Intro: The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME, to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.

Melanie Cole, MS (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And today, we are highlighting groundbreaking therapeutic mRNA cancer vaccine research. Joining me to discuss this exciting research is Dr. Elias Sayour. He's a pediatric hematologist-oncologist and a Professor in the Department of Neurosurgery at the University of Florida College of Medicine. He's also a Stop Children's Cancer Bonnie R. Freeman Professor of Pediatric Oncology Research in the UF Departments of Neurosurgery and Pediatrics.

Dr. Sayour, thank you so much for joining us to discuss this very exciting topic. As we get into this, I'd like you to explain a little bit about the complexity of cancer, the ecosystem, how is the field of mRNA cancer vaccines advancing the concept of personalized cancer therapy?

Elias Sayour, MD: Yeah. Thank you for having me, Melanie. Certainly, cancer is very complex. And that complexity is one of the real grand challenges to cancer vaccines. Cancer is not just a bunch of cells that divide indiscriminately. So, a lot of people think of cancer as just exponential growth, 2, 4, 8, 16, 32.

But in truth, cancer is more than that. Tumors divide like that, but benign tumor is not the same as cancer. Cancer is defined by its ability to invade, destroy tissue. And also, cancer is not just cells. It's an environment. It's an entire ecosystem. In this ecosystem, cancer has its own blood vessels; cancer has its own metabolism; cancer has its own immune system in many contexts, an immune system that doesn't fight the cancer or see it as foreign, an immune system that sees the cancer as self or a wound that it has to heal. And that healing environment that a clumsy immune response is creating, it actually facilitates the cancer growth. And so, you have chronic inflammation in these tumors that facilitates the tumor growth.

Everything I mentioned is a part of an ecosystem that is extraordinarily challenging for a cancer vaccine to work. Even if a vaccine elicits an immune response, that immune response often cannot penetrate this environment, survive in an environment like this. And even if it could, the cancer, as it's doing all of this, continues to evolve, evolves away from the immune system. And these are significant challenges for a cancer vaccine and, in my mind, one of the major reasons why vaccines haven't worked for a really, really long time, but it's also my hope that mRNA will overcome these obstacles.

Melanie Cole, MS: Dr. Sayour, you've described this work as both deeply scientific and deeply personal. Tell us a little bit about the moment when this approach to the mRNA cancer vaccines first felt possible, and why did you believe this platform could achieve this, that prior efforts really could not. What did you see in those early models that told you that this wasn't just another incremental advance?

Elias Sayour, MD: Yeah, a great question. So, mRNA, we've been studying mRNA for 10, 15 years now, our group. And really, we've made some pretty remarkable discoveries, in that time that really have allowed us to believe this can be the solution to getting cancer vaccines, or I should say therapeutic cancer vaccines, to work.

And when I say therapeutic cancer vaccines, I mean treatment vaccines, treating something after it's already started. And one of those things that we discovered was mRNA could reprogram these ecosystems. mRNA can create an environment even in the cancer with a single dose that could reprogram the tumor microenvironment from a chronic inflammatory response that facilitates the tumor growth to a response that actually starts fighting the cancer. And the fact that this could happen as rapidly as we observed, within 24 hours of pet dogs with brain cancer, as an example, within 24 hours of a single dose, that we could see in these tumors, the immune system starting to wake up against cancer. That was very heartening for us. So much so that it created this idea of using mRNA as a universal tool. We discovered this reprogramming, this rapid reprogramming could happen with nonspecific mRNA vaccines, meaning of an mRNA that wasn't even specific to the tumor. And that idea of a universal cancer vaccine is something that I think can now be created and engineered through mRNA.

But number two, we found that personalized vaccines, if the mRNA is specific to the cancer, it works even better. And the beauty of mRNA, unlike a lot of cancer vaccine platforms, is it can adapt. You can update the vaccine to be more and more relevant to the cancer. Meaning you make a vaccine when you first biopsy a tumor, but then you can make updated vaccines if that tumor were to recur or come back. Meaning your vaccines can evolve as the cancer is evolving. And in that way, you can now provide almost an updated vaccines that outcompetes the evolution of the cancer. And so, that's something that can happen really through the groundbreaking power of mRNA, that you can build these to target as many things as you want and update them in a way that can be done through a single approach.

Melanie Cole, MS: That's absolutely fascinating and really, really exciting. And, Dr. Sayour, so this exciting observation you were just discussing that even a vaccine not specific to any particular tumor or virus, as long as it's mRNA vaccine, could lead to tumor-specific effects. What patient populations or tumor types characteristics appear most promising for this approach at this stage?

Elias Sayour, MD: This idea of a universal cancer vaccine really started in our lab, this discovery that again something completely irrelevant to the tumor could wake it up and could sensitize response to other immunotherapies, like immune checkpoint inhibitors. We saw that in mouse models of melanoma. This was before the pandemic.

