In May 2001 a middle-aged woman named Sharon visited her oncologist for what she thought could be her final appointment. Two months earlier, Sharon had been diagnosed with metastatic melanoma, and her condition was already well beyond dire. Her liver was riddled with metastases, a massive tumor was slowly collapsing her left lung, and fluid was pooling in the pleural cavity of her chest. Doctors didn’t expect her to live more than a few weeks.
At the time, metastatic melanoma was a death sentence. When melanoma is localized—known as stage 0 or stage 1—it is threatening but easily cured with surgery. But when the disease spreads and finds a home in other organs, it transforms into a brutal killer, resistant to radiation, chemotherapy, and, until recently, everything else doctors had devised. When Sharon was diagnosed, just two drugs had ever received FDA approval to treat her stage-4 disease: a chemotherapeutic agent that had never shown a survival benefit and an immune-boosting white-blood-cell protein called interleukin-2, which worked only sporadically and was so toxic that dosing it was, according to Antoni Ribas, one of Sharon’s doctors, “the equivalent of giving a patient a septic shock every eight hours for five days.”
Sharon, a mother of two from the Los Angeles suburb of Woodland Hills, went about exhausting her bad options. After seeing Ribas for the first time in March, she had undergone treatment with interleukin-2. It succeeded only in sending her to the ICU. The next month, Ribas had administered an experimental vaccine that in other patients had worked with little more than lottery odds. Sharon hadn’t won the lottery.
Now, as she sat in an office at UCLA’s Jonsson Comprehensive Cancer Center, Sharon needed to decide whether to continue fighting the disease. She had one more option, a new drug that would come to be known as ipilimumab, which was then beginning its initial phase I trial at a private oncologist’s office in Long Beach. Phase I trials mark the first time a drug is given to patients. The trials aren’t designed to determine the efficacy of a treatment; they are designed to determine whether it is even safe for humans. If Sharon volunteered for the ipilimumab trial, she would be one of the first patients to ever receive the drug.
Ipilimumab was based on a new approach to fighting cancer, the first in a class of drugs called checkpoint inhibitors. Instead of attacking cancer cells directly, checkpoint inhibitors unleash the body’s own T cells—the soldiers of the immune system—to fight malignancies. Without the presence of these drugs, tumors are able to press on the “brakes” on the surface of T cells—these brakes are known as checkpoints—that halt the body’s immune response in its tracks. Checkpoint inhibitors disable these brakes, allowing T cells to sustain an attack against the tumors. Still, when Ribas told Sharon about the drug, this was little more than a theory. In experiments on mice, ipilimumab had performed wonders: tumors vanished, relapses were squashed before they began, cancer was cured. But promising animal results have a poor track record of translating to humans, particularly when the results involve the immune system and cancer. “Nobody had faith in this responding long term,” Ribas told me.
Ribas, though, was a cautious believer. A colleague once likened Ribas’s pursuit of immunotherapy treatments to a man who climbs to the top of the Empire State Building, throws 100 marbles off the side, and watches as 99 plummet to the ground and a single one stays floating in midair. He told Ribas, “You are studying the one that stays floating.”
So when Ribas sat down with Sharon, he offered some reasons for guarded optimism. He believed that miraculous recoveries were possible, and with enough study, they might even transform into widely applicable science. But Ribas was also practical enough to know his patient’s chances. Sharon had no good options. “What else could you do?” Ribas told me. “Either it was that or go into hospice care.”
Sharon didn’t deliberate for long. She didn’t expect a miracle, but she hoped that ipilimumab might let her live to see her son graduate from high school. The ceremony was a month away.
Fifteen years later, James P. Allison, the chairman of the department of immunology at the University of Texas’s MD Anderson Cancer Center, in Houston, would stand at a lectern in Baylor College of Medicine’s Cullen Auditorium describing Sharon’s case to a crowd of two hundred clinicians, scientists, and students. Allison had met Sharon only once, but few people could speak with more authority on her case. That’s because the 68-year-old Allison had been the scientific pioneer and indomitable advocate behind her last-ditch treatment.
Projected above Allison were images from two CT scans. The scan on the left showed Sharon’s torso in May 2001, a massive tumor impinging her left lung, the pleural effusion flooding her chest. The scan on the right also showed Sharon’s chest, but this image was clean, normal, empty. The scan showed only some scar tissue and two functioning lungs. Above the two slides were the words “The longest survivor on ipilimumab?”
