preroll: 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 here today to highlight mRNA cancer vaccine advantages and how to adapt mRNA to treat patients with cancer is Dr. Elias Sayour. He's an Associate Professor in the Department of Neurosurgery at the University of Florida College of Medicine. He is a Stop Children's Cancer/Bonnie R. Freeman Professor of Pediatric Oncology Research in the UF Departments of Neurosurgery and Pediatrics at the University of Florida.

Dr. Sayour, thank you so much for joining us today. I'd like you to start by telling us about the field of mRNA cancer vaccines and advancing the concept of personalized cancer therapy.

Dr. Elias Sayour: Well, thank you, Melanie. Thank you for inviting me. Very happy to be here and discuss this topic, which is, you know, very important to me. I can't talk about mRNA cancer vaccines without really talking more broadly about the fields of cancer vaccines. And so, cancer vaccines have been an idea that has been around for a very long time, over 150 years really, of research and efforts to try to develop cancer vaccines. And I can summarize that really by saying these cancer vaccines have been developed to prevent cancer. And there are some very famous examples, Gardasil, which can basically prevent the formation of human papilloma-mediated cancers, hepatitis B-driven cancers, and the list goes on. But preventing cancer that is virally mediated has been shown to be true. The problem is, when you give even those same vaccines in the context of treatment, they don't perform as well. And so, the field really has been very much challenged in the development of what we refer to as therapeutic cancer vaccines, which in some ways is an oxymoron. You're trying to treat something as it's happened with a vaccine, when the idea of vaccines are really to prevent something before it starts. And this is really where mRNA comes in.

mRNA has several advantages that can allow it to reconcile personalization for an individual patient and an individual patient's cancer with the evolution of that cancer to allow treatment responses in real time, at least that's the hope. And in many ways, that's what separates mRNA, I think, from many different classes of vaccines, the ability to keep up with the evolution of the tumor and treat it as such.

Melanie Cole, MS: This is a fascinating conversation that we're having, Dr. Sayour. So, how does the delivery system of mRNA vaccines influence their efficacy and safety in cancer therapy?

Dr. Elias Sayour: So, mRNA, with all of these advantages, has one big disadvantage. And the disadvantage is RNA is not very stable. RNA can degrade very quickly in the environment. RNA can degrade very quickly even inside the body. And so RNA needs a delivery vehicle to protect it from degradation, and a delivery vehicle to also ensure that it gets delivered to the right places and the right cells. And so, these delivery vehicles that have been developed for RNA are what we refer to as lipid nanoparticles, which are essentially-- this is an oversimplification-- but basically, spheres of lipids, fat, where the RNA is stored inside of that. And that protects it, and simultaneously helps shuttle it to immune cells.

Once this particle is inside an immune cell, the RNA is released and communicates with that immune cell, basically tells that cell the information that I have inside of me is foreign. And so, if you have RNA from your tumor or RNA that's specific to information in your tumor, that can now be communicated to an immune cell through these fat droplets in a way that activates the immune response. And when that immune response is active, it can go to the site of the tumor, kill it, remember it, survey the body forever to prevent that cancer from coming back.

And so, these delivery systems have been shown largely to be safe in the context of the COVID-19 mRNA vaccines. And that same delivery system is now being used for Moderna's mRNA vaccines in cancer patients. They have some promising data in melanoma in early phase I and phase II studies. And they're as far along now as phase I studies for this cancer vaccine in melanoma, where they identify what's foreign in a patient's tumor, make the RNAs, load them into these lipid nanoparticles, and give the vaccine locally as an intramuscular injection. And phase III is really the final test. And if it works in phase III, and there's a lot of hope that it will, this will be a new standard of care for melanoma with many different possibilities and potentials for other cancers.

And there are also other different lipid particle approaches being pursued by other companies, BioNTech, our group here, my lab here at the University of Florida to really help ensure that the delivery of this information elicits the best immune response against cancer as possible.

Melanie Cole, MS: Doctor, can you discuss the challenges that you encountered in the early stages of this type of vaccine research and how did you overcome them? Tell us a little bit about the process itself.

Dr. Elias Sayour: Well, one of the challenges as mentioned really is ensuring RNA is protected and delivered to the appropriate cells. And again, these lipid particles have been developed by companies like Moderna and BioNTech and by our own lab, but in different iterations. We certainly use a different formulation than the aforementioned companies.

Other challenges, of course, are how to really ensure that the immune system is not only activating against information in the tumor, but keeping up with the evolution of that information. These tumors are evolving. And as they evolve, they may gain new information. And as they gain that new information, the immune system has to really be able to compete with that.

And so, unlike the COVID vaccine, for example, where you're targeting one thing, which is spike protein, in cancer, you really need to target many things simultaneously. And the collective ability to target those many things simultaneously can lead to an effective response against that cancer. And so, what we and others have had to grapple with is, well, what do you target? And how do you target these many things at once?

And so, everyone has pursued different ways of approaching this. Our group has largely decided to vaccinate against all the information in the tumor, to alert the immune system in a way, to the totality of that cancer environment, to the totality of that cancer ecosystem, and allow the immune response really to see the whole thing and then develop a response that can overcome that in a way that is evolved, robust, and maintaining efficacy until every cancer cell is killed.

Melanie Cole, MS: Doctor, I'd like you to speak about evaluating the success of the mRNA cancer vaccines and the potential that they have as you've seen when used in combination with other cancer therapies such as immune checkpoint inhibitors, targeted therapies. What are some of the key regulatory challenges in bringing this vaccine from bench to bedside?

