The idea of using cells from your own tumor to develop a personalized vaccine that guides your immune system to fight your cancer goes back several decades. Today, we are on the verge of using messenger RNA to bring this concept to a new level, one that could change how we treat melanoma and other cancers. Dr. Margaret Callahan, chief of our Division of Hematology and Oncology and medical director of the clinical trials office, joins Dr. Anthony Alessi to explain how immunotherapy works and why it holds so much promise.

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Transcript

Dr. Alessi: Welcome to the Healthy Rounds Podcast, where we provide you with up-to-date and timely medical information provided by national and international leaders in their fields. This podcast is brought to you by UConn Health, with support from the Department of Orthopaedic Surgery and a grant from Coverys. I’m your host, Dr. Anthony Alessi, and it’s important for me to mention that this podcast is not an indication of what you should be doing in regard to your personal health. It is only there for information, and any personal health decisions should be provided between you and your personal physician.

I’m very happy to have as my guest today, Dr. Margaret Callahan. Dr. Callahan is a professor of immunology and medicine here at UConn Health. In addition, she’s chief of the division of hematology and oncology. Maggie, welcome to the show.

Dr. Callahan: Thanks so much for having me, Tony. Delighted to be here.

Dr. Alessi: One of the things that prompted us to do this show today has been a lot of new information for the treatment of melanoma. But before we get into that, let’s backtrack a little bit, and if you could, tell our listeners a little bit more about skin cancer and melanoma. When I think of those topics, I think, when I was young, we didn’t have SPF, right? People used to go to the beach to get tanned. Some still do. I remember people using baby oil and iodine combinations, right? And now, I mean, we have so many levels of SPF, and we are more alert to the fact of skin cancer. When did that shift change?

Dr. Callahan: Well, I’d say in the past couple decades, and if we bring it to today, where I slather my kids up with, I think it’s SPF 70 now, multiple hours at the pool, some of that just comes from knowledge of the biology of skin cancers.

Skin cancer is the most common cancer we see in humans, and there are two big families. There are keratinocyte skin cancers, which are basal and squamous skin cancers, and these are usually very treatable, but they are related to sun exposure, so you can save yourself some trouble by avoiding or safely interacting with the sun.

The more dangerous cancer that we’re talking about today, melanoma, starts with the pigment-producing cells in the skin. Those same skin cells that give you a great tan, they produce that pigment, and the tan we’re looking for can also go awry and become melanoma. And the reason we get scared about melanoma is because if it’s not caught early, it can spread to other organs and become a bigger problem.

Dr. Alessi: Maggie, are we becoming more aware of it also? Has it become more dangerous? Now, I’m talking about in the last 40 or, 40 or 50 years. Has the sun become a more potent enemy?

Dr. Callahan: Oh boy, this is a little outside of my area of expertise as a medical oncologist, but I do think the evidence out there is that changes in the environment and environmental exposures are exposing us to a little bit more UV, and maybe also changes in patterns of behavior.

But I do think part of the reason that we are seeing more melanoma comes from a couple of good problems we have. First, we’re living longer, and skin cancer and other cancers are often a disease of accumulated exposure over lifetimes. So the longer you live, the more exposure you’ve had. That’s a good problem to have.

Dr. Alessi: Oh, absolutely.

Dr. Callahan: And second, we’re looking harder, and we have better tools to find skin cancer, and so we’re finding more. And that’s also, in a way, a good problem to have. On a positive note, and to circle back to this idea that sun avoidance or safe sun exposure is a good strategy, according to the American Cancer Society, even though skin cancer rates are rising in people 50 and above, for people 50 and under, those folks who maybe were exposed to this high SPF environment, skin cancer rates are actually stable or slightly down. And so it does appear that maybe there are some modifiable risk factors that we can control our risk.

Dr. Alessi: Well, that’s interesting because, I’m encouraged, because it sounds like we’re having some benefit from all these new fabrics we’ve designed and people are wearing, and you see so many, especially children, in the pool wearing long sleeves and, and covering up.

Dr. Callahan: Hats. I’m a big fan of hats.

Dr. Alessi: You know, hats are key, especially with a big brim.

Dr. Callahan: Yeah.

Dr. Alessi: Because I’ve seen, and have had friends, where they get it right on the top of their ears with that exposure. But can we talk a little bit about what is messenger RNA? We all have come to know this term from COVID. How has that helped us design vaccines, and how is that helping us with designing a, a treatment for cancer?

I have to say, and I appreciate you sending me over some articles because I never heard the term “neoantigen” before, despite my years in medicine, so I’ve learned a lot, and that’s the advantage of doing this show.

