by Sam Kean
Previously, researchers had created a fake key called a chimeric antigen receptor, or CAR, that matched a particular lock, CD19, on B-cells, which is where Ludwig’s leukemia was. During the trial, Ludwig’s doctors removed as many of Ludwig’s T-cells as they could, and June’s team inserted the CAR using a modified form of HIV, which can edit genes. Then they returned the T-cells to Ludwig.
Ten days later, Ludwig started to have chills and fever, like he had the flu. He was so ill that doctors moved him to the intensive care unit. But then, less than a month later, he was in remission. The T-cells had located and demolished the cancer, the same way they would a virus.
When case studies of the first three patients were published in scientific journals, mainstream media went crazy: “Cancer treated with HIV!” they shouted. But it was a later study that showed that the furor was warranted: when the Penn team partnered with the Children’s Hospital of Philadelphia to try CAR-T cell therapy against B-ALL in children, the cancer disappeared in 24 out of 27 patients.
Novartis was the drug company that partnered with the University of Pennsylvania to turn June’s treatment into a drug for the general public, and the company submitted results of all three required levels of tests to the Food and Drug Administration early this year. If the FDA approves the drug, any child who has B-ALL and has failed her first therapy can have her white blood cells removed, frozen, and shipped to Novartis’s processing facility in Morris Plains, New Jersey, where molecular engineers will insert the new “key” and send the T-cells back. The patient gets a one-time infusion, and there’s an 83 percent chance she will be cured.
“We also do a second measure of remissions where we look to see if there’s any measurable disease at all,” says David Lebwohl, Novartis’s global program head for CAR-T treatments. “A more sensitive test than just looking in the blood. And that was also negative for 83 percent of the patients.”
An 83 percent cure rate in children who would otherwise die is a monumental achievement. If there is a moment where a culture hits on an idea that can cure a disease—vaccines, for example, or penicillin—we are in it. It is difficult to overstate this: humans have been trying to create a cell therapy for cancer patients for generations. “People said: That can’t be done, You can’t make them from cancer patients, You can’t make them, You can’t get them, It’s too complicated,” says Crystal Mackall. “But it’s happening.” Though Novartis couldn’t confirm an official release date, Mackall suspects the drug will become widely available this year.
Cancer being cancer, of course, there are limitations: until it clears further FDA hurdles, Novartis’s drug will be available only for children with B-ALL and not for any of the dozens of other types of cancers that affect children and adults. In solid tumors, the CAR-T cells aren’t strong enough to kill the whole thing, or they die before they finish the job. Worse, once attacked, some leukemia cells will remove their CD19 proteins and go back into hiding. “The thing about cancer is, it’s quite a foe,” Mackall says. “The minute you think you’ve got the one thing for it, it’ll outsmart you.”
Slowly, though, the successes are mounting. At City of Hope National Medical Center just outside Los Angeles, Behnam Badie, an Iranian-born brain surgeon who has the kind of bedside manner you’d dream of if you ever required a brain surgeon, is developing a surgical device that can continuously infuse CAR-T cells into the brain tumors of cancer patients while he operates. For a while, he was working with the California Institute of Technology to build a magnetic helmet that could move the cells to the correct places, but the project ran out of money.
Meanwhile, Crystal Mackall is working on a backup target for the CAR-T cells, CD22, in case a child’s cancer resists the ones targeted to CD19. She is also trying to make the cells live longer. Working with similar but slightly different engineered cells, she has managed to get her therapy to stay alive and working for up to two years in patients with solid sarcomas. One of her patients has since gotten married and bought a farm. Another went on a volunteer trip to Africa.
Mackall likens genetically engineered cells to rudimentary machines. Over the next decade, she says, scientists will refine them until they can control where they go and what they do and when. “We’re going to be in a situation,” she says, “where a doctor can tell a patient to take pills to activate his cells one week and then rest them the next.” In fact, a biotech company based in San Diego called BioAtla has already developed conditionally active markers that could tell a T-cell to kill or not kill based on where it is in the body.
Eventually, programmable cell machines could fight autoimmune diseases, or arthritis. They could be used to rebuild collagen in athletes’ knees. But, because such powerful new technology requires a ton of risk to attempt, none of this would have been developed without an adversary as vile as cancer to require it. “We treated 49 kids at the National Cancer Institute with refractory leukemia. Every single one of those kids had exhausted every other therapy available. If it weren’t for the CAR-T cells, they were gonna die,” Mackall says. Sixty percent of those children went into remission, and a sizable fraction of those appear to be cured. “You’re able to take the chance only in that situation, when people don’t have other options.”
People will die waiting for CAR-T therapy to really, truly happen. In the United States, doctors aren’t permitted to experiment on patients who have other options, and it will take a long time for CAR-T to prove itself better than the treatments already available. But someone has to choose to take the first walk down the path to the future. In a final act that is equal parts self-preservation and sacrifice, that person is usually a cancer patient. And soon, more of them will be able to make the decision for themselves.
Interlude
“What’re ya down here for?” asks an older gentleman at the bar of a tourist barbecue joint near my hotel in Memphis. I’m halfway through a plate of pickles and dry-rubbed ribs. I explain that I’ve spent all day at St. Jude.
