Latest / Medicine Matters: The Springer Medicine Podcast / Episode 25: Therapeutic cancer vaccines

Transcript

Episode 25: Therapeutic cancer vaccines · Medicine Matters: The Springer Medicine Podcast

• 0:03
  Speaker 2: Welcome
• 0:03
  Speaker 1: to Medicine
• 0:04
  Speaker 2: Matters, the Springer Medicine
• 0:06
  Speaker 0: Podcast.
• 0:11
  Speaker 2: I'm Dr.
• 0:11
  Speaker 0: Jane Godsland
• 0:12
  Speaker 2: and in this episode we're looking at a brilliant advance that is exciting oncologists and which should interest all of us working in medicine.
• 0:21
  Speaker 2: I'm talking about therapeutic cancer vaccines.
• 0:25
  Speaker 2: Unlike traditional preventive vaccines, these therapies are designed to treat existing malignancies.
• 0:31
  Speaker 2: by training the immune system to recognise and attack tumour-specific targets.
• 0:36
  Speaker 2: With advances in genomics, neoantigen discovery and delivery platforms, the conversation is shifting from is this possible to how soon will this integrate into routine care?
• 0:49
  Speaker 2: In our conversation today, we unpack how these vaccines work, what clinical evidence is emerging, the cancers where progress is most promising and what practicing physicians should understand as these therapies move from trials towards real-world clinics.
• 1:05
  Speaker 2: So, whether you're coordinating care for patients on complex treatment pathways, navigating survivorship conversations or simply trying to stay ahead of fast-moving science, this is a discussion you will not want to
• 1:18
  Speaker 1: miss.
• 1:26
  Speaker 1: I'm delighted to welcome as my guest today, Dr.
• 1:28
  Speaker 1: Elias Sayur from the University of Florida in the USA to discuss the really very exciting topic of cancer vaccines.
• 1:35
  Speaker 1: Welcome to the show, Dr.
• 1:36
  Speaker 1: Sayur.
• 1:38
  Speaker 1: Before we get going, please could you tell our listeners a little bit about yourself?
• 1:42
  Speaker 0: Well, one, thank you so much for having me.
• 1:44
  Speaker 0: It's just an honor and a privilege to be here.
• 1:47
  Speaker 0: This is my favorite topic, so I very much enjoyed talking about this.
• 1:51
  Speaker 0: I'm a pediatric oncologist, physician scientist at the University of Florida.
• 1:56
  Speaker 0: Our lab works on mRNA cancer vaccines.
• 2:00
  Speaker 0: We've made discoveries based on preclinical lab work.
• 2:04
  Speaker 0: We've translated some of these discoveries, and we're running human clinical trials with these mRNA cancer vaccines.
• 2:11
  Speaker 1: Brilliant.
• 2:11
  Speaker 1: Thank you so much.
• 2:12
  Speaker 1: I can tell that you're keen to get started on the topic, so we'll just go into that.
• 2:16
  Speaker 1: So we are all, of course, really familiar with the idea of vaccines against infectious diseases, but what does it actually mean to vaccinate against cancer?
• 2:25
  Speaker 0: Yeah, that's a great question.
• 2:26
  Speaker 0: So when most people talk about vaccines, of course, the first thing that comes to mind is infectious prophylaxis.
• 2:34
  Speaker 0: And the idea of an mRNA cancer vaccine or a therapeutic mRNA cancer vaccine is kind of an oxymoron.
• 2:43
  Speaker 0: You're trying to treat something after it's started.
• 2:47
  Speaker 0: when the idea of vaccine is to prevent something before it happens.
• 2:52
  Speaker 0: I do think, though, that the idea of a cancer vaccine, not just to prevent cancer from happening in the first place, but to treat it after it's happened, is fair.
• 3:02
  Speaker 0: And here's why.
• 3:03
  Speaker 0: So many cancers can't be completely eliminated, even if you've removed the entire tumor.
• 3:12
  Speaker 0: For example, the most common malignant brain cancer, glioblastoma.
• 3:17
  Speaker 0: You could take out that entire tumor.
• 3:19
  Speaker 0: There could be no evidence of disease after surgery, and you know the tumor will come back in almost all patients if they don't get what we refer to as systemic therapy, basically treating the microscopic disease.
• 3:33
  Speaker 0: So this is a form of secondary prevention.
• 3:36
  Speaker 0: A lot of patients need preventative chemotherapy to prevent the cancer from coming back.
• 3:41
  Speaker 0: And so the idea of a cancer vaccine, at least in this context, in this treatment context, is really as a secondary prevention to prevent that cancer, that tumor from coming back.
• 3:53
  Speaker 0: And I do think for right now, for today, although I do believe there will be a time and an era for preventative vaccines, primary preventative vaccines, I do think today the best use of cancer vaccines are in this secondary prevention setting.
• 4:08
  Speaker 1: Thank you.
• 4:09
  Speaker 1: That makes it really clear.
