Episode 3: Beating Cancer - Transcript

Release date: 16 March 2023

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TRANSCRIPT

00:00:10:04 – 00:00:51:20

Dr Richard Fagan

Hello, listeners. My name is Dr Richard Fagan and I am Director of BioPharm at UCL Business. We are the wholly owned subsidiary of UCL and we are a tech transfer organisation for UCL. It’s my pleasure to introduce you to Professor Charlie Swanton. It’d be fair to say that Charlie has multiple, multiple roles. He is a professor at UCL, with a laboratory at UCL. He’s also a Principal Group Leader at the Francis Crick Institute, and he’s also the Chief Clinician for Cancer Research UK. Morning, Charlie.

 

00:00:51:20 – 00:00:52:20

Professor Charles Swanton

Good morning, Rick.

 

00:00:53:20 – 00:00:57:03

Dr Richard Fagan

So, Charlie, tell me, how does one person handle three roles like that?

 

00:00:57:07 – 00:01:54:00

Professor Charles Swanton

Well, I guess I haven’t always been doing three roles. It’s a more recent phenomenon, and I think the answer to your question is probably early mornings, late evenings and seven days a week working. There’s always something to do. But the job that I do, principally a scientific-driven focus of the work, is so intrinsically exciting and interesting that it doesn’t really feel like work.

At weekends, in the evenings – you’re just constantly thinking about this and so that enables you to be more efficient, more efficient with your time and free up time during the weekdays to do other things, including work with Cancer Research UK and of course my clinical role at UCLH, which albeit modest, is still a significant component of what I do on a week-to-week basis in the context of how it informs the science, the questions and the aspiration to make lives better for patients.

 

00:01:54:09 – 00:01:56:20

Dr Richard Fagan

Wow, you’re a role model.

 

00:01:56:20 – 00:01:59:11

Professor Charles Swanton

Wouldn’t go that far, but it’s a great job.

 

00:01:59:23 – 00:02:12:15

Dr Richard Fagan

So, we’re here today to talk about a part of your work, TRACERx, and a company that was formed out of that work. Can you tell us about TRACERx, Charlie?

 

00:02:12:15 – 00:04:20:11

Professor Charles Swanton

Yeah, of course, Rick. TRACERx is a longitudinal program that was conceived at University College London, in partnership with the Francis Crick Institute back in 2013, to understand how cancers evolve over space and time.

The idea was that we would recruit about 800 patients into a clinical study of non-small cell lung cancer of early-stage disease, where we would take their surgically resected samples, and follow patients over time to either cure at five years or recurrence.

If the patients suffer disease recurrence after primary surgery, which we estimated about 50% will, we asked for a recurrence biopsy of the metastatic disease. That is the disease that’s spread beyond the chest, to understand how this process of what we call tumour metastasis evolves – that is the dissemination of cancer cells from the primary tumour in the lung, through to distant sites in the bone, the liver, the brain, etc.

The reason we’re interested in that is that we know that metastatic disease kills the patient and we have to understand that process much better, and its growth is an evolutionary phenomenon stemming from a few single clones within the primary tumour.

We reasoned that if we had this longitudinal cohort study, we would begin to ask some very fundamental questions about how cancers evolve and adapt over space and time, how they adapt to evolutionary pressures like drug treatment, how they adapt to colonise new sites of disease like in the brain or the bone or the liver, and ultimately how that relates to what we call this sort of heterogeneous primary tumour, this sort of cauldron, if you like, of diversity that ultimately fosters the evolution of new clones that may be fitter from the last, that enables cells, cancer cells and clones to spread over space and time.

By understanding that process and also understanding how the immune system restricts this process, we figured we might come up with better biomarkers, and hopefully better therapeutic approaches to limit metastasis and drug resistance.

 

00:04:20:12 – 00:04:27:17

Dr Richard Fagan

Of course, you’re doing this study in lung cancer. Would this be applicable to all cancers, like prostate cancer?

