The EPSRC Interdisciplinary Research Collaboration (IRC) in Targeted Delivery for Hard-to-Treat Cancers ended in 2024. Here, George Malliaras, Prince Philip Professor of Technology at the University of Cambridge and Director of the IRC, talks about its achievements, the ingredients of its success and the future.
Why did the IRC focus on three different cancers and three new drug delivery technologies?
Survival rates for most cancers have doubled over the last 40 years, with 50% of patients surviving 10 or more years. But for hard-to-treat cancers such as glioblastoma, mesothelioma and pancreatic cancer, survival rates remain below 14%. This is because although doctors have effective anti-cancer drugs, it is difficult to get these drugs to where they need to be. Certain cancers have their own defence mechanisms. As well as being difficult to fully remove by surgery, brain tumours such as glioblastoma are also protected from conventional chemotherapy by the blood-brain barrier. Pancreatic and mesothelioma tumours have a stroma, a fibrous outer layer making it difficult for drugs to reach the cancer. The key problem, therefore, is one of bioavailability; to treat these cancers more effectively, we need new ways of delivering drugs to their targets.
What was the IRC’s goal?
The IRC was very ambitious programme, bringing together chemists, physicists and biomedical researchers with manufacturing experts, clinicians and patient groups. Working with 20 principal investigators across nine UK universities, our shared goal was to develop new technologies capable of delivering high levels of drugs to these cancers, paving the way for human trials and – ultimately – improving survival rates for patients with these cancers. We selected three technologies for the following reasons: all were at early stages of development and needed to be moved forward; over the six year programme all could be progressed to – or close to – first-in-human trials; and together they formed a complete portfolio enabling us to attack these three different scenarios.
What are these new technologies and how can they overcome the cancers’ defences?
The IRC put together a portfolio of three technologies: an implantable device capable of delivering drugs intratumorally; a special kind of drug-containing gel that could be used after surgical removal of a tumour; and a systemically-delivered vehicle capable of targeting tumours anywhere in the body and releasing its drug there, which would be useful for metastatic cancer. The first technology, an implantable device to deliver drugs, has not been widely used before. The mechanism we leveraged was unique, which enabled us to patent the concept. The second is a dynamic hydrogel which changes its nature under shear forces. These are forces which act parallel to a surface, causing it to deform or slide. When you load a syringe with this hydrogel, the force of the plunger makes the gel fluid enough to be deposited onto the margins of a tumour and then re-jellify. The third technology we developed is based on metal organic frameworks. These MOFs can encapsulate very large amounts of a drug, as well as drugs which are difficult to encapsulate.
Tell me about the different disciplines and stakeholders in the IRC?
The IRC was the quintessential interdisciplinary programme. It’s extremely important that ‘clinical pull’ is matched by ‘technology push’. As an engineer, I'm very close to the latter. We have lots of hammers, and we are always looking for nails, but over the years I’ve discovered that this isn’t the best way to operate. The technology push must be matched early-on by a clinical pull. That’s why I have embedded clinicians in my group. The challenge is to find ideas that excite both sides; these are rare but they are the only ones worth pursuing. Most ideas engineers come up with are met with skepticism from the medical community, either because they do not meet an existing need or they solve a problem that doesn't exist. Conversely, clinicians’ ideas can be either too boring to pursue or physically impossible given the state of technology.
Leading a multidisciplinary, multi-centre programme is challenging. How did you approach this?
At the start of the IRC I was new to Cambridge and this was a major advantage. Because I was free from existing alliances and collaborations in the UK, I could take a fresh look, focus on what was new and exciting, and recruit the best people. My leadership style is simple – get the best people and let them do their job. It's how I run my research group, and how I led the IRC, and they really delivered. Of course, challenges and issues arise. When they do, it’s a case of listening and making the right decisions.
How did the IRC evolve over the six years?
When the IRC began, it was a consortium of 16 principal investigators working across five universities, Cambridge, Imperial, UCL, Glasgow and Birmingham. By 2024, it had grown to 20 principal investigators across nine universities, including Nottingham, Leeds, Liverpool and Strathclyde. During a six-year programme, things change and needs evolve. The way the IRC was funded meant it was agile and responsive. EPSRC deserves much credit for this. They asked us to reserve 10% of the funding to add new teams as and when required. It’s an excellent approach and it was so successful that I have now adopted it for all my large grant proposals. During a six-year programme things change and needs evolve. It’s a mechanism I would advocate for other large grants with long-term ambitions.
What are the IRC’s key achievements?
By the end of the IRC in late 2024 we had reached the stage of looking into manufacturing at GMP (good manufacturing practice) quality, the precursor to moving into clinical trials. The pre-clinical work is largely complete and the next step is manufacturing. Before the IRC started, EPSRC asked me what success would look like. I told them that if I returned after six years and asked for more funding to advance these technologies a bit further down the road – that would be failure. Our goal was to take these technologies beyond technology readiness level 3 (TRL3). TRLs are a way of measuring progress by assessing a technology’s maturity and was developed by NASA for space exploration. Readiness moves from basic principles (TRL1) to operation (TRL9). TRL5 is usually when you transition technology into industry. Our aim was to take these technologies beyond EPSRC’s remit, which spans TRL1 to TRL3. By the end of the IRC we were well beyond this, so the IRC has been a major success.