Now, the pandemic allowed us to ask a really interesting question. And that question is, if a non-specific mRNA vaccine can wake up the immune system and sensitize response to checkpoint inhibitors, what happens to melanoma patients and non-small cell lung cancer patients who are receiving another non-specific mRNA vaccine? This being the SARS-CoV-2, the COVID-19 mRNA vaccines within a hundred days of also receiving conventional immunotherapy with immune checkpoint inhibitors.

And looking backwards, which is an important distinction, we're looking backwards in these studies, these are retrospective studies that have to be validated in prospective studies, forward-looking studies. But looking backwards, we found a near doubling in survival outcome of patients receiving the COVID-19 vaccine, receiving conventional immunotherapy of immune checkpoint inhibitors within a hundred days of those vaccines. And you're doubling in survival for patients with skin cancer (melanoma) and lung cancer (non-small cell lung cancer).

So, we've gone back and even shown that the COVID vaccine works in our mouse models to sensitize response to checkpoint inhibitors. This all basically tells us that perhaps we already have a universal cancer vaccine in our midst that can improve response, this being the COVID-19 mRNA vaccine. Now, it's worth mentioning the COVID-19 vaccine was not designed specifically for cancer. And even if that were to not work in forward-looking trials, we still believe we can make a universal vaccine that works much better in waking up the immune response and sensitizing response to checkpoint inhibitors, one vaccine, one master vaccine for all patients. But if indeed these forward-looking trials actually look promising, meaning the COVID-19 vaccine works to awaken the immune response, you know, we think that could really transform the field.

Melanie Cole, MS: Wow, that's unbelievable. Now, immune activation along those lines raises safety concerns. What's reassured you most about the tolerability of this approach?

Elias Sayour, MD: I think that's really the most exciting thing about the COVID-19 mRNA vaccine. I mean, this has been deployed hundreds of millions of times over and over again. And really, that safety profile that we have from so many patients who've been dosed with this, that gives us some confidence in this approach as what we believe would be a very safe way of activating the immune response in a universal manner.

At the same time, we have to run the trials to really get a really good indication of comprehensive safety in conjunction with these immune checkpoint inhibitors. That's why those trials are important to run, but we're certainly heartened by the safety data in trials that have been conducted to date for infectious COVID prevention.

Now, if that vaccine doesn't work and needs to be engineered to be even stronger for cancer, we think that's an approach that could work. But then, also, when you're activating the immune response in an even stronger manner, there are more side effects that people might be at risk for. And Those are things that we're very cautious about. That's why we have to run these forward-looking trials and make sure that these things are safe, and why we're heartened that the COVID vaccine could be an answer because of its safety profile. But ultimately, we have to run these trials to know for certain.

Melanie Cole, MS: So from a clinician standpoint, Dr. Sayour, how complex is it to deliver this therapy compared with other advanced immunotherapies? How does the delivery system of specifically mRNA vaccines influence their efficacy and safety in this type of cancer therapy?

Elias Sayour, MD: Yeah. Great question. Right now, the COVID vaccine we know is intramuscular. Again, if that works, we think that could be a safe opportunity to non-specifically activate the immune response to awaken it for response to immunotherapy. But if it doesn't work, we think there are ways of making it stronger.

One way to do That is to maybe give an intravenous vaccine, and maybe a vaccine that's designed to elicit an even stronger non-specific immune response. We've certainly made our own vaccines here at the University of Florida, an onion-like design of mRNA, aggregates that we inject right into the bloodstream that can be very, very powerful in activating the immune response. The dog studies I mentioned earlier was that vaccine, again, a non-specific vaccine that can reprogram the brain tumors in less than 24 hours. But when you do that, there are also more side effects. There are risks of cytokine response syndrome. That's where you activate a lot of signals of the immune response that can cause fever, cause muscle pain, can it cause drops in blood pressure, even cause increases in oxygen requirements in some patients. So, those are all potential concerns and why, if we started using more aggressive approaches in activating the immune response, we think those could work even better. But because of these side effects, these have to be really done in very controlled studies.

Melanie Cole, MS: And we're looking retroactively, as you say to those studies and as this work emphasizes personalization, Dr. Sayour, how challenging is it, do you think, practically to design patient-specific mRNA vaccines at this scale that we're looking forward to?

Elias Sayour, MD: Yeah, another great question. Anytime you personalize something, there is increased cost, there is increased complexity; most importantly, increased time, time being the most valuable resource that patients have. And so, if it's taking an extra two to six weeks to make a personalized vaccine, that's time that the cancer has to grow.

That's also why I believe so much in giving something universally at first, waking up the immune response as rapidly as possible, which can buy time for that personalization. But as you've stated, yes, it does take time. It takes us here at the University of Florida about six weeks right now to make personalized vaccines. But I will tell you that I think that timeline is going to shrink. I do see an era where we can make personalized vaccines almost instantly. I see the future of mRNA akin to that of a keyboard by the patients bedside, where you type in the sequence that you want, and then out the other end of a box comes the vaccine. I do see that future. And mRNA is really in the early phases of being advanced into patients with all sorts of diseases, not just cancer, but for autoimmunity, for neurodegenerative conditions as a gene therapy.

