Children and young people with a form of leukaemia will have access to a groundbreaking treatment after NHS England secured a deal with the drug manufacturer.
SEPTEMBER 5, 2018 Tisagenlecleucel, a form of chimeric antigen receptor T-Cell (CAR-T) therapy, has been shown to cure some patients with B cell acute lymphoblastic leukaemia.
NHS patients will be the first in Europe to have routine access to the treatment, which costs £282,000 per patient at full list price, following the agreement with pharmaceutical company Novartis.
The deal comes less than 10 days after the therapy was granted European marketing authorisation and represents one of the fastest funding approvals in the history of the health service, NHS England said.
It will be announced by Simon Stevens, chief executive of NHS England, at the Health Innovation Expo in Manchester on Wednesday.
“CAR-T therapy is a true game changer, and NHS cancer patients are now going to be amongst the first in the world to benefit,” Mr Stevens will say.
“Today’s approval is proof-positive that, in our 70th year, the NHS is leading from the front on innovative new treatments.
“This constructive fast-track negotiation also shows how responsible and flexible life sciences companies can succeed – in partnership with the NHS – to make revolutionary treatments available to patients.”
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CAR-T cell therapy is the most exciting advance in treatment for childhood leukaemia for decades
Dr Alasdair Rankin, Bloodwise
CAR-T therapy is a personalised treatment, which reprogrammes a patient’s immune system cells to target the cancer.
Tisagenlecleucel, also known as Kymriah, has been shown in trials to “cure” some patients, even those with advanced cancers who have not responded to other treatments, NHS England said.
The therapy is licensed for use in patients up to the age of 25 with B cell acute lymphoblastic leukaemia that is refractory, in relapse post-transplant or in second or later relapse.
It has been approved for use by the National Institute for Care and Excellence (Nice) through the NHS Cancer Drugs Fund.
Three UK hospitals in London, Manchester and Newcastle are awaiting approval to provide CAR-T therapy and, if successful, could begin treating patients with Tisagenlecleucel within weeks, NHS England said.
Dr Alasdair Rankin, director of research at blood cancer charity Bloodwise, said: “CAR-T cell therapy is the most exciting advance in treatment for childhood leukaemia for decades.
“Intensive chemotherapy can now cure the vast majority of children but a significant number still tragically die every year because they do not respond to treatment.
“CAR-T cell therapy offers the genuine chance of a long-term cure for children who otherwise would have no other hope.”
Simon Stevens, the NHS England chief executive, will announce on Wednesday that a deal has been done with the drug company Novartis, which makes the immunotherapy drug under the name Kymriah.
How does CAR-T therapy work?
CAR-T therapy is a new type of immunotherapy. The novel idea is to collect T-cells from the blood of the patient and engineer them to recognise the cancerous cells that have been hiding in the body unnoticed and that they have failed to destroy.
T-cells are lymphocytes or white blood cells. They are key players in the immune system, moving around the body to attack infection and diseases.
They should attack a cancer, but sometimes fail to identify cancerous cells as the threat they are. CAR-T therapy aims to teach the T-cells to recognise and attack the target.
A child with acute lymphoblastic leukaemia (ALL) which has returned in spite of a number of different treatments would be eligible for CAR-T therapy (CAR stands for chimeric antigen receptor and the T is for T-cell).
The first step is to insert a tube in each arm. Blood is then withdrawn from one arm and T-cells are removed by passing it through an apheresis machine. The rest of the blood returns to the body through the tube in the other arm.
In a lab, the T-cells are genetically engineered to recognise and target a specific protein on the cancer cells. The CAR-T cells, as the changed cells are now called, multiply in the lab, while the patient is given chemotherapy to kill off any remaining T-cells in the body.
Then the child is given a transfusion of CAR-T cells, which will hopefully attack and kill the cancer cells in the blood.
The list price of the drug is £282,000 per patient and treatment costs for the NHS could double that. In the United States, the total cost of the therapy can reach $1m.
But Stevens and others have said this form of cancer treatment, known as CAR-T therapy, is the future. It works by genetically engineering the patient’s own immune system’s killer T-cells to recognise and destroy cancer cells.
“CAR-T therapy is a true game changer and NHS cancer patients are now going to be amongst the first in the world to benefit,” Stevens will say in a speech at the Health and Care Innovation Expo in Manchester.
However, only 15 to 20 children with acute lymphoblastic leukaemia (ALL) are expected to be eligible for the drug. It will be given only to those who have failed a series of earlier treatments, including stem cell transplants.
Kymriah has also been licensed to treat adults with a more common blood cancer, diffuse large B-cell lymphoma (DLBCL), but a decision is yet to be made by the National Institute for Health and Care Excellence (Nice) on whether the NHS can afford it. The bill would be substantially higher because about 200 adults could be eligible. A similar drug for adults, Yescarta made by Gilead, has been turned down because of the cost, which is $373,000 (£290,000) in the US.
When Stevens revealed his intention to make CAR-T available to the NHS in April, he appealed to Novartis to reduce the price of Kymriah. Any discount that the manufacturer has offered is a commercial secret.
CAR-T therapy has to be developed for each patient. It involves taking blood and engineering the patient’s own immune system T-cells to recognise and fight the cancer before transfusing them back into the body.
There have been spectacular results in clinical trials, with response rates in blood cancer patients with advanced disease of over 80%. But there have also been deaths, when patients’ immune systems have overreacted to the therapy.
Alasdair Rankin, the director of research at the blood cancer charity Bloodwise, said he was very pleased that children and young adults would get the treatment. “It is very exciting for children with leukaemia,” he said.