• 4:10
  Speaker 1: And also, we do have some prophylactic cancer vaccines.
• 4:13
  Speaker 1: So, you know, we've seen great success with vaccinating against HPV and HPV.
• 4:18
  Speaker 1: But that's a very different mechanism and a different process.
• 4:21
  Speaker 1: And that's not what I'm going to focus on.
• 4:23
  Speaker 1: I really am more interested in the therapeutic ones.
• 4:26
  Speaker 0: So you make a very good point.
• 4:27
  Speaker 0: And I do think people should be aware that, you know, we do have primary preventative prophylactic cancer vaccines, HPV, hepatitis B, the list goes on.
• 4:40
  Speaker 0: I wish there were more non-viral preventative vaccines and I do think they will happen in the primary preventative setting.
• 4:47
  Speaker 0: but for today I think we have a lot of priming secondary prevention therapeutic cancer vaccines in the pipeline.
• 4:55
  Speaker 1: That's kind of what I want to focus on.
• 4:57
  Speaker 1: So one of the things is because obviously this is not a newish new story but it seems to be gaining a bit more momentum in recent times and I'm just wondering what advances have led to this kind of almost renewed interest in the topic.
• 5:09
  Speaker 0: As someone who's been in the field for well over a decade plus now, at least in my opinion, I don't know that there is renewed interest, yes, globally, society-wide, certainly, at least for those of us, many of us who have been in this field.
• 5:29
  Speaker 0: There's been sustained interest.
• 5:30
  Speaker 0: There's been sustained interest, I would say, for nearly a hundred and fifty years in the subject of cancer vaccines.
• 5:36
  Speaker 0: Really, the whole idea of cancer immunotherapy, in my opinion, really started with this idea of a cancer vaccine, an incitue vaccine, where you could take something inflammatory.
• 5:49
  Speaker 0: This was the work of William Coley in the late eighteen hundreds.
• 5:52
  Speaker 0: you know, take bacterial products, extract those bacterial products, inject them into tumors, almost as an in situ vaccine.
• 6:00
  Speaker 0: And, you know, he noticed some remarkable results in some patients, not only with the lesion that he injected those products into, not only would those disappear, but sometimes cancers on the opposite side of the body would disappear, really the first evidence of cancer immunotherapy.
• 6:18
  Speaker 0: And I would say for a hundred and fifty years, people have been trying very hard to create, not just in situ vaccines, but systemic vaccines that could create that response, that systemic response, eliciting epitome spreading that could get rid of the cancer all over the body.
• 6:35
  Speaker 0: And I think the reason people have perhaps more society-wide have been a little frustrated with the field.
• 6:44
  Speaker 0: is it?
• 6:45
  Speaker 0: Even though it was one of the most exciting things that I think helped launch the field, it really hasn't led to the FDA approval, certainly the therapeutic context, to the same extent as other cancer immunotherapies, cell therapies, CAR T cells, immune checkpoint inhibitors especially.
• 7:03
  Speaker 0: And so while the field of cancer immunotherapy has just exploded over the last fifteen-plus years, I would say that the whole field of cancer immunotherapy kind of, you know, waned for a large period of time when people couldn't really take some of these anecdotal findings and turn them into tangible results.
• 7:24
  Speaker 0: And cancer vaccines have kind of been part of that.
• 7:27
  Speaker 0: But with the emergence of cancer immunotherapy, I think there has been kind of this restoration in the idea of a cancer vaccine.
• 7:36
  Speaker 0: And importantly, I think that has basically exploded even further with the COVID-in mRNA vaccines.
• 7:44
  Speaker 0: I think that's really lended itself to this idea that you could make vaccines and change them, right?
• 7:50
  Speaker 0: The COVID vaccine gets updated, you know, it gets updated based on the variants of SARS-CoV-II that are brewing.
• 7:57
  Speaker 0: And being able to kind of iterate that quickly and stay ahead of viral evolution is very exciting to people.
• 8:04
  Speaker 0: Why couldn't we do that for cancer?
• 8:05
  Speaker 0: Why couldn't we use this type of an approach where we can basically evolve as the cancer's evolving using mRNA?
• 8:13
  Speaker 0: So the affordability, the commercialization of something like that.
• 8:18
  Speaker 0: and the ability to personalize it, I think has created a lot of enthusiasm.
• 8:24
  Speaker 0: And that's now juxtaposed to all the enthusiasm around cancer and immunotherapy.
• 8:28
  Speaker 1: I guess we have a silver lining from the pandemic, as they say, every cloud.
• 8:34
  Speaker 1: At least it's, you know, as you say, it provides this setting to accelerate development a bit further.
• 8:40
  Speaker 1: So I'm going to ask you a couple of technical questions.
• 8:43
  Speaker 1: I've been reading, it seems there are lots of different types or platforms that are being used to design these therapeutic vaccines.
• 8:49
  Speaker 1: So can you just tell us a little bit about some of the different ones and which one you think is the most promising?