“God bless you,” he says. “I couldn’t do it.” The man is from Texas—he works in shipping or packing or something or other.
The bartender, a bubbly twenty-three-year-old, offers the gentleman another beer. “You know, I was treated at St. Jude. Diagnosed at ten. Cured at thirteen,” he says, beaming.
“Was it awful?” I ask. “Getting cancer as a kid?”
“Naw, I loved going to St. Jude. I remember I looked forward to school being over so I could go over to the hospital and get chemo. Your doctors are so happy to see you.”
The bartender is studying to be a truck driver so he can visit California. He’s not sure if he’ll settle down there, but it seems nice.
The man from Texas looks at the bartender hard for a good minute, says, “You’re a lucky man, son.”
IV. Postmodern Radiation—Or, Any Other Ideas?
To get to the Los Alamos National Laboratory in New Mexico, you drive from Santa Fe through peach-parfait mesas and off into the sunset. Even on the public roads, there are checkpoints where security officers will ask to see your driver’s license. The deeper you go, the more intense the screening gets, until finally you end up in a place employees just call “behind the fence.”
After the public roads but before “behind the fence” are the hot cells: four-foot by three-and-a-half-foot boxes where employees use robot hands controlled by joysticks to process non-weapons-grade isotopes. The isotopes are made on another mesa, by a linear particle accelerator that shoots rare metals with proton beams.
Just outside the hot cells, Eva Birnbaum, the isotope production facility’s program manager, asks me if I know what a decay chain is. She points in the direction of an expanded periodic table that, despite a year of college chemistry, means about as much to me as a list of shipbuilding supplies from the 1600s. Birnbaum launches into a primer on radiochemistry: Isotopes are chemical elements with too many or too few neutrons in their centers. Some of these are unstable and therefore release energy by shooting out various typ
es of particles. Unstable isotopes are radioactive, and the particles they shoot out are known as ionizing radiation.
As for what a decay chain is: when radioactive isotopes release radiation, they usually turn into another radioactive isotope, which releases radiation until it turns into another radioactive isotope, and so on, until it hits on something stable. The pattern by which a particular isotope morphs is its decay chain. Today, in addition to whatever goes on behind the fence, Los Alamos National Laboratory is the primary producer of certain isotopes whose decay chains make them useful for medical scans, such as PET scans and heart-imaging techniques. Scientists at Los Alamos deliver the parent isotope in a container called a cow. As the parent decays, doctors “milk” the daughter isotope off to image patients’ hearts.
Decay chains present both an opportunity and a responsibility for the U.S. government. You can’t just throw decaying radioactive isotopes into a landfill, so after the nuclear age and a half-century Cold War with the USSR, there are caches of radioactive uranium and plutonium isotopes sitting around gradually turning into other stuff. One of these caches is uranium-233, which was originally created for a reactor program and is currently stored at the Oak Ridge National Laboratory in Tennessee. Over the last 40-some years, it has been slowly turning into thorium-229.
Thorium-229’s decay chain leads to actinium-225, which is of interest to cancer researchers for several reasons. For one thing, actinium-225’s decay chain goes on for several generations. It turns into francium-221, then astatine-217, then bismuth-213, then mostly polonium-213, then lead-209 before finally hitting a hard stop at bismuth-209, which is stable. In most of these generations, the radiation released consists of alpha particles, which can destroy cancer cells but have low tissue penetration—they leave the surrounding healthy cells mostly alone. Currently, all but one of the radioactive isotopes used in cancer treatment release beta radiation, which causes considerably more collateral damage.
If a drug company could attach an atom of actinium-225 to a targeting system—like, say, the kind in CAR-T cells—the actinium-225 could continuously attack cancer for days at a time, like an artificial, radioactive version of the immune system. Newer chemotherapy drugs called antibody-drug conjugates already use this technique, directing chemotherapy agents that are too strong to give intravenously precisely where they are needed. At least two of these, Kadcyla and Adcetris, have already been approved by the FDA (for HER2-positive breast cancer and Hodgkin’s lymphoma, respectively).
The U.S. system of national laboratories is already in talks with drug companies about making antibody-based radioactive drugs a reality. They seem promising: in a paper released last July in the Journal of Nuclear Medicine, one late-stage prostate cancer patient treated with three cycles of targeted actinium-225 at the University Hospital Heidelberg in Germany went into complete remission and another’s tumors disappeared from scans.
But of course, there’s a problem: now that the reactor program and the Cold War are both over, no one is making uranium-233 in the United States (or anywhere). And because it takes more than 40 years for uranium-233 to turn into enough thorium-229 to be useful, it wouldn’t matter much even if they did. There are currently only about 1,500 to 1,700 millicuries of actinium-225 anywhere in the world, which would just treat 100 to 200 patients a year.
Which brings us to the reason Los Alamos has gotten deeply involved in actinium-225 at all: they’re going to figure out how to make more from scratch.
Interlude
A roughshod man with bloodshot eyes rolls a cigarette outside a coffee shop in Taos, New Mexico. I can’t be sure if he is the backpacker who was playing a flute at this table earlier or a new person. “You a reporter?” he asks.
