Mary Parker:
I'm Mary Parker, and welcome to this episode of Eureka's Sounds of Science. I'm joined today by three experts from Charles River, Dan Rocca, senior research leader, and Louise Brackenbury, science director from our discovery site in Portishead. And Mike Templin, senior scientific director of scientific advisory services from our Reno site. They're here to give me a crash course in cancer vaccines. Welcome, Dan, Louise and Mike.
Louise Brackenbury:
Hi, nice to chat to you.
Dan Rocca:
Hello.
Mike Templin:
Thank you.
Mary Parker:
Thank you so much all for being here. I'm really excited to learn more about this topic. So can we start with each of your backgrounds? How did you get into this line of work and what is your title? Louise, can we start with you?
Louise Brackenbury:
Sure. So I'm a science director in the biotherapeutics division of discovery. I've been with Charles River about 10 years now, and before that I was in academia. So by training I'm a cellular immunologist and I've got over 27 years experience both across academia and discovery. And I guess what's really driven me throughout this part of my career or my career in general is I'm fascinated by immunology and how the immune system really works and how it pervades across nearly every single disease really, how it can be involved in all of those.
Mary Parker:
How did you end up getting involved in science at all? Was it always your career aspiration?
Louise Brackenbury:
So for me, my mum was actually sick with cancer when I was a teenager and it really made me want to try and find cures for illness. That was something that really drove me throughout my latter part of my childhood really. I really wanted to try and find cures for things and I was fascinated by science and by human biology so that was really what drove me to look for a career in this area.
Mary Parker:
That's excellent. I think there's a lot of people at Charles River and other similar institutions that have similar paths. How about you Dan?
Dan Rocca:
So yeah, hi Mary. So my name's Dan Rocca. I'm a senior research leader in the same division as Louise. I've been with the company about five years. Before that I was actually in academia for about 13, 14 years. I actually trained as a neuroscientist even though my undergrad days were in immunology. But I decided to take the jump and join Charles River a few years back now, and I really got interested in mRNA vaccines, particularly cancer vaccines for two reasons really.
One was the pandemic and the success of those mRNA COVID vaccines and that really drove me to have an interest in this area, not least because some of the big players behind those vaccines were actually cancer vaccine companies before. So that really spurred my interest in this area. And it's really kind of the work that particularly Louise and I do at the site of Charles River we're in, so it's kind of those two things married together and the interest hasn't stopped since.
Mary Parker:
That's excellent. I haven't heard of COVID having a positive effect on anybody's career before, so that's actually really nice to hear. Mike, how about you? How'd you get started?
Mike Templin:
Like most people, I had a winding path to get where I'm at. So I'm currently in the scientific advisory services group here at Charles River and primary goal of helping out with nonclinical drug development. I got here surprisingly by an undergraduate in pharmacy. While it's always a little strange when I say it, but I went into pharmacy school with... While a pharmacist is a great way to make a living, very rewarding, it was the education that actually attracted me to pharmacy school in anatomy, physiology, pharmacology, toxicology, and it gave me a very rounded education to then go into graduate school. Had a traditional graduate school experience based more in chemicals because they are more popular when it comes to research efforts and those things.
But drug development really gave me the opportunity to bring in my pharmacy background, also recognizing that ultimately there's always a patient at the end of everything that we do and we always need to keep that in mind. Again, this gave me the opportunity to use basic science again, anatomy, physiology, pharmacology, toxicology, but apply it to a direct situation in a medical field that I was also interested in. So one of those unique and great opportunities for everything coming together.
Mary Parker:
That's great. It sounds like we have a wide range of expertise here, which is going to make this particularly interesting for me, so I'm excited about that. So to get started, can we just quickly differentiate between the preventative cancer vaccines like the HPV vaccine that is one of the ones that I've heard of and the therapeutic kind that we're going to be discussing today?
Louise Brackenbury:
Sure. So cancer vaccines have been around for a long time now. The first one was really Coley's toxin way back in 1893. But essentially in terms of the different types of cancer vaccine you can develop, there's really preventative cancer vaccines like the HPV or the hepatitis B vaccine that you mentioned. But then really we're talking about the sort of opposite to that is therapeutic vaccines where we're actually treating patients with cancer and trying to find ways of boosting the immune response to attack the cancer.
And so with the preventative vaccines, they're really looking to drive neutralizing antibody responses so you can actually prevent infection by different viruses that actually are associated with cancer development, whereas with a therapeutic, primarily people are often looking at driving cytotoxic CD8 responses to really drive tumor killing. But along with that, they're sort of really looking to also support that through development of CD4 T cell responses to support the CD8. So essentially the cell types that the cancer vaccines are really targeting are slightly different, but they each have their incredibly important place in preventing cancer or treating cancer.
Mary Parker:
So basically the idea is to boost the immune system to recognize the cancer since with a lot of cancers there is kind of a high chance of relapse?
Louise Brackenbury:
So yeah, so with the preventative vaccines, it's preventing the infection with a virus that causes cancer, whereas in the latter for the therapeutic, it's trying to boost or drive an immune response that can actually control the tumor or clear the tumor. Yeah, essentially that.
Mary Parker:
I had no idea that this went all the way back to the 1800s. That is actually really cool. Could you give me the elevator pitch for that one real quick? I love that sort of thing.
Louise Brackenbury:
So the initial cancer vaccines weren't necessarily true and specific vaccines in quite the same way as some of the current vaccines, but it was really using Coley's toxin to treat cancer patients and what they found was that some patients so responded to that by actually clearing the cancer. So yeah, it was a very long time ago now.
Mary Parker:
That's really cool. Can we get further into the weeds and define the difference between like a personalized versus a general cancer vaccine?
Dan Rocca:
Sure, I can help with that one. So as the name suggests, personalized vaccines are specific to an individual. So if you think about a cancer cell, tumor cell, they have mutated genes and these give rise to mutated proteins and it's those that are actually processed and presented to the immune system and they flag a tumor to the immune system. And with personalized vaccines, these so-called neoantigens are encoded that are specific to an individual. They're not shared across different cancers or actually different people in many cases. And that's a really interesting concept. That's a much newer concept for cancer vaccines than what we've done before, which are the general cancer vaccines where you look for shared antigens across tumor types or across people. And traditionally those haven't worked as well. It's perhaps just one in the clinic, which is kind of a peptide loaded dendritic cell. There is efficacy in the clinic, but it's not all that was promised from these kinds of cancer vaccines. So the field really has moved towards personalized cancer vaccines at the moment.
Mary Parker:
And how personalized can they get? Do they take the patient's individual cells? Do they take different groups of patient cells that can be adapted to at least a few hundred people? How far down does it go?
Dan Rocca:
Yeah, that's a very good question, Mary. So it's exactly that. You will take tumor tissue from an individual that's suffering from whatever cancer type and you can DNA sequence that tumor and you can start to get that information about what's specific to that person compared to healthy individuals. And that really opens the space and the flavors of those vaccines because I think what we realize now is that tumors are very heterogeneous within an individual and across individuals. So you can potentially identify these neoantigens that are so specific for an individual but others don't have them.
Mary Parker:
I'm wondering... So I know with a lot of vaccines and antibiotics, treatments that are supposed to cover a wide range of people, you can get the problem of cancer or other viruses becoming immune to those, like mutating, getting stronger. This is actually a question I had for later, but it kind of fits here. So does that actually improve with personalized vaccines as well? Because it seems like if you're making something so specific, then the cancer is less likely to be able to adapt to it.
Dan Rocca:
Yeah, that's a great question because I think elements to that are true and then there's still some room to really investigate that kind of question. So what we know is that if you design your vaccine in a way that covers the heterogeneity of the tumor... So you have lots of different neoantigens and some of those will drive the cancer, some will be mutated but not drive the cancer and you really want to cover all of those because actually what happens is that you will target specific clones within that tumor that express those neoantigens and you will sculpt that tumor. So your immune system edits the tumor.
And just from an evolutionary perspective, what's really happening is this tussle between the immune system and the tumor cell. So you are changing the tumor by directing the immune system to it. It happens naturally anyway, but you are skewing that balance with the cancer vaccine. So if you don't pick your neoantigens wisely, what will happen is that you will get immune escape and that tumor will mutate in different ways or you eliminate the neoantigen containing clones within that tumor until you're left with a different type of tumor that is resistant to your vaccine in the first place. And I think that's a big question in the field is how you avoid that, particularly as it's a natural phenomenon.
Mary Parker:
Louise, anything to add to that? Is there some way that we can solve for this issue?
Louise Brackenbury:
No, as I think Dan alluded to earlier, the way around it is to encode multiple antigens in your vaccine so you can... Assuming one is no longer functional, then essentially you can drive an immune response against other antigens that do elicit an antitumor response so it's really about covering as many possibilities as possible to actually support that antitumor immunity.
Mary Parker:
All right. And so how are these therapeutic vaccines delivered? What's the mode of delivery for them?
Mike Templin:
I can touch on that one a little bit. Really, it comes down to probably two main questions that come in it. The first will be the usual one of what does it mean to me or what would be the impact? And I say that because we all know that one of the hesitations for vaccines is that they involve needles. And in this case the majority of those that are currently in development or being in use, they are delivered by what we expect for most vaccines and we're familiar with for flu, RSV and those. It does involve an injection into the muscle or under the skin.
But I would emphasize while that's being used, there are also other groups working at different opportunities, things like nasal spray, there was a nasal spray for influenza at one time as well, patches on the skin. So just don't think of the vaccines as it always involves the needle word. There are various ways to do this and as we make progress some of that will be resolved into better options or options that people have a higher preference for. The other of course is for any type of therapeutic, you need to get it to the right place at the right time. So there's also the case of how do we deliver these to the right cells within the body?
Again, if you do an intramuscular injection, that's not necessarily where you need it to be to have the pharmacology and the effect that you want. So we are using things like very specialized and adapted viruses, so we're using them as a shuttle in order to get them not just into the body but to interact with the appropriate cells. We also use other technology. Sometimes this goes by LNP or lipid nanoparticle, it's again a way of making an external shell of the product so that it can appropriately interact with cells and get to the right place at the right time. There are also a number of groups working on novel approaches to this, and so the future is actually quite bright and encouraging in that there'll be multiple ways of getting them into the body and once in the body, interacting with the correct cells.
Mary Parker:
And this speaks to the flexibility of the mRNA type vaccines, right? Because it kind of has the same method of delivery for anything you want it to do, it's just different targeting different areas. Or is that an oversimplification?
Mike Templin:
Yes and no. It's an oversimplification, but that's the best way to look at these. Messenger RNA is an extremely attractive way to do this because of the specificity and flexibility that goes along with it where sometimes you don't have both of those, but in this case you can make them very specific and across a very broad spectrum of types of cancers. But messenger RNA is an entity that can be fragile in certain ways. So we've been able to adapt as an industry and in research groups, how do we protect it when on its transport from site A to site B and then release it there? So it's allowing for a lot of different ways in order to do this and in some ways the options are extremely open-ended, we just have to figure out what works best for treating the disease, on cancer in this case, and is most easily adaptable to the patient.
Mary Parker:
Yeah. And from what I understand, this also makes mRNA style vaccines popular because a lot of the baseline safety work is done so unlike with other drugs where you're kind of designing something brand new every time, the delivery vehicle has been vetted and it's just the new addition that you put on it that needs to be tested, which makes for less work.
Mike Templin:
It does. My hesitation for saying that is we always have to consider what are the ultimate objectives and how do we figure out what's the most efficient and effective pathway to get there for both time, money and ultimately patient benefit?
Mary Parker:
Right. At what point in the cancer treatment process would a vaccine be useful? Can you give some examples of specific cancers that might fall into this category?
Mike Templin:
It definitely depends on the cancer. It definitely depends upon the patient. Of course, the obvious answer is as early as possible. The smaller the tumor, the less negative impact it's had on the body, the better. But I also emphasize there's probably no limit to where it cannot be used. We just have to figure out, again, what approach are you taking and at what point many of these are designed to bring the immune system in and use the power of the immune system in order to do that?
