The trans-Atlantic quest to find a winning combination of cancer drugs

In a corner of our head office, sits a team of six people. And since 2010, they’ve been quietly, but resolutely helping to develop new treatment options for cancer patients.

This is the team behind the Combinations Alliance, one of several projects run through the Experimental Cancer Medicine Centre network (ECMC).

The Alliance brings together UK researchers and drug companies from around the world to explore new combinations of cancer drugs. By combining multiple drugs in a single clinical trial, they can test whether or not the combination is better at treating cancer than the standard treatment available.

It’s a unique scheme that’s increasing treatment options for patients, and tackling drug resistance – arguably one of the biggest problems in cancer treatment.

And a new deal signed today will see a combination of drugs tested in mesothelioma, non-small cell lung and pancreatic cancers for the first time.

A match made in heaven

The Combinations Alliance works very much like a match-making agency for researchers and drug companies. The goal of developing these relationships is to hopefully launch clinical trials that test promising new combinations of drugs to treat different types of cancer.

The Combinations Alliance focuses on therapies that wouldn’t progress without our support

– Dr Ian Walker, director of clinical research and strategic partnerships at Cancer Research UK

So why exactly was the Combinations Alliance set up? Surely companies have thought of collaborating in this way before? Well, this can be tricky. Each company has a different way of working.

So it’s often much simpler for many drug companies to go it alone. But they’re beginning to see how limiting this approach is. Despite huge resources, it’s simply impossible for any company to test every combination of drugs.

But our Combinations Alliance offers a structured way for drug companies – alongside researchers – to work together. And, ultimately, get better treatments to patients, sooner.

How the initiative works

Our team begins by meeting a drug company that’s developing promising cancer drugs. Researchers within our ECMC network then consider which drugs could work together in a clinical trial.

So far 10 partners have signed onto the scheme, with many more set to join in the next few years.

Alternatively, the team receives an idea from a researcher to combine two or more drugs, which aren’t necessarily owned by an existing Alliance partner.

The team then approaches the company who owns that drug for permission to use it in a clinical trial.

Most trials to date have tested a single company’s experimental new drug in combination with a drug that’s already available as standard treatment for patients – or with radiotherapy. There have also been a few trials involving two new experimental drugs owned by the same company.

But for the first time today, the Alliance has brought together two drug companies to test an exciting combination of two drugs: one an immunotherapy drug, the other a so-called ‘targeted’ cancer treatment.

And it’s thanks to the inspirational idea of two researchers – Dr Stefan Symeonides, at the University of Edinburgh, and Professor Dean Fennell, at the University of Leicester.

The bright idea

Together, Symeonides and Fennell designed the combination clinical trial that will be managed at Cancer Research UK’s Clinical Trials Unit in Glasgow. It’s an idea that’s based on work from another of our researchers, Professor Margaret Frame, at the University of Edinburgh.

But designing the trial was only one part of the story. To run it, Symeonides and Fennell needed approval to use the drugs, which are owned and made by two different drug companies.

Let’s step back a couple of years to see how the team made this happen.

Finding a drug that works

Back in 2014, a small drug company based just north of New Jersey in Massachusetts in the US, called Verastem, got in touch with the team.

They’re an existing Alliance partner, introduced by Fennell, and have been working on a drug called VS-6063, which switches off a molecule called FAK that’s found inside cells.

The drug works by stopping FAK forming a cellular barrier that blocks the body’s immune system.

But once the barrier is down, how can the body attack the tumour itself?

Symeonides and Fennell believe that Verastem’s drug could work better with another drug that boosts the immune system and the army of cells it unleashes. And they had a good idea of what could work.

The final piece of the jigsaw

Fast-forward to 2015 and the answer to this problem could be found back in New Jersey at a different drug company, MSD, which is one of the largest drug companies in the world.

Although not an Alliance partner at the time, they were in talks with the team, and agreed to let Symeonides and Fennell use an immunotherapy drug called pembrolizumab (Keytruda) for the trial. Pembrolizumab is designed to target an antenna-like molecule that sticks out on the surface of certain forms of immune cell.

Normally, this ‘antenna’ – called the programmed cell death 1 (PD-1) receptor – picks up signals, preventing the immune system from inappropriately reacting to certain triggers. But in people with some types of cancer, the same antenna receives signals stopping the body’s immune system from recognising the cancer cells, allowing the tumour to remain undetected.

Pembrolizumab blocks these signals, jumpstarting the immune system into recognising, targeting and destroying tumours.

• Watch an animation showing how these immunotherapy drugs work

Symeonides and Fennell thought that once the barrier surrounding the cancer cells has been taken down by Verastem’s drug, MSD’s pembrolizumab could then activate cancer-killing immune cells to attack the tumour.

Pembrolizumab on its own has shown promise in treating bladder, melanoma, kidney and non-small cell lung cancer, but it’s had little effect in people with other types of cancer. So this would be a chance to see if the drug could treat more types than originally thought.

Fast-forward to today, and both Verastem and MSD have agreed to the use of their drugs in combination for the first time in a clinical trial. The trial will look at whether the two drugs can be used safely together, and test whether the combination is better for treating people with mesothelioma, non-small cell lung and pancreatic cancers – all of which have very low survival.

What’s next?

By working with UK researchers, and drug companies around the world, there are still many more trial ideas to be explored. These aren’t limited to those involving drug combinations, but using radiotherapy and surgery too. It’s just about getting the right people with the right drugs to start working together.

What the Combinations Alliance team have achieved to date is no small feat. They’re responsible for pulling in some of the best science and making sure that these trials are run in the UK (MSD and Verastem are both American companies and logistically, it’d be a lot easier for them to run the trial in the US), so that patients here can benefit first.

It’s early days, the trial isn’t recruiting patients yet – but it should be up and running later this year.

So far 356 people have taken part in a Combinations Alliance trial and have been given another shot at tackling cancer that’s come back.

One trial in particular was so promising that it’s now progressed to the next step, a larger clinical to see how well it actually works in a larger number of people.

The Combinations Alliance team might be sitting quietly in the corner in our office, but make no mistake, they’re causing quite the stir outside it.

Amille