The Best American Science and Nature Writing 2020

by Michio Kaku

  Was it possible to rebuild T cells in order to increase their sensitivity to cancerous interlopers? In the late 1980s and early ’90s, an Israeli immunologist named Zelig Eshhar, who was a beekeeper in his youth, had set out to create a peculiar hybrid of the two wings of the immune system. Instead of the usual receptor, this T cell would mount a molecular chimera on its surface—​a protein that would use the Velcro-like property of an antibody to attach to a cancer cell, combined with the receptor protein that activates the cell to mount an immune response. He called these genetically manipulated entities T bodies. The hope was to bring together the detective skills of a T-cell receptor and the destructive properties of an antibody: these were meant to be drug-sniffing dogs with sharp teeth. But, though Eshhar’s cells could detect their targets, they didn’t have the long-term potency needed to control cancer.

  A crucial breakthrough arrived in the nineties. Michel Sadelain, a postdoctoral researcher at the Massachusetts Institute of Technology, began to work on methods to introduce foreign genes directly into T cells. This gene-delivery technology would soon give rise to a new generation of T cells, able not just to target cancers but also to mount long-term, durable immune responses by amplifying the receptor signals in critical ways. “T cells could die or become exhausted if their signals were not amplified and sustained,” Sadelain told me. “The strategy was to activate immunity by genetically weaponizing them.” Skeptics questioned the logic of the approach. “Why would you do that?” Sadelain recalls his critics asking. T cells, after all, were already capable of recognizing and attacking aberrant cells. Why try to reengineer them with the properties they naturally possess? Wasn’t that like forcing remedial Spanish lessons on a Spaniard?

  It’s true that donor T cells, in marrow-graft patients, could hunt down the host’s cancer cells, but they were indiscriminate in their hostilities, in ways that could be lethal. The trick was to get T cells to recognize and respond to cancers both more selectively and more effectually. Merely equipping a T cell with an antibody on its surface wasn’t enough. That antibody had to behave as if it were an integral part of the T cell’s system of binding, recognition, activation, and memory. Helene Finney, a researcher at the biotech company Celltech, had also begun to design such a receptor for T cells. The result—​genetically modified T cells equipped with “chimeric antigen receptors” that were fully integrated into their immune functions—​would be termed CAR-T cells, or CAR-Ts. In the course of the nineties, Sadelain and his team perfected the “weaponization” of a T cell into a CAR-T cell. They found that these CAR-T cells could kill cancer cells not only in petri dishes but also in mice carrying human tumors, and that they would persist in the mice even after the tumor had vanished. It was Sadelain who later described them as “living drugs.”

  But what molecular target should an engineered T cell be instructed to recognize? By 1997, Sadelain’s team had come to focus on a molecule called CD19, which is present in certain blood cancers, including many kinds of lymphomas and leukemias, in which a class of white blood cells—​B cells—​proliferate in a malignant form. Unfortunately, CD19 is not cancer-specific: normal B cells also have CD19 on their surface. The engineered T cells would target those healthy cells too. But biology occasionally grants escape hatches for experimental therapies: B cells are not absolutely required for human survival. There would be a cost to their destruction—​without these cells, patients can’t generate proper antibody responses, and so become immunocompromised—​but patients could be kept alive with transfusions of antibodies.

  In December 2003, June began a collaboration with two scientists, Dario Campana and Chihaya Imai, who were working at St. Jude Children’s Research Hospital, in Memphis, to craft T cells that would target CD19. (The collaboration, cordial to begin with, spiraled into an acrimonious dispute. St. Jude successfully argued that its researchers weren’t properly credited with having designed the receptors for the chimerized cells.) Then June, in the wake of Sadelain’s work, grew the modified cells in petri dishes and transferred them into mice, where they seemed to be startlingly active, capable of killing leukemia cells. Sadelain, by then at the Memorial Sloan Kettering Cancer Center, in New York, had devised and was preparing to launch clinical trials to study the effectiveness of an anti-CD19 T-cell therapy. So were Riddell and the oncologist-immunologist Michael Jensen, in Seattle. And so, too, was Steven Rosenberg, at the NCI, in Bethesda.

  “Was it a cooperative group?” I asked June. I recalled that Rosenberg’s team was the first to publish human data on a CD19-targeting therapy, in July 2010; June and Sadelain followed, in August and November 2011, respectively.

  He hesitated, a wary smile inching across his face. He looked like John Malkovich, with his hollow cheeks and arresting intensity. “Yes and no,” he said. “We were competing with one another, but we were also writing grants together.”