“This is my favorite slide,” Allison said. “She got a single injection of ipilimumab, and six months later her tumors were completely gone.”
The phase I trial had been a tentative beginning, but it represented the start of a seismic shift in the landscape of oncology. Not only had Sharon returned rapidly to a healthy life from the brink of death, but her own immune system—not a surgeon’s scalpel or high-energy X-rays or toxic chemicals—had saved her. In the decade and a half that followed, the field of immunotherapy would transform from a Hail Mary intervention into the fourth pillar of cancer treatment.
From the fifties until the very recent past, oncologists focused their energies on three approaches to battling cancer: surgery, radiation, and chemotherapy. In the dark humor of the cancer ward, these are known as “cut,” “burn,” and “poison.” Over this period, politicians and activists mounted a sweeping war on cancer modeled on the Apollo program and the Manhattan Project; the federal government, nonprofit institutions, pharmaceutical companies, and private citizens dedicated untold billions to finding a cure; and generations of doctors still depended largely on early detection and prevention, cycling through drugs whose effectiveness was often measured by the few extra months of life they could provide.
The rise of immunotherapy hasn’t shifted that reality overnight, but it has sent a new jolt of energy into an age-old dream: that maybe, just maybe, medical science can turn terminal cancers into survivable conditions. Since the FDA approved ipilimumab, in 2011, median survival rates have increased and the number of people experiencing lasting responses has spiked not only for metastatic melanoma but for several other common, previously-all-but-fatal malignancies, among them advanced cancers of the lung, kidney, and bladder. In the past two years alone, the FDA has approved three second-generation checkpoint inhibitors, and two other arms of immunotherapy—cancer vaccines and a therapeutic approach known as adoptive T cell transfer, in which a patient’s own T cells are engineered outside the body and reinjected into the bloodstream—are showing ever-more-promising results.
The clinical successes have not gone unnoticed. Pharmaceutical companies are locked in a multibillion-dollar arms race to develop new and better drugs, billionaire philanthropists—among them Sean Parker and Michael Bloomberg—have helped set up dedicated immunotherapy centers, and more and more patients are receiving and benefitting from immune-modulating treatments. When former president Jimmy Carter was dying of metastatic melanoma in 2015, his doctors gave him the checkpoint inhibitor Keytruda and watched as his T cells eradicated the tumors in his brain and liver. Now patients suffering from metastatic melanoma ask for the “Jimmy Carter drug.”
“Fifty years from now, it’ll be unusual for someone to die of cancer—it’ll be like pneumonia,” Patrick Hwu, a melanoma oncologist at MD Anderson who works closely with Allison, told me. “And it’s our hope that we can compress that time to more like ten or fifteen years.” This would be an astounding accomplishment. In 2016 an estimated 595,690 people will die of cancer in the United States alone.
If immunotherapy leads the way to cancer cures in the coming decade, it’ll be tempting to look back on its development as inevitable, a breakthrough that was merely waiting for technology and biological research to make it possible. This would be true to some extent—scientists have hypothesized for over a century about the potential for the immune system to beat back tumors—but such a view would overlook the human choices and biases that shape the course of science. It would also overlook the power of small groups of individuals to spark major advances by bucking conventional wisdom and seeking out new frontiers. In other words, it would ignore the life of Jim Allison—a shaggy-haired, patchily bearded son of small-town South Texas whose creativity, diligence, and zest for pursuing a seemingly quixotic path far from the front lines of cancer research have added up to a revolution.
First, Allison labored for years on the fringes of the cancer world, working in a little-known lab in his home state—still evolving into the leader of cancer treatment it is now—where he began to make a series of biological discoveries that upended how science understood T cells. Then, in a flash of brilliance, he envisioned how those discoveries could be used to create a drug to combat cancer. And finally—over a frustrating, grueling, and ultimately triumphant decade-and-a-half-long quest—he evangelized for the potential of such a drug, trying to convince legions of skeptics that immunotherapy could not only work but potentially save countless lives. Many of his peers expect that he will soon win the Nobel Prize, and they have already bestowed on him lofty praise. “It is rare that such a sea change can be traced to any one individual,” asserted the scientific journal Cell in 2015, after Allison won the Lasker-DeBakey Clinical Medical Research Award, “but the advent of checkpoint therapy would have been highly unlikely without the efforts of James Allison.”