And the ability to customize a therapy just by changing the sequence, I think, we're going get much quicker and better at doing that. And as we cut down the time to personalization, I also think we'll cut down the cost and some of the complexity around this, hopefully, to the point where it may even be a bedside therapy. But right now, there is certainly time, associated with making these, so much so that I do think the universal approach as a bookend to personalization is a really important step forward.

Melanie Cole, MS: Wow. And I mean, as I see it and listen to you possibly even into preventive oncology, and I mean, it is groundbreaking as we say. Now, one of the things I was thinking about when I was writing these questions is how do you, Dr. Sayour, balance the scientific rigor we're discussing here today, the importance, the technicality of it all, with the urgency that patients and families feel around these breakthrough therapies-- people with melanoma, people with non-small cell lung cancer, people with these cancers where this type of immunotherapy could really be beneficial save lives? How do you balance that need? It must make you in the lab every day go, "Okay, we have to get this right"?

Elias Sayour, MD: Yeah. This is a very hard question, something I do grapple with every day, we in the lab have to grapple with, the sense of urgency to move this forward as quickly as possible. But also, to take the appropriate time that we need to make sure the studies are done rigorously to make sure that we're putting our best foot forward, to make sure it's done as safe and as well as possible.

It's hard. You know, I'm a pediatric oncologist, so seeing children suffering and dying of diseases that we think that we can improve through these types of therapies, through advancing these trials. I mean, it's hard when those trials aren't there yet. All I can tell you is that it is an incredible motivator, as you've mentioned, in helping us move forward as quickly as possible. But we have to sometimes, go slow to go fast. And I have to remind myself that, that going slow, taking time now means we'll be able to accelerate tomorrow, that we have a responsibility to the patients of tomorrow, to the people that haven't been diagnosed yet, to make sure that we give them the best chance of having a good outcome.

And if we make a mistake now, that compromises everything. So, it's hard. Believe me, I want to be in clinical trials for everything and help especially all these children. But we also have to make sure that this work has legs for all patients. And that this technology shows promise for other researchers and other people doing work that really mandates, I think, a strong foundation. So, we're trying to balance that. We certainly don't want to take any extra time than we need, but I also want to make sure we take the necessary time to make sure the studies are done correctly and that we answer the most fundamental questions.

Melanie Cole, MS: You're a good man and a patient one too. This is such important work you're doing. And finally, Dr. Sayour, as both a physician and a scientist, what advice would you give young clinicians, scientists trying to bridge that gap between bench science and real patient impact? And for trainees and early career physicians listening, what do you feel this work teaches us about the future of physician scientists in oncology? And if you and I were to revisit this conversation in a few years, what do you hope we'll be talking about differently?

Elias Sayour, MD: Yeah. What I would tell people really is it's important to be patient as you described, but also have a willingness to challenge existing paradigms. And when you have a willingness to challenge existing paradigms and to believe-- I use this word all the time, belief-- believe that it's possible, then I do see that as the groundswell of something great that can be created.

But to create something great not only requires that belief and that vision, but also a willingness to take all of those small steps that are necessary and make sure every one of those steps are correct. And there are times where we don't take the right steps. There are times where maybe we've moved off the right track. But it's important sometimes even to take those steps to learn where the right track is.

And again, that's where patience comes in and understanding that even our failures are teachers for success. And certainly, I think if we try to see the end of the journey through each and every one of these steps and work as hard as we can to ensure every one of these steps is as rigorous and as well done, then I think we're getting closer and closer to that destination.

It's hard, I think, for junior people who see suffering, especially clinicians who see suffering, which is so significant in the clinic and know how long this journey takes. But I do think that journey is-- we have to get that right and it takes time. And it's important to not only be patient, but to believe that we're taking the steps that we need to make the world a better place.

And the only thing I would add to that is community, working with others, others who challenge us, others who bring other layers of innovation to this. That's what creates synergy. And synergy to me is critical. One plus one has to equal 111 for us to do something extraordinary like curing cancer.

But I think the willingness to believe, the willingness to take every one of these steps, the willingness to create synergy through collaboration and working with and for others, all of that is part of the secret ingredients, I would say, towards that greatness that we're all trying to achieve.

Melanie Cole, MS: This has probably been one of the most fascinating shows that I've done in a very long time. And, Dr. Sayour, I can't thank you enough. This is exciting, exciting research, and a very exciting time in your field specifically. And if anybody can do it, you are certainly the man to do it with your team. And I thank you so much for joining us and sharing this research, letting us know what's on the horizon, because it is a time of advancements and technology and things are moving quickly. And you're right there at the heart of it. So, thank you so much.

And to learn more about this and other healthcare topics at UF Health Shands Hospital, please visit innovation.ufhealth.org. And to listen to more podcasts from our experts, you can always visit ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. Thanks so very much for joining us today.