The Promise and Price of Cellular Therapies

But it was Patient No. 7, treated at the Children’s Hospital of Philadelphia (chop), who altered the history of T-cell therapy. In May, 2010, a five-year-old girl named Emily Whitehead, from central Pennsylvania, was diagnosed with acute lymphoblastic leukemia (ALL). Among the most rapidly progressive forms of cancer, this leukemia generates very immature B cells, and tends to afflict young children. The treatment for ALL ranks among the most intensive chemo regimens ever devised: as many as seven or eight drugs, given in combination, some injected directly into the spine. Although the collateral damage of the treatment can be daunting, it cures about eighty-five per cent of pediatric patients. Emily’s cancer, unfortunately, proved treatment-resistant; she relapsed twice, after two brief periods of remission. She was listed for a bone-marrow transplant—the only option for a cure—but her condition worsened in the meantime.

“The doctors told me not to Google it,” Emily’s mother, Kari, has recalled, of the specific mutation that Emily had. “So, of course, I did right away.” Of the children who relapse early, or relapse twice, few survive. Emily arrived at the chop in early March, 2012, with nearly every organ packed with malignant cells. She was seen by a pediatric oncologist, Stephan Grupp, and then enrolled in a clinical trial for CAR-T therapy.

“We were working against time,” June told me. A few hundred feet from where we sat was the cell-manufacturing unit—an enclosed, vaultlike facility with stainless-steel doors, aseptic rooms, and incubators—where Emily’s T cells were brought in, infected with the virus, and multiplied. The infusions themselves were largely uneventful: Emily sucked on an ice pop while Grupp dripped the cells into her veins. In the evening, she returned with her parents to her aunt’s house, nearby, where she got piggyback rides from her father, Tom. On the second evening, though, she crashed—throwing up and spiking an alarming fever. Her parents rushed her back to the hospital, and things spiralled downward. Her kidneys began to shut down. She drifted in and out of consciousness, verging on multi-organ system failure.

“Nothing made sense,” Tom Whitehead told me. Emily was moved to the pediatric intensive-care unit (PICU), placed on a ventilator, and put into an induced coma. Her parents and Grupp kept an all-night vigil.

“We thought she was going to die,” June recalled. “I wrote an e-mail to the provost at the university, telling him the first child with the treatment was about to die. I feared the trial was finished. I stored the e-mail in my out-box, but never pressed send.”

Doctors at CHOP and at Penn worked overnight to determine the cause of the fever. Once again, they found no evidence of infection; instead, they found elevated blood levels of cytokines. In particular, levels of a cytokine known as IL-6 were nearly a thousand times higher than normal. Ludwig had barely survived his cytokine storm; Emily’s was a full-on hurricane.

By a strange twist of fate, June’s own daughter had a form of juvenile arthritis, and so he knew about a drug for the condition—approved only recently by the F.D.A.—that blocks IL-6. As a last-ditch effort, Grupp rushed a request to the hospital pharmacy, asking for the off-label use of the new drug. The medication was supplied, and a nurse injected Emily with a dose in the PICU.

Days afterward, on her seventh birthday, she woke up. “Boom,” June said, waving his hands in the air. “Boom,” he repeated. “It just melted away. We did a bone-marrow biopsy twenty-three days later, and she was in a complete remission.”

“I have never seen a patient that sick get better so quickly,” Grupp told me.

The deft management of what has come to be known as cytokine-release syndrome—and Emily’s startling recovery—probably saved the field of CAR-T therapy, and helped energize cell therapy in general. She remains in deep remission to this day. No cancer is detectable in her marrow or in her blood.

“If Emily had died,” June told me, “it’s likely that the whole trial would have been shut down,” and perhaps not just at CHOP. (Other hospitals were offering experimental CAR-T therapy, too.) He wonders whether, without her recovery, there would be any living drugs.

In August, 2017, the F.D.A. approved the use of engineered T cells for chemo-resistant or relapsed ALL in children and young adults. A version of the therapy that June’s team pioneered was brought to market by Novartis and sold under the trade name Kymriah, an echo of the word “chimera.”