 

00:04:27:18 – 00:04:42:06

Professor Charles Swanton

Yes, very much so. The tools we’ve developed through TRACERx are already being used in other diseases. In fact, we’ve also set up other TRACERx programs, including one in renal cancer that Samra Turajlic runs at the Francis Crick Institute in the Royal Marsden.

 

00:04:43:01 – 00:05:46:12

That has taken a similar approach to understand how tumours evolve in kidney cancer. Now, I think it’s fair to say that there are commonalities between kidney and lung, but there are also differences. What is in common, of course, is the approach and the software tools that we have developed that we hope will enable the community to better understand disease evolution.

I think the thing about lung cancer is it’s a disease with a very high, what we call, mutational burden because the majority of patients smoke and smoking induces DNA mutations. These tumours have a very high number of mutations, much higher than most other cancers, and they also have a high degree of what we call chromosomal instability where the chromosomes rearrange.

So, in the context of cell to cell variation, I think lung cancer is probably at the most extreme end and most other cancers will display features similar but not identical to lung cancer, and probably less severe in extent and diversity.

 

00:05:47:03 – 00:05:52:01

Dr Richard Fagan

When did you start thinking about doing this?

 

00:05:53:02 – 00:07:19:03

Professor Charles Swanton

Funnily enough, I was thinking about that question on the way over here this morning, and I guess probably in the mid 2000’s, when I was a trainee oncologist, it was clear that these sort of so-called magic bullet therapies like Herceptin and EGFR inhibitors like Tarceva and what have you were having efficacy. But the efficacy, despite their terms ‘magic bullets’, would be limited. It would last maybe 6 to 8 months, possibly 12 months, and all patients would develop resistance.

Now, that didn’t make sense in the context of what we knew about cancer evolution at the time, which is sort of a linear model of evolution where essentially all cells in a tumour were the same. So, we reasoned that for resistance to be most elegantly explained, tumours would have to be evolving in a branched evolutionary manner, much as Peter Noel had postulated in 1976, but his work had been pretty much ignored. So, we revisited it, but now with new technologies and we applied those new technologies in the context of TRACERx to decipher whether or not branched evolution, so-called Darwinian evolution, was occurring in humans and of course, it is, and was, and always has been.

That, ultimately, is the reason for drug resistance – why we fail to cure metastatic disease, because the disease is so heterogeneous, so diverse, and every cancer cell is different. There will always be a cancer cell in the body resistant to one or more therapies that a doctor uses.

 

00:07:19:03 – 00:07:26:16

Dr Richard Fagan

Is this why cancer vaccines which were much hyped, say, in the eighties – ‘Ah, this is gonna be the magic bullet’ – really, have not been successful?

 

00:07:26:16 – 00:09:06:06

Professor Charles Swanton

Yeah. That’s an excellent question. I think there are several reasons why cancer vaccines have been less than successful, it’s fair to say. First of all, I think they’re being used in the wrong setting. They’ve been tested and trialled in general in advanced metastatic disease, so just like you wouldn’t use a vaccine to treat an established COVID infection, why would you use a vaccine to treat an established cancer?

Where I see the benefits a potential opportunity of vaccine therapies would be in a preventative setting firstly, so that is trying to vaccinate a patient before they get cancer to prevent cancer onset. In the Cancer Research UK Lung Centre at UCL, we have investigators like Kevin Litchfield thinking about these very problems, establishing such trials where we would vaccinate, for example, heavy smokers against common driver mutations associated with smoking like the KRAS G12C mutation.

The other area I think we are going to see efficacy of vaccines in will be in the adjuvant setting after surgical resection of the primary tumour when the disease burden is very, very low indeed, as to your point when heterogeneity is very, very low. There, we can give personalised vaccines against the patient’s own primary tumour to prevent the cancer from coming back.

I think the main reason why vaccines are not efficacious in established disease is because of the ongoing immune suppression. The cancers have the sort of evolutionary tug of war, if you like, between cancer and the immune cell that sort of anaesthetises the immune cell and puts the immune cell to sleep. So, there’s such extensive immune suppression in the established disease that vaccines can’t reawaken or reinvigorate the immune response.

