Living Cancer Drug CAR T-Cell Therapy Turns 10: The Lives It Has Changed Will Amaze You

10 years ago, every treatment Dr. Stephan Grupp could offer a 6-year-old child with acute lymphoblastic leukemia had been exhausted. The doctor turned to uncharted territory in pediatric cancer treatment.

Dr. Grupp, a pioneer of cellular immunotherapy at Children's Hospital of Philadelphia, conducted the first clinical trial in children of chimeric antigen receptor (CAR) T-cell therapy, a phase-1 trial.

“The trial opened a last-minute window that could help my little patient. There was nothing else to buy time to make decisions about her future… It had to open then or never.”

The patient was Emily Whitehead, who has since become the poster girl for these new treatments. After receiving a single dose of CAR T-cell therapy in 2012, she was freed of her leukemia and has remained in remission—showing no signs of disease—for more than 10 years.

Dr. Grupp says he has finally started using the word “cure (complete recovery).”

“I am not just a doctor; I am also a scientist—and a single case is not enough to have confidence in a new treatment. More patients need to have received this new treatment over a longer period before we can say what is called a ‘cure.’ CAR T-cell therapy is now given to hundreds of patients at the hospital where I work, and—we are unique in this—we have several dozen patients who have not needed any treatment for 5, 6, 7, 9 or more years. That is a cure.”

The First ALL Patient

Emily was the first patient with ALL (acute lymphoblastic leukemia) to receive this treatment, and she was also a child. It was a landmark case. After more than 10 years at an impasse, the field of CAR T-cell therapy had recently achieved a breakthrough thanks to Grupp's colleague Carl June and his team at the University of Pennsylvania. By taking 2 key steps in genetically modifying T cells, June's team successfully treated 3 patients with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.

However, using the treatment in a child and for a different form of leukemia was a daunting prospect. Grupp candidly emphasized to Emily's parents, Tom and Kari Whitehead, that there are no guarantees in cancer treatment, especially in phase-1 trials.

But the Whiteheads had no time to lose and no other options. Her father, Tom, describes the situation: “Something outside the ordinary—this would give her a chance.”

Grupp, who describes himself as the last cowboy in oncology, was ready to begin treatment. None of them knew that it would make Emily even sicker and land her in intensive care. Yet a combination of some luck and a great deal of brainpower led to a breathtakingly rapid recovery.

The Magic Formula

CAR T-cell therapy involves collecting the patient's immune-system T cells and modifying them in the laboratory with a chimeric antigen receptor to target CD19, a protein on the surface of ALL cancer cells.

Before the University of Pennsylvania team refined the process, clinical trials of the treatment had produced only a small number of positive results. Grupp explained why: “The modified T cells are very potent in the short term, but have almost no capacity to multiply once they are returned to the patient. What matters is not how many cells you give the patient, but whether they multiply to the level needed to control leukemia in that patient.”

June's team found what Grupp calls the “magic formula”: bead-based manufacturing that produces younger T-cell phenotypes with a “tremendous” capacity to multiply, and a lentiviral approach to genetic modification that enables long-term expression of CAR T molecules.

“Was it risky? Frankly… We were all diving into water whose bottom we could not see. So I can say, yes, it was risky, and I would also say that we knew almost nothing about the risk.”

Cytokine Storm

The most serious risk Grupp and his team faced was unexpected. At the time, they could not name it. Three adults with CLL who received CAR T-cell therapy had experienced a mild version of what researchers described as “tumor lysis (breakdown) syndrome.” For Emily, however, day 3 of the CAR T-cell infusion brought a storm of severe reactions, later named cytokine release syndrome (CRS).

Her father, Tom, described his daughter's condition:

“Things took a turn for the worse. I remember her blood pressure being very high. The doctors took her to intensive care; she was in a coma, and they put her on a ventilator. It was brutal to watch her like that. Blood was bubbling around the ventilator tube in her mouth. I remember the third or fourth night, a doctor called me into the hallway and said, ‘When the sun comes up, your daughter has a one-in-a-thousand chance of being alive.’ And I said, ‘Well, I will see you on rounds tomorrow, because she will still be here.’”

