VAXXED: Game on, with BASE and WEHI

Cancer vaccines are an area that anyone who is anyone is getting into, but it's a field  led largely by academics, not-for–profits, and specialist researchers. So this week we go back to basics - science that is. 

Australia may not have many cancer vaccine biotechs but – as we pointed out in episode one with the godfather of cancer vaccines, professor Dr Ian Frazer – it has heft in its research. 

Dr Seth Cheetham from the University of Queensland's Base Facility, a specialist mRNA manufacturing lab, explains why they went from COVID19 to cancer. 

And Dr Shalin Naik from the Walter and Eliza Hall Institute of Medical Research explains why he's bringing back a spectre of the past, and why he believes it could be the winner of this biotechnology cage match. 

Chapters

• 1:41 BASE group leader and deputy director Dr Seth Cheetham
• 14:31 WEHI laboratory head Dr Shalin Naik

Transcript

Rachel Williamson: 0:01

The OG of cancer therapy vaccines is back, but mRNA is the hot new thing. So if you're an investor, which angle do you back? 

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

In this episode, we're getting out the tape measure and putting two Australian innovation centres back to back. 

At the University of Queensland, the BASE mRNA manufacturing facility is cashed up and going deep on cancer. In Melbourne, a team of researchers is reviving dendritic cells. They're the source of the first success in cancer therapy vaccines, and a nightmare that still haunts investors dreams. 

They're both operating in a global landscape that is leaning heavily to mRNA. BioNTech, Moderna and Merck have phase three trials underway for non small cell lung cancer and the latter two also have a vaccine for melanoma in a phase three trial. 

And they and a gamut of researchers from the likes of the University of Florida to the Memorial Sloan Kettering Cancer Center are showing their mRNA vaccines work for a range of hard to treat cancers. What all of these companies and organisations are aiming for is to be the second cancer therapy ever to win US Federal Drug Administration approval. 

Filling the mRNA cancer gap in the Australian market is the project led by molecular biologist, Dr Seth Cheetham out of Queensland, and that is BASE. The federal government funded the University of Queensland facility in 2021 to solve, at the time, a major problem. Australia had zero mRNA manufacturing sites.

Seth Cheetham: 2:05

And that kind of left us, you exposed during the COVID 19 pandemic because you really saw the success of the Moderna and Pfizer BioNTech COVID vaccines which were based on the mRNA technology.

Rachel Williamson: 2:16

There wasn't time to build a factory and start making mRNA vaccines in 2021. But the federal government didn't want Australia to miss out.

Seth Cheetham: 2:26

So they set up BASE which is a collaboration between, um, Therapeutic Innovation Australia, which is a federal government body that funds infrastructure around Australia and the University of Queensland. And the mission of BASE was initially very simple which was just to provide high quality mRNA to researchers around Australia. What's nice about that is that it's really given us that kind of view through the sector and we've been able to see how technology has evolved and how the applications of it have really changed over time.

Rachel Williamson: 2:58

Fast forward to 2023 and COVID isn't such a feature of our lives anymore, but they doubled down and this time as a cancer vaccine hub. Seth and his team have seen a shift from COVID 19 vaccines to trying mRNA out on chronic conditions, and now a really deep swing to cancer. This year, they got a $3.3 million grant from the Medical Research Future Fund to do personalised mRNA cancer vaccines. So I had to ask, why cancer? What is it about this particular disease that is moving the dial for mRNA research funding?

Seth Cheetham: 3:40

I guess the reason that we, um, applied and were, you know, were successful in getting this specific funding is cancer vaccines are quite fundamentally different from other kinds of mRNA products. And the challenges here are really different from infectious disease vaccines. So infectious disease vaccines, it's all about scale. You know, you're trying to vaccinate the entire world's population. For cancer vaccines, it's about speed. So you're really trying to turn that vaccine around as quickly as possible, but only enough for a single person.

Rachel Williamson: 4:08

But why cancer vaccines? Why not one of the other mRNA applications?

Seth Cheetham: 4:16

We've kind of settled on quite a strong internal focus on cancer. And the reason for that is, um, you know, it's a very new technology, right? There's very promising results coming from early phase clinical trials from BioNTech and Moderna and some academic centres. And it's a very exciting application of the technology. So, I mean, the word personalised medicine gets thrown around a lot. But usually when people talk about a personalised medicine, they're talking about using advanced diagnostics to really match a drug to a patient. So you have the best chance of that drug working for for that individual. But this is an application where you're talking about actually manufacturing from scratch, a drug for a single person. So it was really kind of the right time, I guess, to kind of establish this focus.

Rachel Williamson: 5:01

In cancer vaccines in a way that I haven't seen across other biotech fields, you have a really strong two hander between commercial companies and organisations like yours. Normally it's the biotechs that claim all the glory, they're running the trials, they've got the results, it's their thing, but in this particular area, you know, you've got the LungVax clinical trial in the UK that's University of Oxford is leading that, but that's using AstraZeneca's tech. BioNTech is using Latrobe University's new manufacturing facility. And in the US you've got a range of clinical trials being run by The Cleveland Clinic, the Memorial Sloan Kettering Cancer Center, University of Texas, they're taking the lead on this. So why are not for profits, research entities, academia, taking the lead in a way that they perhaps haven't in the past?

Seth Cheetham: 5:59

Yeah, I think part of the reason for that is that the mRNA technology, while it's been kind of worked on quite a lot in the background for a long time there's so much innovation still happening, right? So this isn't like a completely mature, finished technology. So, for example, there was a recent paper in Cell earlier this year from the University of Florida, where they had a completely different way of constructing these mRNA vaccines using this kind of layered onion like structure with lipids to deliver mRNA vaccines for brain cancer. 

So there's a huge amount of that kind of technical development that's still happening. The other thing I would point to as well is a lot of these trials are quite complex. So it's a really different way of doing clinical development. So in a typical clinical trial, you've got your cohort of patients and they're all getting the same thing. In this case, everyone's getting what is essentially a different drug and so there's a lot of innovation that's still happening on the trial design side of things. And also proving that technology. 

So that's why you see a lot of collaboration between some of the really large academic medical institutes, such as like Memorial Sloan Kettering, collaborating with BioNTech on some of their, um, vaccines. So I think this real synergy between the biotech landscape and universities is kind of because of the rapid emergence of this field and that there's so much innovation going on.

Rachel Williamson: 7:21

Seth says the cancer mRNA field is reminiscent of the emergence of biotechnology, in the first place. From collaborations at a handful of Californian universities, to the creation of industry pioneers such as Genentech. But figuring out how to make mRNA work for cancer is just the start of the journey. Seth mentioned the challenge of creating personalised medicine for each individual patient. But what does that even look like in massive phase 3 trials or even once it's approved and on the market? How do you inoculate thousands of people with their own personalised vaccine and how do you do that quickly? I asked Seth whether that was the role base might play in a future with an mRNA cancer vaccine.

Seth Cheetham: 8:12

So what you really need is a very agile manufacturing solution. Um, so I mean, in addition to the cancer vaccine grant that we recently got, we also recently got funding from the MRFF to establish a phase one trial manufacturer site, which is over at the Translational Research Institute, which is under development at the moment. And so for a traditional drug, when you're looking at getting that into patients, it's usually manufactured at a huge site. So one of the nice things about mRNA technology is that it is so scalable, and you can really it has a very small footprint compared to for example, small molecule drugs. So you can really have these, like, relatively small manufacturer sites that can enable clinical trials. So that's exactly what we're looking at establishing and for these personalised vaccines. That's really key because you want product. You don't want to deliver that huge scale, but you want it quickly.

Rachel Williamson: 9:02

How fast? How fast will you be able to receive the material that you need to make a vaccine and then get it to a patient?

Seth Cheetham: 9:10

Yeah, so in theory, these things could be made as quickly as about eight weeks, which is very fast. It's a very, uh, complex manufacturing solution because if you're thinking about a clinical trial that might have, you know, even as few as ten patients in it, in an early stage trial, you're still having to manufacture ten different drugs for that trial. So there is, there is certainly a large amount of complexity here. But the good thing about mRNA is that. You can make it really quickly and you don't need a bespoke manufacturing solution for each mRNA. So if you think about manufacturing other kinds of biomolecules like proteins, each one that you manufacture will behave really differently. But with the mRNA vaccines, each one that you manufacture will behave in that manufacturing pipeline very similarly, which allows you to kind of turn them around much faster.

Rachel Williamson: 9:59

It helps that they're also not working with DNA extracted from bacteria in a lab. That's a source of DNA which is so problematic that a Nature article this year said nearly half of samples have design errors. Instead they're pioneering a synthetic DNA template and cutting weeks off the manufacturing process. But Seth isn't just in charge of streamlining getting mRNA from A to B faster. His team is doing some of the new basic research into cancer vaccines themselves. I asked Seth what they're up to.

Seth Cheetham: 10:35

We're just getting started at the moment. But certainly the areas that we're focusing on are kind of improving the potency of the mRNA vaccines, both through engineering the mRNA itself, so looking at how different modifications can enhance that immune reaction that you get. And also different formulations. So we recently had a manuscript that we've put online on using targeted delivery. So it's being able to deliver the vaccine specifically to different cell types. Um, There's a huge amount still left to be uncovered, even about what an effective vaccine looks like. So for example, the vaccines that companies like Moderna are using, might have 34 different sequences that they're trying to raise immunity against, but in a patient when they inject that it might only be one or two that's actually driving immunity. So there's a huge amount of work to be done there in terms of understanding why particular antigens are effective and others are. So, I would say the field of mRNA cancer vaccines is, is very embryonic and then, you know, there's a huge amount of potential for these things to get even better than they're now.

Rachel Williamson: 11:41

That was BASE Group Leader and Deputy Director, Dr. Seth Cheetham. Seth's backers are convinced mRNA cancer vaccines are on track to become a real therapy. They're basing their view on positive results from global clinical trials, the multi sector collaborations, and the support this concept is getting from other countries and funders. But could there be something even better out there? Something that has been proved to work before? We'll find out after the break.

Charis Palmer: 12:16

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: 12:55

If mRNA is the cancer vaccine therapy of the future, then dendritic cells are the vaccines of the past. 

Dendritic cells were discovered by Canadian physician Dr. Ralph Steinman in 1973. In 2011 he won the Nobel Prize in physiology or medicine for his discovery -- three days after he died. Normally you have to be alive to win a Nobel, but the committee decided that since he wasn't dead, when the decision was made, he's still qualified. 

For many years, researchers have been trying to get DCs, as they're known, to work for cancer immunotherapy. That's because DCs are the cells that patrol the body and find foreign invaders. They then educate the soldier cells, the T cells, to attack. The general idea in the past was to take the DCs out of a patient, rub their little noses in a cancer antigen and put them back in. And in the 1990s and 2000s, there was a huge number of clinical trials using monocyte derived dendritic cells to try and do this. Of all of these trials and all of the money that backed them, just one drug, Provenge, for late stage prostate cancer, was approved. 

That was 2010, it was so expensive it bankrupted its owner Dendreon. It was revived at the end of the decade to treat early stage prostate cancer. But in many ways, the 1990s and 2000s were two decades wasted. And this is why.

Shalin Naik: 14:31

It turns out they're the wrong ones. We've been using the wrong DCs for a long while, in my opinion.

Rachel Williamson: 14:39

This is Shalin Naik. He's the lab head at the Walter and Eliza Hall Institute of Medical Research, or WEHI for short. His research is the foundation for a potential revival of dendritic cell cancer therapy vaccines.

Shalin Naik: 14:55

We didn't know any better until Ken Shortman at WEHI in 1992 discovered this obscure subset of dendritic cells called the, DC1s. He called them the CD8 positive dendritic cells. Anyway, it turns out this is the crucial subtype for kick starting cytotoxic T cell immunity, the killer immune cells. But no one's been able to make them in large numbers in a dish and that's because they're super tricky.

Rachel Williamson: 15:22

Why are they so tricky?

Shalin Naik: 15:23

So, we've been chasing the wrong growth hormones to grow DC1s. We knew the ones that grew monocyte derived DCs, not the one that grew DCs1s. Then during my PhD with Ken Shortman back in the early 2000s, I discovered that it was FLIT3 ligand that in culture could really stimulate great DC1 production in mouse. So then I sat back, I published the paper in 2005. I sat back, I said, right, someone's going to go and make these in a human form and inject them into patients. and then here we go. I was waiting, waiting, waiting, and no one did.

Rachel Williamson: 16:01

Had people just been too burned by trying to make another Gardasil, trying to make DC vaccines work? And just were like...

Shalin Naik: 16:07

Yeah, I reckon that's part of it. People were, people are still are investors are seriously burnt by monocyte derived DCs, so they're like gun shy about any, any, use of the word dendritic cell. They kind of run a mile, but it's gradually creeping back into the kind of collective psyche that this is something we need to be thinking about.

Rachel Williamson: 16:27

Shalin and his team have spent the last few years figuring out how to grow DC1s from human stem cells. They've found a secret source that can make 10 times more DC1s at 10 times greater purity. So they've solved two problems, finding a dendritic cell that will work and getting enough to test it on a real live human.

Shalin Naik: 16:53

It suddenly tips the balance that we can inject a decent number of DCs, that would be comparable to what we've done in the monocyte derived DC area to really test the idea. Can we test this? Does it work? And if you can't generate the numbers, you can't test if it works. So we finally cracked that that, problem.

Rachel Williamson: 17:10

Shalin, one of the problems with the original attempts at DC vaccines was they could only get an immune response of 5 to 15 percent and this is because the way solid tumors suppress immune activity also dampens the behavior of dendritic cells. So what are the other unsolved challenges that you're having to wade through now? And with peptide and mRNA vaccines getting so close, what's your competitive advantage with DC1s?

Shalin Naik: 17:40

Yeah, those are two really great questions. The first question is just cause you can make enough of them, will they go and work in the tumor? And the answer is we hope so, but possibly not. And the reason is that we know that the tumor microenvironment is highly immunosuppressive, and that is also the case for dendritic cells. So cytokines like IL 10, TGF beta, basically the tumor secretes these factors that dampen down the DCs, they kind of turn them off, and they can't do their job. 

But the great thing is we're partnering with a lab here next to us at WEHI, from Stephen Nutt's group. And Stephen Nutt's group have developed a novel CAR that is dendritic cell specific. So a reminder, chimeric antigen receptors, which is CAR T cells, they've revolutionised the immunotherapy of, heamatological cancers, liquid cancers, like lymphoma and myeloma now. But they haven't really worked in solid cancers. But what the Nutt lab have done has taken a CAR that binds a cancer, change the cytoplasmic tail to be very DC specific to activate them. and now that solves what in the dendritic cell, we call the DC activation timing problem.

Rachel Williamson: 18:55

Shalin says you've got to time DC activation perfectly. If it's too early, the DCs won't see the tumour antigen. If it's too late, it could start working for the enemy. The tumour can actually put it to work, suppressing the immune response to the cancer. He says it means there are a few moving parts they need to think about.

Shalin Naik: 19:18

We're really thinking about how do we get it into the tumour, how do we make sure it's not immunosuppressed, and how do we kickstart the immune response in the appropriate way once we do see the cancer.

Rachel Williamson: 19:28

And so how are dendritic cell vaccines, and specifically DC1s, going to have an advantage over other cancer vaccine theories?

Shalin Naik: 19:38

So we think it just comes down to two words. Epitope spreading.

Rachel Williamson: 19:43

Great. What does that mean?

Shalin Naik: 19:44

What does epitope spreading mean? Alright. Epitopes are the cancer antigens that are different from normal tissue, that allow the immune response to recognise it and kill it. But the tumour evolves and it changes and there's, uh, these new antigens arise, but also if you go and attack those tumour cells, then some of the tumour cells that mutated those further or didn't have them might rise again. 

So this idea of tumour heterogeneity means it can be like a, you know, a Medusa's head. It can just, you know, grow out by avoiding several arms of the immune response. 

And so while we believe that peptide vaccines, personalised antigen vaccines could be useful, they're also liable to escape because you have to make a choice. And if you choose, I don't know, seven antigens, but there's a plethora of antigens, if you get those wrong or they don't eradicate 100 percent of the cancer, a cancer can bounce back and you have to go back to the drawing board. 

The beauty of dendritic cells is it is agnostic to the antigen. It means it doesn't, it doesn't care. It's like whatever is there, it will take up, it'll process, and it'll present to the T cell. And if there is a T cell around that recognises that it will get activated. So what epitope spreading is, The DC takes up the tumour, it activates the T cells. The T cells go and kill the tumour cells that have the antigen. If some of them escape, new DCs can pick up new tumours, educate new T cells for the new antigens, go back and they will get killed, and so on and so forth. 

So once you kickstart that process, it's sort of like a self sustaining therapy. And that's how checkpoint inhibitors work. It's not only the T cells that are happening here, it's, it's the whole network of dendritic cells, T cells, tumour killing, new antigens are lysed, and so on. And so we believe dendritic cell therapy will work similarly, but in an advanced way compared to checkpoint inhibitors, in that it will allow epitope spreading and a tumour clearance longer term. That's the hypothesis.

Rachel Williamson: 21:45

Shalin is hoping human trials at the Peter McCallum Cancer Center could be just a couple of years away. Which raises an interesting question. He works at the purer end of medical research. So I asked him, how much do researchers at this end of the biotech spectrum have to factor in crass commercial considerations? Like producing something that is simple to make and not eye wateringly expensive, over something that just works.

Shalin Naik: 22:16

So I'm new to this world, right? I'm very much a dendritic cell biology researcher. I am not a clinician. I am not a biotech company CEO.

Rachel Williamson: 22:24

So you are the perfect person to be asking about this thing, because this is something that maybe you are thinking about right now.

Shalin Naik: 22:30

There's certainly considerations there, But the other advice we have is, get into patients, see if it works, and you don't have to be perfect in the first trial for cost in that regard. It will be expensive. Cell therapies are expensive by definition. But if it works, well then we can think about how do we make the manufacturing process shorter? How do we make it cheaper? First up, we'll be doing autologous dendritic cells, which basically means the patient's own DCs. 

But in the future, can we have an off the shelf product? Can we take cord blood stem cells from newborn babies? They're a renewable resource as long as we keep having them. Have a DC1 biobank. And when a patient comes along, we just do a matching exercise like we do with bone marrow transplants. We match them, We pull them out of the freezer, and we, we treat the patient. That's the ultimate goal. Now, whether it's from a baby derived stem cell or an iPSC derived DC1, that remains to be seen.

Rachel Williamson: 23:32

mRNA vaccines have kind of been the reason why cancer vaccines have been popularised, particularly this year. How do you think you guys are going to go up against that concept, which has so many big names behind it, has so much money behind it? You're coming at it from academia and going, This works! We can do this! We can make it work! Versus Merck and Pfizer being like we've just spent a huge amount of money on huge mRNA manufacturing facilities, and why would we even look at that when we're spending so much money elsewhere?

Shalin Naik: 24:10

Yeah, I, I completely agree that that is something we should be thinking about. So mRNA is great. It's fantastic. In fact, we use mRNA LNPs In our manufacturing process. They're a fantastic delivery modality, either in a dish or directly in a patient. They've been tested. They're by and large safe. They are efficacious at generating an immune response and the right kind of immune response. Is it going to work for cancer? You have to choose something to target. So is that choice a pan cancer vaccine? I think it's going to be unlikely you find a magic bullet there. Is it going to be a personalised vaccine? That's the kind of approach many people are taking. You sequence the tumour, You identify the cancer specific antigens, you formulate it in a mRNA and you deliver it into a patient. But again, if tumour heterogeneity is sufficient to bypass those few peptides that you select in the vaccine, well then you're back at square one.

Rachel Williamson: 25:17

That was WEHI Laboratory Head, Dr. Shalin Naik. Shalin found the way to make lots of the kinds of dendritic cells that actually do what we want them to in a cancer vaccine. But his current work is a long way back in the race to build a successful and monetised cancer therapy vaccine. 

In our next and final episode of VAXXED, we ask our usual question, what does the future hold for this emerging line of cancer therapy inquiry? How does it fit into the competitive constellation of cancer cures? And which modality will be the first to commercialisation?