 

00:09:06:18 – 00:09:19:01

Dr Richard Fagan

Right. Thank you. So, you started thinking about this and when did it become reality? You received funding from CRUK. When was that?

 

00:09:19:01 – 00:10:20:03

Professor Charles Swanton

That was in 2013. So, the trial was formally opened in early 2014 and as of last week, we’ve recruited about 820 patients into the study with a median follow up of about 4 to 5 years. So, we have very extensive follow up. We have tens of thousands of biological specimens from these individual patients who’ve generously given their time and tumour material to the study.

I’m excited to say that I think the team, and I mean the team – it’s a consortium, it’s not me; it’s a team across UCL and Manchester, and actually across the planet – have made some major advances in this disease and our understanding of how lung cancer evolves, how the immune system shapes the evolution of non-small cell lung cancer, how lung cancers ultimately evade the adaptive immune response through loss of recognition molecules like the human leukocyte antigen and ultimately, we think how the metastatic process operates. We’ve got papers coming out, we hope, in the not-too-distant future that will allude to that very point.

 

00:10:20:22 – 00:10:44:18

Dr Richard Fagan

UCL’s involvement in the whole TRACERx study is I know that we are sponsors, so UCL receives the grant from CRUK, and we are administrating actually running the trial through the UCL Cancer Trials Centre with Allan Hackshaw. What’s the Crick’s involvement?

 

00:10:44:18 – 00:13:12:07

Professor Charles Swanton

So, let’s just go back to UCL’s involvement first before I answer the Crick’s involvement. So, first and foremost, this study wouldn’t have been possible without University College London. As you say, they sponsor the study. We have a world class clinical trial centre run by Professor Allan Hackshaw, the cancer trial centre that is just phenomenal has been a huge support and their leadership of TRACERx really from its inception to now has been outstanding, and Allan has just been a great colleague and friend and my hat’s off to them really for everything they’ve done. They’ve just been superb and we really wouldn’t be here without them and, of course, UCL for supporting it.

You asked how I do all of these jobs. Well, UCL is a fantastic employer to work for. They really enable me to roam freely with my ideas and do the sort of ambitious work we’re doing, and also link that between the Crick, UCL and the UCL Cancer Institute, which obviously being central to the success of this programme too.

My job is split roughly 50/50 between the Crick and UCL, and I have labs on both sides. UCL Lab predominantly is involved in processing the tissue, storing the tissue, extracting DNA, RNA sequencing the tissue. The Crick, by and large, is involved in analysing that – the data that we get off the sequencing pipelines.

The major sequencing does occur at the Crick. The clinical sequencing occurs here at UCL and the Cancer Institute. The sequencing data from the Crick goes into the Crick servers and through into the lab, both at the Crick and UCL, where our biometricians will analyse the data to be able to understand and ultimately decipher the evolution of each patient’s disease on a patient-by-patient basis.

The Crick really provides the computational firepower, the sequencing firepower, and space and support for probably ten dry lab scientists, the biometricians that enable this work, and also wet lab scientists that take our hypotheses that we get from the TRACERx sequencing data that enable us then to test those hypotheses in the laboratory.

It’s really a beautiful synergy, I think, between the university, the hospital, the BRC that also have supported TRACERx to the tune of about 10 or 15% of all of its investments – so hugely generous – and the Crick. So, it’s a wonderful synergy between all three organisations.

 

00:13:13:09 – 00:13:23:17

Dr Richard Fagan

Moving on. A company was set up around TRACERx. What do you see as the commercial application of TRACERx?

 

00:13:23:24 – 00:14:55:00

Professor Charles Swanton

That’s an excellent question, also. I think the commercial application of TRACERx is one where we have to embrace complexity, we have to embrace an understanding of cancer evolution, and we have to turn evolution against the tumour. So, the question is how do we do that?

We’ve, you know- I’ve been thinking about this for some time, and I say we – this has been a collaboration between Sergio Quezada, Karl Peggs and Mark Lowdell, three UCL and Royal Free professors who have been really leading the way in the concepts of tumour immunology. I always felt that if we were going to beat cancer evolution, it would be through leveraging the body’s own immune system. The question is how do we do that?

