James GallagherScience and health correspondent
bbcA therapy that would once have been considered a feat of science fiction has reversed aggressive, incurable blood cancers in some patients, doctors report.
The treatment involves precisely editing the DNA of white blood cells to transform them into a “living drug” that fights cancer.
The first girl to receive treatment, whose story we report in 2022, is still free of the disease and now plans to become a cancer scientist.
Eight more children and two adults with T-cell acute lymphoblastic leukemia have now been treated, and almost two-thirds (64%) of patients are in remission.
T cells are supposed to be the body’s guardians, seeking out and destroying threats, but in this form of leukemia they grow out of control.
For trial participants, chemotherapy and bone marrow transplants had failed. Aside from experimental medicine, the only option left was to make his death more comfortable.
“I really thought I was going to die and I wouldn’t be able to grow up and do all the things that every child deserves to be able to do,” says Alyssa Tapley, 16, from Leicester.
He was the first person in the world to receive treatment at Great Ormond Street Hospital and is now enjoying life.
The breakthrough treatment three years ago involved removing his old immune system and developing a new one. He spent four months in the hospital and was unable to see his brother in case he contracted an infection.
But now his cancer is undetectable and he only needs annual checkups. Alyssa is doing her A-level exams, the Duke of Edinburgh’s Award, studying driving lessons and planning her future.
“I’m thinking about doing an internship in biomedical sciences and I hope that one day I’ll also get into blood cancer research,” he said.
The team from University College London (UCL) and Great Ormond Street Hospital used a technology called base editing.
The bases are the language of life. The four types of bases: adenine (A), cytosine (C), guanine (G) and thymine (T), are the basic components of our genetic code. Just as the letters of the alphabet form words that have meaning, the billions of bases in our DNA constitute our body’s instruction manual.
Base editing allows scientists to zoom in on a precise part of the genetic code and then alter the molecular structure of a single base, converting it from one type to another and rewriting the instruction manual.
Researchers wanted to harness the natural power of healthy T cells to seek out and destroy threats and turn them against T-cell acute lymphoblastic leukemia.
This is a complicated feat. They had to engineer good T cells to hunt down the bad ones without the treatment being wiped out.
They started with healthy T cells from a donor and set out to modify them.
The first base edition disabled the targeting mechanism of the T cells so that they could not attack the patient’s body.
The second removed a chemical mark, called CD7, found on all T cells. Removing it is essential to prevent the therapy from self-destructing
The third edition was an “invisibility cloak” that prevented a chemotherapy drug from killing cells.
The final stage of the genetic modification instructed the T cells to look for anything that had the CD7 mark.
Now the modified T cells would destroy all other T cells they encountered, whether cancerous or healthy, but they would not attack each other.
The therapy is infused into patients and, if their cancer cannot be detected after four weeks, patients receive a bone marrow transplant to regrow their immune system.
“A few years ago this would have been science fiction,” says Professor Waseem Qasim of UCL and Great Ormond Street.
“We basically have to dismantle the entire immune system.
“It is a deep and intensive treatment, it is very demanding for patients, but when it works, it works very well.”
The study, published in the New England Journal of Medicine, reports results from the first 11 patients treated at Great Ormond Street and King’s College Hospital. It shows that nine achieved deep remission that allowed them to undergo a bone marrow transplant.
Seven remain disease-free between three months and three years after treatment.
One of the biggest risks of treatment includes infections while the immune system is destroyed.
In two cases, the cancer lost its CD7 markings, allowing it to hide from treatment and bounce around the body.
“Given how aggressive this particular form of leukemia is, these are quite surprising clinical results and I’m obviously very happy to have managed to offer hope to patients who otherwise would have lost it,” said Dr Robert Chiesa, of the bone marrow transplant department at Great Ormond Street Hospital.
Dr Deborah Yallop, consultant haematologist at King’s, said: “We have seen impressive responses in eliminating a leukemia that seemed incurable – it is a very powerful approach.”
Commenting on the research, Dr Tania Dexter, medical director of UK stem cell charity Anthony Nolan, said: “Given that these patients had little chance of survival before the trial, these results provide hope that treatments like this will continue to advance and become available to more patients.”
