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Speaker: [00:00:00] Hi everyone. I'm Kara Button.

Speaker 2: And I'm Michelle Abello.

Speaker: We're general surgery residents and behind the Knife Surgical Education fellows. We're excited to bring you today's episode about cancer vaccines, what they are, how they work, and what surgeons should know about them. To help us explore this topic, we're joined by Professor Robert Jones, a liver surgeon at Liverpool University Hospitals.

He's the UK National Institute for Healthcare Research, Co-Lead for the Cancer Vaccine Innovation Pathway and the Bowel Cancer UK and Royal College of Surgeons, UK Lead for Research into Advanced Bowel Cancer. He's also the UK chief investigator for BNT 1 22 0 1 a phase two clinical trial assessing the efficacy of a personalized mRNA vaccine in patients with stage two and stage three colorectal cancer.

Professor Jones, thank you so much for joining us today.

Speaker 3: Thank you very much for the invitation. I'm a long time listener and first time caller, so it's, uh, it's great to be here.

Speaker 2: Well, we're super excited to have you. So, Dr. Jones, to get us [00:01:00] started, can you tell us what, what even is a cancer vaccine?

Speaker 3: Yeah, of course.

I mean, everybody will be familiar with vaccines. We will have had vaccines when we were kids. If we've got kids, we would've seen our own kids get vaccines. Most of us will have had vaccines during, during the COVID pandemic. The concept of a vaccine is it's something that can train your immune system to recognize something as foreign, and then your immune system is then primed to go round, and when it sees that thing again in the future, it can go round and tackle it.

And cancer vaccines really. Extend that from the infectious diseases space, which is where most of the vaccines we will have had exist through into the cancer space. And they, they move that over into that way.

Speaker: Now for medical school, we probably all remember that there are different types of vaccines that we can get.

So for cancer, is that true? Are there different types of vaccines for cancer?

Speaker 3: Yeah, so cancer vaccines, there's various different ways you can [00:02:00] categorize 'em. The way I, I like to think of them. In the current landscape is there are preventative cancer vaccines, and then there are cancer vaccines for established cancers.

And so if we think about preventative cancer vaccines, one of the great success stories here is HPV vaccination in the uk and young females. We know that HPV is one of the causative agents for spike cancer. And by having a population wide national immunization system to eradicate HPV. There's been a risk reduction of 39% in cervical cancer in that group.

So an absolutely huge impact. And so that is treating cancers before they come on. The second group is in people in whom there are established cancers. Can we use vaccines to treat those established cancer? [00:03:00] Within those, there's different types of vaccine technology that we use. Some of them are what we call cell-based cancer vaccines.

These are quite complicated. You have to engineer dendritic cells, so these are the cells that present your antigens through immune immune system, and you have to preload them, you engineer them. It's individualized. It's really complicated and costly. But the advantage of that is that you put these dendritic cells in.

That are presenting the antigens and they trigger a really, really strong T-cell response, a really strong immune cell response. You'll remember T cells are the cells that are going around hunting for your infectious agent or your cancer agent. People have used virus based vaccines, which is where they take things like adenovirus or HSV, and they engineer it to deliver tumor antigens.

That's really attractive because they're scalable. You can make them really quickly. The problem is that most of the viruses that we use to deliver these [00:04:00] vaccines humans have already been exposed to. So we are slightly, our immune system's, slightly ambivalence about them, so we don't get quite as strong immune response.

There's then peptide based vaccines, which is where you make peptides that represent tumor antigens. They are safe, they're cheap, they're easy to manufacture. But again, the problem is that they are limited immunogenicity unless you give them with a really strong combination therapy. And then the final group and the group of, of vaccines, which are probably of the most interest at the moment, are mRNA vaccines.

So this is where you make a short piece of genetic code for. Something that's gonna trigger the immune system. You wrap it in a little fatty envelope and you inject it into the patient and that fatty envelope's taken up by your dendritic cells. The mRNA codes turned into an antigen. It's popped up on the surface of the dendritic cell.

And then your immune system looks at it and says, right, I'll go hunting for that. And it goes [00:05:00] off. And mRNA is the kind of the new technology on the block

Speaker 2: that really is super interesting. With these mRNA vaccines, how do you determine the target for the cancer vaccine? Are these vaccines individualized?

