CAR T-cell treatment hailed as ‘a true living drug’
First gene therapy on the cusp of FDA approval, successfully treated lethal cases of leukemia
When doctors saw the report on Bill Ludwig’s bone-marrow biopsy, they thought it was a mistake and ordered the test repeated. But the results came back the same: His lethal leukemia had been wiped out by an experimental treatment never used in humans.
“We were hoping for a little improvement,” remembers the 72-year-old retired New Jersey corrections officer, who had battled the disease for a decade. He and his oncologist both broke down when she delivered the good news in 2010. “Nobody was hoping for zero cancer.”
The pioneering therapy with Ludwig and a few other adults at the University of Pennsylvania hospital paved the way for clinical trials with children. Six-year-old Emily Whitehead, who was near death, became the first pediatric recipient in 2012. Like Ludwig, she remains cancer-free.
Such results are why the treatment is on track to become the first gene therapy approved by the Food and Drug Administration. An FDA advisory committee will decide Wednesday whether to recommend approval of the approach, which uses patients’ own genetically altered immune cells to fight blood cancers.
If the panel gives the nod, the agency probably will follow suit by the end of September. That would open the latest chapter in immunotherapy — “a true living drug,” says Penn scientist Carl June, who led its development.
The CAR T-cell treatment, manufactured by the drug company Novartis, initially would be available only for the small number of children and young adults whose leukemia doesn’t respond to standard care.
And childhood leukemia is just the start for a field that has attracted intense interest in academia and industry. Kite Pharma of Santa Monica, Calif., has applied for FDA approval for aggressive non-Hodgkin lymphoma, and a similar Novartis application is close behind. Researchers also are exploring CAR T-cell therapy’s use for multiple myeloma and chronic lymphocytic leukemia, the disease that afflicted Ludwig. They’re also tackling a far more difficult challenge — using the therapy for solid tumors in the lungs or brain, for example.
The excitement among doctors and researchers is palpable. “We’re saving patients who three or four years ago we were at our wit’s end trying to keep alive,” said Stephen Schuster, the Penn oncologist who is leading a Novartis lymphoma study. Both the study and a Kite trial have shown that the treatment can put about one-third of adults with advanced disease — those who have exhausted all options — into remission.
Yet along with the enthusiasm come pressing questions about safety, cost and the complexity of the procedure.
It involves extracting white blood cells called T cells — the foot soldiers of the immune system —from a patient’s blood, freezing and sending them to Novartis’s sprawling manufacturing plant in Morris Plains, N.J. There, a crippled HIV fragment is used to genetically modify the T cells so they can find and attack the cancer. The cells then are refrozen and sent back to be infused into the patient.
Once inside the person’s body, the T-cell army multiplies astronomically.
Novartis hasn’t disclosed the price for its therapy, but analysts are predicting $300,000 to $600,000 for a one-time infusion. Brad Loncar, whose index fund focuses on cancer immunotherapy treatment, hopes the cost doesn’t prompt a backlash. “CAR-T is not the EpiPen,” he said. “This is truly pushing the envelope and at the cutting edge of science.”
The biggest concerns, however, center on safety. The revved-up immune system becomes a potent cancer-fighting agent but also a dangerous threat to the patient. Serious side effects abound, raising concerns about broad use.
“Treating patients safely is the heart of the rollout,” said Stephan Grupp of the Children’s Hospital of Philadephia, who as director of its Cancer Immunotherapy Program led early pediatric studies as well as Novartis’s global trial. “The efficacy takes care of itself, but safety takes a lot of attention.”
One of the most common side effects is called cytokine release syndrome, which causes high fever and flulike symptoms that in some cases can be so dangerous that the patient ends up in intensive care. The other major worry is neurotoxicity, which can result in temporary confusion or potentially fatal brain swelling. Juno Therapeutics, a biotech firm in Seattle, had to shut down one of its CAR T-cell programs because five patients died of brain swelling. Novartis has not seen brain swelling in its trials, company officials said.
To try to ensure patient safety, Novartis isn’t planning a typical product rollout, with a drug pushed as widely and aggressively as possible. The company instead will designate 30 medical centers to 35 medical centers to administer the treatment. Many of them took part in the clinical trial, and all have gotten extensive training by Grupp and others.
With FDA approval seeming imminent, the researchers who were so instrumental in the therapy’s development and testing are almost giddy. Grupp is especially pleased that the advance will be available first to children. “Usually everything is developed first for adults,” he noted recently, “and children are an afterthought.”