But can you talk a little bit about messenger RNA and what role that is playing in what I consider almost a revolutionary change in medicine?

Dr. Callahan: Yeah. Messenger RNA, in part because of the success with the COVID vaccine as a strategy, has gotten a lot of press, and it’s a tool, and I’m going to try to explain how this tool works.

So if we think of DNA, our genetic material, DNA, as kind of a master cookbook, has all the recipes we need to do whatever our cells need to do, a messenger RNA is like a photocopy of that recipe, like, a single little recipe from the whole cookbook, and you can deliver it, bring it to the kitchen and say, “Hey, can you make, I don’t know, a donut?” And the cell reads that recipe, makes the donut, and throws it away. The messenger RNA vaccine is simply taking that little snippet, that little recipe of messenger RNA, putting it in a little fat bubble to protect it, and delivering it to the cell, and then the cell carries out that recipe, but it doesn’t change your DNA. It’s a temporary instruction. The mRNA degrades, and it’s gone.

Dr. Alessi: OK. And I hope we really get that out there because I think there’s this fear of messenger RNA even from the people who determine our funding, right? I think right now, NIH and the federal government no longer provides funding for messenger RNA studies.

Dr. Callahan: Gosh, it’s hard to keep track, and I wouldn’t purport to be an expert in what’s approved and not approved right now from a federal funding level. But certainly there’s been a lot of concern, and I think some concern along the lines that, that maybe just fundamentally show some misunderstandings or some mistaken understandings.

Like I said before, this does not change your genetic material, it’s a temporary message, and so maybe not as scary as some people have led us to think about it as. And then from a scientific standpoint, the real advantage, the reason this is being embraced as a technology is it is fast and flexible, meaning we can invent this recipe, deliver this recipe, as you saw with the COVID vaccine, in a matter of months, expediting the delivery of new therapies in a way that’s almost inconceivable, and manufacture it, get it to patients, and really help them out very quickly.

Dr. Alessi: Well, clearly the pharmaceutical companies have not turned their back on messenger RNA since I think that’s where most of the research, whenever we hear of research coming out, it’s coming out from Biogen and companies such as that. But if we’re to move on, how have we used messenger RNA to treat melanoma?

Dr. Callahan: Well, up until now, we haven’t, meaning messenger RNA platforms up until now have mostly been applied to vaccines in a more classic setting in infectious diseases, COVID being a good example of that. And so what’s really novel here is marrying the technology of messenger RNA, which is novel and cool in and of itself to a second really cool idea, and that’s the idea you alluded to before, which is neoantigens.

Dr. Alessi: Right.

Dr. Callahan: So infection-oriented vaccines are going to give you a little taste of whatever infection we want to prevent in advance of you being exposed to the infection and try to get your immune system geared up and ready to fight off that infection if it comes along.

But this is a very different challenge we have in cancer We’re not preventing cancer with these vaccines yet, not in this setting. What we’re doing is taking patients who have had melanoma, where we can cut them out, cut out the melanoma with a surgery, but we know there’s a risk that the melanoma will come back, and we’re using the vaccines in this setting to try to redirect the immune system to pay attention, eradicate residual melanoma cells, and protect the patient from the melanoma coming back. And the strategy we’re using here is a little different than the preventive vaccines we use for infection.

Dr. Alessi: So one of the things, this all falls into the idea of personalized medicine, right? So when we create a specific vaccine versus a tumor, that’s a vaccine that could only be used by that individual. Am I correct?

Dr. Callahan: That’s right. In this platform, this particular platform is a personalized vaccine. And so to go through it a little bit slowly, but, when a tumor grows, it accumulates mutations. Part of the reason we have tumors is because of this accumulation of mutations, and some of the mutations are necessary for the tumor to grow, but some of the mutations are just passenger mutations that accumulate over time.

These mutations can actually be seen by the immune system because they’re different. They’re different than your normal cells, and that’s what the immune system likes to see. So every patient’s tumor has a unique set of mutations. My neoantigens are different than your neoantigens, and so this vaccine is genuinely made to order.

Dr. Alessi: Now, I understand UConn and UConn Health are not new to this, and you have mentioned Dr. Srivastava, who did some of the original work on that. Can you talk a little bit about the origins of this work and UConn being involved in that?

Dr. Callahan: Sure. So the idea of a vaccine against cancer is not a new one. It is something the field has been working on for, gosh, decades and decades and maybe even a century, depending on when you, when you measure, measure this. And Dr. [Pramod] Srivastava, who’s our cancer center director here at UConn Health, led some pioneering studies in the 1980s and 1990s that demonstrated the potency of neoantigens as a cancer-fighting tool, really identified that the immune system is attracted to differences between normal tissue and cancers, which are explained by these mutations.