Are they applicable to all patients? And then how many different antigens do you, do you need to create like an immune response to have our own immune systems recognize the tumor?

Speaker 3: And that is, um, that is one of the kind of fundamental questions with, with vaccinating against cancer. So if you think about flu, if you've had a flu vaccine this winter, what will have happened is people will have worked out what the dominant flu strain is likely to be this year.

They will then develop some antigens from that flu strain. You then must produce vaccines against those antigens and you give it to everybody and you hope that it works. [00:06:00] And on a population basis, for most people it will make a difference. Okay. But cancer's very different because we're less interested in this setting in treating populations.

We're more interested in treating the individual who's had cancer. And if you think about every cancer cell in your body that originally formed as a normal functioning cell. Okay, so what you need to do is you need to identify antigens that are only present in the, in the cancer cell, which are different to what that cell was like when it was normal.

Does that make sense? So these have come on during the evolution from normal to to cancer,

Speaker 2: and these are what we call the neoantigens, right?

Speaker 3: So these are what we call neoantigens. Yeah, yeah. Now, some of those for some disease types are very well conserved. So, for instance, head and neck and, and, and bladder cancer, they have well conserved antigenic structures between patients.

And so you [00:07:00] can predict which which antigens most people are going to have, and you can make a vaccine that contains those antigens. And you must produce that. And it's an off the shelf vaccine strategy. And the evidence is that that works really well. But then there's other cancers. So colorectal pancreatic cancer, which don't have that same conserved antigen structure.

They have very unpredictable antigen structures, and so it's difficult to make an off the shelf vaccine for those. So this is where an individualized approach is, is necessary.

Speaker: Now, where do the cells come from to make these mRNA vaccines? And I'm thinking of, say, a patient who has metastatic disease, they might have multiple sites of metastasis, that there's some poly [00:08:00] clonality of the tumor deposits.

So how do you tell what. Is the best target for making one of these vaccines.

Speaker 3: So this is another known unknown. There's a famous American once said, you know, at the moment what we are doing is treating these based on primary sequencing of primary tumor. Okay? If you get recurrence after. Treatment and resection of a primary tumor, and you get metastasis.

Do we need to re-biopsy? Is the clone that has formed the metastasis a completely different lineage? And does it have a completely different n neoantigen profile? Is it conserved? We don't know. So within some of the trials now, there are sequential biopsy models going in, so you would have. Surgical resection, you would have adjuvant vaccines.

You would then [00:09:00] have biopsy on recurrence, see whether you need to generate a new vaccine or whether you can use your original generated vaccine. But we don't. We really dunno the answer to that.

Speaker: I think this is along the same lines, but. Do we have an idea of when the best time to give a cancer vaccine is?

Speaker 3: Yeah. So again, it's a good question. For vaccines to work, you need to have neoantigens that are unique to the tumor, so your immune system can discriminate between yourself and the cancer cells. Okay. But then what we also need to know is that those antigens. Are going to be presented you. You remember MHC molecules, the immune presentation molecules on the cell surface.

So it needs to be co-expressed with MHC and then that needs to trigger an immune response. So there's now, before you do anything, there's a huge amount of bioinformatics that goes into [00:10:00] play and increasingly we are able to predict with greater and greater degrees of certainty, which antigens will trigger an immune response.

Obviously generating these new interventions and testing them on a per patient basis is really, really difficult, so we want to have confidence that it's going to be co-presented. It's gonna trigger an immune response for the immune system To then work, you need to make sure that you have a functioning immune system, so we know that in advanced malignancy you get immune suppression.

And whether you get immune suppression as a function of the malignancy or as a function of repeated rounds of treatment is difficult to say, but you have a suppressed immune system. The other thing is that you require CD four and CD eight cells to go in and touch the tumor cells and destroy them. Okay?

As [00:11:00] metastases become established and they become bigger. We know that they become immune colder, so they have fewer and fewer CD four and CD eight cells in the metastasis. And there was a really nice paper in in nature last year looking at the immune infiltrate. As metastasis get bigger and there there's a number of CD four cells, very few CD eight cells when things are a cluster of cells.