When I first met Allison, in May, he was fresh off visiting with two icons. He had recently returned from a conference at the Vatican, where he’d been invited to speak on a panel about the progress of immunotherapy, and, not long before, he’d scored a dream gig, playing harmonica onstage with his musical hero, Willie Nelson. (Allison’s regular musical counterparts are a band of blues-playing cancer researchers known as the Checkpoints.) True to form, he recounted his experience in the Holy See with a lack of diplomatic awe. “Someone asked me which was more exciting, playing with Willie or meeting the pope,” Allison said. “That’s not a very good question.”
Allison’s playful irreverence is not an affect. As a whip-smart kid growing up 45 minutes west of Corpus Christi in the town of Alice, he cultivated it as a survival mechanism. He was born in 1948, the youngest of three brothers, and his family had deep roots in Texas. His father was a country doctor and Air Force Reserve flight surgeon, the son of shoe-shop owners near Waco whose forebears had fought with General John Bell Hood’s Texas Brigade in the Civil War. Allison’s mother, an Alice native, passed down family lore about cattle drives up the Chisholm Trail. “She had an aunt who had this thousands-and-thousands-of-acres ranch near George West with this big house on top of a hill,” Allison remembered. “It almost looked like Giant.”
Allison never really fit into the Alice of the fifties and early sixties. He didn’t like football—being on the bottom of a pile once was enough. His older brothers, six and eight years his senior, were jocks who “thought I was kind of worthless because all I did was read.” He was bored with small-town life and got his kicks in his garage laboratory, dissecting frogs and building small explosives that he’d ignite in the woods. (“They were like small firecrackers,” Allison laughed. “It turns out, in my years of meeting a lot of scientists and having a few drinks, there are a surprising number of people who built bombs.”) When his guidance counselor suggested that he might like to channel his enthusiasm into enrichment science courses at the University of Texas at Austin during the summer after eighth grade, he jumped at the chance.
Still, Allison’s youth in South Texas shaped him and his sense of mission profoundly. When Allison was a boy, his mother fell ill with lymphoma. He didn’t know what cancer was, but he knew what he saw; undergoing radiation treatment with an advancing disease, his mother looked increasingly gaunt and had painful burns on her skin. One afternoon, when Allison was eleven, he was leaving his house to go swimming at the local country club with some friends. “Then somebody came out and said, ‘No, he’s gotta come back,’ ” Allison said. “And so I went back, and they said, ‘Come and see your mom.’ ” He was holding his mother’s hand when she died.
The tragedy forced Allison to become more independent. His father was grief-stricken at home and often absent on the weekends for duty in the Air Force Reserve. His brothers were already deep into their teen years and had little time for him. So Allison ended up spending hours with his homemade bombs in the woods.
Before his senior year, Allison learned that his high school’s biology teachers refused to teach evolution for religious reasons. He asked to see the course syllabus and grew irate. “It was classification and a little bit of citric acid cycle stuff, and that was about it,” Allison recalled. “I said, ‘I’m not going to take this.’ You can’t teach biology without Darwin. It’s like teaching physics without Newton!” With the help of his father and a few sympathetic teachers, he worked out a deal to take an advanced high school biology correspondence course offered through UT. He never looked back.
Next to Alice, UT-Austin, where Allison arrived in June 1965 at age sixteen and stayed until finishing his Ph.D., in 1973, felt like Valhalla. After ditching his premed track (“I didn’t really have the discipline to memorize stuff”), he became fascinated with immunology. T cells had only recently been discovered and were still disputed science.
“My professor Bill Mandy taught about them in class, but when I would go to his office and chat with him about stuff, he’d say he didn’t believe in them necessarily,” Allison said. This made Allison only more interested in the immune system; the field was wide open, full of both mysteries and extraordinary potential. In one experiment, he gave a mouse a tumor, cured the animal with an enzyme used to treat human leukemia, then reinjected the same mouse with more tumors. This time the mouse rejected the cancer without treatment. Its immune system recognized the tumors as enemies.
“I couldn’t have done that today, because you’d have to write a protocol and think of an experiment,” Allison said. “I was just in the mouse room, and I said, ‘I think I’ll just inject that guy!’ ”
Allison’s sense of play and spontaneity wasn’t confined to the mouse room. G. Barrie Kitto, a recently retired UT biochemistry professor who Allison worked with, remembers the young researcher devising a novel method to clean test tubes using an acetone spray, then accidentally burning off all his hair when he lit up a cigarette next to the highly flammable product. (Kitto: “He looked like Telly Savalas.” Allison: “It only singed off my eyebrows, and I quit smoking after that.”) When Allison decided he wanted to stay on as a graduate student, the biochemistry department’s professors had to meet specially to discuss his case. “Jim’s grades were either A’s or F’s,” Kitto told me. “If Jim thought a class was useless, he just walked out and never bothered to drop it.” The graduate school admitted Allison anyway.
