Cancer cells don’t work alone.

They’re masters of disguise and manipulation, and they survive by fooling other cells with their tricks. Their act can even convince immune cells called macrophages, which are meant to help us recover from wounds and infections, to build barriers that protect tumours from treatments.

But treatments can work together, too.

That’s the idea behind a new “companion drug” developed by our researchers at King’s College London (KCL). It’s a daily pill designed to break down tumours’ immune barriers, so chemotherapy treatments can help more patients.

Now, the first lab study of the drug has shown that it boosts the effectiveness of chemotherapy in mouse models, making chemotherapy-resistant tumours vulnerable.

“We discovered that macrophages guard the tumour and can block effects of chemotherapy,” says Professor James Arnold, head of the Tumour Immunology Group at KCL and one of the co-leads of the research. “They’re acting as gatekeepers stopping cancer-fighting immune cells from coming in and supporting the treatment, but, by targeting the right pathway, we can open the door.”

Arnold and his colleagues, who we funded with the Medical Research Council, have now set up a company called Aethox Therapeutics to take their drug to clinical trials.

Breaking into the tumour microenvironment

The new drug, named KCL-HO-1i, has been almost 13 years in the making. 

Arnold first set up a lab to study the role of macrophages in and around tumours (in the tumour microenvironment) in the early 2010s. Early on, the team noticed that these “tumour-associated” macrophages produce a suspiciously high amount of an enzyme called heme oxygenase-1 (HO-1). They’ve been focusing on it ever since.

“It’s an enzyme that’s almost become part of the family,” Arnold says. “I’ve spent many sleepless nights trying to understand how it works.”

Those nights paid off. The research team discovered that HO-1 can shield tumours from the body’s defences.

“What we ended up finding was that these macrophages, and heme oxygenase-1, are sitting around blood vessels in the tumour and playing quite fundamental roles in regulating the immune response against cancer, which has major implications for the efficacy of chemotherapy,” explains Arnold.

That last part came as a bit of a surprise. We usually think of chemotherapy, which kills fast-dividing cells, separately from the immune response, which can target cells that don’t look like they belong. There’s another type of treatment, immunotherapy, specifically designed to help immune cells identify cancer cells and destroy them.

And yet, as they kept researching, Arnold’s team kept finding evidence that the most successful chemotherapies also seem to harness the immune response against cancer – primarily by activating potent cancer-killing cells called T cells. 

There’s more to find out about exactly why this happens, but we now know that when chemotherapies start killing tumour cells, they can prime T cells to start attacking the cancer too. It’s a one-two punch – but, to deliver the second part of it, T cells need to get inside the tumour. That’s the problem. Macrophages respond to different signals, and they know how to block.

“The macrophages think they’re meant to protect the cancer, so they make heme oxygenase-1 to keep T cells out,” says Arnold. “When we targeted the heme oxygenase-1 using KCL-HO-1i, we found that chemotherapy was much more effective – purely because it could generate a stronger immune response in the cancer.”

The immune system, evolution and cancer

Even though it’s one of the best-established ways to treat cancer, chemotherapy only really came to prominence in the 1960s. The problem the KCL team are addressing goes back much further. Our macrophages have been confused by millions of years of evolution.

For most of human history, most people have died before they got old. So, the immune system has developed to protect us from problems that are common at younger ages. In general, it can turn itself up to fight off infections, or it can turn itself down to help wounds heal.

Now, as we’re living much longer, we’re more likely to face situations where neither of those options is quite right.

“The immune system just hasn’t got that third arm to deal with a disease like cancer,” says Arnold.

Unlike the pathogens that cause infections, cancer cells don’t come from outside the body. They’re our own cells growing and dividing uncontrollably, and every division gives them a chance to evolve a new disguise.

To macrophages, then, a tumour that’s producing lots of new cells can look more like a wound that’s trying to heal than a threat that needs dealing with. And one of the ways macrophages support wound healing is by closing parts of the body off from T cells, which can interrupt the healing process. They make heme oxygenase-1 to give wounded tissue space and time to recover, but it can end up helping cancers grow and spread.

“The immune system is basically not understanding the site it’s in, and it ends up doing something catastrophically inappropriate,” Arnold says. “Our therapeutic basically rewires that microenvironment to now allow these T cells in. It’s taking away the tumour’s defences.”

From a discovery to a drug

Arnold’s lab was able to identify an age-old problem, but turning a discovery into a new cancer drug is a different type of challenge

Helpfully, they didn’t have to start entirely from scratch. Other researchers are already testing a heme oxygenase-1 blocker as a treatment for jaundice in newborns. From that, the team knew that drugs could be designed to safely and effectively target this cancer defence system. Still, the jaundice treatment is designed to be a one-time infusion in hospital. A chemotherapy companion drug would need to be modified to make it easier to use repeatedly.

Enter Arnold’s KCL colleagues James Spicer, Professor of Experimental Cancer Medicine, and Miraz Rahman, Professor of Medicinal Chemistry.

Using Rahman’s knowledge of chemistry and Spicer’s clinical expertise, the team developed KCL-HO-1i, a new drug that can be given as a daily pill. That means people receiving chemotherapy could take it at home between treatment sessions. It has the potential to make hospital treatments more effective without requiring any more time in hospital.

Coming together to improve chemotherapy

“This is all thanks to so much teamwork across different disciplines,” says Arnold. “We realised this could be a new drug opportunity for people with cancer, and that motivated so many talented individuals, like Dr Meriem Bahri, the lead author of our paper, to get us to this point. The paper really brings all this work together, so this is a lovely position to be in.”

The next stage, which Arnold thinks should be possible within two years once funding is acquired, is to start testing the new drug in the clinic alongside established chemotherapies.

“There’s a whole array of chemotherapeutic drugs that are approved and used widely,” he says. “We’re calling this a companion drug because, in theory, you could give it to any patient receiving chemotherapy and it could allow for them to have a better response.

“First, we’ll just be working with standard doses of a chemotherapy drug called gemcitabine, but if we’re able to boost responses, it could mean that doctors could also use milder chemotherapy treatment plans.”

It’s evolution, applied to some of our most common cancer treatments.

“We’ve got a lot to explore,” Arnold says, “but in future there could be a range of different combination cancer treatments that could include KCL-HO-1i.”

Tim