Medical first: Gene-editing tool used to treat girl’s cancer
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In what’s being billed as a medical first, scientists in London have used a new kind of biological scissors in a last-ditch effort to cure a child with otherwise untreatable leukemia. They edited genes in immune cells to make them hunt down and destroy the malignant blood cells that threatened the year-old girl’s life.

The experimental procedure was performed in June at Great Ormond Street Hospital, physicians there announced on Thursday. The hospital said it was the first time that a genome-editing technology called TALEN had been used to treat a patient.

TALENs is one of three genome-editing tools that scientists and companies are racing to test in humans as possible treatments for everything from cancer to cystic fibrosis, sickle cell disease, and Huntington’s disease.

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In another step toward moving genome-editing technology into the clinic, Editas Medicine announced this week that it hopes to launch a clinical trial using a rival technique. At the EmTech conference at MIT sponsored by MIT Technology Review, Editas CEO Katrine Bosley said the Cambridge, Mass.-based startup aims to begin enrolling patients in 2017 for a trial that would use the gene-editing technique CRISPR to treat a rare form of blindness.

A third gene-editing technology, called zinc fingers, is already in a clinical trial for AIDS sponsored by California-based biotech Sangamo BioSciences, with hopeful results in more than 80 patients.

“I think it’s great,” Sangamo president Edward Lanphier said of the London case. “It’s further demonstration of the ability to use genome-editing technologies” in patients.

“This is a landmark in the use of new gene-engineering technology.”

Waseem Qasim, University College London

The three-way rivalry in genome editing pits zinc fingers, the oldest such technology, against TALENs against CRISPR, the newest and the one that has revolutionized the field. Zinc fingers and TALENs (transcription activator-like effector nucleases) use proteins to edit genomes, but because proteins are difficult and time-consuming to construct, scientists had sought a better technique. CRISPR  took the genome-editing field by storm starting in 2013 because it uses easy-to-construct nucleic acids like RNA to edit genes.

But while CRISPR became the cool new kid on the block, several companies have stuck with the older, protein-based genome-editing toolkit. One is a French biotech company Cellectis, whose TALEN technology was used in the London case.

“We think CRISPR is much less useful for therapeutic purposes than TALENs,” chairman Andre Choulika told STAT this summer. “TALENs get to the target,” he said, while CRISPR often isn’t so precise. “And CRISPR has off-target effects,” he added, meaning it can cut DNA at spots other than the intended one.

In the London case, an infant identified only as Layla had received chemotherapy for her acute lymphoblastic leukemia (ALL) after it was diagnosed in September 2014. But her leukemia was what doctors called one of the most aggressive forms of the disease they had ever seen; she relapsed within seven weeks.

Physicians considered using a relatively new technique in which a patient’s immune cells are collected and genetically engineered to produce special molecules on their surface. The molecules grab onto matching molecules on tumor cells. When billions of the custom-made immune cells (grown in a lab) are infused into the patient, they multiply and home in on the tumor molecules like programmed drones. If all goes as planned, the immune cells kill every cancer cell with the telltale surface molecule, or antigen.

Unfortunately, like many leukemia patients, Layla didn’t have enough immune cells for this “chimeric antigen receptor (CAR) T cell” approach. The team at Great Ormond Street, which included investigators at University College London and Cellectis, therefore turned to donor T cells.

They used TALENs to edit the genomes of the donor cells in two specific ways: cutting out genes that made them vulnerable to a powerful leukemia drug that would otherwise kill them — the T cells had to survive in Layla to do their job — and inserting genes to make the donor T cells target the specific antigens on her malignant blood cells.

The investigators had been planning a clinical trial of such edited, off-the-shelf, “universal” donor T cells. But this summer they received approval from an ethics committee to try the treatment on Layla.

“The approach was looking incredibly successful in laboratory studies, and so when I heard there were no options left for treating this child’s disease, I thought, ‘Why don’t we use the new [cells]?’ ” gene therapy researcher Waseem Qasim of University College London said in a statement. Layla’s parents, told that their daughter’s only other option was palliative care, agreed.

The infusion of engineered T cells, in June, took about 10 minutes. Layla then spent several months in isolation so she would not be exposed to infections at a time when her immune system was weak from her cancer treatment.

Tests showed that her leukemia began to respond to the engineered T cells after a few weeks. She then underwent a bone marrow transplant. She is now recovering well at home, the hospital said.

“We have to be cautious about claiming that this will be a suitable treatment option for all children,” Qasim said. “But this is a landmark in the use of new gene-engineering technology” that, if replicated, “could represent a huge step forward in treating leukemia and other cancers.”

Cellectis plans to test its off-the-shelf engineered immune cells against leukemia in a clinical trial starting early next year, the company said.

Scientists not involved in the case were cautious about the claims, partly because the London team has not published a description of their work in a journal; they have submitted an abstract summarizing it to the annual meeting of the American Society of Hematology, which will be held next month in Orlando. More important, the four months since the treatment is not long enough to know whether it will provide a lasting benefit, the outside scientists said.

Nevertheless, Sangamo’s Lanphier said the off-the-shelf engineered immune cells “offer enormous advantages” over taking and editing cells from each patient, and he welcomed another entrant in the genome-editing world. “From someone who’s been in the genome-editing space for years, I say, ‘Come in, the water’s fine.’ “

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