Experimental CRISPR technique has promise against aggressive leukaemia

A 13-year-old girl whose leukaemia had not responded to other treatments now has no detectable cancer cells after receiving a dose of immune cells that were genetically edited to attack the cancer

By Michael Le Page

A teenager with aggressive leukaemia now has no detectable cancer cells after becoming the first person to receive a treatment involving a new kind of CRISPR called base editing. However, it will not be clear for some years whether she will remain free of the condition.

The 13-year-old girl, called Alyssa, hadn’t responded to other treatments. As part of a trial, she received a dose of immune cells from a donor that had been modified to attack the cancer. Twenty-eight days later, tests revealed she was in remission.

“This is quite remarkable, although it is still a preliminary result, which needs to be monitored and confirmed over the next few months,” said Robert Chiesa, one of the doctors treating Alyssa, in a statement released by Great Ormond Street Hospital in London.

Leukaemia is caused by immune cells in the bone marrow multiplying out of control. It is usually treated by killing all bone marrow cells with chemotherapy and then replacing the bone marrow with a transplant. This is successful in most cases. If it fails, doctors can try an approach known as CAR-T therapy.

This involves adding a gene to a type of immune cell known as a T cell that causes it to seek out and destroy cancerous cells. The modified cells are known as CAR-T cells.

Initially, all CAR-T treatments involved removing a person’s own T cells, modifying them and replacing them in that individual. If T cells from another person are used, they attack every cell in the recipient’s body. This personalised approach is extremely expensive and often it isn’t possible to obtain enough T cells to create CAR-T cells when an individual is very ill.

To overcome these drawbacks, different groups of doctors have been gene-editing T cells so that those from a single donor can be used to treat many people. In 2015, Waseem Qasim at the University College London Great Ormond Street Institute of Child Health and his colleagues were the first to try this, successfully treating a 1-year-old girl called Layla for whom all other treatments had failed.

This approach is now approved in the UK for people with leukaemia that involves so-called B cells, another type of immune cell. Alyssa’s leukaemia was caused by T cells and if CAR-T cells are modified to attack other T cells, they just kill each other.

Qasim’s team therefore made an additional change to the CAR-T cells by knocking out the gene for the receptor that identifies them as T cells. Creating these CAR-T cells requires making four gene edits at once, which leads to yet another problem.

Conventional gene editing involves cutting DNA strands and relying on a cell’s repair machinery to rejoin the ends. When lots of cuts are made at once, cells sometimes die. Even if they survive, the wrong ends can be put back together, leading to major mutations that can potentially make the cells cancerous. The more gene edits that are made, the more likely this is to occur.

So Qasim and his team instead used a modified form of the CRISPR gene-editing protein that doesn’t cut DNA, but instead changes one DNA letter to another, a technique known as base editing. Alyssa is the first person ever to be treated with base-edited CAR-T cells.

“We are very pleased that she is in remission for the first time,” says Qasim.

“Base editing is particularly promising, not just in this case but for genetic disorders,” says Robin Lovell-Badge at the Francis Crick Institute in London. Many other treatments involving CRISPR base editing are being developed, he says.

The only other existing trial that involves this base-editing technique got underway in New Zealand in July this year. A company called Verve Therapeutics hopes to show this approach can treat an inherited genetic condition that causes dangerously high cholesterol levels.