Experimental CRISPR technique shows promise against aggressive leukemia

A 13-year-old girl whose leukemia hadn’t responded to other treatments has no detectable cancer cells after being given a dose of immune cells genetically modified to attack the cancer


December 11, 2022

Alyssa the day she received cell therapy edited in May

Alyssa on the day she received genetically modified cell therapy in May

Great Ormond Street Hospital for Children

Teenager with aggressive leukemia no longer has any detectable signs cancer cells after becoming the first person to receive treatment involving a new type of CRISPR called the basic edition. However, it will not be clear for a few years if she will remain unscathed.

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

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

Leukemia is caused by immune bone marrow cells multiply uncontrollably. It is usually treated by killing all the cells in the bone marrow with chemotherapy, then replacing the bone marrow with a transplant. This succeeds in most cases. If this fails, doctors can try an approach known as CAR-T therapy.

It involves adding a gene to a type of immune cell called a T cell that causes it to seek out and destroy cancer cells. The modified cells are called CAR-T cells.

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

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

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

Qasim’s team therefore made an additional modification to CAR-T cells by deleting the receptor gene that identifies them as T cells. Creating these CAR-T cells requires making four genetic changes at once, which which poses yet another problem.

Conventional gene editing involves cutting strands of DNA and relying on a cell’s repair machinery to rejoin the ends. When many 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 make the cells cancerous. The more genetic changes there are, the more likely this is to happen.

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

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

“The core set 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 in development, he says.

The only other existing trial involving this basic editing technique started in New Zealand in July this year. A company called Verve Therapeutics hopes to show this approach can treat an inherited genetic disease that causes dangerously high cholesterol levels.

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