By Matt Smith, Brenda Goodman, MA
August 30, 2017 -- The FDA has for the first time approved a treatment that uses a patient’s own genetically modified cells to attack a type of leukemia, opening the door to what the agency calls "a new frontier" in medicine.
The approval Wednesday allows a process known as CAR T-cell therapy to be used in children or young adults fighting an often fatal recurrence of the most common childhood cancer -- B-cell acute lymphoblastic leukemia.
And it clears the way for a new approach to fighting cancer by harnessing the body’s immune system -- a long-sought goal of medical researchers.
“This is a dream come true,” says Henry Fung, MD, director of the Fox Chase Cancer Center-Temple University Hospital Bone Marrow Transplant Program. “It’s now limited to one disease in children only, but that platform potentially can benefit a lot of different types of cancer patients, particularly blood cancer patients.”
'A New Frontier'
FDA Commissioner Scott Gottlieb, MD, called the approval of the therapy -- brand named Kymriah -- a "new frontier in medical innovation."
In a news conference on Wednesday, Gottlieb said the FDA had 76 active investigational new drug applications related to CAR T-cell products, and more than 500 for gene therapy products are being studied for a variety of ailments, ranging from genetic disorders to autoimmune diseases, diabetes, cancer, and HIV.
"New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses," Gottlieb says.
Fung, who's also vice chairman of hematology/oncology at Fox Chase, says the treatment could help patients beat back an illness that has resisted conventional treatments like chemotherapy and radiation, leaving them facing death. “This is the breakthrough of the century,” he says.
And Hetty Carraway, MD, an acute leukemia doctor at the Cleveland Clinic, says the newly approved therapy represents a first step for a new way of treating cancer. “If it can bring this kind of paradigm to other types of cancers, that’s really where I think the larger implications are,” she says.
Taking the Fight to Cancer
B-cell acute lymphoblastic leukemia attacks the blood cells that make antibodies, which help your body fight off disease. Most of the time, it’s treated successfully with chemotherapy, radiation, or by transplants of bone marrow, which produces blood cells. But in some cases, treatment fails to beat back the cancer, or it comes back. When that happens, the odds of survival fall to as little as 1 in 10.
The new treatment is a one-time infusion developed by researchers at the University of Pennsylvania and the pharmaceutical company Novartis. Officially known as chimeric antigen receptor T-cell therapy, it starts with doctors extracting disease-fighting white blood cells, known as T cells, from a patient’s blood. The cells are frozen and shipped to a laboratory, where they’re genetically engineered to attack a specific protein on the cancerous B cells.
They’re then put back into the body, where they seek out and destroy cancer cells. And because they’re cells taken from the patient’s own body, there’s no need for anti-rejection drugs, which are needed after transplants.
“This is really combining everything together,” Fung says. “This is truly using patients’ own immune cells to fight cancer.”
Dangerous Side Effects Remain a Concern
The therapy can have dangerous side effects -- mainly a condition known as cytokine release syndrome (CRS). That happens when T cells release a lot of a chemical messenger into the bloodstream. This affects the vascular system, causing high fevers and sharp drops in blood pressure. More than 60% of patients in clinical trials had side effects due to cytokine release, Novartis reported, but none of those reactions were fatal.
Emily Whitehead, the first pediatric patient to try the therapy in 2011, had such a bad reaction initially that she was in a coma for 14 days. Her doctors told the family to say their good-byes.
“They believed she had less than a 1-in-1,000 chance of surviving to the next morning,” says her father, Tom Whitehead.
As a last hope, doctors gave Emily the arthritis drug Actemra (tocilizumab), which blocks one of the main inflammatory signals driving the CRS. On Wednesday, the FDA also approved Actemra as a treatment for CRS. In fact, under the conditions of approval, doctor's can't use CAR T therapy unless they also have Actemra on hand to manage side effects.
Within 12 hours, Emily started to recover. She has been cancer free for five years.
Because of the side effects, Kymriah won't be available everywhere. Hopsitals and clinics will have to be specially certified to administer the treatment. Doctors and other staff will also have get additional training before they can prescribe it.