Back in 2016, my lab in collaboration with Sergio’s, found evidence of these flags on tumour cells, which we call clonal antigens. These are mutations that are found in the earliest tumour cell, present in all tumour cells across the body, and surprisingly we found immune cells, T cells that specifically recognise these immune flags.

Now, we have a system set up where we can extract immune cells that specifically recognise these clonal or truncal antigens, and we can expand them ex vivo and give them back to patients and the idea is by doing so, we hope to achieve long term control of tumours to prevent tumours from developing resistance because in contrast to modern cancer-targeted therapies which only ever target one flag in a tumour’s trunk of the evolutionary tree, we’re developing T cell therapies that target multiple truncal mutations in the patient’s evolutionary tumour tree to prevent drug resistance from occurring, we hope.

 

00:14:55:19 – 00:15:41:23

Dr Richard Fagan

Yes, and it was the basis of that I formed I believe it was two patent filings that we filed, UCLB and Cancer Research UK, because this is a Cancer Research UK funded study, so we collaborate with them in those.

I started speaking to Syncona which, back then, was the Wellcome Trust investment arm, but it’s now a fully fledged VC on its own, about setting up a company around this and I worked with Phil L’Huillier from CRUK and Veronique Birault from the Crick in regards to setting this company up – it wasn’t a small feat.

 

00:15:41:23 – 00:15:44:12

Professor Charles Swanton

I remember it well, yes.

 

00:15:44:12 – 00:15:46:22

Dr Richard Fagan

Because you’ve got three different almas, you’re looking after three different institutions: CRUK, the Crick and UCLB looking after UCL. We all had to make sure that our interests were all aligned.

 

00:15:58:01 – 00:16:01:23

Professor Charles Swanton

That’s right. A phenomenal achievement, actually.

 

00:16:01:23 – 00:16:30:18

Dr Richard Fagan

That was very interesting. So, that was set up in 2016 with a £17.5 million investment by Syncona. Now, when you get into a commercial setting, it’s quite different from an academic setting. What was your involvement in the beginning and what’s your involvement now?

 

00:16:32:18 – 00:18:35:11

Professor Charles Swanton

In the beginning, my involvement in the commercial set up was obviously to help write the business plan, to think about how we could take these findings that you mentioned that we patented into the clinic through the commercial umbrella of this company, Achilles, and that was done in partnership with Karl Peggs, with the surgical side of Mark Lowdell, and Syncona, principally Iraj Ali, who really has been the business/scientific brains behind Achilles since its inception.

We turned that into reality and my role was always to provide the evolutionary insights and support in the context of bioinformatics and to transfer our pipelines into the company that would enable Syncona’s new fully fledged company, Achilles, to develop bioinformatics algorithms to be able to predict clonal mutations, truncal mutations in tumours, essentially without the need for much human oversight. Our laboratory collaborated with Syncona and Achilles during that period to set things up.

Since then, my position’s mainly been based as a sort of scientific advisor. I’m on the Scientific Advisory Board that meets regularly throughout the year. We troubleshoot results. Sergio and I, and Karl, talk regularly about the progress of the company, what’s working, what’s not working, how we can make things better etc. and it’s been a huge amount of fun, I have to say. It’s been very rewarding, I’ve learnt a lot. I’ve also learnt that the commercial world is very different from the academic world and we can talk about that in a minute or two, which is fascinating in its own right. And I really have huge admiration for people who give up everything in a way and move from science into business and take these big risks, these giant leaps of faith, that are going to be required to advance patient care, because as we know, probably less – far less than 10% of biotech companies – will end up surviving.

 

00:18:36:15 – 00:18:50:12

Dr Richard Fagan

Yeah. So, I’ve been working with you for probably about ten years now. Maybe if not, a bit longer. And of course, when we set up a company, you have to look out for the commercial interests of that company.

 

00:18:50:12 – 00:18:50:22

Professor Charles Swanton

Oh, yeah.