Where we are with each of the three technologies?
Professor Oren Scherman is pursuing GMP manufacturing for the hydrogels. For the implantable devices we have patented the technology and are looking at a spin out or licensing. And for the particles, there is already a company pushing for commercialisation of the technology.
What about the IRC’s wider lessons and legacies?
In medical technology, an infinitesimally small fraction of devices developed by universities successfully transition to industry. We need to do more to maximise this. How we nurture nascent technology from academia to industry is a key question for me at the moment. The first three stages in the chain of technology translation – from idea to proof of concept – currently happen in universities. After this, technologies move from academia to industry, because of the funding and expertise required. But whether this is the best stage for universities to wave goodbye to spinouts, or we should incubate spinouts for longer is a crucial question. Large companies may be reticent and risk averse when it comes to new technology, so releasing spinouts into the wild prematurely may not be the best idea. There is a better way of doing this. Sheltering spinouts from the elements would increase their chances of success. Universities like Cambridge could support spinouts for longer, and provide GMP facilities, for example. This is a pet project of mine.
What were the IRC’s main challenges, and why was involving patients, academics and clinicians so important?
The IRC faced two main challenges. The first involved the modes of delivery for each device. That’s why early in the programme, we sought feedback from patients to clarify delivery scenarios. For the implantable, for example, we considered two extremes. The first was implanting the device, delivering a mega dose of drug, then removing the implant and sending the patient home. The second involved implanting the device plus a small port more permanently, with the patient attending outpatients at regular intervals for a dose of chemotherapy to be delivered. While patients preferred the first scenario, clinicians told us only the second would work. These discussions featured regularly within the IRC and were very educational for everyone. The IRC’s second challenge was the choice of drugs. Clinicians urged us to use existing chemotherapies – drugs they knew well and used routinely in the clinic – and focus on developing new delivery technologies. They felt this would be more likely to succeed and facilitate clinical trials. The pharmaceutical industry felt differently. They pointed out that if we also used the new molecules they were developing, they would have greater incentive to invest. These conversations shaped our thinking and we opted for a twin-track approach.
Now that the IRC has officially ended, what happens next?
In 2023, a year before the IRC ended, we began discussing splitting the three technologies to enable each to follow its own path. The IRC always wanted to explore synergies between the three technologies. All three were at a very early stage, and all three faced similar issues. But as they matured, they began to diverge. By the end of the programme we succeeded in reaching the point where there was no further synergy between the MOFs, hydrogels and implantable devices.
How did the IRC impact the people involved?
Recruiting good people and letting them do their thing worked really well. We had a very good management board which met regularly, and the climate was excellent. Pastoral care of postdocs was a key priority. Postdocs hosted each other between labs through pizza and seminars, and it made for a very happy cohort. During the six years of the IRC, we had around 10 postdocs at any one time. Each stayed for two or three years so each post had two or three postdocs over the course of the programme. New postdocs integrated well into the group and when they left, they did very well, which is a key indicator of success.
What did postdocs gain from being part of the IRC?
It takes the continuum of stakeholders to develop medical devices. The IRC involved engineers and clinicians, patients and their advocates, regulators and ethicists, and it's important to engage with them at an early stage. Working with diverse stakeholders was hugely beneficial for the IRC’s postdocs. They gained invaluable ‘soft’ skills and networks as well as scientific skills. I often tell people that if there's one thing they learn from me, it’s to engage with as many stakeholders as early as possible. This was part of the IRC’s DNA from the outset and is part of EPSRC’s approach too.
What has been personally most satisfying about the IRC?
Seeing the technologies develop, and sensing that there was some healthy competition between the three technologies, was something I enjoyed very much. And being part of a large, long-term programme was hugely rewarding.
In a 2021 IRC blog you argued for long-term funding, particularly for translational research, why is that so important?
There are few sources of funding that provide this continuity, yet it’s essential to maintaining expertise within a project. Typically, projects are funded via a succession of grants, and gaps between grants result in the loss of expertise. Longer-term contracts are key to attracting the world’s best postdocs as well as building sustainable collaborations.
What were the key ingredients for the IRC’s success?
I believe that good things happen when you bring the right people together in the right environment. It’s what enables researchers to thrive. This underpinned the IRC and it’s how I work in my group. Unhappiness arises when you micromanage, when critical components are missing, and when people feel unable to advance their work or their careers. When I was young and starting my academic group in New York, I was very involved in the social life of the group, which had great collaborative culture. Once I got married and had children this changed, but my group remains happy despite my being less involved socially. My conclusion is that group spirit establishes itself naturally, provided you don’t damage it. It’s all about getting good people, providing them with the right environment and empowering them to do their best. Young scientists need to see a clear runway ahead of them and feel equipped for their careers to take off. There’s noting more frustrating than having obstacles thrown in their way.
What happens next? You talked about applying for talk about funding for GMP?
In 2023, a year before the end of the IRC we won some funding through the Biomedical Research Centre. We are now troubleshooting things that are a bit further down the TRL states, for example, connections. How do you connect the device to external electronics? What external electronics should we use? At the same time we're looking for commercialisation via licensing or spin out.
Where do hope these delivery devices will be in another six years?
As an academic group, we continue to explore the use of technology in different contexts. I hope that the device work will have transitioned to the commercial sphere and hopefully be applied in the clinic.