“We know and expect that type of side effect will happen, and we know that we can successfully manage it,” she says. “But it needs to be managed by people who are familiar with this type of side effect and how best to support patients,” Carraway says.
Other side effects included anemia, nausea, diarrhea, and headaches.
In three trials involving about 150 people, the remission rates were 69%, 83%, and 95%. A total of 17 patients died after receiving the treatment; 14 of them from the disease and three from infections, according to documents the company filed with the FDA.
“We believe this treatment can change the world,” says Tom Whitehead, who frequently speaks about his daughter’s experience and testified before the FDA about the treatment. He also helps raise money for children’s cancer research through The Emily Whitehead Foundation. “But we know some children relapse and we know children who didn’t make it.”
Big Possibilities and a Big Price Tag
Another concern is the price tag associated with the therapy: The process is reported to cost as much as $475,000.
In a press release, the Center for Medicare and Medicaid Services (CMS) announced that it was exploring "innovative payment modes and arrangements" for Kymriah and other potentially life-saving treatments.
In a news release, Novartis, the company that makes Kymriah, said it was collaborating with CMS on an outcomes-based approach to pricing, which would mean that the company would only be reimbursed if a patient responds to the therapy by the end of the first month of treatment.
“Certainly, it’s far and above the expense that we typically see for drugs,” Carraway says. But current treatments can also run into the low six figures, sometimes with little success. The number of patients with relapsed acute lymphoblastic leukemia is small, “and the options for them in their young lives are pretty limited.”
“Our hope is we’ll get better at making these medications, and hopefully, with time, the cost of this will decrease,” she adds.
Novartis spokeswoman Julie Masow says the company will do “everything we can” to help get the treatment to patients who need it.
“We are carefully considering the appropriate price for CTL019, taking into consideration the value that this treatment represents for patients, society, and the health care system, both near-term and long-term, as well as input from external health economic experts,” Masow says.
The therapy was produced “via pioneering technology and a sophisticated manufacturing process,” she says -- however, “We recognize our responsibility in bringing this innovative treatment to patients.”
'He's Started School'
One of the more recent patients to have CAR T-cell therapy is 5-year-old Liam Thistlethwaite. He has been cancer free for 4 months since starting the therapy to treat his acute lymphoblastic leukemia.
First diagnosed shortly before his second birthday, Liam had gotten 32 months of different kinds of chemotherapy drugs to poison the cancer out of his small body. The treatment is harsh but almost always successful. Doctors told Liam’s parents he had a 96% chance of a cure if he could finish it.
But 8 months later, Liam’s cancer came back, with a vengeance. Leukemia cells spread to his spinal fluid. Tumors grew on two glands in his brain.
Liam’s doctor, Ching-Hon Pui, MD, chairman of the Oncology Department at St. Jude, had recently been to a medical conference that discussed the results of the CAR T-cell therapy. He convinced Children’s Hospital of Philadelphia to put him on its waiting list, which was about 6 months long at the time.
Because Liam was relatively healthy and had a low cancer burden when he was treated, his father thinks he avoided some of the most severe side effects of the therapy. He spiked very high fevers and spent a few days in the hospital but pulled through.
“He’s started school. He’s doing wonderfully,” says Patrick Thistlethwaite.
Major Questions Remain Despite Optimism
One of the unanswered questions is how long CAR T cells can last in the body. In some patients, they’ve persisted for as long as 5 years. Others have their cells die in weeks or months. Another big question is whether the cancer will come back if the CAR T cells are gone.
The Thistlethwaites say it was very hard to know whether to try CAR T on a toddler.
“Our physician truly felt that we’d have the same odds, so to speak, as going into a stem cell transplant with heavy radiation. He believed CAR T to have high side effects up front, but no high long-term side effects," Patrick Thistlethwaite says.
They knew radiation to Liam’s brain and spinal cord could cause long-term damage.
“We still have those options,” Patrick says. “We hope we never have to use them.”
“We hope CAR T is the end of it all.”