. Justin Johnson: Thank you.