Beating cancer with superCARs

By Nisharnthi Duggan

Microscopic image of green, red and blue killer T cells surrounding a blue cancer cell against a black background.

When you hear the word "car", you might think of family road trips, the morning commute or Formula 1 racing.

But to scientists, CARs are something very different.

They're tiny, engineered molecules that can help immune cells chase down cancer and destroy it.

They sit on modified immune cells known as CAR T-cells, the driving force behind a type of immunotherapy that’s transforming cancer treatment.

Doctors already use CAR T-cell therapy to treat certain blood cancers. For some people, it’s succeeded where every other treatment has failed.

But researchers believe CAR T-cells are still only in first gear.

Across the UK and beyond, scientists are working to make these treatments more powerful, more durable and accessible to more patients.

And for children and young people with cancer, they could provide an urgently needed new route to better treatments.

Why do children and young people need new treatments?

Today's treatments, including chemotherapy and radiotherapy, help many children survive their disease. But these treatments were originally developed for adults and can be particularly difficult for growing bodies to endure. Cancer in children and young people is different from cancer in adults.

Many adult cancers develop over decades as cells gradually accumulate genetic changes. Children’s and young people’s cancers often arise for very different biological reasons, many of which researchers are still working to understand.

Even when treatment is successful, many children and young patients are left with lifelong side effects.

And for some, no effective treatment options even exist.

For the more than 4,200 of children and young people affected by cancer every year in the UK, more needs to be done.

We urgently need safer, more effective treatments. CAR T-cell therapy could be part of the solution.

What is CAR T-cell therapy?

T cells are immune cells that patrol the body, searching for threats.

They're great at finding viruses and infections, because those invaders are clearly foreign. Cancer is trickier. Cancer cells are our own cells gone wrong, so T-cells can’t always spot them.

CAR T-cell therapy gives T-cells a new set of directions.

CAR stands for chimeric antigen receptor; it’s a tiny molecule that’s programmed by scientists to recognise a certain feature on a cancer cell.

In CAR T-cell therapy, scientists collect some of a patient's T-cells and equip them with a CAR.

Once these upgraded cells are returned to the patient's body, they can seek out and attack cancer.

This cellular "CAR chase" has already transformed treatment for some children and young people.

But despite these remarkable successes, the field is still far from its destination.

At the moment, CAR T-cell therapy is only approved for some blood cancers. Researchers believe the technology could do much more, but several challenges still stand in the way.

Some CAR T-cells lose momentum over time and stop working effectively.

Then there’s the difficulty of treating solid tumours. Unlike blood cancers, they create environments that can block immune cells from reaching their target.

But perhaps one of the greatest challenges is operational. Because CAR T-cells are made individually for each patient, producing them can be complex, expensive and time-consuming.

Now, our researchers are now tackling each of these challenges.

Microscopic image of blue T cell against black background.

Credit: NIAID

Better navigation, longer journeys

For CAR T-cells, keeping cancer at bay can be an endurance event rather than a drag race.

Some modified cells remain active for years, providing long-term protection against the disease. Others become exhausted and can’t keep up the chase. When that happens, cancer can return.

Professor Sara Ghorashian, whose work we support at Great Ormond Street Hospital and University College London, wants to understand why.

Her team are digging into the mechanics of the most successful CAR T-cells, and studying what makes them so durable in treating blood cancers.

They’ve already identified a unique set of genes, nicknamed the ‘Persist-sig’, which appears to help CAR T-cells persist in their chase.

But now they need to understand why. It’s not just about those genes being present in CAR T-cells, it’s about how they’re switched on.

"We're not talking about inherited genetic differences between people's T-cells," says Ghorashian. "We're talking about the current biological status of that CAR T-cell and how it got there, which is programmed by the minute-by-minute activation of genes in the cell."

This complex gene switching process means that it’s not as simple as programming these persist-sig genes into all their CAR T-cell treatments.

You can paint a car red and slap a badge on it, but that doesn’t make it a Ferrari. It’s about how the car was made and how all its different parts work together.

"It's important to know what those genes do, but they might not actually be relevant. They might just be a marker of the programming rather than a direct consequence of that programming," Ghorashian explains.

Her team are now working backwards to understand the biological processes that create these highly persistent cells in the first place.

"In order to be able to reliably and faithfully produce CAR T-cells with these persistent features, I will unpick the programming steps that have enabled them to attain this status. Hopefully we will then know more about how we can actively make CAR T cells last in all patients.”

If they succeed, future CAR T-cells could stay on the road for longer, helping more children and young people remain cancer-free.

But endurance is only one challenge.

Clumps of cells under a microscope — CAR T-cells growing in culture. Credit: Professor Sara Ghorasian.

CAR T-cells growing in culture. Credit: Professor Sara Ghorasian.

Professor Sara Ghorashian