Reprogramming the body’s immune cells to fight cancer tumours saves lives, but it can backfire. The treatment, called immunotherapy, can be deadly if these reprogrammed cells attack the wrong target inside a patient’s body. So researchers at the University of California in San Francisco, led by Wendell Lim, have designed a molecular safety switch to keep them on a tight leash.
Richard Boyd, an immunologist at Melbourne’s Monash University, calls the idea “brilliant. The science is very slick.”
In 2013, immunotherapy rescued seven-year-old Emma Whitehead. She was diagnosed with leukaemia at age five and had relapsed after multiple rounds of chemotherapy. Her doctors, who were running out of options, put her forward for an experimental therapy.
Cancer kills because it can be very good at evading the immune system. Whitehead’s doctors extracted some of her T cells (a type of white blood cell essential for human immunity), genetically engineered them to recognise her cancer and then re-injected them into her body.
These engineered cells are known as chimeric antigen receptor (CAR) T cells. They are equipped with precision tumour-targeting equipment, consisting of two main parts. The first is a protein that works somewhat like a barcode scanner – it can recognise cancer cells by identifying the proteins and sugars found on their surface. The scanner is hooked up to the second component – a switchboard inside the cell that, once it receives an alarm signal from the scanner, puts the cell on the attack.
Like T cells, CAR-T cells can roam the body for months or longer, allowing them to make a sustained attack on cancer cells. But their longevity also poses a problem if the treatment goes awry. “The problem is that you put them in and then you can’t do anything,” says Lim.
When T cells attack, they release small molecules called cytokines – messengers that recruit more immune cells. But if the immune response triggered by the CAR-T cells is too powerful, the resulting “cytokine storm” can cause potentially fatal fevers. Emma Whitehead nearly died from the fevers that followed her treatment, before making a full recovery.
Another potential problem is “cross reactivity”. This occurs when a normal healthy cell produces a protein or sugar that is similar to the cancer markers the CAR-T cells have been primed to recognise. This can cause the CAR-T cells to attack normal tissues by mistake.
So Lim’s team designed a control switch.
“It’s really pretty simple,” he says. They genetically engineered CAR-T cells to carry the barcode scanner and switchboard as two separate parts, so they can scan and stick to the target but can’t attack the cell. Only when a special glue is added – in this case, a drug called rapalog – do the parts snap together, completing the circuit and allowing the cell to launch an offensive. By withdrawing the drug doctors can switch off the T cells if things go awry.
Lim’s team found the “switchable” CAR-T cells only killed cancer cells in mice when the mice were also given rapalog. In a petri dish, they also showed they could use rapalog to dial the CAR-T cells up or down like a dimmer switch. The more rapalog, the more cancer cells died.
Doctors could one day inject these switchable CAR-T cells to let them roll around the body and “hope they stick to cancer cells like flies on a cake,” as Boyd puts it. Doctors could then slowly ramp up their cancer-killing power by increasing the rapalog dose, while keeping a close eye on any side effects. Should they see excessive fever or signs of cross-reactivity, doctors could stop and the T cells would become inactive. Rapalog is excreted by the body after only a few hours.
“We’re very excited,” says Lim. “We weren’t sure if we could get this kind of tuneable control but we’ve really shown we can. And that could really help move this therapy forward – right now.”
Lim’s next step is to find a better, longer-lasting glue so an effective dose can be sustained. Rapalog is excreted a little too fast for a practical treatment.
Boyd says he is optimistic about the place of CAR-T cells in a wide range of new cancer therapies: “The immune system is remarkably sophisticated and it’s going to be the smartest way to treat disease.”