Does it really matter that engineered T cells—or gene therapies or genetically modified viruses and microbes—are now defined and marketed as “drugs”? Is this more than a semantic quibble? Throughout the history of medicine, students have distinguished between the history of drugs and the history of procedures, akin to separate royal lineages. In one procession are the discoverers and synthesizers of various antibiotics for infections, chemotherapeutic agents for cancers, corticosteroids for lupus, and the like. In another are the pioneers of various procedures, handcrafted by surgeons and experimental physicians and often named for their inventors: the Halsted mastectomy, Mohs surgery, the Whipple pancreatectomy. Procedures come alive in the tinkering, fussing hands of their operators, who navigate seemingly insurmountable challenges: the bone-marrow transplanter who countenances eighty-three deaths before mastering the method, the surgeon who figures out how best to transfer a piece of liver from a donor to a patient, the cardiologist who learns to maneuver a catheter through an arcing highway of the aorta just so, curving at precisely the right junction to snip a stenotic valve.

What’s transmitted—manually, individually, artisanally—to the next generation of surgeons is a process rather than a product, a skill rather than a pill. An apprentice practices the procedure over and over, as if taking lessons in an immensely complicated musical instrument; the teacher looks for the sharpness, the fettle that comes with a hundred attempts. An Emirati surgeon once described the state to me as being “in yarak,” referring to the moment when a falcon is fully primed to hunt. Procedures are typically created, nurtured, and perfected in a few hospitals, and they spread as the apprentices gain mastery, move to new places, and promulgate their know-how: see one, do one, teach one.

A drug, in contrast, is a depersonalized entity—perhaps manufactured in New Jersey, packaged in Phoenix, stamped with a name, and dispensed by an anonymous pharmacy on Fourteenth Street. It’s hooded in patents, but it’s never in yarak. Nor does an antibiotic or an antihistamine leave a patient permanently altered. But the patient who enters the operating room for a mastectomy, or is infused with CAR-T cells, emerges permanently changed, anatomically, physiologically, or genetically. And she is, in a way, a collaborator in the treatment as well as its subject.

We don’t entirely know how to regulate, or even conceptualize of, this new generation of drugs. Should the irreversible alteration of a body be governed by different rules from those that are used for conventional pharmaceuticals? Should it be priced through an alternative structure? If your cells are being genetically modified and reinfused into you, who should we say owns them? Once the cellular therapy has been created, could you store it by yourself—in your home freezer, if you chose—for future use? Emily Whitehead’s extra chimerized T cells are frozen inside a steel tank at the Penn hospital. Each freezer has a nickname based on a “Simpsons” character. Hers is called Krusty the Clown.

Perhaps the most immediate implication of the blurring of lines between procedure and drug is the conundrum of price. A single dose of Kymriah for pediatric ALL is priced at $475,000; for Yescarta, a CD19 T-cell therapy designed for certain types of non-Hodgkin’s lymphoma, that number is $373,000. These prices rival those of some of the most expensive procedures in American medicine. (A kidney transplant can be priced at $415,000, a lung transplant at about $860,000.) And these price tags don’t include the delivery of post-therapy care to CAR-T patients, who typically suffer complications from the infusion. Subsequent hospital stays and supportive care can drive the total costs to a million dollars or more. Merely counting the seventy-five hundred U.S. patients who meet the current F.D.A. indications for Yescarta, the estimated annual expenditure could be three billion dollars.

Dozens of labs around the world are now developing CAR-T therapies that work on different targets and different cancers. In May, a multicenter study demonstrated striking response rates for an experimental CAR-T therapy aimed at relapsed multiple myeloma. My own laboratory, at Columbia, is creating T cells aimed at relapsed cases of acute myelogenous leukemia, for which the survival rates have been dismal. Other teams are testing chimerized natural-killer cells against glioblastoma and certain lymphomas. If the number of patients responsive to such therapies increased severalfold—as clinical indications expand, and as these therapies go from last ditch to front line in certain patient groups—the expense would dwarf the annual budget of the N.I.H. and could bankrupt the American health-care system.