But when they start to get bigger, that population becomes smaller. So the implication is. Once metastasis are established, then the ability of a vaccine induced immune response to tackle them will be limited. And so the ideal time to me would seem to be in the adjuvant setting. And I, you know, a conflict of interest.

I spend most of my working life cutting metastatic disease out of people's liver. But if you can get macroscopic [00:12:00] complete resection of all sites of disease with surgery and then you only have occult micro metastases, then that seems to be the ideal time to intervene, both from a an active immune system point of view and also from metastatic penetration point of view as well.

Does that make sense?

Speaker: Absolutely.

Speaker 2: Yeah. I definitely think so. So. We talked a lot about getting the immune system kind of primed to be able to respond to this vaccine and to find these tumor cells and kill them. Do you think that there is any benefit or any role of combination with immunotherapy or any other systemic therapy in giving these vaccines at the same time?

Speaker 3: Absolutely. If you look at probably one of the most exciting papers in this space, it was a, it was a single center series from Memorial and they looked at pancreatic cancer and they did the same technology. They did an mRNA vaccine [00:13:00] personalized to with person's pancreatic cancer, and they gave them systemic triplet cytotoxic chemotherapy.

So that's pretty standard. But they also gave them some pulse dose of immunotherapy. It was the combination of those that seemed to elicit the, the most dramatic immune response. And interestingly, they, they showed very, very elegantly that it was about half the patients where the vaccines triggered an immune response and those half of the patients who had an immune response, so they made a T-cell populations hunting for something the vaccine had told 'em to hunt for.

They were the ones who did really well, and it was that amazing. If you've seen it, you'll never forget it. It was just a straight horizontal curve in overall survival in pancreatic cancer, uh, which, you know, is unheard of. So the combination therapy definitely seems to be the, the way to go here.

Speaker: Are there other examples of solid organ cancer vaccines that [00:14:00] surgeons should be aware of?

Speaker 3: Yeah, um, so one really exciting. Technology is being developed by a team led by David Church and the guys in Oxford in the UK in combination with Moderna. So you've heard of Lynch syndrome, which is where people are predisposed to getting these malignancies. So they have inherited mutations, which mean that they develop pre cancers and cancers.

The problem is with precancerous that not all precancerous present the same kind of neoantigen pattern. So lung cancer, you have hotspot mutations, colorectal cancer, you kinda get a frame shifts in things like ovarian cancer, you get arant splicing. But in Lynch syndrome, you get a relatively predictable pattern of frameshift mutation, uh, hotspot mutations.

So what they've done, they have a big UK registry of patients with Lynch and [00:15:00] they've worked out what these hotspot mutations are and what they're likely to be. And so they're doing a trial where they're taking patients who have Lynch syndrome, who we know are going to get cancer. We know what antigens these cancers are going to produce, but they haven't got them yet, and they are going to vaccinate these patients before they have any cancer to see whether they can stop those cancers evolving.

I mean, the first time I heard about that I thought, this is, this is like Star Wars stuff. Is it, it crumbed my mind. But it, you know, it is one of those things, you look at it and you just think that it's the coolest, the coolest thing going. That's amazing.

Speaker 2: Yeah. Yeah. That's pretty unbelievable. I wish we could do that for, uh, I mean, there's so many different genetic disorders that people get all these types of cancers.

That's pretty remarkable.

Speaker 3: It is, and it, you know, it, it's, it's a. It's a, it's a fantastic synergy between an academic group led by David who've always been interested in this, and then [00:16:00] Moderna who had vaccines in the same, the same space. And they kind of, they came up with this novel, it's not an academic trial, it's not a commercial trial.

It is a true shared shared technology that they're bringing on. So that's really exciting. So yeah, all surgeon should know about that, I think.

Speaker 2: Yeah. That's really cool. And is that an mRNA vaccine also?

Speaker 3: Yeah.

Speaker: Given the state of vaccine hesitancy and, uh, lack of mRNA vaccine funding in the United States right now.

But with this type of technology, how realistic is it to make a vaccine for every, you know, say, colorectal patient in the US or the uk in terms of cost, time, feasibility? I know this is still in clinical trial, but looking ahead to the future, what might that look like?

Speaker 3: Yeah. And that's, that's a great question because if you think about the process at the moment, so if you are making a [00:17:00] personalized mRNA vaccine, the patient comes to see one of you guys consents for the vaccine trial.