• 8:54
  Speaker 0: Sure, sure.
• 8:55
  Speaker 0: I probably disclosed my bias already a little bit here.
• 8:58
  Speaker 1: I think I might have an idea which one you're going for.
• 9:01
  Speaker 0: So typically to vaccinate against cancer, you have to have a target in mind.
• 9:07
  Speaker 0: These can be something called neoantigens, basically something that's totally far into the tumor that you can vaccinate against.
• 9:13
  Speaker 0: They can be tumor-associated antigens, things that are overexpressed in the cancer that may have lower expression in the normal body.
• 9:20
  Speaker 0: You have to be careful depending on which of those targets you're picking.
• 9:23
  Speaker 0: Sometimes people just take all the information from a cancer cell, basically take tumor lysate or radiated tumor cells, use that as a vaccine, but you need
• 9:33
  Speaker 1: a platform
• 9:34
  Speaker 0: to deliver these.
• 9:36
  Speaker 0: The platforms could be peptide, basically taking the peptides out of these, or peptides that more or less are targeted against these antigens, whether they're neo-antigens, tumor-associated antigens, and so peptide vaccines, those have been around for quite some time, and those... You know, one of the challenges with peptides is, for the most part, they're not immunogenic on their own, so you need adjuvant.
• 10:00
  Speaker 0: And that's true for many vaccines.
• 10:02
  Speaker 0: You need adjuvants to basically awaken the immune response to the peptide vaccine.
• 10:07
  Speaker 0: Nucleic acids are another platform.
• 10:10
  Speaker 0: This is not just RNA, mRNA, which tends to be my bias, but DNA.
• 10:14
  Speaker 0: Interestingly, DNA was really considered much more attractive than RNA decades ago.
• 10:22
  Speaker 0: And the reason for it is the DNA is the real source of the information with mRNA really being the intermediary between DNA and protein.
• 10:31
  Speaker 0: And moreover, RNA is not very stable.
• 10:33
  Speaker 0: It's very labile.
• 10:34
  Speaker 0: It degrades very easily.
• 10:36
  Speaker 0: Whereas DNA is much more stable.
• 10:38
  Speaker 0: So there was a lot of excitement around DNA and DNA vaccines.
• 10:43
  Speaker 0: And I'm certain people are still working on this.
• 10:45
  Speaker 0: But nucleic acid in general, DNA, RNA, having basically information, nucleic acid that encode for those peptides, those proteins, that's another platform.
• 10:58
  Speaker 0: Now, just as peptides need adjuvants, nucleic acid vaccines more or less need delivery systems.
• 11:06
  Speaker 0: As information, they need to be delivered.
• 11:08
  Speaker 0: You need a courier system.
• 11:09
  Speaker 0: These tend to be more nanoparticles, nanoparticular delivery systems, but I shouldn't say in the old days a lot of people still do this.
• 11:16
  Speaker 0: The way to deliver nucleic acid vaccines is through cells, to load cells with nucleic acid.
• 11:23
  Speaker 0: Cells could even be loaded with peptide.
• 11:25
  Speaker 0: So, you know, you could take antigen-presenting cells, dendritic cells from patients.
• 11:29
  Speaker 0: These are the master cells of the immune system and igniting a response.
• 11:33
  Speaker 0: In many ways, this was the real evidence, the early evidence that mRNA could work really through these dendritic cell vaccine trials that have taken place over the last several decades.
• 11:43
  Speaker 0: But there are challenges to these.
• 11:45
  Speaker 0: Cell therapy is very niche, meaning every place kind of manufactures a little differently.
• 11:51
  Speaker 0: The growth medium they use to maybe mature dendritic cells is a little different.
• 11:56
  Speaker 0: And in some ways it's like cooking.
• 11:57
  Speaker 0: If one person follows a recipe and another person follows a recipe, you may have completely different results.
• 12:03
  Speaker 0: And that's really one of the challenges with cell therapy is how do you create kind of that same process that could be writ large deployed to many, many patients.
• 12:13
  Speaker 0: So that's very challenging.
• 12:15
  Speaker 0: It's very challenging to commercialize.
• 12:17
  Speaker 0: And that's why cell therapy has largely been kind of a niche therapy for depending on the institutions.
• 12:24
  Speaker 0: Now, mRNA, though, based on those early results has evolved into using lipid particle delivery systems.
• 12:33
  Speaker 0: And again, the beauty of the pandemic was early on, they had to figure out things like cold chain.
• 12:39
  Speaker 0: How do you make these vaccines and create a cold chain to make sure that the product is viable when you're shipping it from one place to another, internationally even.
• 12:50
  Speaker 0: And there was a ton of investment, billions of dollars, but that infrastructure was created.
• 12:57
  Speaker 0: you know, create these mRNA constructs, how to preserve them, how to ship them, how to quality assure, quality release them.
• 13:03
  Speaker 0: And then on the cancer front, there have been biotech, Moderna as major companies have some very, very promising data with personalized vaccines where they can predict neoepotopes and cancers and then load them into these lipid nanoparticles.