Dr. Elias Sayour: Generally speaking, having the mRNA vaccines approved as quickly as they were for the COVID-19 pandemic really created a major breakthrough in overcoming many of the regulatory and other hurdles in moving this forward to cancer. There are additional challenges in cancer, which I mentioned, meaning what are you targeting? How do you keep up with that evolution? You're not just targeting one thing, but several things in many of these contexts. But the basic infrastructure to develop vaccine manufacturing, to ensure that RNA is stable in a lipid particle, deliver it from central manufacturing through sites around the world, a lot of that complexity has largely now been overcome as a result of the COVID-19 pandemic. And this, I believe, will usher in a new wave of RNA therapeutics, which include cancer vaccines and mRNA vaccines. I mentioned the Moderna trial, which is as far along as phase III. BioNTech has developed a different mRNA vaccine approach, but similar idea where they predict what's foreign in a patient's tumor, and they load it into a lipid particle design that they've engineered. And what they've done is they actually inject it intravenously. And the reason they do this is they want to make the information from that patient's cancer look even more dangerous. And by injecting it intravenously, they can make that patient's cancer look even more like a natural viral infection in the bloodstream.

Our group has taken this a step further, we think. And what we're doing is also injecting these RNA lipid particle vaccines intravenously, but we're clustering these particles, like an onion, and that makes it even look more dangerous. So, being able to take these particles, cluster them, introduce them intravenously, will make the material in that vaccine, the RNA that's specific to that patient's tumor, look profoundly dangerous to that individual's immune system.

And so, these are different ways of engineering these vaccines to look more and more dangerous. And this is important depending on the cancer context. When we're talking about melanoma, the immune system is there. It's even before you vaccinate, we know that the immune system is active in melanoma. It's just behind a little bit. And you can even rescue these patients with just checkpoint inhibitors, as you mentioned. Sometimes, though, the checkpoint inhibitor is not enough. And maybe Moderna's vaccine, especially with promising results, will get that in combination with checkpoints, keep the immune system ahead and keep it ahead for life.

But there are other cancers where the immune system is not even off the starting line. This is certainly true for pediatric cancers. And in some cancers, like glioblastoma, which our group focuses on, the immune system has not gotten off the starting line, it's going backwards. And so, how do you restore the immune response in these contexts? And that's where some of these other delivery vehicles, these other engineering approaches come in. By virtue of the fact that they can induce really stronger immune responses, they may be able to take some of these other tumors that are so resistant and really get the immune system up to speed.

Melanie Cole, MS: Well, that leads very well into my next question. Isn't this interesting? How do you envision your research translating directly to patient care? Tell us how this could be the new paradigm for how you treat patients, a new platform technology for how you, as you just described, can modulate the immune system.

Dr. Elias Sayour: it is very exciting, Melanie. I mean, I see a future where we will be able in a factory to make all the information across all human cancers available as RNAs. And when a patient has cancer, they'll come in and very quickly be diagnosed and we'll know exactly what their RNA profile is. And we'll be able to go to that factory and pull off the shelf the RNAs that are specific to that patient's tumor. And depending on the tumor they have, we may even choose one of these delivery vehicles, Moderna's, BioNTech's, our own, as the best means of inducing an immune response to keep up and overcome that cancer.

And in many ways, this could be leveraged around the world for every cancer in a personalized manner if this factory exists. And now we know as a result of the COVID-19 pandemic, you can make these factories, these repositories of RNA, and actually mass distribute them to the world over. So, I do see a future where this can be leveraged to treat all patients with personalized therapy all over the globe.

Melanie Cole, MS: Wow. As we wrap up, doctor, I would just like you to speak to other providers in the medical community, ensuring equitable access to mRNA cancer vaccines, particularly in low resource settings. As you just said, the possibility to make these global is there and will hopefully be there, but I'd like you to speak to them about your research specifically, what you would like the key takeaways to be. If they have any questions, what would you like to tell them right now?

Dr. Elias Sayour: Well, our research is very much trying to develop these vaccines as breakthrough therapies for some of the hardest and most recalcitrant tumors. Right now, the mRNA vaccines that Moderna and BioNTech are using are in combination with checkpoints and look very promising in these indications.

Right now, we're just testing our vaccine alone in glioblastoma, and we're trying to move this forward in pediatric cancers and other really difficult-to-treat tumors. And, generally speaking, we do see this as a platform for all patients with all cancers and want patients to have access to these no matter where they are in the country and across the globe.

But in order for us to get there, we have to answer questions such as safety and what's the dose, and how can we give as many doses as possible to stay ahead of someone's cancer with as little side effects as possible and as little toxicity as possible. And that might be different in glioblastoma versus osteosarcoma versus other tumors like pancreatic cancer and lung cancer.

So as we gain that information through phase I, phase II trials, the hope is we'll start developing some of these as breakthrough therapies in these tumors with significant capacity to now evolve into other indications. And then, even starting to look at combinations and what combinations work really well and synergistically. And those can also now lead to new treatment paradigms. So, there's a long way to go, but I certainly think that what keeps us going is the hope that this can be a therapy for really all patients in all places.

Melanie Cole, MS: Thank you so much, doctor, for joining us today. What an exciting time in your field and really exciting research that you're doing. Thank you so much for sharing that with us. 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, please visit ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole.