VAXXED: From Gardasil to mRNA, with Dr Ian Frazer and Wilsons Advisory

Cancer vaccines started out as prevention. Think Gardasil for cervical and oral cancers caused by HPV, and the hepatitis B vaccine for liver cancer.

But today the science has moved on, to therapy vaccines. Vaccines that take immune cells and "rub their little noses in the antigen" - the substance that forces the body to sit up and take notice of a foreign invader or unusual activity.

Clinical trials abound, by some of the heavy hitters in mRNA and pharmaceuticals, but nothing yet has been commercialised. Wilsons Advisory senior equity analyst Dr Shane Storey reckons we're five years away from a vaccine from the most-likely candidate of mRNA.

In this episode we talk to the coinventor of the first smash hit in cancer vaccines, Gardasil, professor Dr Ian Frazer, and Shane about where the field has come from, and where it's going. 

Chapters

• 2:48 Professor Dr Ian Frazer
• 14:31 Wilsons Advisory senior equity analyst Dr Shane Storey

Transcript

Rachel Williamson: 0:00

Cancer vaccines are like Hollywood wartime spies. Some offer an elegant subterfuge. Effectively undermining a tumour from the inside. 

Others are more like Ernest Hemingway. Larger than life. Expensive. And not all that useful to their Russian handler. 

I'm Rachel Williamson, and this is Phase III. 

Cancer vaccines started as prevention. First, there was a vaccine for TB. It is still used as a frontline therapy for bladder cancer today. 

Then in the 1980s, you had the hepatitis B vaccine. Stop Hep B and you can prevent the side effect of liver cancer. 

Finally there's Gardasil, the revelatory vaccine that prevents human papillomavirus or HPV. It has reduced cervical cancer rates by 60 to 90%. And it's saved thousands of women's lives since launching in 2006. 

But these are all cancers that are caused by viruses. In this series, we will investigate the new frontier: cancer vaccines as therapy. That is, when the cancer has already started. 

Therapy vaccines don't vaccinate the body against something. Instead, they show the immune system what a tumour is by highlighting the neoantigens on its surface. A neoantigen is a mutant protein that is unique to the tumour. Doing that turns the formerly hidden tumour cell into a glowing target. Add a drug that ramps up the immune system, and the body can get to work. 

Merck and Moderna are so close to getting an mRNA vaccine for melanoma to work. It's in phase three clinical trials. Elicio Therapeutics has a peptide vaccine for pancreatic cancer in phase two trials. Bavarian Nordic is a bit different, using a virus to light out prostate tumours and to deliver a toxic payload. It's in phase three trials. 

These are just a handful of these still small number of clinical trials and research going into cancer vaccines today. But to look forward, sometimes we need to look back first. Back to 1989, where Dr. Ian Frazer met virologist Dr. Jian Zhou and started on the path to making Gardasil. 

Dr. Zhou died in 1999. But Ian is still actively advising cancer vaccine hopefuls. 

I'm very excited to talk about your history and your work because it has affected all the women I know, really. You famously co invented the human papillomavirus or HPV vaccine. Now, this tricks the immune system into recognising the real thing using what's called a virus like particle or VLP. Where did the VLP concept originally come from?

Dr Ian Frazer: 3:17

Oh, I have to go back quite a bit in time for that, uh, to Professor Harald zur Hausen, who was working in the 1940s and 1950s on the connection between papillomavirus infection and cancer. That led to a lot of work mapping out, first of all, that there was a unique papillomavirus which was associated with cancers in humans, HPV 16. We now know there are several other ones but 16 was the dominant one and still is. And then people started to work out how perhaps the virus could cause cancer, and that turned out to be due to the virus infecting cells and not producing more virus, but rather changing the program of the cells so that they became able to grow indefinitely and then perhaps become cancerous.

Rachel Williamson: 4:08

Seems like a simple fix, right? Stop HPV, stop cervical cancer. But here comes challenge number one. You can't grow an HPV virus in the lab. 

Why not? Because the only place to get material is from cervical cancer patients. And cancer cells don't contain the whole HPV virus genome. Which meant the usual experiments a virologist could do were off the table. But Ian and Jian found a work around.

Dr Ian Frazer: 4:39

We knew the virus was basically coated with two particular proteins, which we called L1 and L2 for no particularly good reason,  and that, those two proteins packaged up the infectious material, the genetic information of the virus. So we started thinking about could we make a virus in the lab by expressing L1 and L2 proteins using the-then new technologies of genetic engineering. And that was, sounded easy in principle, but in practice turned out to be quite hard.

Rachel Williamson: 5:16

And here is challenge number two. They struggled to find a complete L1 or L2 genome. 

Why? Because the material they had to work with was from cancer. And what is cancer notorious for? Changing genetic information. 

Jian and Ian started their work in the UK before moving to Australia. But it was Australia where they got lucky with a sample that contained the real code for L1. It took a year, but they were able to build a complete gene for both proteins.

Dr Ian Frazer: 5:50

Much to our surprise, if we express these genes in the test tube in the right way, we found these things called virus like particles. And these virus like particles were not virus. They were empty. There was nothing infectious about them. But they looked like the virus as far as the body's immune system was concerned.

Rachel Williamson: 6:13

What made the HPV virus so amenable to creating a virus like particle? Because a lot of other companies have tried this for cancer and gotten absolutely nowhere.

Dr Ian Frazer: 6:30

Well, you have to understand, of course, that the vast majority of cancers are not triggered off by infection. You know, the basic message in cancer is that the genetic information of the host cell that's going to become a cancer is altered. And it can be altered by radiation, it can be altered by drugs, it can be altered by, uh, virus, but, uh, the, the, there are really only a few cancers that are caused by virus infections. 

And the virus causes cancer not using the capsid, not using the outside, it uses the genetic information inside the virus to change the nature of the cells so they become cancerous. So we have, we have to basically stop the infection with the virus getting into cells in order to stop the cells becoming cancerous. 

So that, that was basically what we aimed to do and what we were able to show we could make an antibody that didn't cause cancer. Basically stop the virus getting into cells - that took a bit of work - and once we had done it, other groups copied us, checked that we could, that we'd got it right. Some claimed they got there first, but in the long run, it turned out that we were probably first.

Rachel Williamson: 7:46

The patent battle over this blockbuster drug was intense. Several groups were working on the same concept around the same time. In 2005, a US court awarded the patent to a team from Georgetown University, saying Ian's and Jian's work was inaccurate. Two years later that was reversed on appeal. It's been a ride. 

But preventative vaccines are also a form whose time has kind of passed. At least in terms of cutting edge science. Using vaccines to infect tumours, therapeutic vaccines, that is where the science is at. 

After Gardasil, Ian's next step was into treating the cancer caused by HPV. 25 years on. That's still the goal. And not just for him. Pairing a vaccine to light up cancer cells with a drug that turns up the volume on the body's immune system is the dream. 

One of these paired immunotherapies are monoclonal antibodies. These are lab-made proteins that mimic the antibodies produced naturally by the immune system. But herein lies another challenge. I'll let Ian explain.

Dr Ian Frazer: 8:59

Of course, there are complications from that as well. If you turn up the immune system, your immune system doesn't really distinguish well between cancer and normal cells, and therefore there's always a risk that there will be side effects caused by too much immunity. We're in an interesting situation at the moment that we're learning very rapidly that an idea which was had a long time ago, that the body's own defences against infection, also control to some extent against cancer, is probably true. In other words, we have an immune system, which is really there to prevent us getting infected with viruses and bacteria. But the immune system can also recognise a tumour if it's sufficiently different from ourselves. We know that there must be something really significant there because if you lack an immune system, you become more prone to cancer. And so that, uh, that, that gives us confidence that we can use the immune system. We can immunize patients with something that the tumor might have that the body hasn't had a chance to fight.

Rachel Williamson: 10:08

Again, this sounds simple. But in fact, it's really hard. Because if you remember, cancer cells change. 

When it comes to the work Ian is doing with another company, which is working on a vaccine to treat cancer caused by HPV. To some extent, every treatment has to be personalised to that patient's cancer. I asked Ian whether that means an allergenic, or off the shelf, vaccine treatment for cervical cancer is possible.

Dr Ian Frazer: 10:37

Well, it's not quite as bad as that. I mean, there are, what we're now beginning to realize is that those abnormal pathways include parts of the immune system, and we're trying to correct, if you like, the missing bits of the immune system to push the immune response along and try and help to heal the cancer. So the idea is more complicated for a therapeutic vaccine than it is for a preventative vaccine, where we know there's a virus and we just want to make sure the virus doesn't get in and cause cancer.

Rachel Williamson: 11:08

Therapeutic vaccines seem to be having a moment right now. Which modality do you think is going to have the most legs?

Dr Ian Frazer: 11:19

Well, right at the moment, monoclonal antibody therapy definitely comes into that category for treating cancers when they can't just be cut out. We recognize that for some sorts of cancers they can be curative, and for others they can at least prevent the cancer spreading. 

Uh, in the future, there are other possibilities which are more experimental. mRNA, I mean, let's call it immunotherapies. I don't like the word vaccines for these things. mRNA is just one mode of turning on the immune system, programming the immune system, but it can also, mRNA can also be used as a specific means of targeting a cancer. I think that it can kill cancer cells using non-immunological mechanisms. 

We're very much at the experimental stage of mRNA vaccines at the moment. Obviously, COVID, I think COVID has moved them along very much more rapidly than would otherwise have been the case. 

That means we're still, we're sort of catching up our scientific knowledge with the practical knowledge that these can be useful. And I think that the important thing with all of this is to remember that we, that you invest in the science because it gives you a logical way of dealing with something rather than just an empirical way of doing it. And the more we understand about what we're trying to do, the more likely we are to be on target. And that's true whether we're talking about vaccines, whether we're talking about cancer treatments, it's always the science that drives the steps forward which are logical rather than just trial and error.

Rachel Williamson: 12:55

That was Dr. Ian Fraser, the co-inventor of HPV vaccine Gardasil. If building a vaccine from nothing sounds hard, building Trojan horses to infect tumours is too. But that's what the financiers are backing these days, as we'll find out after this break.

Charis Palmer: 13:16

Hi there, I'm Charis Palmer, producer of Phase III. When Rachel and I set about building a new podcast for life science leaders, scientists, and long suffering biotech investors, we looked at what was missing in this space. We believe Phase III serves an unmet need for in-depth conversations in a world where nuance matters and AI-written investment articles simply won't cut it. If you agree, please follow us and sign up to our newsletter via LinkedIn, pledge financial support at phasethree.Buzzsprout.com and rate and review the podcast on the podcast platform you use, to help bring it to the attention of others. Now, back to the show.

Rachel Williamson: 13:55

Cancer vaccines will be a success story thanks to three pieces of technology: Neoantigens. AI. And better ways to get vaccines inside the body. That and the startling rise of mRNA, of course. 

Wilson's Advisory lead healthcare analyst Dr. Shane Storey is fascinated by the elegance of vaccines. Instead of using a single toxic drug to hammer the body, engage the power latent within the body itself. So I had to ask him: what is so alluring about the vaccine concept for cancer?

Shane Storey: 14:32

Well, I've always loved it. I looked at it maybe 20 years ago. I've always been intrigued by it. I think it's an alluring idea because it, you know, it gets us away from the single drug, single receptor, very simplistic kind of view that one interaction is going to solve all the things. And, and when you see the opportunity to, you know, recruit the sophistication and just the power, you know, sitting there in every cell in the immune system. 

The system is already doing half the job for you in that, in the healthy individual. The immune system is constantly doing surveillance and checking for transform cells it needs to get rid of. And it's got such a devastating range of weapons that if you are able to get it, to work on your behalf, then you'd think that you would have a very good chance of being able to impact, you know, the disease much more so than you can with like a single cytotoxic drug so that's why it's always been such an appealing idea.

Rachel Williamson: 15:39

Are investors backing in the vaccine concept yet? Given it hasn't proved itself to be particularly successful yet.

Shane Storey: 15:49

I think investors are backing in the RNA

Rachel Williamson: 15:55

But not the cell based, or or

Shane Storey: 15:58

And what I mean by that. If you look at the last five years, maybe, I think there's probably been, you know, three things that have come through that have made vaccines for cancer doable again in most people's mind. 

Checkpoints is one of them. The other is, ideally, working side by side with checkpoints is something that's quite selective. And so those subtle differences between, uh, cancer cells and human and normal cells, they're called neoantigens. I think there's been a lot of advances in identifying which ones they are, which ones will work, which ones won't work, you know, ideally with the immune system that you're trying to get it to interact with.

Rachel Williamson: 16:42

Checkpoints and neoantigens. These are two really important elements of modern cancer treatment that come with a backstory. 

Checkpoint inhibitor therapy targets the immune system's built in checkpoints. Basically, it targets proteins that act as brakes on the immune system. But it doesn't always work for patients whose immune system is already weakened. And it doesn't work for cold tumours: tumours which hide and don't kick off immune activity. These include pancreatic and ovarian cancers. 

One way to turn a secretive tumour into a bright red glowing hit me button is to infect it with a vaccine. Antigens trigger an immune response. Neoantigens are specific to tumours. They can be used to light up cultures to make personalised cancer therapies and even give T-Cells a memory of what the cancer looks like.

The University of Oxford LungVax clinical trial was launched this year and it uses neoantigens to create targets for the immune system to attack. But these are not the most significant pieces of research to come out in the last decade. I'll let Shane explain.

Shane Storey: 17:59

Ultimately,  possibly the most important bit and one that was probably, you know, not foreseeable, maybe even 10 years ago, was like the amazing rise and rise of RNA as, uh, as a modality. 

I think drug developers of my age would never have picked RNA to have won the war in COVID. We would've chosen something entirely different, and I think it's just because we're part of that traumatised generation who could just never work with RNA in a lab, never thought it would ever get to a point where it has just been so miraculously industrialised. 

So if you look at the companies that are doing, you know, the most interesting work now and some of even in combination with checkpoints, as we've been discussing, like BioNTech and Moderna, I think investors backing in the RNA concept and vaccines more generally. But then increasingly looking at, well, it might also pull the cancer vaccine thing off too. Um, so I think the, I think they're backing RNA in and I think, yeah, they'll, they'll get vaccines, they'll get vaccines for free.

Rachel Williamson: 19:07

There was some early success with the vaccine Gardasil, the very, very famous HPV vaccine, and that borrowed from infectious disease vaccines. What did that do for the growth and commercialisation attempts of that early science?

Shane Storey: 19:24

That was a terrific vaccine and it worked because Ian Fraser and Jian Zhou, the inventors, they worked out that to get an immune response against human papillomavirus. All you had to come up with, I say all you had to was actually quite technically very difficult and worse and harder to manufacture, it was to create an empty virus particle. So a virus particle that had the external capsid, is what it's called, but had none of the guts, had none of the infectious, you know, nucleic acid inside it. And of course, because that virus has a causative impact on cervical cancer and oral cancer and other cancers, by extension, you, you immunise people against HPV and those forms of cancers. 

And that was, you know, commercially an incredible success for Merck and for CSL and for, you know, for UQ as well. But then that didn't always work people then went after Epstein Barr and a couple of other different viruses and found that you know like many viruses they're actually quite tricky to do.

Rachel Williamson: 20:21

What impact did that have? Did it spur a lot of companies and commercialisation attempts for, for other ideas?

Shane Storey: 20:30

No, it definitely did. And it probably led a lot of vaccine developers down the wrong path. And it probably, and by that I mean, if you look back around the time when Gardasil was successful, so the early 2000s, I think it was approved 2006. If you look around that era, um, cancer vaccines, I mean, viruses were, were part of the scene. They were either being used directly in the Gardasil way, or they were being used as vectors to you know, to try and create what were called vector mediated vaccines, or even DNA vaccines. And they were the initial attempts. 

And I can't even imagine why we didn't think of RNA at the time, because you think of the complications of trying to get a DNA molecule inside a cell, inside the nucleus, not have it integrate in some problematic piece of the genome, hopefully get transcribed into RNA. And that, that, like, it was just so complicated. When you just go in with an RNA and the thing just sits in the cytoplasm and just works and makes proteins like it just was obvious, but maybe, maybe Gardasil led people down the wrong path and none of those vaccines work.

Rachel Williamson: 21:49

Let's talk about one that has worked. Sipuleucel T, which is better known by its brand name Provenge. It treats prostate cancer. What has that taught us about how to build a therapeutic cancer vaccine? Both from a science perspective, from building a company or a infrastructure to actually sell it, given the failures of the past.

Shane Storey: 22:17

Well, it was smart, right? So Provenge was really almost like in vitro immunisation in that they took the immune cells out of the patient, rubbed their noses, their little noses in the antigen and then put the cells back in the patient. And because those cells have learned to go after a particular protein on prostate cancer, that was the vaccine, right? So it was a very clever idea and it did work and it achieved the benefit for the patients. 

In the end, though, it didn't work really as a product because that manufacturing was so expensive because every patient basically gets the bespoke little manufacturing process and that, I mean, the same is true these days of CAR-T therapies where the manufacturing costs are fairly prohibitive, which means the product price has to be so high that then the insurers don't like to pay it and so it kind of all unravels. So, brilliant scientifically, but I'd have to say probably failed as a product because...

Rachel Williamson: 23:21

Is that a direction that companies are at again today?

Shane Storey: 23:26

They still are. Yeah, they're still looking at it and they're getting even more sophisticated in what they do and how they, how they make them. But there are still, yep, there are still, I guess they're called dendritic cell vaccines. There's still a couple in development, not many. Between you and me, I just don't think they're going to win the war. You know, I think, um, I think RNA is going to win, um, in this setting.

Rachel Williamson: 23:53

Now after years in the desert, the big comeback for cancer vaccines, as we've mentioned, has been obviously mRNA and, what Moderna and Merck and BioNTech and a few others are doing, much of it in Melbourne from what I can see. What are these doing for the industry? How excited are people? What sort of money are they bringing in to back science? What are they building?

Shane Storey: 24:20

Look, it is really exciting time, and yes, you're right. A lot of it is being done here locally, and a lot of it is with RNA. But then it's not as simple as that. So go back, go back to the, the idea of the antigens, which, you know, none of this is going to work without good antigens. There's science that's going on there where you can either, and this is really interesting, where you can either try and find, uh, an antigen that is made in, uh, a wide number of patients who have a particular cancer. And in that case, it allows you to sort of have an off the shelf sort of vaccine that you hope will protect a lot of people to varying degrees. Or you can now look for a whole range of personalized neo antigens that you get for an individual patient by sequencing that patient's tumour. And you can come up with some of those vaccine candidates now, come up with a very powerful personalised, you know, vaccine. 

Rachel Williamson: 25:18

It sounds very expensive.

Shane Storey: 25:19

But it's not with RNA. See, because with RNA, you can just dial up a change in the sequence and then you can, you can actually do that in a modular kind of way. So it's nowhere near as expensive as the dendritic cell thing we discussed before. That's really expensive. 

But you can dial that up pretty simply in a small scale batch manufacturing with RNA and do it that way. And there are trials that Moderna have and I think BioNTech got that personalised approach in some of their phase 3 programs. The other interesting thing is using AI to, so rather than sequence a patient's tumour, if you get the genetic information, use AI to sort of detect just from those sequences, which are likely to be good neoantigens. And also likely to interact with the right bits of the immune system in the right way at the right time to do the right things. You know, that's where you're starting to see a lot of really interesting research.

Rachel Williamson: 26:16

What companies are really exciting you right now?

Shane Storey: 26:19

We've spoken about RNA as, you know, as the, as the key here, but there's still some drawbacks there that a number of companies are looking at really is to do with how they're delivered. 

The vaccine industry is still absolutely over-dependent on say intramuscular injections. So, um, there's hardly any immune cells in a muscle. So I like companies like Vaxxas who are doing a way with needles and they're using patch based technologies to put antigen just underneath the surface of the skin where, surprise, surprise, all the antigen presenting cells hang out, right? So you, you're putting the antigen in the right place, which is a terrific start, so we like that. 

We also like companies like Arcturus, in the States, who are doing RNA, but their RNAs are self replicating, so they make copies of themselves inside the cell. So you really, a sixth of the material is needed to generate a superior immune response because the vaccine has that self replicating nature. 

So I guess the companies that we look for are those that are trying to solve the delivery issues. If we start from the assumption that RNA is probably going to win, what companies can we find that are going to help it win even more? I think they're the ones that interest us as analysts.

Rachel Williamson: 27:48

That was Dr. Shane Storey, head of the healthcare team at Wilson's Advisory. Shane says mRNA cancer vaccines will be on the market in five years, and these will change the way the cancer immunotherapy industry works. They can be made cheaply enough to give in combination with an expensive checkpoint inhibitor. In contrast, a cell vaccine like Provenge is never going to work just on cost. 

In our next episode, we start deep diving into companies that are making cancer vaccines in Australia. But doing so just a little bit differently again.