When it comes to creating lifesaving medical therapies, one small observation can make all the difference.
In September 1999, Jesse Gelsinger, an 18-year-old boy from Tuscon, Arizona, was admitted to the Hospital of the University of Pennsylvania for a novel form of gene therapy. Jesse had suffered from birth from the lack of an enzyme, called ornithine transcarbamylase, which was necessary to rid his body of ammonia: a breakdown product of protein metabolism. High levels of ammonia in the bloodstream can cause coma, brain damage, and death. To avoid this ammonia build-up, Jesse ate a low-protein diet and took 32 pills a day.
After he was admitted to the hospital, doctors injected Jesse with a virus (adenovirus) that contained the gene that he needed to avoid his restrictive diet and complicated medical regimen. The hope was that the virus would travel to the liver, enter liver cells, and deliver the gene that Jesse needed to avoid ammonia build-up. Prior to Jesse’s injection, this particular gene therapy had been tested in mice, monkeys, baboons, and one person. As far as the researchers knew, it was safe.
But it wasn’t safe in Jesse. Within days, Jesse developed “cytokine storm.” Cytokines are proteins made by immune cells that help the body to fight infection. Sometimes, however, cytokines set off a cascade of events that can be fatal. In other words, in an attempt to ward off foreign invaders, our immune system can occasionally kill us in a reaction called a cytokine storm; that cytokine storm eventually killed Jesse.
Fast forward 11 years. In 2010, 5-year-old Emily Whitehead was diagnosed with acute lymphoblastic leukemia (ALL). After just one round of chemotherapy, she was in remission. Seventeen months later, however, she relapsed. A second round of chemotherapy brought her back into remission, but four months later, she relapsed yet again (PDF).
Emily’s leukemia involved a type of immune cell called a B-cell. Mature B-cells make antibodies. Patients with chemotherapy-resistant, relapsed, B-cell ALL have an extremely poor prognosis. Even aggressive therapies like bone marrow transplants don’t offer much hope. One of Emily’s doctors recommended hospice care.
Emily’s parents weren’t ready to give up, though. They wanted to try something, anything, even if it was highly experimental, to save their daughter’s life. So they took her to the Children’s Hospital of Philadelphia (CHOP) where one particular therapy was in its infancy—a therapy that was developed by a team of researchers headed by Dr. Carl June at the University of Pennsylvania School of Medicine. This particular therapy had never been tested in children. Emily would be the first.
Called CAR-T therapy, this novel treatment involved taking one type of the patients own immune cells, called T-cells, and re-engineering them. People have different kinds of T-cells. Some T-cells, called helper T-cells, help B-cells make antibodies. Other T-cells, called cytotoxic T-cells, kill virus-infected cells. The University of Pennsylvania researchers believed that they could take Emily’s cytotoxic T-cells and re-engineer them so that instead of killing virus-infected cells, they would kill Emily’s cancer cells. The protein that would be recognized by these killer T-cells, which resided on the surface of Emily’s cancerous B-cells, was called CD19. The therapy was named CART-19. (CAR stands for Chimeric Antigen Receptor.)
When she was 7-years-old, Emily was injected with T-cells that had been engineered to kill her leukemic cells. Initially, she felt fine. No immediate reaction to the therapy. Four days later, however, when she developed a low-grade fever, Emily was taken to the hospital where she could be observed more closely. The next day, when her fever worsened, she was brought up to the intensive care unit. Within hours, she went into shock, requiring three intravenous medicines to support her blood pressure. Then her lungs filled with fluid, requiring mechanical ventilation. Emily was dying, and it wasn’t clear why.
Dr. Stephan Grupp was the oncologist at CHOP in charge of Emily’s care. As per protocol, Emily’s blood was periodically sent off and tested for many indicators, one of which was the presence of cytokines. Cytokines are proteins made by immune cells that help the body to fight infection. Sometimes, however, cytokines set off a cascade of events that can be fatal. Said another way, in an attempt to ward off foreign invaders, our immune system can occasionally kill us in a reaction called “cytokine storm.” Grupp wasn’t willing to wait two weeks to find out whether Emily was suffering from cytokine storm. He insisted that the University of Pennsylvania laboratory test Emily’s blood immediately for the presence of these potentially destructive cytokines.
Two hours after Emily’s collapse, the Penn lab found that one particular cytokine, called interleukin-6 (or IL-6), was elevated to a level 1,000-fold greater than baseline. “No one thought we should be thinking about this thing: IL-6,” said Grupp. “It isn’t even made by T-cells.” June knew that a monoclonal antibody directed against IL-6, which was used to treat rheumatoid arthritis in children, was commercially available. What he didn’t know—and what he asked Grupp to check out—was whether CHOP’s formulary had any on hand.
Fortunately, it did. Rather than having to wait two days to get the drug shipped into the hospital, Emily received it that night. Her improvement was immediate. She was weaned quickly off of the medicines that supported her blood pressure and the ventilator that supported her breathing. On her 7th birthday, Emily woke up. Eight days later, following the results of a bone marrow, she was declared cancer-free. Today she is a thriving, happy 12-year-old. Her survival re-energized a therapy that at the time had been floundering.
In August 2017, the Food and Drug Administration approved the first CAR-T therapy, Novartis’ tisagenlecleucel, for patients up to 25 years of age who, like Emily, has relapsed or refractory ALL. To date, 83 percent of the more than 60 children who have received this therapy have completely eliminated their cancer within three months. CAR-T therapy has also been shown to be effective against aggressive non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Forty companies are now in partnership with academic institutions to develop CAR-T therapies for a myriad of diseases. Of interest, 78 percent of the patients who have received CAR-T therapy have suffered cytokine storm. But now, thanks to Grupp’s quick thinking, doctors know what to look for and what to do about it.
Had Emily not survived her CART-19 therapy, as Grupp has noted, the field of CAR-T therapy might have died with her (PDF). In some respects, that’s exactly what happened to gene therapy in 1999, when Jesse Gelsinger died from the same disorder that almost killed Emily Whitehead. The difference between these two stories shows how tenuous medical advances can be. The difference between Jesse and Emily was that Jesse’s doctors didn’t know at the time which specific cytokines had caused the problem. And even if they had known, and known quickly, the IL6-specific monoclonal antibodies that were available to treat Emily weren’t commercially available in 1999, when Jesse suffered his fatal illness. As a consequence, progress in gene therapy was delayed by about a decade.
Medical knowledge invariably comes with a price. And although we would like to believe that it is easily avoided, the suffering inflicted during the early stages of development—whether it is from bone marrow transplants or kidney transplants or heart transplants or novel chemotherapies or antibiotics or lipid-lowering agents or neurological drugs or novel surgeries—is invariant. “There was no way to predict a great deal of what we learned,” Grupp recalled. “The toxicity issues can only be learned from human beings.” In the end, Jesse Gelsinger’s death helped to prevent Emily Whitehead’s death. If only there was another way.