[Corrected, 10/10/17, 2 p.m. ET. See below.] It’s not a stretch to say that Greta Oberhofer is alive thanks to the genetically modified cell therapy called CAR-T. At three and a half months old, she was diagnosed with acute lymphoblastic leukemia, or ALL, an aggressive blood cancer. At 10 months old, she had a bone marrow transplant, which required chemotherapy. She had a bad reaction: Her kidney and liver shut down, and fluid built up in her heart and lungs. She was on a breathing machine. “It was pretty rough,” says her father, Andy.
When the transplant failed about three months later, “we thought it was a death sentence,” says Andy. But Greta qualified for experimental CAR-T therapy, available only to patients with no other recourse. In August 2014 she received a dose of her own T cells, extracted from her blood, modified and expanded outside her body, then infused back into her bloodstream to zero in on the life-threatening cancer.
Now, at four years old, she seems to be cured, one of dozens of kids and adults who have been brought back from the brink of death by this remarkable and still mysterious new form of genetically engineered therapy.
Most CAR-T programs remain experimental. Only healthcare giant Novartis (NYSE: [[ticker:NVS]]) has won marketing approval—an historic moment three weeks ago. The FDA nod was for the same pediatric cancer that nearly killed Greta.
But the Novartis CAR-T wasn’t what cured Greta. She was too young at the time to enter the experimental trial for that program. Instead, her parents enrolled her in a study for a different CAR-T program, at Seattle Children’s Hospital, which was accepting patients as young as a year old. Greta (pictured above, with her sister Charlotte, 6, behind her) first had to put on weight—lots of French fries and milkshakes, says her mother, Maggie—then go through another round of chemo, but she managed to hang on for her CAR-T treatment.
Greta and Charlotte were chattering in the back seat of the family car when I spoke to her parents recently. They were driving from their home in Portland to a weekend vacation in Canada.
Greta isn’t the only kid with a desperate case of leukemia saved by the Seattle Children’s CAR-T program. Forty-one of 45 patients who enrolled in the first phase of that trial, called PLAT-02, were basically cancer-free after a month. The remarkable rate was similar to Novartis’s CAR-T, which produced one-month remissions that prompted children’s cancer specialist Timothy Cripe, reviewing the data this summer, to say, “It’s the most exciting thing I’ve seen in my lifetime.”
So why did the Novartis treatment, developed at the University of Pennsylvania and now called tisagenlecleucel (Kymriah), get the golden ticket of an FDA approval to treat kids like Greta, while the Seattle Children’s CAR-T has remained an experimental therapy? The answer, in part, is that the Seattle Children’s team, lagging behind Novartis, decided to shoot for a more audacious goal. But by doing so, it made a fast approval nearly impossible for its corporate partner, Juno Therapeutics (NASDAQ: [[ticker:JUNO]]). Juno has shown no interest in going head-to-head with Novartis in children’s leukemia.
“The Novartis approval is great for patients,” says Mike Jensen, who directs the Seattle Children’s Research Institute CAR-T efforts. “But it does put further development in that indication on thin ice in terms of feasibility.”
Seattle Children’s is now aiming for CAR-T therapy not for the most desperate cases, but to treat, even cure, kids earlier in the course of the disease. The decision has also left Novartis, which is charging $475,000 per treatment, with no competition for the time being. Cripe, chief of the blood cancer and bone marrow transplant division of Nationwide Children’s Hospital in Columbus, OH, sees other programs eventually giving doctors more options, especially more cost-effective “off the shelf” CAR-T therapies that use donor blood cells instead of a patient’s own cells.
But competition isn’t necessarily a cure for sky-high prices, says Peter Bach, director of Memorial Sloan Kettering’s Center for Health Policy and Outcomes in New York. “Brand-to-brand competition doesn’t really drive down prices,” Bach says, speaking generally about the industry. “In fact, you often see evidence of parallel price hikes across competitors.”
RELAPSE AFTER CAR-T: A “DISMAL DIAGNOSIS”
An overview of trial data shows the rationale behind the Seattle Children’s decision. In many kids who were cancer free after one month, the cancer soon comes roaring back. In Novartis’s key trial, called ELIANA, 52 of 63 kids (83 percent) who received the treatment were in remission after a month. Of those 52, 33 (64 percent) remained in remission after 12 months. In the Seattle Children’s study, PLAT-02, 41 of 45 (89 percent) enrolled in the first phase of the trial were in remission after one month. Roughly half, or 22, were still in remission after 12 months.
That’s 93 remissions after one month, down to 55 after 12 months.
(It’s tempting to compare data from the two trials, but there are many caveats, including different age minimums and subtypes of T cells used for each treatment.)
The return of a patient’s cancer is always bad news. But a relapse of pediatric ALL after treatment with CAR-T therapy is what Rebecca Gardner, Greta’s doctor at Seattle Children’s, has called “a dismal diagnosis.”
Three years later with no relapse, Greta is one of the lucky ones. The dim outlook for many others, however, has spurred Jensen, Gardner, and their colleagues to press on with more cutting-edge versions of CAR-T that they hope in a few years are not just replacements for the Novartis therapy, but alternatives to bone marrow transplants, which have fairly high cure rates but also a high risk of death.
Jensen says the reality struck about two years ago. Novartis had momentum toward a big trial. The first couple dozen patients in Seattle Children’s PLAT-02 trial, meanwhile, were showing signs of relapse after stellar one-month results. A pattern was emerging, says Jensen, that pointed not to chasing Novartis with