• 13:19
  Speaker 0: Moderna's vaccines largely employ the same lipid nanoparticle delivery systems for their cancer vaccines as they use for their COVID-xv vaccine.
• 13:27
  Speaker 0: And they will likely, in my opinion, have a phase three signal probably soon.
• 13:33
  Speaker 0: Now, there was a cancer vaccine that was approved, actually, in twenty-ten Provenge, Cipollusal T. That was a cell therapy vaccine.
• 13:40
  Speaker 0: And as a cell therapy vaccine, You know, there are a lot of complexities around that in terms of cost, deployment, and, you know, for the extended time benefit.
• 13:50
  Speaker 0: My understanding is it hasn't been a major standard of practice.
• 13:53
  Speaker 0: But if these mRNA vaccines do show signals in phase three, I think that will catapult the field even further.
• 14:00
  Speaker 1: Thank you for that brilliant overview.
• 14:02
  Speaker 1: You've actually answered a couple of my next questions.
• 14:04
  Speaker 1: So I'm just going to skip ahead to... kind of, and again, you've alluded to this a little bit, but what are the most exciting results?
• 14:10
  Speaker 1: So what's looking good in clinical trials at the moment in terms of therapeutic vaccines, but specifically mRNA vaccines?
• 14:16
  Speaker 1: What are you looking forward to?
• 14:18
  Speaker 0: Yeah, so, you know, I think the Moderna Bio and Tech have, you know, created a great foundation for personalized vaccines.
• 14:27
  Speaker 0: We all wait with bated breath for the results of these phase three trials, certainly from Moderna.
• 14:34
  Speaker 0: They've done something a little different.
• 14:36
  Speaker 0: Their personalized neoepitope vaccine is actually given intravenously.
• 14:41
  Speaker 0: And that is using liposomes, which is something that our group does as well.
• 14:47
  Speaker 0: And what they've shown, again, these are early phase studies, but they've shown you could get breakthrough immunity or something like pancreatic adenocarcinoma, which is unlike melanoma lung cancer, this is a... very hard setting to induce an immune response.
• 15:05
  Speaker 0: These are very immunosuppressive tumors.
• 15:07
  Speaker 0: You don't have a great endogenous response in these tumors.
• 15:10
  Speaker 0: And while a lot of people would believe that in immunogenic cancers like melanoma, where there may be a really good preexisting T cell response, you could boost that further with a vaccine.
• 15:21
  Speaker 0: But in a setting like pancreatic ductile adenocarcinoma, glioblastoma, these are very challenging settings to induce a response.
• 15:29
  Speaker 0: And so, The bio and tech group has pioneered a formulation that's given intravenously, interestingly enough, really to reset the immune response against the neoepotopes that they're vaccinating against.
• 15:42
  Speaker 0: And for them to have published very promising early phase findings in pancreatic adenocarcinoma, I think is a testament that perhaps we could engineer these vaccines as a mainstay for all cancers if they work in not just immunogenic tumors, but poorly immunogenic tumors.
• 16:00
  Speaker 0: And in some ways, this may be the first step.
• 16:02
  Speaker 0: The first step of cancer immunotherapy is to induce these kinds of responses with technologies like mRNA that are becoming more affordable, more easy to engineer.
• 16:14
  Speaker 0: And certainly, when we think of artificial intelligence, we may be able to personalize and build these much faster, much quicker than we even are today.
• 16:22
  Speaker 0: But as a first step, mRNA may really now set the stage for other therapies that are coming down the line, immune checkpoint inhibitors, other things.
• 16:31
  Speaker 0: The fascinating thing about the BioNTech trial for pancreatic cancer is this, the mRNA vaccine was built around a standard of care, so other things were happening as well.
• 16:40
  Speaker 0: So really the beauty of that is mRNA may really can now be built perhaps as kind of a mainstay as part of backbone therapies for patients to awaken that immune response.
• 16:52
  Speaker 0: So, very excited about that.
• 16:54
  Speaker 0: You know, our own group has some exciting results in glioblastoma as well, where we also are giving intravenous administration of mRNA lipid particles.
• 17:05
  Speaker 0: These are a little different in that they're aggregates, they're multi-lemellar aggregates, again, designed to amplify a very rapid, danger response to awaken the immune response in glioblastoma.
• 17:18
  Speaker 0: And recently, we've shown that you can perhaps use completely nonspecific mRNA vaccines to awaken immunity.
• 17:26
  Speaker 0: May even the SARS-CoV-II, COVID-IX mRNA vaccine, may be used to awaken the immune response.
• 17:34
  Speaker 0: So we think that a universal backbone could be used, yes, as a vaccine, as a universal vaccine, but These may function as universal immunomodulators where they just reprogram the immune system in such a way that it now alerts it and awakens it against cancer.