  It had taken nearly a decade to perfect the engineering of T cells for human testing. But the biggest hurdle was the amount of tinkering required for their manufacture and production. Working independently, June, Sadelain, and Rosenberg, among other researchers, had to infect a culture of T cells with a virus—​which had been disabled so that it couldn’t cause disease—​that would deliver the chimeric receptors. The engineered strain of cells then had to be multiplied in a special brew of nutrients and growth factors. Technicians and postdoctoral scientists nurtured the cells like a million hungry babies, watching them grow day by day. “We had to set up the virus production and build a cell-therapy facility at Penn,” June recalls. “It was not trivial.”

  By 2010, the first patient at Penn was ready to be treated: a sixty-five-year-old retired corrections officer named Bill Ludwig, who had enrolled in the CAR-T trial that June was leading together with the oncologist David Porter. Ludwig had a relapsed, chemo-resistant form of chronic lymphocytic leukemia, in which malignant B cells proliferate. A previous experimental trial, at the National Institutes of Health, had almost killed him, and his cancerous B-cell counts were rising every day. He had some T cells extracted, and, in ten days, the cells had been infected with the virus and grown seven-hundredfold—​enough for several doses.

  On August 3, Ludwig was infused with the first dose of his genetically modified T cells. Two more infusions and a few days of waiting followed—​and then he fell terrifyingly ill. Every system was failing rapidly—​lungs, kidneys, heart—​amid a racking fever. Porter was convinced that Ludwig had contracted some unusual infection, but no bacteria or virus could be found. He spent the next week in the ICU.

  “But then, all of a sudden, he woke up,” June told me. “It was only then that we examined his nodes, and the tumor masses had disappeared. We did a bone-marrow biopsy on day twenty-eight and there was no leukemia. I didn’t believe it, so I asked them to do another biopsy at day thirty-one. And, again, no leukemia.”

  It was weeks before Porter and June realized that this febrile illness—​in which Ludwig’s core body temperature had climbed to 105 degrees (“The nurses threw the thermometers away, thinking that they had broken,” June recalls)—​was a result of T cells and their target cells secreting potent inflammatory factors called cytokines. Ludwig had experienced one of the most active inflammatory responses ever witnessed. The infused cells were, in fact, destroying the cancer, slicing apart its membranes, mincing its innards. Nearly a month after his infusion, Ludwig recovered from his illness and went into a complete remission. Nine years later, Penn’s Patient No. 1 remains alive and cancer-free.

  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 d
rugs, given in combination, some injected directly into the spine. Although the collateral damage of the treatment can be daunting, it cures about 85 percent 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 spiraled 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 email 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 email 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 1,000 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 FDA—​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 FDA 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 7,500 U.S. patients who meet the current FDA indications for Yescarta, the estimated annual expenditure could be $3 billion.

  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 chi
merized 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 NIH and could bankrupt the American health care system.

  Drug pricing is, of course, at the center of a familiar and inevitably acrimonious debate. The pharmaceutical industry defends high prices as a means to recoup the costs of drug discovery and development. Consumers, insurers, and governments argue that the prices charged for drugs are out of control, and bear no relationship to their real costs. But with cellular therapies the problem isn’t merely profiteering—​it is that, unlike conventional drugs, cell therapies are inherently expensive to produce. The estimated cost to manufacture a typical CAR-T infusion is close to six figures. In short, even if CAR-T therapy were offered with no margin of profit, it would still rank with some of the most expensive procedures in medicine. Extracting cells from an individual patient, purifying them, genetically modifying them, and expanding their numbers into the millions will never be akin to churning out amoxicillin in a factory.

  When Novartis brought Kymriah to market, in 2017, it sought to offset concerns about its daunting price with an extraordinary offer: if the therapy did not work after the first month, treatment centers wouldn’t be charged. That’s almost unheard of in medicine, and it represents an extraordinary degree of optimism, which may or may not prove justified in the long term. June points out that we don’t yet know which patients are likely to respond to the therapy. Ninety-four percent of relapsed and chemo-resistant ALL patients treated at CHOP achieve a complete remission at one month; many, like Emily Whitehead, are likely cured. For a certain class of drug-resistant patients with another form of leukemia, called CLL, the response rate with CAR-T therapy is around 75 percent, to judge from the most recent trial data. Eighty-five percent of drug-resistant patients with multiple myeloma—​a malignancy of the blood’s plasma cells—​have either a complete or a partial response to the therapy, but more than a third of complete responders relapse within a year. (When it comes to yet other cancers, particularly solid tumors, such as pancreatic and ovarian cancer, cellular therapies have yet to produce reliable results.)