“Er, yeah. Just got off the phone with a drug company that thinks they can cure cancer.”
“A drug for cancer already exists,” the man says. “More people need to be looking at marijuana. It can cure all kinds of sicknesses, but the thing is, the government doesn’t want people knowing about it.”
A light breeze rustles the wind chimes. We are hiding from the sun under a pergola on the shop’s back porch. Another man attempts to come to my rescue: “But wasn’t Obama trying to change the rules about experimenting—”
“Obama doesn’t want to change the rules because he’s not like us,” says the first man. “He’s got pharaoh DNA that they blend with lizard blood up in the mountains.” He inclines his chin toward Los Alamos.
“So he’s like a monster?” asks the second man.
“Nah, they’re physical, like us, but they only have three chakras, so they’re not as balanced.” He nods, sagely. “Highly carnivorous.”
V. Policy Reform—Or, Divided We Fall
Imagine cancer researchers as thousands of ships attempting to cross the Pacific, all with skills and tools that they have perfected in their home countries. Some have expert navigators. Others build the most watertight ships. If someone could combine the skills of the entire group, they could build a supership the likes of which has never been seen. Instead, they seem to communicate mostly by throwing paper airplanes at each other.
“All you could do with government-funded academic research, in the age of paper, was share information in person, so you had these huge cancer meetings once a year where everybody holds their research until they get there,” says Greg Simon, the executive director of former vice president Joseph Biden’s Cancer Moonshot, an initiative launched by the Obama administration in 2016. “We haven’t changed it since.”
The system of medical journals, subscriptions to which can cost thousands of dollars, are hardly the only baked-in obstacle to progress in cancer research. Clinical trials are still designed the same way they were 50 years ago. Funding, applied for and received in crazed round-robins of grant-writing, tends to reward low-risk experiments. There’s secrecy and competition and slowness and inherent bureaucracy. The system wasn’t created to be inefficient, but now that it is, it is intractably so.
Just this week, Simon has flown all over the country trying to bring bullheaded institutions with impossibly huge data troves into a single kumbaya circle of progress. This morning, he gave a speech at the 28th Annual Cancer Progress Conference. Now he is entertaining a journalist at a sushi lunch in the lobby of a Manhattan hotel. By rights, he should be asleep at the table with his face on a plate. Instead, he orders plain fish, no rice, in a disarming southern accent. (Simon is from Arkansas.)
When Simon was twenty-eight, he played drums in a rock band called the Great Zambini Brothers Band. Then he decided to do something with his life, “quit the band, waited tables, went to law school, got a job, and hated it,” he says. A friend found him work in Washington and by forty-one, Simon was working in the White House as an aide to then vice president Al Gore. Then he cofounded a Washington think tank called FasterCures. Then he worked as senior vice president for patient engagement at Pfizer. If anyone on Earth knows how to get from here to there, Simon is the guy.
Since he left the White House (again) in January, Simon and his team have begun developing, out of a WeWork space, a spin-off of the Cancer Moonshot they’re calling the Biden Cancer Initiative. It will be its own separate nonprofit, apart from government or charity. Its goal: fix policy and make connections so that those with the expertise to cure cancer have a clear path to the finish line.
To achieve such a feat, Simon will work against a scientific version of the tragedy of the commons—an economic theory in which each person, acting in his own best interest, screws up the whole for everyone else. Convincing people and institutions to act against their own best interest will be much like governing, which is to say, slow and impossible. And yet it’s hard not to believe in Biden, a man who helped run the most powerful country in the world at the same time he lost his own son to brain cancer.
“We won’t be funding research. The world doesn’t need another foundation with money,” says Simon. “What it needs is someone like Biden, who’s willing to
knock heads together . . .” He pauses. “Or cajole heads together, to make the changes that everyone has an excuse not to do: I wanna make money, I want tenure, I wanna get published, I want this, I want that.”
The fragmentation in medical research—the lone ships out on the ocean—doesn’t exist as much in other sciences, says Simon, because scientists in other disciplines have no choice but to share equipment: telescopes or seismology sensors or space shuttles. Industries that have managed to work together have sent humans to the moon. “We don’t even know how much progress we could make in our cancer enterprise because we’ve never had it up and running at a level that would be optimal,” he says.
Simon himself had cancer. Three years ago. It was CLL. “I found it through a physical,” he says. “I never had any of the raging symptoms, like bleeding. During the chemo I didn’t notice it at all. Zero side effects. I thought I’d lose my hair so I grew a beard. But I didn’t.”
Interlude
“You are writing. Are you writer?” asks the flight attendant on Delta Flight 3866 from LaGuardia to Memphis in a thick Eastern European accent. It’s a late flight—post-work—and many of the passengers are asleep. My reading light is one of just three that are illuminated.
“I had cancer,” she says. “Breast cancer. I still have no boobs. After my surgery, they put in a balloon that they inflate step by step. After a few weeks I say to the doctor, ‘I am still as flat as pancake!’ And he says, ‘Ah, there must be a hole.’”