• 17:53
  Speaker 0: And how you now bridge that to personalized vaccines, immune check point nebuters, other therapies, I think is going to be really exciting and interesting as we design those studies and really start to get a lot of use out of combination treatments.
• 18:08
  Speaker 1: Really amazing results, especially the, as you say, in pancreatic cancer, which is so difficult to treat.
• 18:13
  Speaker 1: Again, you've kind of answered my next question a little bit as well, because I was going to ask you about how to integrate vaccines with other treatments.
• 18:20
  Speaker 1: And it sounds like it's more of a work in progress rather than knowing how that works yet.
• 18:24
  Speaker 1: So one thing I'm going to ask is just around the timings of generating these vaccines, because, you know, often treatment needs to start quite quickly for certainly some of these cancers once it's diagnosed.
• 18:36
  Speaker 1: What's the kind of timeframe at the moment for generating a personalized vaccine?
• 18:40
  Speaker 0: Yeah, so it takes our group about six weeks.
• 18:43
  Speaker 0: I think that's pretty competitive to industrial production of personalized vaccines, which is around the same, if not longer timelines for production of personalized vaccines.
• 18:53
  Speaker 0: But to your point, that's six weeks, eight weeks plus sometimes where patient isn't getting a personalized therapy.
• 19:01
  Speaker 0: And if you ask me, that's far too long, because what we know about cancer is it's changing in real time.
• 19:09
  Speaker 0: I tell people when a surgeon closes, that tumor is different, twenty-four hours later.
• 19:16
  Speaker 0: You've changed the environment of the tumor.
• 19:18
  Speaker 0: You've introduced a wound healing environment, and the cancer is now going to adapt to that.
• 19:23
  Speaker 0: And by the time you have your vaccine, you have a vaccine against a cancer that was there six weeks ago, but how much of that cancer now, six weeks later, is going to be represented by this vaccine.
• 19:36
  Speaker 0: So that's a huge challenge.
• 19:37
  Speaker 0: Speed is really, really important.
• 19:40
  Speaker 0: One of our hopes about universal vaccination is that you could actually very rapidly alert the immune response.
• 19:49
  Speaker 0: I personally believe these universal vaccines should be given before even surgery to awaken that immune response and then perhaps bookend it with personalized vaccines.
• 19:58
  Speaker 0: But the technology is coming.
• 20:00
  Speaker 0: where I think we can have these things, believe it or not, personalized vaccines one day by the bedside.
• 20:08
  Speaker 0: If you can even imagine that, I actually see that as a reality.
• 20:12
  Speaker 0: So to me, the future of mRNA is this keyboard over here, right?
• 20:18
  Speaker 0: mRNA, it's four letters, right, to ACG and U.
• 20:21
  Speaker 1: And,
• 20:22
  Speaker 0: you know, if computers run on, or software systems run on ones and zeros, our body runs on these four letters.
• 20:29
  Speaker 0: And so, I do see a future, especially with artificial intelligence, where we can very rapidly predict what we should be targeting in an individual's cancer, and then type the sequence into a computer, and at the other end of a box will be your mRNA vaccine.
• 20:46
  Speaker 0: I can actually see that happening one day by the bedside of a patient, and it quite frankly has to happen, because while I believe in universal vaccines, and I do think that will be a treatment for many patients, I think if we really want to cure cancer at large, we have to get at the personalization of disease.
• 21:03
  Speaker 0: And that personalization is going to require something as flexible as mRNA, where we can literally deploy a therapy near instantly.
• 21:11
  Speaker 0: And I do think that future is coming faster than people may imagine.
• 21:17
  Speaker 1: I think certainly faster than I imagine.
• 21:18
  Speaker 1: I wouldn't have thought that at all before you said it.
• 21:21
  Speaker 1: But then equally, we know things speed up.
• 21:24
  Speaker 1: It used to take months to sequence.
• 21:26
  Speaker 1: even a small bit of DNA.
• 21:27
  Speaker 1: And now it's super quick.
• 21:29
  Speaker 1: So why not for vaccines?
• 21:31
  Speaker 1: And so you talked about speed is one of the challenges.
• 21:33
  Speaker 1: But do you see any other challenges in terms of making this a clinical reality?
• 21:39
  Speaker 0: I think certainly there's been a lot of misinformation around vaccines.
• 21:44
  Speaker 0: And I do think that is a challenge.
• 21:48
  Speaker 0: I personally have gotten involved in this field.
• 21:50
  Speaker 0: I'm a pediatrician.
• 21:51
  Speaker 0: I've gotten involved in the cancer vaccine space because of the Really, the incredible success of pediatric infectious disease vaccines as a primary prevention, I mean, eradicating some of the most horrible diseases, things that were even around in the eighties, like hemophilus influenza type B are essentially gone, and really want to do that for cancer.
• 22:13
  Speaker 0: And these fields learn from each other.
• 22:15
  Speaker 0: I do think that the ability to create products at the speed that we need them in, and actually, mRNA as an example, There's so many ways to engineer these things.