Grupp explained:

“We were facing an unknown side effect… Intensive care went all out to keep her alive. They used everything they had to keep a person alive; there was nothing else they could do. At one point, we ran out of options—we were spent.”

Time to Make a Move

The team then had several strokes of luck. The first came when they decided to examine her cytokines.

“All our accumulated knowledge came together at that moment, precisely when Emily was so ill. Could we get the result quickly enough? The laboratory dropped everything to do the test.”

They ordered an extensive cytokine panel with 30 parameters. The results showed “incredibly elevated” cytokine levels. These included interleukin-6 (IL-6).

IL-6 is not even produced by T cells, so nobody in the world could have predicted that it would be important. Had they ordered a smaller panel, they might not have noticed it.

“Yet this was the only cytokine for which we had a drug: tocilizumab. So that was luck. Another stroke of luck was that the drug was in the hospital because there were rheumatology patients receiving it. After identifying elevated IL-6 and finding at 3:00 that there was a drug for it, we gave it to her at 8:00. Emily's clinical condition then turned around very quickly. I mean, within hours.”

On her seventh birthday, Emily awoke from a 14-day medically induced coma. Eight days later, her bone marrow showed complete remission. Emily's father, Tom, says the doctors “had never seen someone so sick recover so quickly.”

Emily had undergone a series of leukemia treatments. After 22 months of unsuccessful standard treatment, she was cancer-free just 23 days after receiving her first dose of CAR T-cell therapy.

Emily, now 17, has been in remission for 10 years. Grupp finally wants to use the word “cure”—but it took him a long time to reach that point.

“This is not a miracle. We can get patients into remission more than 90% of the time—but some patients may relapse—and there are risks at that stage, such as a potentially life-threatening cytokine storm. Currently, in our experience, around 12% of patients enter intensive care, but almost none become as sick as Emily… because we now give tocilizumab much earlier.”

Since their daughter's recovery, Tom and Kari Whitehead have devoted much of their time to raising awareness of the treatment that saved Emily's life. Tom testified at a United States Food and Drug Administration (FDA) committee meeting in 2017 when approval was being considered for the CAR T-cell product Emily had received. The product is tisagenlecleucel-T (Novartis), and the committee unanimously recommended approval at that meeting. It was the first CAR T-cell product to reach the market.

As cofounders of the Emily Whitehead Foundation, Tom and Karis have helped raise more than 2 million dollars to support research in the field. They travel the world to “advance this revolution” and tell their story. They say that, alongside the science that saved their daughter, luck and faith were also with them.

On several occasions, Tom and Kari declined treatment offered to Emily. But Tom recalls telling his wife: “I told Kari that Emily was definitely going to beat cancer—I had seen it. I do not know how it will happen, but we are going to teach her to walk again in those bone marrow transplant corridors. I know many doctors do not want to hear anything about ‘a sign’ or something guiding us, but I do not think we have to separate faith and science. I think it takes everything for something like this to happen.”

• Related topic: Delivering CAR T Cells in a Special Gel Could Make a Difference in Cancer Treatment

A Lasting Effect

Grupp said that cell proliferation was the key to the CAR T-cell breakthrough that led to Emily's treatment, and that the effect has persisted beyond all expectations. Genetically engineered T cells remain detectable in Emily and in other patients in long-term remission.

“The fundamental question is whether the cells are still working or whether the patients are cured and no longer need them.”

“Oncologists have different ideas about what the word ‘cure’ means. My position is that if the probability of a disease recurring is lower than other risks in your life, such as getting in your car and driving to an appointment, that constitutes a functional cure.”

“I am probably still the doctor who sees Emily most often, but frankly, the conversation is not entirely about leukemia. She has B-cell aplasia, so we have to treat that, and then we talk about making sure there are no long-term side effects from the entirety of her treatment. Generally, for a patient who has received a moderate amount of chemotherapy and CAR T cells, this should not affect fertility. Has any patient in the history of the world relapsed more than 5 years after treatment? Of course. Is it incredibly rare? Yes, it is.”

As for the Whiteheads, they are focusing on Emily's college applications, her new driver's license and a project to write a film about her story with a Hollywood filmmaker. Tom says the one thing he hopes doctors take from their story is that sometimes a parent's instinct goes beyond science.

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