But it was Patient No. 7, treated at the Children’s Hospital of Philadelphia (chop), who altered the history of T-cell therapy. In May, 2010, a five-year-old girl named Emily Whitehead, from central Pennsylvania, was diagnosed with acute lymphoblastic leukemia (ALL). Among the most rapidly progressive forms of cancer, this leukemia generates very immature B cells, and tends to afflict young children. The treatment for ALL ranks among the most intensive chemo regimens ever devised: as many as seven or eight drugs, given in combination, some injected directly into the spine. Although the collateral damage of the treatment can be daunting, it cures about eighty-five per cent of pediatric patients. Emily’s cancer, unfortunately, proved treatment-resistant; she relapsed twice, after two brief periods of remission. She was listed for a bone-marrow transplant—the only option for a cure—but her condition worsened in the meantime.

“The doctors told me not to Google it,” Emily’s mother, Kari, has recalled, of the specific mutation that Emily had. “So, of course, I did right away.” Of the children who relapse early, or relapse twice, few survive. Emily arrived at the chop in early March, 2012, with nearly every organ packed with malignant cells. She was seen by a pediatric oncologist, Stephan Grupp, and then enrolled in a clinical trial for CAR-T therapy.

“We were working against time,” June told me. A few hundred feet from where we sat was the cell-manufacturing unit—an enclosed, vaultlike facility with stainless-steel doors, aseptic rooms, and incubators—where Emily’s T cells were brought in, infected with the virus, and multiplied. The infusions themselves were largely uneventful: Emily sucked on an ice pop while Grupp dripped the cells into her veins. In the evening, she returned with her parents to her aunt’s house, nearby, where she got piggyback rides from her father, Tom. On the second evening, though, she crashed—throwing up and spiking an alarming fever. Her parents rushed her back to the hospital, and things spiralled downward. Her kidneys began to shut down. She drifted in and out of consciousness, verging on multi-organ system failure.

“Nothing made sense,” Tom Whitehead told me. Emily was moved to the pediatric intensive-care unit (PICU), placed on a ventilator, and put into an induced coma. Her parents and Grupp kept an all-night vigil.

“We thought she was going to die,” June recalled. “I wrote an e-mail to the provost at the university, telling him the first child with the treatment was about to die. I feared the trial was finished. I stored the e-mail in my out-box, but never pressed send.”

Doctors at CHOP and at Penn worked overnight to determine the cause of the fever. Once again, they found no evidence of infection; instead, they found elevated blood levels of cytokines. In particular, levels of a cytokine known as IL-6 were nearly a thousand times higher than normal. Ludwig had barely survived his cytokine storm; Emily’s was a full-on hurricane.

By a strange twist of fate, June’s own daughter had a form of juvenile arthritis, and so he knew about a drug for the condition—approved only recently by the F.D.A.—that blocks IL-6. As a last-ditch effort, Grupp rushed a request to the hospital pharmacy, asking for the off-label use of the new drug. The medication was supplied, and a nurse injected Emily with a dose in the PICU.

Days afterward, on her seventh birthday, she woke up. “Boom,” June said, waving his hands in the air. “Boom,” he repeated. “It just melted away. We did a bone-marrow biopsy twenty-three days later, and she was in a complete remission.”

“I have never seen a patient that sick get better so quickly,” Grupp told me.

The deft management of what has come to be known as cytokine-release syndrome—and Emily’s startling recovery—probably saved the field of CAR-T therapy, and helped energize cell therapy in general. She remains in deep remission to this day. No cancer is detectable in her marrow or in her blood.

“If Emily had died,” June told me, “it’s likely that the whole trial would have been shut down,” and perhaps not just at CHOP. (Other hospitals were offering experimental CAR-T therapy, too.) He wonders whether, without her recovery, there would be any living drugs.

In August, 2017, the F.D.A. approved the use of engineered T cells for chemo-resistant or relapsed ALL in children and young adults. A version of the therapy that June’s team pioneered was brought to market by Novartis and sold under the trade name Kymriah, an echo of the word “chimera.”