And he had a paper in 1993 where he specifically introduced the idea that each tumor’s unique mutations could generate individual, distinct tumor-specific antigens that can drive an immune response and can be used for therapy. And this concept really paved the way conceptually for this modern era of neoantigen vaccines.

What’s happened in the interim since that was a concept in the 1980s and 1990s, is that the technology we have, mRNA vaccines, for example, high-throughput sequencing, bioinformatics, has caught up in such an amazing way to make what was a cool idea something that we can actually do.

Dr. Alessi: Your career is kind of interesting, just being a professor of immunology and hematology oncology. Did you foresee this when you created your specialty or when you started your work? Did you foresee that immunology and cancer treatment may be coming together in the future?

Dr. Callahan: Boy, I wish I could take credit for that. No, I was simply really an interested, curious MD Ph.D. student, and I came across Dr. Srivastava’s work on neoantigens, and I thought it was the coolest thing I’d ever heard. I just thought, “This is such a cool idea, and I want to be part of the research, understanding how the immune system can fight cancer.” At that time, the field honestly had a pretty dismal track record, lots of failures, lots of advice from people saying, “This is never going to work. We’ve been trying forever and failing.” But I was really governed by where my interest led me.

Dr. Alessi: It’s like a baseball player going to play for a losing team, right? You’re thinking, “Listen, I can only help at this point.” Which has turned out to be phenomenal. How big a deal is this, what we’re reading about in terms of, in my mind, I keep thinking it’s a major step forward. Am I kind of pie in the sky and too optimistic, or is this a major breakthrough for the future?

Dr. Callahan: Oh, I think it’s definitely a major breakthrough. And I think immunotherapy has already transformed cancer care. So if we look in my disease, the disease I treat, melanoma, 20 years ago, a diagnosis of stage four melanoma was a death sentence, with a median survival of six months.

Checkpoint inhibitors, which now have been around for a decade and are widely used immunotherapies, have had an enormous impact. They have changed the death rates, the, the survival benefit for patients with melanoma such that half my patients are alive five and 10 years later. But the checkpoint blocking antibodies do one thing. They are like a gas pedal. They accelerate an immune response that’s already there, and they sort of pump up the immune system.

Dr. Alessi: Are those drugs like... is that why in this study they use Keytruda? Is that one of those checkpoint inhibitors?

Dr. Callahan: That’s right. So Keytruda is one of those checkpoint inhibitors. So is Opdivo. There are a number that are in clinic now.

Dr. Alessi: So we see those ads on TV. So we might as well u- we can use brand names here.

Dr. Callahan: Oh. Got it. Yes. These are all FDA approved, and I’m not endorsing one or the other, but just giving a couple of examples and telling you how commonly they are out there. And they’ve been a big game changer. Survival rates for melanoma are better today than they ever have been because of these drugs. But If we think of checkpoint inhibitors as the gas for the immune system, these vaccines are like the steering wheel. They’re going to direct the immune system towards the right target, towards the cancer, and, I think we’ll all agree, your car works better with both a gas pedal and a steering wheel. And so I think there’s a tremendous amount of promise that combining these two modalities really sort of helps us capture a better portion of the potential of the immune system to fight cancer.

Dr. Alessi: All right. So what’s next? I’m going to ask you to take out your crystal ball and tell me what’s next. Are we going on, are we taking this technology to lung cancer, ovarian cancer, brain cancer? Where are we going with this?

Dr. Callahan: Well, I think that’s one of the really exciting things about immunotherapy, and something we learned from immune checkpoint blockade, which is these therapies, they don’t work directly on the cancers. They work on your immune system, and let your immune system do the job. And so they tend to be somewhat cancer agnostic, meaning they can be applied to lots of other cancer situations, and we’ve seen that with checkpoint blockade. I think 100% we’re going to see that with vaccines as well.

I think the other thing I’m really excited about is as the technology and our capability to understand the immune system evolves, we’re going to get so much better at understanding how individual patient’s immune system works, and therefore which of these levers, which of these tools are going to be most helpful in shaping their immune system and getting it to fight their cancer, and that’s work that I do in my own research.

Dr. Alessi: Maggie, thank you.

Dr. Callahan: You’re very welcome.

Dr. Alessi: Thank you for your time today, and really an enlightening talk, and really thank you for all you do for our patients here at UConn Health.

If you have any questions or ideas for future programs, you can reach out to me at healthyrounds@uchc.edu. Jennifer Walker is executive producer of the Healthy Rounds Podcast. Chris DeFrancesco is the studio producer of the Healthy Rounds Podcast. Until next time, this is Dr. Anthony Alessi. Please stay healthy.