They then go, they have surgery, the specimen comes out, and then the specimen's taken to the path lab. It's cut up. Then some of it is sent formal and fixed paraffin embedded. It's then sequenced. It is then run through the bioinformatics protocol to work out what's gonna trigger an immune response. Those an antigens are then sequenced and made into a little string of mRNA.

They have some quality control. It's then wrapped in a fatty envelope and it shipped back to the back to the patient. And at the moment, we can do that. In about eight weeks. So we can do it in a clinically meaningful timeframe. If you think most adjuvant studies have told us we need to start treatment within 12 weeks, if you can get the, the, the specimen batam in eight weeks, the vaccine batam in [00:18:00] eight weeks, then that's a clinic clinically meaningful timeframe.

And each of those steps individually are complex and difficult, but equally it's just logistics. And if Jeff Bezos can. Deliver two crates of dog chew a backpack and a iPhone charger to my door the next morning. It's only a matter of time until we can work out the same, the same logistics with this, the sequencing.

You know, if you think about the cost of sequencing a genome, we all will have read those articles in the Sunday papers about the exponential tumbling and the cost of sequencing. There is no reason why the same thing shouldn't happen as the bioinformatics gets better. That will become scalable. And then the production again is scalability.

So yes, it's ambitious. Yes, it's personalized and it's difficult. But [00:19:00] is it impossible? No, I don't think it is. And equally, as the trial and the evidence base increases and we start to know which disease types we should be focusing on. The number of patients that we're trying to do this to will become fewer and fewer.

And so we can target our resource and our efforts, you know, where it is, where it's gonna make a difference.

Speaker 2: Yeah. I'm still so impressed that you guys can get all that done and turned around and back to the patient in eight weeks, I think that's amazing.

Speaker 3: Yeah. And, and you know, you guys are doing, doing that in the states as well?

Speaker 2: Yeah.

Speaker 3: Uh, it is. It is just logistics.

Speaker 2: So when I was reading a little bit about your trial, it focuses on patients that are CTDNA positive, and when you look up the rates of ctdna positive in colorectal cancer, it's about 10 12%. Correct?

Speaker 3: Yeah.

Speaker 2: So do you think that that's the main group that's gonna benefit from this type of cancer [00:20:00] vaccine people with circulating tumor DNA, or do you see this kind of being available to most patients with colorectal cancer or with any type of cancer?

Speaker 3: Yeah. So we looked at patients who were ctdna positive. 'cause as I mentioned earlier, we wanted to identify patients who had small, what we presumed were non established metastatic lesions, but had residual disease somewhere. Okay. So we chose that because we think that's a target rich environment for us to do a trial in.

Uh, and this is where we are likely to. To see the greatest signal if there, if there is one. And so we've, we've chosen a CTDNA positive population. Would that be the only population in future? Probably not because we know, even if you ctdna negative, there is a not zero risk of you getting disease recurrence, although it's, it's much, much lower.

The [00:21:00] other thing is that at the moment we use CTDNA to, in colorectal cancer, to deescalate adjuvant treatment. So we say if you ctd negative, you stage two, you might not need it. But, and that's the risk benefit, because the risk of chemotherapy, you know, surgeons, I think we're a bit blase about this, but the risk of chemotherapy is not insignificant.

It's not like having two tablets with Uix every morning. It's onerous, it's toxic, it, it has. Profound side effects. If you are giving someone an mRNA vaccine, that's the same kind of vaccine that you will have had, you know, for the flu or for COVID. And the worst that might happen is you get a sore arm for a couple of hours and that's it.

So the risk benefit suddenly shifts and you, to my mind, you would only need a much smaller potential benefit to make it the individual risk worth, worth taking for the vaccine. Do I think CTDNA positive patients are the [00:22:00] only group we should do it in? Well, no, because there is also increasing evidence.

There was some really stark data ASCO last year from due TS group that if you are ctdna positive after surgery, you're gonna do pretty badly, whatever we give you, whether it's doublet, triplet, change of agent, you know, and, and so. Are these people predestined to do poorly, irrespective? So the short answer Ctdna seem, seems and feels like a sensible discriminator at the moment.

I'm sure in five, 10 years time we'll all be looking back, you know, rolling our eyes saying How could we be so naive? But we don't have anything better.