Of course, one of the challenges and unfortunate parts about treating oncology is that there are a lot of things that are impacting the patient's health, including how robust their immune system is. So if you're truly dependent on a very robust and active immune system, of course the farther you are down the line, will the immune system be able to respond? Doesn't mean we won't be able to treat those patients. I don't want to suggest that because there are, of course, other ways to supplement and boost the immune system, it just means we'll also have to think about this as not just what can the vaccine do and what may be its limitations, but how do we boost the body in other ways in order to get the best benefit?
Mary Parker:
Are there also scenarios where you might use a more traditional cancer treatment and then assuming it works and everything goes well afterwards, use a vaccine to help prevent the cancer from coming back after their immune system has recovered more?
Mike Templin:
I can give a couple of comments, but I'm definitely interested in what Dan and Louise have to say as well. To me the answer is yes, cancer is a very complex disease and trying to tackle it with any one single point or any one single approach is going to be difficult. Thus we want to be able to hit it at multiple points. We just as nonclinical, clinical and research scientists, where do we maximize the benefit if you go in there with multiple drugs or multiple approaches and also minimize the impact on the patient? Because, of course, we always want to make sure those therapies are giving them the best risk benefit profile. But Dan, Louise?
Louise Brackenbury:
I guess one way in which... So obviously in patients often their immune system is slightly less functional than a healthy individual and one way in which you can actually try and support and help the immune system to work better is to use things like checkpoint inhibitors in combination with the vaccine to try and really boost the immune response as much as you possibly can. That's an approach that quite a few people have actually taken in the clinic and I think it does appear to really drive the immune response better.
Dan Rocca:
Just to add to that, particularly for the personalized cancer vaccine, Louise is absolutely right. That approach is the most common one where you're using things like checkpoint inhibitors in theory can reinvigorate the immune system to some extent. And actually those personalized cancer vaccines are really working well in patients that are in remission, but they're at high risk of relapse recurrence of the tumor and that's where they're working well probably because the immune system is probably more functional and that you have that kind of additional combinatorial approach to treating the tumor. It's a really open field now, and I think Mike's right, the more ways you can attack the tumor, the cancer, the better chance you have of treating the disease.
Mary Parker:
Yeah, that makes perfect sense. So Dan and Louise, continuing with your line of expertise, how do you discover a potential target for a cancer vaccine? What does a good vaccine look like?
Dan Rocca:
Yeah, you can split it up into two parts, really. Traditionally what you would have looked at are tumor-associated antigens. They are proteins that are more expressed in a tumor, for instance, but that are also present on healthy tissues or have been present because sometimes some of these antigens, the expression reduces as you age. And traditionally those antigens were used in cancer vaccines and they didn't work as well. And partly that's perhaps because they're less immunogenic because they aren't normally expressed in tissues and to some extent individuals are tolerized to those proteins. That may be one explanation as to why those don't work.
For the personalized vaccines, you really get into the age of finding these new neoantigens I described before, so these mutated peptide products that are presented to the immune system and elicit immune response that Louise will tell you about in a moment. And there are numerous ways to do that and very sophisticated ways to do that. And initially what you can do is use next-generation sequencing to sequence the DNA and RNA of a tumor to look for those mutated genes and how they're expressed. And then you can start to use computational tools, and this is where it gets really exciting these days, which are underpinned by AI that can start to predict which of those mutated peptide products are likely to be presented to the immune system on receptors that do that both in tumors and other parts of the immune system.
And these are really sophisticated tools, particularly when you think of some of the big players in this field, but can they really predict a good neoantigen? That is the question at the minute. What they can do is tell you about whether they can bind some of those receptors that I just mentioned and some of them are getting more sophisticated to the point that they can start to predict whether a T cell might respond to those peptide products. But that's really where we're at the cutting edge and whether they can truly do that is an open question. And whether the big surge in progress we're seeing in AI can have an impact on those kind of computational tools remains to be seen. But I think it's likely that it will.
