A 7-year-old pixie named Emily Whitehead has erased any remaining doubts about the power of a University of Pennsylvania gene therapy to eradicate certain blood cancers.
The therapy is personalized using each patient's immune system "T cells." Three weeks after Emily's infusion in April, she was completely free of the leukemia that had been on the verge of killing her.
Just as important, she showed that the T cell therapy can have catastrophic side effects, and pointed the way for her doctors to find an antidote.
Without that antidote, she, and probably several later patients, would be dead. And a novel therapy that has tamed terminal leukemia in seven of the first 10 patients might be deemed too risky for further testing.
"Previous patients got sick, but it wasn't clear at the time whether it was due to the T cells or an infection," said pediatric oncologist Stephan Grupp, who oversaw Emily's care at Children's Hospital of Philadelphia. "Now we know the main reason they were sick was the cells. But now we can intervene. She taught us."
"In the war against cancer," Emily's father, Tom, said from their home in Philipsburg, Pa., "there is no one in front of Emily."
The Penn research team, led by gene-therapy pioneer Carl June, was to present results from the first 10 patients at a medical conference beginning over the weekend.
Although 10 is a tiny number, the outcomes have been so stunning the world has noticed. After journals published results from the first three patients last year, pharmaceutical giant Novartis rushed to team with Penn to develop and license the technology.
Of the 10, only two patients have not gotten better on the T cell therapy, even though all had stopped responding to conventional treatments. Four patients have had a complete response - their leukemia was eradicated - with the longest so far lasting 28 months. In four other patients, leukemia diminished dramatically.
"We believe we know why the two patients didn't respond," said Penn physician David L. Porter, a cancer and blood specialist. "If we're right, it's something we can fix."
The therapy, culminating 20 years of research, involves genetically engineering T cells - the immune system's big guns - to attack B cells, the blood component that turns malignant in chronic lymphocytic leukemia and acute lymphoblastic leukemia.
Interfering with the immune system, however, is dicey. From the start, it was clear the designer T cells had side effects that caused flulike symptoms.
Not until the seventh patient - Emily - were those effects life-threatening and unmanageable.
Her bad luck was a pattern.
When she was diagnosed with leukemia around her fifth birthday, her parents were told that it was highly treatable and that she had an 85 percent chance of beating it. Instead, despite repeated, massive batteries of chemotherapy and a bone-marrow transplant at a central Pennsylvania hospital, she had only brief periods of remission.
By March, when she qualified for the T cell therapy, "she was out of options," her father said.
She received three intravenous T cell doses on consecutive days. Soon after the last one, she went into a tailspin. Fever of 105. Dangerously low blood pressure. Hallucinations. Breathing difficulty. Terrible pain.
Despite a ventilator and an arsenal of medications, including morphine and steroids, she got worse.
"Emily may not make it through the night," her mother, Kari, wrote online on the fifth day.
What the researchers now understand is that when Emily's modified T cells began attacking her B cells, it set off a self-destructive chain reaction.
The T cells flooded her body with signaling chemicals called cytokines, particularly interleukin 6. The interleukin, in turn, stimulated cells called macrophages that normally consume cellular debris.
In Emily, the macrophages went on a rampage, gobbling her red blood cells. "Envision a little Pac-Man," Porter said, referring to the old video game.
The thing that saved her sounds like it could have come from an episode of House, the TV show about medical super-sleuths. With the lab analysis that revealed Emily's high level of interleukin 6, her doctors frantically searched the medical literature for a drug designed to block it.
June, the team leader, suggested trying tocilizumab (Actemra), a new rheumatoid arthritis drug he was following.
Overnight, Emily's vital signs went from hopeless to nearly normal.
Said Porter, "It was incredibly moving, really somewhat earth-shattering. Our whole team was on the phone, back and forth. There was such excitement and relief for this little girl and her family."
The relief was qualified. The doctors could not tell whether hindering interleukin with Actemra also rendered the T cells ineffective. That possibility led Walter Keller, 59, of Upland, Calif. - treated a month after Emily - to beg them not to give him Actemra even as he lay gravely ill from the T cell side effects.
"I kept saying, 'Don't give me the reversal drug.' I knew those T cells had to go in and do their job," Keller said. "They went 11 days before they gave the drug to me."
Keller, like Emily, is now in complete remission.
But the team's roller-coaster learning curve continues. The oldest patient, a 79-year-old man, had to be given Actemra just three days after his T cell infusion.
His cancer did not go into remission, suggesting his T cells were derailed.
Then, six weeks later, the toxic effects suddenly resurged, suggesting his T cells were working, after all. His leukemia, though not gone, has receded. The doctors can't yet explain it.
"I think we have a very good handle on how to manage the side effects," Porter said. "What we don't know is when is the right time to administer [Actemra] and whether it will interfere with the tumor response."
Emily and her parents are confident the team will figure it out. The last time at Children's," her father said, Emily "took a pen and wrote on a whiteboard: 'Thanks for the T cells,' followed by the names" of her doctors.