Two of Allison’s colleagues from different eras of his life described his prevailing philosophy as “work hard, play hard,” and at UT in the late sixties and early seventies, he had no trouble finding kindred spirits. Allison and his friends relished spending all day in the lab, taking an early evening break to drink 90-cent pitchers of Lone Star, then heading back to campus to continue their experiments deep into the night. On the weekends, they’d hit the Armadillo World Headquarters, the Split Rail, and the Soap Creek Saloon, or drive out to the Hill Country for days of canoeing and nights at the old dance halls in Luckenbach and Gruene.
After UT, Allison did a postdoctoral stint at the Scripps Clinic, in La Jolla, California, but he soon found a permanent professional home back in Texas. MD Anderson had opened a new scientific research facility on the edge of Buescher State Park, just outside Smithville, and as Allison describes it, the vibe was that of a science summer camp. Nearly everyone was in their twenties and thirties. Most of them lived within a few miles of one another, and all the scientists pitched in to help with one another’s experiments. As he had often been at UT, Allison was the ringleader of both the seriousness and the fun. He had a Norton Commando 850 motorcycle, and he would spearhead group outings to discuss the latest journal articles over hamburgers at Hut’s, in nearby Austin, piling colleagues into a 1954 Mercedes sedan that he’d rebuilt.
At the time, the holy grail of immunology was identifying the T cell antigen receptor, and at Smithville, Allison launched himself into the hunt. The antigen receptor, then only theorized, is the mechanism that allows T cells to “see” foreign invaders. If you could figure out how T cells recognized their enemies, the thinking went, then you might be able to tweak them to better engage with all manner of maladies.
In 1982 Allison published a paper in the Journal of Immunology—considered far from a top-tier publication—that reported the results of his first groundbreaking experiment: he had found a protein on the surface of T cells that looked to be the coveted antigen receptor. Allison had enough evidence to make a supposition, but not quite enough to fully prove his case. Still, the paper changed his career.
“I didn’t have a pedigree. I was at this place nobody had ever heard of. I wasn’t on the tour of the big meetings or anything,” Allison remembers. But more-established scientists found the work compelling, and soon the University of California at Berkeley offered him a position on the faculty.
“I was really nervous about it, because it was big-time science,” Allison said. “I was afraid I would get into one of those competitive things where it’s cutthroat and everyone is trying to outcompete everyone else, no matter the cost.” He made the leap anyway. He’d have more resources and a better chance of doing work that would really matter.
When Allison left for Berkeley, in late 1984, he didn’t think of himself as a cancer researcher. He worked with petri dishes and lab mice, not humans, and he’d never come anywhere close to devising medical treatments. Yet cancer lingered in the back of his mind.
“It’s like that Jerry Jeff Walker song: ‘With one eye on my lady and one eye on the open road,’ ” Allison told me. “I was thinking most about the immune system, but I was also looking down the road a little bit, thinking, ‘Okay, how can I pull this over?’ ”
Allison’s mother was not the only member of his family to die from cancer. As a young man, Allison watched as an uncle died of melanoma and another succumbed to lung cancer. As a middle-aged scientist, Allison buried one of his brothers, who had been ravaged by an aggressive prostate cancer. In 2005, less than a week after his brother had died, Allison got a prostate biopsy and received a diagnosis of cancer himself. Surgeons removed Allison’s prostate, and he has had no recurrence. Earlier this year, a few of Allison’s MD Anderson colleagues noticed a mass on his nose and advised him to see a dermatologist. The mass was invasive melanoma, and the tip of Allison’s nose is now punctuated by a crescent-shaped scar. “The guy helping me through the surgery prep said, ‘We want to get this out before you have to get that drug of yours,’ ” Allison told me. “I said, ‘Yeah, I don’t want that.’ ”
Given Allison’s family history, it’s not surprising that cancer eventually became the focus of his research, but he knew enough about the history of immunotherapy to proceed carefully. For nearly as long as doctors have known about cancerous tumors, they have been trying to cure them with an immune response. This history dates at least as far back as the ancient Egyptian physician Imhotep—who tried to eliminate tumors by causing an infection at their sites—and encompasses, more recently, the notable efforts of a New York bone surgeon named William Coley, who, starting in the 1890s, treated his sarcoma patients with an immune-stimulating bacterial concoction that came to be called Coley’s toxins. Coley treated nearly nine hundred patients with the toxins over a four-decade period, achieving a cure rate of more than 10 percent. But these efforts are footnotes in the history of humanity’s fight against cancer. Even when they succeeded, their results were difficult to replicate, and they were initiated with far more experimental brio than scientific knowledge.