Speaker 2: Yeah, I mean, I understand the, you're trying to identify people that you think have, you know, micrometastatic disease might benefit from it the most, are most likely to recur and to see if you can find a benefit in that population.

And it maybe applied to everybody, if you can find one there. And so I do pancreas cancer research and [00:23:00] some of, you know, the CTD A stuff, some of the vaccine stuff has been in the pancreas cancer world. Do you see this being applied to all types of cancers, just mRNA vaccines in general? Do you think that this is the direction.

That that cancer therapy is gonna go in the next 10, 20 years?

Speaker 3: Hard question. Yeah.

Speaker 2: There's no right answer.

Speaker 3: I mean, what I will say is that this excites not just me, it excites lots of people across the field, you know, in most solid organ cancers. With a few notable exceptions. We've been using the same.

Four drugs, five drugs in various concentrations, various frequencies, various durations for 40 years, you know, color or five year oxaliplatin, iron T can three months, six months, lots, not too much. It, and it, it makes very little difference. [00:24:00] Immunotherapy was a big game changer for a, a subset, 10% of colorectal cancers.

And that was that, you know, that was a step change. You think about Glevec in Gists, that was a, again, a TKI that, that, that made big differences. The, the hope is that this technology will, will explore a completely new avenue rather than going down the same avenue with limited hope of change and success.

I think the immediate impact of things like the fixed vac program. That's gonna be slightly easier to check and quantify and validating trial settings. I think at the moment, although I was very, very confident about it just being logistics for personalized mRNA vaccines, the fact is we're not there yet.

And so at the moment these are expensive products to manufacture and produce. And so although as clinicians we want to test it on everyone in everything, and we wanna do it now, you know, there needs to be a degree of. [00:25:00] Of staging a pragmatism is probably the best answer I can give you Without, without answering your question, I think,

Speaker 2: I mean, it doesn't seem like my question really had an answer.

I would hope that as precision medicine gets a little bit more popular, that you know, you can, we'll continue to see advances in this, this space.

Speaker 3: Yeah. Yeah. Yeah.

Speaker: I do have one question just in terms of patient perception of the cancer vaccines in patients that you hope to enroll in this trial. Obviously we're in the US where there is a lot of vaccine hesitancy and probably uk, but how do patients perceive the idea of having the antigens from their cancer re-injected into them?

Speaker 3: Yeah, great question. So I mean, the first thing is. Is, and during the pandemic there was a, a degree of vaccine skepticism over here as well. You weren't unique in having that [00:26:00] maybe to a slight, a slightly greater scale. The difference here I think is the risk benefit.

Speaker: Mm-hmm.

Speaker 3: So there was skepticism because with the, the, the code vaccines, because I think a lot of people thought that.

COVID wasn't a threat to them, and so they didn't feel that the vaccine was worth it, but I think everybody would acknowledge that if you've got cancer inside you, it is a threat to you. So the risk benefit paradigm on an individual basis shifts massively. We didn't approach any patients. Who told us they didn't want to take part because it was a vaccine.

There was no issue in that. But we also had to be very conscious about why that vaccine hesitancy had happened during the pandemic and, and I [00:27:00] think a lot of that was, and people have their own views, but a lot of that was, a lot of that was the perception that doctors telling you what to do and you don't.

Really have a say and also the perception that we were blinding people by science. So we went to great pains to make sure that we made the concept of this technology and the understanding of this technology as simple as possible. And so one of the, one of the best things we did in our trial was we made a little, little patient cartoon animations, which were 90 seconds long, and they described the technology in really simple patient friendly terms, and it articulated what was gonna happen, how it was going to work, and what we were hoping.

And so instead of getting a 200 page document with lots and lots of long words. That you're never gonna read and you're never going to understand. This gave patients a really simple conceptual framework about what this was, [00:28:00] and so suddenly they were familiar with it, and so they weren't scared of it because they kind of understood why we were doing it and what we were doing.

But there was more on the great learning points for me, for any trial I do in the future, irrespective of what it is, I will start there and work backwards. Because if you get that patient facing comms right, your recruitment is just so easy because everybody, you approach, everybody you approach looks at it and just like, you know, I'm sure you can tell I've got excited talking about vaccines today.