 

00:18:50:22 – 00:19:48:09

Dr Richard Fagan

But you’ve also got to be able to carry on with your academic research at UCL, at the Crick etc. That in itself has brought some challenges regards to making sure that when we are looking to collaborate with other people using the intellectual property which was licensed into Achilles, we live up to our obligations with Achilles, but also allow you the academic freedom that you need.

Quite often, I will be speaking to the Crick, making sure that we’re all on board, and also working with CRUK to make sure that we don’t cross a line that we shouldn’t cross.

 

00:19:48:09 – 00:21:57:13

Professor Charles Swanton

Yeah. Absolutely. I made a decision very early on that whilst I wanted to be involved in setting up a company, and wanted to see what the other side was like and to experience the sort of commercial side, I didn’t want to jump ship completely and lose my academic job because I get so much enjoyment out of discovery science and being able to just pursue my own views, thoughts and ideas freely without the pressure of delivering on the bottom line, so to speak, and both UCL and CRUK were incredibly supportive of that, as was Achilles actually, to be fair.

I’ve been able to have just the right level of input into Achilles, I think it’s fair to say, and that’s enabled me to carry on my lab. But as you say, there have been some challenges and with three partners, CRUK, UCL and the Crick, it can become incredibly complicated when negotiating contracts, negotiating NTAs etc. with other organisations and institutions that want to partner with us.

I think this is all a big partnership. It has to be like a family in a way. Whilst we all have our differences and frustrations, and things may not be moving as fast as we want them to move occasionally, I think we all have known each other for long enough and we know each other well enough that the odd email pointing out problems in the pipeline and what have you is always taken extremely well and I’ve always found UCL Business a pleasure to work with in this domain. I really feel that they have done their best to look out for our academic interests, which was quite a surprise in retrospect because UCLB’s job is to create profit, not necessarily to look after the academic interests of an individual professor, but I really feel they have done that, as have CRUK and the Crick.

It’s been a tremendous journey, actually, and I think that whilst there have been difficulties along the way through nobody’s fault, I think this has been hugely illuminating and extremely rewarding.

 

00:21:58:11 – 00:22:13:09

Dr Richard Fagan

As you said, we set it up in 2016 with a 17 and a half million investment, then in 2019 we went on to raise 100 million in a series B oversubscribed.

 

00:22:13:10 – 00:22:59:12

Professor Charles Swanton

Very surprised. Incredibly surprised, actually. It all happened incredibly quickly. At the time, I thought that was a huge amount of money but it’s only in recent times I’ve realised how expensive it is to run a company and how expensive it is to run these clinical trials. You really need this much money in the bank to be able to do these clinical studies. Another good reason why commercialising our research was the only option if we wanted to see whether we were right or not. I could target neo-clonal antigens, arrest, the development of tumours, and I think that’s an incredibly important question to ask and one that we could not have addressed if we carried on just running our own laboratory exclusively for the next ten years. Achilles and the partnership with UCLB has been absolutely central to extending my laboratory in many ways.

 

00:23:03:20 – 00:23:15:21

Dr Richard Fagan

Yeah, and I agree. We can only take clinical trials so far here in the academic setting. Ultimately, they have to go into a commercial organisation to get it to market and patient benefit.

 

00:23:15:21 – 00:23:17:00

Professor Charles Swanton

Absolutely.

 

00:23:17:00 – 00:23:21:18

Dr Richard Fagan

We are a university, we’re not a drug company.

 

00:23:21:18 – 00:23:40:15

Professor Charles Swanton

If you think about it, the average programme grants at CRUK is about £2 million over five years. We needed £200 million to run these clinical studies, so there’s no way we could get 100 programme grants from one funder. It’s just totally impossible. Unfeasible.

 

00:23:41:01 – 00:23:55:17

Dr Richard Fagan

Yeah. That formed the basis for their public listing in April 2021 on Nasdaq and they raised 175 and a half million, which is just incredible.

 

00:23:52:05 – 00:24:00:20

Professor Charles Swanton

Astonishing. And this is all during the COVID pandemic as well, which made it even more extraordinary.

 

00:24:00:20 – 00:24:04:14

Dr Richard Fagan

Yeah. Yeah. And so, where is Achilles right now?

 

00:24:04:14 – 00:25:15:11

Professor Charles Swanton

Achilles is doing very well. We’re fortunate to have both Sergio and Karl deeply embedded in the company, so Sergio is their CSO and Karl is their CMO, and that makes a huge difference to both the development of the technology and also the implementation of that technology in the clinical setting. They’ve both been fantastic and- so, where are we? We are currently running first in man studies with a new dose schedule of a higher dose, just beginning to test. We’ve already seen some activity in lung cancer, which I’m delighted about. What next? Only time will tell. I think it’s relatively slow to treat patients because of the process. You need to find the right patient that fits the inclusion criteria. It’s not always as rapid recruitment as we would all might like, but then again, so does the preparation of the cell product – that takes time too. There is a combination of challenges here. Suffice to say, I think the company is doing exceptionally well. Iraj is a tremendous CEO and we are very excited to see the next set of data.

 

00:25:15:23 – 00:25:25:11

Dr Richard Fagan

Yeah, because I should’ve pointed out to the listeners, these are very complex treatments. They’re not a small molecule. I’m not saying small molecules aren’t complex, but this is a cell based therapy.

 

00:25:25:20 – 00:25:27:17

Professor Charles Swanton

That’s right. Sorry, I should have explained that.

 

00:25:27:17 – 00:25:36:10

Dr Richard Fagan

Yeah. Yeah. Very, very complex. Great. So, what’s next for Professor Charlie Swanton?

 

00:25:36:21 – 00:28:03:00

Professor Charles Swanton

Well, that’s a jolly good question. We’ve recently developed an interest in lung cancer in never smokers, principally to ask the question, ‘how does cancer start in never smokers?’ reasoning that prevention is better than cure. It’s very difficult to answer that question. Patients often ask me, ‘how did I develop lung cancer? I’m a never smoker, I exercise well, I eat well, but I developed lung cancer. The truth of the matter is that there are associations with the disease but no direct causation. One key association has always been in air pollution in lung cancer.

We set up a study about five years ago to look at that association in more detail and we developed some quite deep insights into this during lockdown through collaborations with Public Health England and others, showing a tight correlation between increasing levels of air pollution and risk of lung cancer in never smokers. Then, we exposed mice to air pollution and showed a dosage-dependent increase in the number of lung tumours in mice exposed to air pollution. But then the question is, ‘how does air pollution cause lung cancer?’ because what we found in these tumours from patients who had never smoked, there’s no increase in mutations, similar to what we see in smoking lung cancer. In smoking lung cancer, there’s a very high number of cancer mutations caused by smoking, but air pollution does not cause those mutations, so how is air pollution causing lung cancer?

What we found is air pollution is causing lung cancer through an inflammatory axis. That is, it’s stimulating a population of white cells called the macrophage to release a chemokine, a protein called interleukin-1 beta and that interleukin 1-beta transforms a progenitor cell in the lung called the alveolar type 2 cell into a cancer stem cell, only if it encodes an EGFR activating mutation.

So, there’s a combination of bad luck. The cell has to have an activating mutation and exposure to air pollution where the macrophage has to be exposed to air pollution to stimulate that mutant cell to form a tumour. This, I think, unravels a whole new area of how cancers initiate, independent of DNA mutations, and what’s fascinating about this is it turns out the majority of environmental carcinogens do not cause DNA mutations, so this may actually open the door to our understanding much more broadly of how environmental carcinogens cause cancer independent of cooling, causing DNA mutagenesis. We’re going to be studying a lot more of that subject over the next five years.

 

00:28:04:00 – 00:28:15:17

Dr Richard Fagan

Excellent. Well, I continue to be excited to work with you, Charlie, and we shall say thank you very much for coming in and speaking to our listeners, and thanks to the listeners.

 

00:28:15:17 – 00:28:22:10

Professor Charles Swanton

Well, a big thank you to you, Rick, for everything you’ve done and your team. You’ve been central to our success. I thank you so much and it’s been a pleasure talking to you today.