This use of CAR-T therapy was “only the tip of the iceberg”, he said, and there were other cancers, from myeloma to solid tumours, that it could help. He likened the arrival of CAR-T therapy to that of radiotherapy, which transformed cancer treatment and substantially improved long-term outcomes.
Prof Charles Swanton, Cancer Research UK’s chief clinician, said: “It’s fantastic news for children and young people with this form of leukaemia that CAR-T cell therapy will be made available on the NHS, making them the first in Europe to have routine access to this exciting new type of immunotherapy. We applaud NHS England, Nice and the company for working together to make this immensely complex treatment available to patients quickly, through the Cancer Drugs Fund.”
The process of producing such a treatment is immensely complex but preparations are in their final stages, according to NHS England, and the first children could be treated within weeks. Three NHS hospitals are going through the international accreditation process for the provision of CAR-T therapy for children, in London, Manchester and Newcastle.
“Today’s approval is proof-positive that, in our 70th year, the NHS is leading from the front on innovative new treatments,” Stevens will say. “This constructive fast-track negotiation also shows how responsible and flexible life sciences companies can succeed – in partnership with the NHS – to make revolutionary treatments available to patients.”
In a new paper published in Science, researchers led by Eric Olson, professor and chair of molecular biology at UT Southwestern Medical Center, reported that he and his team successfully used CRISPR to correct the genetic defect responsible for Duchenne muscular dystrophy in four beagles bred with the disease-causing gene. It’s the first use of CRISPR to treat muscular dystrophy in a large animal. (Previous studies had tested the technology on rodents.) In varying degrees, the genetic therapy halted the muscle degradation associated with the disease.
Duchenne is caused by mutations in the dystrophin gene, which codes for a protein essential for normal muscle function. People born with the disease are often eventually confined to wheelchairs as their muscles continue to weaken, and in the later stages, many rely on ventilators to breathe as their diaphragm muscles stop working. Eventually, they develop heart and respiratory failure.
Olson and his team “fixed” the mutated dystrophin gene in four dogs by splicing out an offending section of the gene using CRISPR. The gene editing technology, discovered in 2012, can cut out sections of DNA at precise locations (and also potentially introduce new DNA as well). In the case of Duchenne, says Olson, simply snipping out a section of the mutated dystrophin gene allows the gene to make enough of the proper protein that muscles need to function.
Olson tried two different methods of injecting the CRISPR molecular scissors. With two dogs he directly injected the CRISPR technology into muscle, while in two other dogs he injected the same CRISPR technology into the bloodstream, so it could travel to more parts of the body and have a broader effect on different types of muscle from the limbs to the heart and diaphragm. Because Duchenne seems to affect the heart and respiratory system muscle preferentially, he also loaded the CRISPR cutting complex onto a molecular vehicle, a cold virus that was modified to seek out and splice DNA in those muscle cells in particular.
“I was frankly exuberant by the results,” says Olson. “It was jaw dropping.”
In the dogs that had received the systemic injections, he found that muscle cells in various parts of their bodies, including the heart and diaphragm, were churning out healthy dystrophin protein at anywhere from 3% to 90% of the normal levels eight weeks after injection. Olson says that muscular dystrophy experts believe that if dystrophin levels in affected people were raised to 15% of normal, it would make a dramatic difference in their lives and their ability to function. The dogs receiving the CRISPR injections directly into their muscle also showed higher levels of dystrophin production, but just in those muscles specifically. Because Duchenne affects deep organs like the heart and respiratory system, Olson says finding a way to deliver CRISPR more widely, without repeated and multiple injections, is preferable.
The idea is that CRISPR would essentially delete the mutation in muscle cells, and return the affected dogs to a nearly normal state. So far, the animals continue to make higher amounts of dystrophin after eight weeks.
The study is the latest in an encouraging string of results in applying CRISPR to treat human disease. Researchers have also successfully used the gene editing technology to splice out HIV from both infected human cells in the laband in living mice and rats, and are close to beginning trials to blood disorders like beta thalassemia and sickle cell anemia. Scientists have even corrected a genetic heart defect in embryos in the lab, which were not allowed to develop further or be implanted for ethical reasons. While serious questions about the safety of CRISPR-based therapies remain — some studies revealed greater than expected side effects from overzealous DNA snipping, for example — both academic and commercial researchers remain committed to investigating CRISPR as a new tool in addressing genetic diseases such as Duchenne.
Olson is encouraged by the results, even if they came from just a few dogs. They provide some reassurance that Duchenne, which is often diagnosed before people start to notice symptoms of muscle weakness, might be halted in its tracks before important skeletal, heart and breathing muscle are damaged beyond saving. A CRISPR-based therapy, he says, may be most effective in treating young people recently diagnosed with the disease, to prevent them from ever experiencing the symptoms of Duchenne.
Even people with more advanced disease might benefit, Olson thinks, as long as there is some muscle left to maintain a certain level of function, whether that’s moving the legs and arms or keeping the heart functioning. “I absolutely believe that whatever stage we intervene with this therapy, it could halt or slow the progression of the disease from that point forward,” he says.
First, however, more studies need to be done in larger animals like dogs. Olson is planning on a longer term study to see how long the CRISPR cells remain in the dogs, and how safe the therapy is.
The hope is that if those animal studies and human trials prove this technique is safe and effective, CRISPR could potentially lead to a cure for Duchenne, Olson says. “We are going for a cure, not a treatment,” he says. “All of the other therapies so far for Duchenne muscular dystrophy have treated the symptoms and consequences of the disease. This is going right at the root cause of the genetic mutation.”
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