• 22:26
  Speaker 0: It's not just the information you're delivering to the immune system.
• 22:29
  Speaker 0: It's how you build the non-coding regions of the mRNA construct.
• 22:34
  Speaker 0: It's, you know, what's your lipid particle delivery system?
• 22:38
  Speaker 0: It's, you know, mRNA, you could have helper mRNAs in there to direct the immune response if you want B cells, if you want T cells, if you want tolerance.
• 22:48
  Speaker 0: There's so many different ways of doing this.
• 22:51
  Speaker 0: And so these fields really learn from each other.
• 22:53
  Speaker 0: And look at where we are right now with cancer vaccines, because of the COVID-in pandemic, because of the SARS-CoV-II mRNA vaccines.
• 23:00
  Speaker 0: I mean, it turbocharged the development, the commercialization of mRNA, it turbocharged lipid nanoparticle delivery systems.
• 23:07
  Speaker 0: And I would hate to see that slow, because some of the dialogue around this, which certainly on social media, is sometimes really flawed, really errant.
• 23:19
  Speaker 0: You know, those are some of the big challenges, but I'm hopeful.
• 23:23
  Speaker 0: I mean, I think people, I mean, we don't want to be, as an oncologist, I don't want to be poisoning my patients with chemotherapy till the end of time.
• 23:32
  Speaker 0: I think we need to have new therapies.
• 23:35
  Speaker 0: We have failed people and patients, in my opinion, when we're using, you know, these crude treatment measures that have been around for so many decades now with really no replacements.
• 23:47
  Speaker 0: And when we talk about next generation sequencing that are incredible molecular diagnostics and the capacity of artificial intelligence, and yet I'm still giving my patients chemotherapy as a mainstay for their cancer, yeah, that's not okay.
• 24:02
  Speaker 0: So I'm hopeful that the public will want these things and there will be an outcry for more personalized, more specific therapies that don't have the same systemic toxicities.
• 24:15
  Speaker 1: With you mentioning the toxicities of chemotherapy, I'm just curious, are there any particular risks associated with the use of cancer vaccines that you might be concerned about?
• 24:25
  Speaker 0: Yes.
• 24:25
  Speaker 0: This is a very important question, and I certainly don't want to just gloss over it and make it seem like this is completely safe.
• 24:32
  Speaker 0: There aren't risks.
• 24:34
  Speaker 0: So people have to be aware of the risks.
• 24:36
  Speaker 0: And when we talk about vaccines, I just want an intellectual discussion about risks and benefits.
• 24:41
  Speaker 0: And look, as providers, whether it's infectious disease, prophylaxis, or treatment vaccines for cancer, we are compelled as physicians and providers to have conversations with patients about risk and benefit.
• 24:54
  Speaker 0: Here are the risks of taking these vaccines.
• 24:56
  Speaker 0: Here are the benefits of taking these vaccines.
• 24:58
  Speaker 0: Here are the risks of not taking these vaccines.
• 25:01
  Speaker 0: And those risk-benefit conversations, I think, happen really well between provider and patient.
• 25:06
  Speaker 0: Maybe what we haven't done a very good job of society-wide is having that same kind of conversation with the public about risks and benefits.
• 25:15
  Speaker 0: Because at all times, we have to make decisions where we maximize benefit and minimize risk.
• 25:21
  Speaker 0: But risk is never zero.
• 25:23
  Speaker 0: I mean, it's never zero with anything.
• 25:25
  Speaker 0: So to answer your question more specifically, These vaccines for cancer, these treatment vaccines for cancer, do have side effects.
• 25:32
  Speaker 0: Certainly, the vaccines we're moving forward and others are moving forward could elicit cytokine storm, where you're trying to wake up the immune response against cancer.
• 25:42
  Speaker 0: And the immune response in cancer is so tolerant.
• 25:46
  Speaker 0: It's not normal.
• 25:47
  Speaker 0: It's not like a normal person.
• 25:48
  Speaker 0: You're trying to prevent something.
• 25:50
  Speaker 0: The immune response in cancer sees cancer as a wound.
• 25:53
  Speaker 0: It has to heal, as opposed to a foreign enemy.
• 25:55
  Speaker 0: It has to fight.
• 25:56
  Speaker 0: trying to overcome that is hard.
• 25:58
  Speaker 0: There's so much noise.
• 26:00
  Speaker 0: And so to overcome that noise, you need usually potent innate stimulation.
• 26:06
  Speaker 0: In fact, sometimes that potent innate stimulation could be so potent, it could be toxic.
• 26:11
  Speaker 0: Patients could develop cytokine storm.
• 26:13
  Speaker 0: Cytokine storm could lead to patients who need to be on a ventilator, could lead to patients who drop their blood pressure so much so that they could
• 26:23
  Speaker 1: crash.
• 26:24
  Speaker 0: And so you know, when we're trying to manipulate the immune response in this manner, especially with brand new products, it's very important that it's done in very controlled settings, you know, to ensure that it's safe.