And I think ultimately the field would love to just use computational algorithms to try and predict those neoantigens. But it's a mix very much of identifying what those peptide products are, those neoantigens through some of those techniques that I've mentioned and then interrogating them with computational tools and then later on perhaps testing those.
Louise Brackenbury:
Yeah, so essentially one of the most important things when you have a cancer vaccine that you're testing is to understand whether or not it drives a robust T cell response that can persist despite the immunosuppressive microenvironment around the tumor. Here really what we're thinking of is cancer vaccines that don't drive T cell exhaustion, which is a concept that really looks at hyperfunctional T cells. So essentially if a T cell is perpetually stimulated by a certain antigen, it can drive them to become exhausted so they don't function as well as they usually do. And so in that situation then it wouldn't necessarily be good to drive T cell exhaustion. But the good news is some of the checkpoint inhibitors can actually prevent some of these mechanisms occurring. So really it's about understanding the quality and the breadth and the depth of the T cell response that's elicited by the vaccine.
Dan Rocca:
Just to add to that, I think what makes a good vaccine is probably quite a loaded question. [inaudible 00:24:23] we've said before that vaccines are very heterogeneous, so you want to encode lots of potentially neoantigens for an example that we talked about a moment ago. But what makes a good neoantigen? And again, some of those computational tools can help you, but I think we're really starting to learn more about what you should encode that is likely to do things that Louise just mentioned that will give you that durable immune response. And there's a few factors like how dissimilar those neoantigens are to a healthy individual. The more dissimilar they are, the better they seem to work, either more immunogenic, can probably lead to the kind of responses that would be durable.
And actually really another interesting point is how similar those neoantigen peptides are to peptides derived from pathogens like bacteria or viruses. And there's an interesting theory going around that either they're good at neoantigens for biochemical reasons that evolution has sculpted T cells and the immune system to respond to certain types of peptides. Or actually that what you're doing with those kind of neoantigens that are similar to pathogenic peptides is that you are activating T cells, for instance, that would normally recognize those pathogens, but they would cross-react with a tumor. And there's some evidence that actually in tumors you will get those cross-reactive T cells. And that's a really interesting concept and I think we're really at the beginning of learning what makes a good neoantigen to make a good vaccine. As we get more data from the clinic and preclinically, we'll be able to better predict what those should be.
Mary Parker:
It sounds like the vaccines could fill a niche where maybe some traditional treatments take care of some parts of the tumor and parts that aren't getting taken care of by traditional methods can be targeted by a cancer vaccine.
Dan Rocca:
Yeah, absolutely. I think that harks back to the combinatorial approach where you're taking that multi-angle approach to try and kill and get rid of the tumor basically.
Mary Parker:
Yeah, I think we'll get into combo in a second, but first let's make sure that these are safe. So Mike, back over to you. What kind of safety models work best for testing these vaccines?
Mike Templin:
These are going to be a combination of the familiar but used in a new way. This is where I'm extremely excited about them. As many people probably know, there are some changes we're doing in general drug development, more emphasis on alternative models. And anytime you have a new approach, it also gives you the opportunity to use your alternatives or modified approaches in order to successfully develop these. But as a few things have been mentioned, there's the opportunity to use in silico, the computer-based models as Dan mentioned, a little bit of that. But that gives us the opportunity to test thousands of different variables possible so we can come in with very intelligent and knowledgeable designs.
Both Dan and Louise have also mentioned things about immune cells, T cells, or those things. Our colleagues in the in vitro space have made excellent strides in how we isolate those cells, how we can use those cells to understand. So it gives us the opportunity to use, again in vitro models, to ask series of questions about how do we best use these?
Ultimately, we may have to understand the system in its full dynamics and that could involve the in vivo models. So there'll be a lot of options, there'll be a lot of opportunities. It really then becomes our responsibility as drug development scientists to say, "What is the best combination? How many questions can we answer in silico? What are key questions that we can answer in vitro?" And then, when necessary, and when appropriate, bringing them into in vivo models.
