WHAT comes next? Last week, it was announced that a 1-year-old girl called Layla has been saved from leukaemia by an experimental gene therapy. It was used as a last resort after all other treatments had failed.

It’s too early to know whether Layla is free of cancer, or if the technique that saved her will work for others. But it is clear that gene editing is set to make an existing method of tackling cancer – genetically engineering immune cells to kill cancer cells – even more powerful and widely available.

“There are lots of genetic tricks we can exploit to make the cells more specific and more potent,” says Adrian Thrasher, who heads the gene therapy programme at Great Ormond Street Hospital in London, where Layla was treated.


“There are lots of genetic tricks we can exploit to make immune cells more specific and potent”

Our immune systems play a vital role in suppressing cancers. There are immune cells called T-cells, for instance, that travel around the body seeking and destroying abnormal-looking cells that may be infected or turning cancerous. They detect these cells with the help of protein receptors on their surface.

It is usually only when cancers manage to evade these hunters that they become dangerous. And cancers have some clever tricks to do this. For example, T-cells have a receptor on their surface called PD-1, which acts as an off switch. It is used to stop cells becoming overactive and running amok. Many cancers evolve ways of flicking the PD-1 switch and deactivating any T-cells that try to attack them.

Many of the most promising new cancer treatments involve boosting the immune response. For instance, a new generation of drugs – called PD1 inhibitors – that stop cancers turning off T-cells are producing good results when combined with other therapies.

Another encouraging approach is to genetically engineer T-cells to target cancers. Cancer cells often have proteins on their surface seldom found on healthy cells. T-cells can be programmed to recognise these by giving them genes for tailor-made receptors called chimeric antigen receptors (CARs). Biologists first began work on CARs in the 1980s, but it is only in the past few years that human trials have begun – and some results have been dramatic.

In one trial involving 53 children with acute lymphoblastic leukaemia – the disease that Layla had – for whom conventional therapies had not worked, 29 are still in remission months or years after treatment. There are now 77 trials of CAR T-cells around the world, for treating several different cancers of the blood.

It is not a miracle cure, of course. CAR T-cells can cause adverse reactions by overstimulating the immune system, particularly in adults. Cancer cells can evolve to dodge the T-cells, by no longer expressing the target protein.

Another issue is that a patient’s T-cells have to be removed, genetically modified and replaced. If T-cells from a donor are used, the donor cells will view all of the patients’ cells as foreign and attack them. This makes the treatment expensive – and in some cases, like Layla’s, doctors can’t get enough T-cells to modify. She was too small and sick.

This is where gene editing comes in. With conventional gene therapy, it is only possible to add genes. With gene editing, though, genes can also be disabled – opening up new, cheaper, possibilities.

The Great Ormond Street team was able to use donor T-cells to treat Layla because in addition to the CAR gene, they used gene editing to disable the gene for the protein that recognises other cells as foreign, thereby preventing the donor cells from attacking Layla’s healthy cells.

The result, at least in this one case, was spectacular. “It’s incredibly encouraging,” says Waseem Qasim of University College London, who helped to develop the treatment. “There are a whole bunch of other disorders we can now create fixes for.”

The aim of this work is to develop “off the shelf” CAR T-cell therapies, so that hundreds of people can be treated with the same batch of cells.

Even so, in many cases there is yet another hurdle to overcome, because the patient’s own immune system will see the donor T-cells as foreign and kill them. This was not an issue with Layla, because her immune system had been wiped out by the treatments she was given.

So Carl June of the University of Pennsylvania in Philadelphia has gone further to allow the therapy to work in other people. His team has used CRISPR gene editing to also disable the gene for the HLA proteins that mark a donor T-cell as foreign, reducing the chances of the recipient’s immune system attacking the donor cells.

Permanently on

June’s team has also disabled the gene that makes the PD1 receptor in the T-cells. In other words, the group removed the off switch, so the cancers can’t use it to deactivate the CAR T-cells. The cells have been successfully tested in mice with a form of leukaemia, the team will tell a meeting of the American Society of Hematology in December.

June’s work was funded by healthcare giant Novartis, one of several companies developing the technology. Novartis hopes that standard CAR T-cell treatments will be approved in the US in 2017. But it may be many more years before off-the-shelf T-cells created with gene editing get approval, says Usman Azam, head of cell and gene therapies at Novartis.

One question is safety: the molecular scissors used to edit genes sometimes make cuts in the wrong place. These “off-target” effects could in theory have rare adverse effects such as turning cells cancerous.

The biggest question is whether this approach will also work against solid tumours. These are harder to attack than blood cancers like leukaemia, not least because they contain many cell types. So far it does not appear that CAR T-cells alone will get rid of solid tumours. But they may work well as part of a combination of therapies, says Azam.

(Image: Sharon Lees/GOSH)

This article appeared in print under the headline “Layla’s gene-editing legacy”