Gene editing saves girl dying from leukaemia in world first

For the first time ever, a person’s life has been saved by gene editing.

One-year-old Layla was dying from leukaemia after all conventional treatments failed. “We didn’t want to give up on our daughter, though, so we asked the doctors to try anything,” her mother Lisa said in a statement released by Great Ormond Street Hospital in London, where Layla (pictured above) was treated.

And they did. Layla’s doctors got permission to use an experimental form of gene therapy using genetically engineered immune cells from a donor. Within a month these cells had killed off all the cancerous cells in her bone marrow.

It is too soon to say she is cured, the team stressed at a press conference in London on 5 November. That will only become clear after a year or two. So far, though, she is doing well and there is no sign of the cancer returning. Other patients are already receiving the same treatment.

Experimental therapy

Layla was diagnosed with acute lymphoblastic leukaemia when she was just three months old, a disease in which cancerous stem cells in the bone marrow release vast numbers of immature immune cells into the blood. She was immediately taken to Great Ormond Street to start the standard treatment of chemotherapy followed by a bone marrow transplant to restore the immune system.

In older children, this treatment is usually successful, says Sujith Samarasinghe, a leukaemia specialist at the hospital and one of Layla’s doctors. But for children as young as Layla, the cure rates are only 25 per cent.

Layla was one of the unlucky ones. Cancerous cells were still detectable after the chemotherapy. Despite this, it was decided to go ahead with a bone marrow transplant. “We hoped for a graft-versus-leukaemia reaction,” says Paul Veys, head of bone marrow transplants at the hospital. This is where immune cells in the donor bone marrow attack the cancer – but this failed too.

Within two months, Layla had relapsed. “At this stage, it is usually hopeless,” says Veys. Her parents Ashleigh and Lisa were told nothing more could be done. But they insisted the doctors did not give up. So the team emailed Waseem Qasim of University College London, who is developing a form of gene therapy to treat cancer.

Cell attack

The basic idea is to remove immune cells from a patient’s body, genetically engineer them to attack cancerous cells and place them back in the body. Several human trials are already underway around world. Some trials involve adding a gene for a receptor called CAR19, which sits on the outside of the T-cells. This programs the T-cells to seek out and kill any cells with a protein called CD19 on their surface – which is found on the cells that cause acute lymphoblastic leukaemia.

But engineering bespoke T-cells for every cancer patient is not cheap. And in Layla’s case, it would not have worked because she didn’t have enough T-cells left to modify. “She was too small and too sick,” says Qasim.

Qasim’s team, however, has been developing “off-the-shelf” treatments, in which T-cells from a healthy donor are modified so they could potentially be given to hundreds of patients. Normally if T-cells from another person were injected into a recipient who was not a perfect match, they would recognise all of the recipient’s cells as foreign and attack them. To prevent this, Qasim’s team used gene editing to disable a gene in the donor cells that makes a receptor that recognises other cells as foreign.

Molecular scissors

Conventional gene therapy can only be used to add genes to DNA. But with gene editing, specific DNA sequences can be cut with “molecular scissors”, introducing mutations that disable a particular gene. Qasim’s molecular scissors were of a kind known as TALEN proteins.

But there was still another problem to overcome. The recipient’s immune system also recognises non-matched T-cells as foreign and will attack them. In leukaemia patients, this is not a problem because they are given drugs that destroy their immune system. Except, one of these drugs – an antibody – also destroys donor T-cells. So Qasim’s team also disabled a second gene in the donor T-cells, which made them invisible to the antibody.

At the time that Qasim was contacted by Layla’s doctors, his engineered T-cells, called UCART19 cells and developed in collaboration with New York biotech company Cellectis, had only ever been tested in mice. “It was scary to think the treatment had never been used in a human before,” said Layla’s father Ashleigh, “but there was no doubt we wanted to try the treatment. She was sick and in lots of pain, so we had to do something.” And it worked within weeks.

This is only the second time that gene-edited cells have been used in people. The first ever trial involved modifying T-cells in people with HIV to make them more resistant to the virus, although these participants were not in immediate danger of dying.

Chop and change

The molecular scissors used to disable genes do sometimes make cuts in the wrong place, which carries a small risk of causing adverse effects such as turning cells cancerous.

But after three months, Layla was given a second bone marrow transplant to restore her immune system. These healthy immune cells recognised the UCART19 cells as foreign and destroyed them, so Layla no longer has any genetically modified cells in her body.

Layla will continue to have regular tests until her doctors are sure the cancer is gone. “It is too early to say she is cured,” says Samarasinghe, but she is alive and well.

Cellectis plans to start full clinical trials early in 2016. Qasim says other patients in the UK are already being treated with these cells, although he would not reveal any details. The team will present the case study at the American Society of Hematology meeting in Florida in December.

We will have to wait for the results of those trials to be sure this was not a one-off, but if they are successful, it would be a huge step forward for treating leukaemia and other cancers, Qasim says. “It’s incredibly encouraging,” he says. “There are a whole bunch of other disorders we can now create fixes for.”

Read: “Cancer’s penicillin moment: Drugs that unleash the immune system“