• 26:35
  Speaker 0: You know, certainly for our vaccines, these multi-lemellar aggregates, we've seen, we've seen cytokine responses that, you know, and we're treating patients in higher acuity settings to make sure that it's safe and tolerable.
• 26:48
  Speaker 0: But those are significant risks.
• 26:49
  Speaker 0: Those are some of the early risks, but they're also late risks.
• 26:53
  Speaker 0: When you vaccinate against cancer antigens, sometimes you could get a spillover effect against normal tissue.
• 27:01
  Speaker 0: And that spillover effect could cause autoimmune toxicities.
• 27:06
  Speaker 0: And those autoimmune toxicities could be some very significant late effects that patients could develop.
• 27:12
  Speaker 0: And if, honestly, if you ask me, and this is unfortunate, but I do think it will happen as we get better and better and better at vaccinating against cancer, and we will.
• 27:21
  Speaker 0: I do believe that your cancer vaccines are coming and they will revolutionize the field.
• 27:26
  Speaker 0: But as we do that, it's invariable that we probably are going to see some toxicities along the way.
• 27:34
  Speaker 0: that's certainly been the history of chemotherapy, right?
• 27:36
  Speaker 0: I mean, to this day, we have still patients who should be cured who die from toxicity of chemotherapy.
• 27:42
  Speaker 0: It's very hard as a provider to see that happen when, you know, patients should have ninety, ninety-five percent cure rate and then dies of sepsis because of chemotherapy exposure.
• 27:51
  Speaker 0: So, look, I think we've gotten a lot better over many, many decades and had a dose chemo safely and achieved the best results in all patients.
• 28:02
  Speaker 0: But when we got started, it was very tough.
• 28:05
  Speaker 0: And our cure rates were not as good and our side effects were much higher.
• 28:09
  Speaker 0: And I do believe mRNA will be a lot better, a lot safer than chemo.
• 28:13
  Speaker 0: But when you're starting with new technologies, you don't know what's the right dose, how do we use it, how do we maximize therapeutic effects and minimize toxicity.
• 28:22
  Speaker 0: And unfortunately, I do think that as we get better at maximizing the effect, there certainly could be some side effects.
• 28:28
  Speaker 0: And that's how do you back down and how do you how do you get the right dose into patients?
• 28:34
  Speaker 1: And like you say, you know, all the learnings from chemotherapy, but also from about ten years of immune shock checkpoint inhibitors, hopefully kind of we have monitoring protocols in place and at least even awareness of things to look out for because before the checkpoint blockade agents, you know, you didn't even know what immune reaction could happen.
• 28:52
  Speaker 0: Absolutely.
• 28:53
  Speaker 0: And some of that, some of those discoveries and some of that infrastructure will certainly help us.
• 28:58
  Speaker 0: you know, in pediatrics, we often have late effect clinics where we'll see patients as oncologists in tandem with endocrinologists and cardiologists and, you know, fertility experts.
• 29:09
  Speaker 0: And, you know, as we get better at treating patients with immunotherapy, we need to make sure that we have kind of the same, you know, monitoring downstream to look for late effects, autoimmune reactivities and toxicities, because you're right, it's going to be more common.
• 29:24
  Speaker 0: And we have seen it with immune checkpoint inhibitors and as we start combining therapies, we're probably going to see more of it.
• 29:30
  Speaker 1: So yeah, it's just really important to get that risk-benefit balance right.
• 29:34
  Speaker 1: And then for my final question, what do you think the future holds?
• 29:38
  Speaker 1: What do we have to look forward to in the next, say, five or ten years?
• 29:42
  Speaker 0: Yeah, so I think we're... You know, very soon, I think we will have phase three results with a neoantigen vaccine.
• 29:50
  Speaker 0: And if and when we do, I think that will prove that this is, yeah, at least mRNA vaccines are a viable strategy to vary specifically in a personalized manner, affect change for patient cancers.
• 30:03
  Speaker 0: I think there are going to be a lot of other now trials for other indications.
• 30:07
  Speaker 0: If you could do this in immunogenic tumors like melanoma, what about poorly immunogenic tumors?
• 30:11
  Speaker 0: What about other immunogenic tumors?
• 30:14
  Speaker 0: And so I think we're going to see more.
• 30:16
  Speaker 0: When one works, it's just like checkpoints, right?
• 30:18
  Speaker 0: Once you have the first trial, now you start seeing dozens of trials propping up, many of which didn't work, by the way, but so many trials now propping up to see.
• 30:28
  Speaker 0: could this work in this cancer.
• 30:31
  Speaker 0: At the same time, it's how do we maximize the benefit, even in the patients that it works in?
• 30:38
  Speaker 0: With vaccines, there are so many variables we don't understand, to be perfectly honest.
• 30:41
  Speaker 0: And even if you have a positive signal, it's so important to understand how to maximize that effect.
• 30:46
  Speaker 0: For example, dose, timing, frequency, do you give before the tumor comes out, after the tumor comes out, how do you boost?