When Allison began to train his one eye on the open road of using the immune system to battle cancer, in the eighties, the perception that immunotherapy was essentially pseudoscience still predominated in the field. As science journalist Stephen S. Hall writes in his book A Commotion in the Blood, a 1997 history of immunotherapy, “tumor immunology had become something of a scientific red-light district: a seedy intellectual neighborhood of fantasy and wishful thinking, a landscape littered with hulks of abandoned hypotheses and charred reputations.”
Allison avoided the seediness by sticking to the confines of his academic labs, but he watched as heavily hyped immunotherapies produced results little better than Coley’s. Interferon, proteins released by cells in the body in response to attacks by foreign invaders, was developed as an anti-cancer therapy, and it was touted in both Time and Life as a potential wonder drug. It worked only occasionally. Interleukin-2, the white-blood-cell protein that would fail to halt tumor growth in Sharon in 2001, garnered even more attention. “Cancer Breakthrough” announced a Fortune cover story in November 1985. A New York Times special report, an NBC News segment with Tom Brokaw, and a Newsweek feature soon followed, as did billions of dollars in investment. But interleukin-2, like interferon, turned out to work only rarely, and even though it gained FDA approval, it proved so toxic that it was never widely prescribed.
Even the failed expectations, though, weren’t as perilous for the field of cancer immunotherapy as a simple question: Was it even possible for T cells to distinguish between a healthy cell and a cancer cell? Did the immune system see cancer cells simply as “self,” or was there anything about them that registered as “non-self”? A cancer cell, after all, isn’t a foreign invader, like a bacteria or a virus. It’s a human cell gone haywire, dividing uncontrollably as it kills off body tissue. Was there anything in a cancer cell that would reveal itself to the immune system as an enemy?
In 1976 a British scientist named Harold Hewitt had published an exhaustively researched paper that to many observers had settled the matter once and for all. After twenty years of studying tumors in mice, Hewitt concluded that only tumors caused by direct injection of cancer cells were immunogenic. Spontaneous cancers, the kind that actually arise in humans, were invisible to the immune system.
Allison didn’t take Hewitt’s study as the last word. He found the conclusions overly sweeping. But in the aftermath of Hewitt’s paper and the repeated failures of immunotherapy wonder drugs, studying the immune system with a focus on cancer treatment was widely thought to be a fool’s errand.
“The eighties were the dark decade for tumor immunology,” Philip Greenberg, the head of immunology at the Fred Hutchinson Cancer Research Center, in Seattle, and one of Allison’s oldest and closest friends, told me. (Greenberg, who looks like a skinny Jerry Garcia, once accompanied Allison to a sold-out Willie Nelson concert in Maui, where they gained entrance after being mistaken for members of the band.) “The field had difficulty attracting really good scientists, so in terms of numbers, it was small but it was also shallow,” Greenberg continued. “That was part of the problem: the quality of the science really wasn’t there.”
The true believers like Allison and Greenberg had to simply ignore the doubters and instead focus on the potential promised by those few miracle cures. After all, interferon and interleukin-2 hadn’t failed entirely. A few patients had responded, and their doctors had watched as their now-turbocharged immune systems melted away their tumors.
“It may have been foolish enthusiasm of youth,” Greenberg told me, “or maybe it was a grandiose idea that you can do something bigger than other people can do, but I think Jim and I and other people in the field saw enough signals that it could work that we weren’t willing to believe that it just couldn’t.”
Allison weathered tumor immunology’s dark decade by doubling down on studying T cells. As other scientists were rushing out new cancer treatments with more hype than results, Allison focused narrowly on understanding the biological mechanism of the immune system. And as each major discovery helped show the way to the next, he laid a deep foundation for the medical applications—the life-saving checkpoint-inhibitor drugs—that would eventually come.
