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 genetically engineered to attack the cancer


December 11, 2022

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

Great Ormond Street Children’s Hospital

A teen with aggressive leukemia now has no detectable cancer cells after becoming the first person to undergo treatment with a new kind of CRISPR called basic editing. However, it won’t be clear for years to come whether she 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 immune cells from a donor that had been modified to attack the cancer. Twenty-eight days later, tests showed she was in remission.

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

Leukemia 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 works in most cases. If it doesn’t work, 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, causing it to hunt down and destroy cancer cells. The modified cells are known as CAR-T cells.

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

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

This approach has now been 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 when CAR T cells are modified to attack other T cells, they just kill each other.

So Qasim’s team made an additional change to the CAR-T cells by knocking out the gene for the receptor that identifies them as T cells. To create these CAR-T cells, four gene edits must be performed simultaneously, which leads to another problem.

Conventional gene editing involves cutting DNA strands and relying on a cell’s repair machinery to bring the ends back together. 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 could potentially make the cells cancerous. The more gene edits that are made, 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 DNA, but instead changes one DNA letter to another, a technique known as basic editing. Alyssa is the first person ever to be treated with base-edited CAR-T cells.

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

“Base editing is particularly promising, not only in this case but also for genetic disorders,” says Robin Lovell-Badge of the Francis Crick Institute in London. Many other CRISPR basic editing treatments are in development, he says.

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

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