Doctors are performing a different kind of surgery to save patients with maladies ranging from HIV to cancer. They’re using molecular scalpels to slice genes.
This gene editing helped push a 1-year-old girl’s leukemia into remission, doctors at the Great Ormond Street Hospital in London announced November 5 at a news briefing. Baby Layla’s medical team treated her with immune cells altered by one type of the molecular surgical instruments called TALENs. It’s the first time TALENs have been successfully used to treat a person.
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Gene editing is becoming increasingly popular in research and clinical trials. Scientists can select from a variety of scalpels, including zinc finger nucleases, TALENs and CRISPR/Cas9. The tools all do the same thing: cut DNA at specific locations.
Zinc finger nucleases and TALENs are pairs of proteins that researchers engineer to latch on to DNA at specific sites and then cut it. CRISPRs are RNAs that researchers program to guide the enzyme Cas9 to a spot on DNA. Cas9 then snips the DNA. Researchers have recently embraced CRISPR/Cas9 because it is easier to wield — and cheaper — than the other molecular scalpels.
Layla is not the first person to get molecular surgery. A company called Sangamo BioSciences started using zinc finger nucleases about five years ago to remove a protein from human immune cells that HIV uses as a door to enter the cells. More than 80 people have gotten this treatment in Sangamo’s clinical trials, says Edward Lanphier, president and chief executive officer of the Richmond, Calif., company.
CRISPR/Cas9 has been used to edit human cells in the laboratory, but hasn’t yet been tried in clinical trials.
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In Layla’s case, researchers used TALENs (transcription activator-like effector nucleases) to engineer immune cells that can seek out and destroy cancer cells without harming the patient. The immune cells are called chimeric antigen receptor T cells, or CAR T cells. T cells help the body distinguish its own cells from invaders, such as bacteria or viruses, and attack the foreign cells.
Layla had a type of blood cancer called acute lymphoblastic leukemia. Her bone marrow made too many immature immune cells called B cells. Layla’s B cells were studded with a protein known as CD19. To treat her cancer, doctors tried an experimental treatment using CAR T cells engineered to carry an antibody that tracks and kills any cell that makes CD19.
In some previous cancer cases, doctors have taken T cells from a patient’s own blood and inserted the tracking antibody to create CAR T cells. The cells are grown in the lab until there are enough to put into the patient to fight the cancer.
That strategy was not an option for Layla. She’d had treatment to kill the cancer and her bone marrow — which makes blood and immune cells — had been replaced in a bone marrow transplant. Researchers were unsuccessful in making CAR T cells from Layla’s bone marrow donor.
Using T cells from yet another donor would have been problematic: Those immune cells would recognize Layla’s body as a foreign entity and attack; likewise, Layla’s immune system would see the donated cells as invaders and repel them.
Layla’s medical team, including Waseem Qasim of University College London, had a way to get around both problems. The team had previously made an experimental batch of “universal” CAR T cells that could be used for any patient.
Qasim and colleagues had used TALENs to cut a gene in the T cells that produces a protein called the T cell receptor alpha chain. That protein allows T cells to distinguish between a person’s own cells and invaders. Cutting out the gene means the T cells “can no longer recognize anything as foreign,” says Mark Osborn, a molecular biologist at the University of Minnesota Medical School in Minneapolis. That modification lets donor CAR T cells attack cells carrying CD19, but leaves the rest of the patient’s cells alone.
The team still had to find a way to stop a patient’s body from rejecting the engineered CAR T cells. So Qasim and colleagues used a different pair of TALENs to remove a protein called CD52 from the CAR T cells. Getting rid of CD52 makes the cells invisible to a recipient’s immune system. It was a clever trick, says Osborn, because doctors could then give a patient an antibody drug called alemtuzumab that would kill the patient’s own T cells, letting the new donor cells grow.
The cells had not yet been tested in clinical trials and researchers had to get special permission to give Layla the experimental treatment. Only one tiny vial containing one milliliter of engineered cells was available, but that was enough.
About a month after she got the treatment last summer, Layla’s doctors couldn’t find any sign of leukemia. Her bone marrow was 90 percent cells from her donated bone marrow, 7 percent cells that came from the CAR T cell treatment and 3 percent of her own bone marrow cells. Because Layla still had some of her own bone marrow, it means that her cancer wasn’t cleared by the bone marrow transplant alone. The finding indicates that the engineered T cells helped kill the leukemia.
Since then, Layla has had another bone marrow transplant and remains free of leukemia. Her doctors don’t know yet if the cancer is gone for good. “We will be more confident as time goes on,” Qasim says. He’s waiting until Layla has been cancer-free for at least 12 months until he’ll consider the therapy “curative.” Qasim will present details of the case at the American Society of Hematology meeting in Orlando, Fla., in December.