Experimental CRISPR Technique Shows Promise Against Aggressive Leukemia

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


December 11, 2022

Alyssa on the day she received gene-edited cell therapy in May

Great Ormond Street Hospital for Children

A teenager with aggressive leukemia now has no detectable cancer cells after becoming the first person to receive treatment involving a new type of CRISPR called base editing. However, it will not be clear for a few years if he will remain free of the condition.

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

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

Leukemia is caused by immune cells in the bone marrow that multiply out of control. It is usually treated by killing all the cells in the bone marrow with chemotherapy and then replacing the bone marrow with a transplant. This is successful in most cases. If it fails, doctors may 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 kill cancer 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 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 get enough T cells to create CAR-T cells when a person is very sick.

To overcome these drawbacks, different groups of doctors have been editing T-cell genes so that cells from a single donor can be used to treat many people. In 2015, Waseem Qasim of 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 named Layla for whom all other treatments had failed.

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

Therefore, Qasim’s team made an additional change to CAR-T cells by deleting the receptor gene that identifies them as T cells. Creating these CAR-T cells requires editing four genes at once, which Which creates another problem.

Conventional gene editing involves cutting strands of DNA and relying on a cell’s repair machinery to reattach the ends. When many cuts are made at once, cells sometimes die. Even if they survive, the wrong ends can snap back together, leading to major mutations that can cause cells to become cancerous. The more gene edits that are made, the more likely this is to happen.

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

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

“Base editing holds particular promise, not only in this case, but also for genetic disorders,” says Robin Lovell-Badge of the Francis Crick Institute in London. Many other treatments involving CRISPR-based editing are being developed, he says.

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

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