But I do want to emphasize the underlying questions for a cancer vaccine are no different than any other drug. We need to understand what is a dose that can be given to a patient, the amount that is given to them, that we have confidence will be effective. We also have to have a reasonable amount of confidence that it can be administered to a patient and be tolerated. So it is important which model you use to answer those questions. It's important to make sure that we robustly answer those two questions.
Mary Parker:
Yeah, the last thing you want to do, the Hippocratic Oath, you don't want to make anybody worse.
Mike Templin:
Absolutely. "First do no harm."
Mary Parker:
Yeah. So are there any cancers that are particularly susceptible to vaccines? Like are solid tumor cancers easier to target or blood cancers?
Dan Rocca:
So I can help with that question. So from the standpoint of personalized cancer vaccines, I think what's been done to date mostly are cancers that have lots of mutations in them that are usually quite amenable to this kind of approach because the more mutations you have, the more neoantigens you can choose from. And it means they're potentially more... There's this potential with the immune system to eradicate the tumor there and [inaudible 00:29:58] considered to be hot tumors. That's been turned on its head a little bit actually with some recent work, some clinical trial data with the vaccines that are targeting usually quite drug resistant tumors like pancreatic cancers that are well-known not to have many mutations in, but they are actually really resistant to any kind of therapy, really.
And what's been shown is actually some of these personalized cancer vaccines can work in those situations. It's just that, again, going back to that question, what makes a good neo antigen, you need to be smart about what you're doing and kind of targeting the heterogeneity of those tumors and the different clones within them. There's some really, I think, solid data coming from the clinic that actually cold tumors, or colder tumors perhaps is a better term, can be amenable to this kind of approach, which is really interesting. And that's also been shown again recently for renal cancers, which also have low mutation rates, but also are amenable to the personalized vaccines.
Mary Parker:
Well, that's good news.
Dan Rocca:
Yeah, absolutely. Absolutely. And I think what's come from those actually is that choosing those neoantigens has [inaudible 00:31:14] key. And what we're seeing is that actually the genes that drive the cancer that are often mutated are not always the best ones to choose as neoantigens. And that's slightly counterintuitive, but actually what's been shown to some extent is that actually those driver genes of cancers are not very immunogenic. And that might be from an evolutionary standpoint, actually that might make sense because then that would make those tumors more immunologically silent. So potentially you can see why that might happen, but actually it's very unclear. And so what a lot of those vaccines have done for the more cold tumors is to pick neoantigens that are spread across the tumor that are often termed passenger mutations that don't necessarily drive the cancer, but they'll still flag the tumor to the immune system. So it is a really fascinating area.
Mary Parker:
What are some of the most common safety concerns that have cropped up so far?
Mike Templin:
In some ways they've been those that would be expected. I mentioned they do involve a long times injections so you can get injection site reactions, but we've talked a lot about the immune system and in some ways that maybe in oncology we need to find ways to make sure that we maximize the interaction with the immune system. But the immune system is definitely one of those... It's always a balance. So again, while we need that vaccine to interact acutely and long persistence, of course we not only want to eliminate a tumor that is present, we want to have effects in the long term. It also means that we have to find ways to, for lack of a better term, boost the immune system without it overreacting. So that's been one of the challenges.
In some patients we can see fever, chills, muscle aches and if those are modest and they are relatively short term, then those are manageable and the patient understands that these can happen and is acceptable. But we also don't want to take that immune system too far, higher fevers or severe muscle aches, or unfortunately sometimes the immune system can start to damage itself or other organs. So we kind of know what we're up against, which is not uncommon in drug development, it's just anytime you have a unique application, you get unique situations and we're going to have to address those as we go along, what's acceptable, what's expected, what is manageable.
Mary Parker:
Absolutely. Well, thank you all three of you for sharing your expertise with me. This has been really interesting and honestly it just makes me feel a little bit better about the status of cancer research right now in the world. So I appreciate that. Thank you.
Dan Rocca:
Thanks very much.
Mike Templin:
Thank you.
Louise Brackenbury:
Thank you.