You, you guys, you seem excited about, you know, uh, patients are the same. They watch these animations. They, they think this is cool. Yeah, I wanna be part of this. So we, we, we really haven't had an issue and I, I doubt you would in the US either.

Speaker 2: Yeah, it's a lot less scary. I think when patients can understand exactly what it is, it takes away a lot of that, like the fear of the unknown.

Speaker: Right. Before we conclude. Because you, you are a surgeon in a space where there aren't a ton of surgeons. You know, I was [00:29:00] curious if you could share with us what you think that surgeons listening to this episode should take home and be able to really understand about cancer vaccines and how they should prepare for the integration of this in the future practice.

Speaker 3: There's various different roles. For surgeons, but I think for most people, whether you are an academic or, or you're, you're not, you can, you, you don't have to drive the research, but you can, you can get involved in it and you can facilitate it. And so the, the great advantage we have as surgeons is that we've taken these patients through these, you know, very traumatic procedures, dark days.

We've got 'em through the other side. So we have this innate relationship with them. And this. This mutual respect. And so when you see a patient in a post-op clinic and they've come through and you've told them that you've removed all of the cancer and they [00:30:00] feel great, if you then say, and by the way, there is a clinical trial that you might be interested, they're instantly receptive.

They're interested, they're keen, they want to find out more because if you guys say that it's good after what you've done for me, I'm, I'm keen to find out more. So in terms of recruitment in the UK for the BNT 1 22 colorectal study that I I ran almost 90% of our recruitment was directed through surgical centers because of that, and that made a huge, that made a huge difference.

The other thing is that we, we know that tissue sampling and tissue processing and, and what, what you call warm ischemic time and time to formula fixation has a, a massive impact on your ability to extract genetic code Now. You can do it if you, if you sample's a bit grotty, you can do it. But you have to, you have to sequence it multiple times.

And if you remember, we talked about that eight week window. If you've got to sequence [00:31:00] somebody more than once, suddenly that eight week window becomes really tight, if not impossible. So making sure the specimens are as high quality as possible. So another thing we did was we did briefings for all our surgical teams about the importance of all ischemia time.

If the case is on a Friday afternoon, don't just. Leave it in the formula and say, oh, somebody will cut it up on Monday. Get it processed on the Friday. That extra bit of effort makes a huge difference. The other thing that surgeons are really good at is identifying the clinical need. You know, we're, we are, a lot of us are surgical oncologists, so we follow these patients up.

We recognize patterns, we recognize behaviors in these cancers. Um, and the companies that want to collaborate us on us in this space, they are also feeling their well way. It's a really fertile time to, to go to them and say, Hey, we've noticed this. [00:32:00] What, what do you think? Because they're unsure where to test and where to move next.

And so we, there's huge opportunities for surgeons to go in and take the lead on that as well.

Speaker 2: Yeah, and I think it's really important to just highlight that, you know, even if the surgeon themselves are not involved in the vaccine process, in the clinical trial, the surgeon's the source of the tissue and you're the one exactly like you said.

That's going to be the first step in determining the warm ischemia time and be the first step to, you know, make sure it. The lab, somebody doesn't just throw it in a piece of formula and as soon as it comes out of the body. And so I think the more that the surgeons know about the process, even if you're not involved in the clinical trial or the basic science research it's super, super important.

So I'm really happy that we got to talk about. That today too.

Speaker 3: Yeah. And it is also been suggested that we as surgeons may be slightly competitive in personality. So

Speaker 2: maybe just a

Speaker 3: warning, if you know that your pal down the road as recruited patients into a vaccine trial, [00:33:00] you are sure as heck gonna wanna do the same.

Um, exactly. That's, that's, and, and that's one of the great things about surgery, isn't it?

Speaker: Definitely.

Speaker 2: Dr. Jones, we really appreciate you sharing your expertise and for your leadership in the BNT 1 22 0 1 trial. Um, this has been such a valuable discussion on the current state of cancer vaccine and the, the current state of the technological innovation that's going on.

Speaker: And for our listeners, we'll provide citations for the trials and literature that we discussed on the show notes. Thank you so much for joining us, and thank you, Dr. Jones for being here.

Speaker 3: You're very welcome. Again, this one's for you, Josh, dominate the day.