• 30:56
  Speaker 0: How do you prime?
• 30:57
  Speaker 0: How do you boost?
• 30:58
  Speaker 0: When we talk about vaccines, you have to typically prime.
• 31:01
  Speaker 0: And so that's with more compressed vaccines.
• 31:03
  Speaker 0: And then you boost with vaccines that are further apart.
• 31:07
  Speaker 0: And in some ways, I hate to say this, but it's kind of like a pseudoscience, where we just kind of randomly pick a priming strategy and then some kind of random boost approach.
• 31:17
  Speaker 0: And when something works, you just go with it.
• 31:19
  Speaker 0: But how could we perhaps be more scientifically rigorous about what that priming boost schedule should look like?
• 31:27
  Speaker 0: And it's probably very different depending on what the technology is.
• 31:30
  Speaker 0: That may be very different for peptide vaccines versus mRNA, and then the type of mRNA vaccines that you're employing.
• 31:36
  Speaker 0: So I do think that what's going to come next is really trying to see how widely available these things could be across different cancers in terms of whether they could work or not, how to engineer them to work even better.
• 31:48
  Speaker 0: So second generation vaccines, third generation vaccines.
• 31:52
  Speaker 0: I also, and I say this in somewhat of a biased manner, but I do think there's a, I do see universal vaccines happening.
• 32:00
  Speaker 0: And I do think that's part of the future of this field.
• 32:03
  Speaker 0: I also see as part of the future really shifting to primary prophylaxis, not just for viral targets, but perhaps cancer targets that we might be able to predict.
• 32:11
  Speaker 0: This is where artificial intelligence comes in.
• 32:13
  Speaker 0: I do think artificial intelligence is going to change the world.
• 32:17
  Speaker 0: But it just so happens that mRNA, in my opinion, is the perfect partner for artificial intelligence.
• 32:24
  Speaker 0: And so this is some of what I haven't fully understood.
• 32:28
  Speaker 0: There's so many fears to artificial intelligence.
• 32:30
  Speaker 0: But the excitement dominates.
• 32:32
  Speaker 0: When we talk about artificial immunity, it's full steam ahead, despite some of those fears.
• 32:37
  Speaker 0: And I wish it were the same around mRNA.
• 32:40
  Speaker 0: I wish it were the same around vaccines.
• 32:41
  Speaker 0: It should be full steam ahead.
• 32:43
  Speaker 0: And the truth is, I think the public is going to be clamoring for it.
• 32:47
  Speaker 0: If you're going to have all this diagnostic information around artificial intelligence, you need to intervene.
• 32:52
  Speaker 0: And the intervention can't just be the drugs that we have available, because they don't treat a lot of stuff and they don't work for everything.
• 32:59
  Speaker 0: So we need new drugs.
• 33:01
  Speaker 0: We need new therapies.
• 33:02
  Speaker 0: We need to customize those therapies, not just for cancer, but for autoimmune disease, neurodegenerative conditions.
• 33:08
  Speaker 0: This is where mRNA can come in.
• 33:09
  Speaker 0: You can very rationally build these vaccines, these constructs, depending on the indication.
• 33:16
  Speaker 0: And I think AI is going to really lead to a ground swell of new targets, new therapies, and Yeah, mRNA can work very quickly, perhaps, to address all of those new discoveries.
• 33:27
  Speaker 0: So I see that all happening kind of in tandem.
• 33:30
  Speaker 0: I do think the next ten years are going to be some of the most exciting ten years in biomedical research.
• 33:35
  Speaker 0: And, you know, I do see mRNA.
• 33:37
  Speaker 0: Again, I'm very biased, but I do see this being at the forefront of these discoveries.
• 33:43
  Speaker 1: So we have lots to look forward to, which is brilliant.
• 33:46
  Speaker 1: I think I could probably talk to you for another hour, but I probably shouldn't take up that much of your time.
• 33:52
  Speaker 1: Well, in that case, thank you very much for your time today.
• 33:54
  Speaker 1: I really appreciate it.
• 33:55
  Speaker 1: And I know our listeners are really going to enjoy this.
• 33:57
  Speaker 0: Likewise.
• 33:58
  Speaker 0: Thank you.
• 33:58
  Speaker 0: Thank you for your interest in this topic.
• 34:00
  Speaker 0: We couldn't come at a more important
• 34:01
  Speaker 2: time.
• 34:10
  Speaker 2: This podcast is intended for healthcare professionals for their ongoing medical education and entertainment.
• 34:17
  Speaker 2: It should not replace the professional advice of a doctor or pharmacist and may not be used as a basis for diagnosis.
• 34:25
  Speaker 2: or any change to the prescribed treatment of disease.
• 34:29
  Speaker 2: The views expressed by our moderators and guests are their opinions and do not represent the position of any third parties.
• 34:38
  Speaker 2: The information given in the podcast is subject to change as the scientific field and clinical advances progress.