Does it really matter that engineered T cells—or gene therapies or genetically modified viruses and microbes—are now defined and marketed as “drugs”? Is this more than a semantic quibble? Throughout the history of medicine, students have distinguished between the history of drugs and the history of procedures, akin to separate royal lineages. In one procession are the discoverers and synthesizers of various antibiotics for infections, chemotherapeutic agents for cancers, corticosteroids for lupus, and the like. In another are the pioneers of various procedures, handcrafted by surgeons and experimental physicians and often named for their inventors: the Halsted mastectomy, Mohs surgery, the Whipple pancreatectomy. Procedures come alive in the tinkering, fussing hands of their operators, who navigate seemingly insurmountable challenges: the bone-marrow transplanter who countenances eighty-three deaths before mastering the method, the surgeon who figures out how best to transfer a piece of liver from a donor to a patient, the cardiologist who learns to maneuver a catheter through an arcing highway of the aorta just so, curving at precisely the right junction to snip a stenotic valve.

What’s transmitted—manually, individually, artisanally—to the next generation of surgeons is a process rather than a product, a skill rather than a pill. An apprentice practices the procedure over and over, as if taking lessons in an immensely complicated musical instrument; the teacher looks for the sharpness, the fettle that comes with a hundred attempts. An Emirati surgeon once described the state to me as being “in yarak,” referring to the moment when a falcon is fully primed to hunt. Procedures are typically created, nurtured, and perfected in a few hospitals, and they spread as the apprentices gain mastery, move to new places, and promulgate their know-how: see one, do one, teach one.

A drug, in contrast, is a depersonalized entity—perhaps manufactured in New Jersey, packaged in Phoenix, stamped with a name, and dispensed by an anonymous pharmacy on Fourteenth Street. It’s hooded in patents, but it’s never in yarak. Nor does an antibiotic or an antihistamine leave a patient permanently altered. But the patient who enters the operating room for a mastectomy, or is infused with CAR-T cells, emerges permanently changed, anatomically, physiologically, or genetically. And she is, in a way, a collaborator in the treatment as well as its subject.

We don’t entirely know how to regulate, or even conceptualize of, this new generation of drugs. Should the irreversible alteration of a body be governed by different rules from those that are used for conventional pharmaceuticals? Should it be priced through an alternative structure? If your cells are being genetically modified and reinfused into you, who should we say owns them? Once the cellular therapy has been created, could you store it by yourself—in your home freezer, if you chose—for future use? Emily Whitehead’s extra chimerized T cells are frozen inside a steel tank at the Penn hospital. Each freezer has a nickname based on a “Simpsons” character. Hers is called Krusty the Clown.

Perhaps the most immediate implication of the blurring of lines between procedure and drug is the conundrum of price. A single dose of Kymriah for pediatric ALL is priced at $475,000; for Yescarta, a CD19 T-cell therapy designed for certain types of non-Hodgkin’s lymphoma, that number is $373,000. These prices rival those of some of the most expensive procedures in American medicine. (A kidney transplant can be priced at $415,000, a lung transplant at about $860,000.) And these price tags don’t include the delivery of post-therapy care to CAR-T patients, who typically suffer complications from the infusion. Subsequent hospital stays and supportive care can drive the total costs to a million dollars or more. Merely counting the seventy-five hundred U.S. patients who meet the current F.D.A. indications for Yescarta, the estimated annual expenditure could be three billion dollars.

Dozens of labs around the world are now developing CAR-T therapies that work on different targets and different cancers. In May, a multicenter study demonstrated striking response rates for an experimental CAR-T therapy aimed at relapsed multiple myeloma. My own laboratory, at Columbia, is creating T cells aimed at relapsed cases of acute myelogenous leukemia, for which the survival rates have been dismal. Other teams are testing chimerized natural-killer cells against glioblastoma and certain lymphomas. If the number of patients responsive to such therapies increased severalfold—as clinical indications expand, and as these therapies go from last ditch to front line in certain patient groups—the expense would dwarf the annual budget of the N.I.H. and could bankrupt the American health-care system.