When Allison had published his groundbreaking 1982 article on the T cell antigen receptor, many scientists had thought that the process of T cell activation would be akin to flipping a light switch. If the antigen receptor recognized an invader, the T cell would turn on. If not, the T cell would stay off. But as scientists began to learn more about T cells in the mid-eighties, it became clear that the mechanism for their activation was more complicated. T cells weren’t like light bulbs that could be turned on and off with a simple switch. They were more like cars, which don’t start moving until a key turns the ignition and a foot presses down on a gas pedal. In this formulation, the antigen receptor was the ignition, and some as yet unidentified part of the T cell—a so-called co-stimulatory molecule—was the gas pedal. Only when a T cell received positive signals from both the antigen receptor and the co-stimulatory molecule would it initiate a response.
In 1988 Allison’s team at Berkeley showed that the T cell’s gas pedal was a molecule on its surface called CD28. It was a major discovery, but Allison and others quickly realized that even this didn’t fully explain T cell activation. A T cell receiving positive signals from both CD28 and the antigen receptor wouldn’t always sustain an attack. Other unknown regulatory mechanisms—likely other co-stimulatory molecules—had to be present.
Around this time, a graduate student named Max Krummel arrived in Allison’s lab and began to study another potential T cell co-stimulatory molecule called cytotoxic T-lymphocyte-associated protein 4, or CTLA-4. “CTLA-4 looked like CD28,” Krummel told me. “If you lined them up next to each other, they had a lot of things in common in terms of how they were organized. People think that in science you do things with really brilliant insights, but sometimes it’s fairly straightforward. In this case, it was, if it looks similar and they’re in T cells and one of them kind of does something important, let’s check out this other one.”
Before Krummel could figure out what CTLA-4 did, though, another lab beat him to it. Peter Linsley, a scientist at Bristol Myers Squibb, published a paper showing that CTLA-4 was indeed another co-stimulatory molecule. CTLA-4 didn’t do anything on its own, Linsley discovered. But if the T cell antigen receptor and CD28 became activated first, then turning on CTLA-4 sent the T cell into overdrive. Allison and Krummel were both disappointed to have been scooped, but they continued with their CTLA-4 experiments anyway. “I don’t think we’d have even done it, except that we were far enough along the track that we thought we might as well continue to look at CTLA-4 with our own eyes,” Krummel said.
As Krummel continued to conduct his experiments on CTLA-4, he had an insight. To engage a specific molecule on the surface of the T cell, scientists use a tool called a monoclonal antibody, in effect a specially designed protein that fits into a given receptor like a key into a lock. Krummel thought he was looking for a gas pedal, so he built an antibody that he likened to a brick. The idea was that he’d place it “on top” of CTLA-4, keeping the gas pedal floored. And it worked: the T cells became highly active. But as the data piled up and Krummel and Allison looked at the evidence, they realized another mechanism might be driving it. Maybe CTLA-4 wasn’t a gas pedal at all. Maybe it was the opposite; maybe it was a brake. And maybe the antibody “brick” that Krummel had built wasn’t sitting on top of a gas pedal. Maybe it was sitting under a brake. Maybe the T cell wasn’t going into overdrive because two gas pedals were being engaged simultaneously. Maybe Krummel’s antibody was inhibiting a T cell’s ability to stop itself.
Once Krummel realized this was a possibility, he began to play. He figured out a way to make the antibody press on the brake instead of disabling it, making the T cell come to a screeching halt. Then he engaged both the gas pedal (CD28) and the brake (CTLA-4) simultaneously, measuring their relative strength. “My dad drives a non-stick with two feet; he can push on the brake with his left foot and the accelerator with his right foot, and sometimes, because he’s older, he does both,” Krummel said. “That’s basically what the experiment was. You could make things move faster or slower, working one against the other. That was a pretty exciting moment.”
Krummel wasn’t alone in his discovery. The lab of Jeff Bluestone, an immunologist at the University of California–San Francisco, had also studied CTLA-4 and come to the same conclusion. But Linsley, the Bristol Myers Squibb scientist, didn’t immediately accept the results and neither did many others in the scientific community. “We got to have a lot of fun at meetings,” Allison told me. “It was back when people weren’t as polite as they are these days. There was usually a fair amount of yelling going on, insults, at least at the meetings where there wasn’t any press.”
When Krummel began his experiments on CTLA-4, he had been pursuing a narrow, basic science question: What does the CTLA-4 molecule do? But once he’d figured that out, he and Allison began to talk about what this discovery meant. “This is one of these things that I remember very vividly,” Krummel said. “We were just standing at a whiteboard going, ‘If we can push T cells whichever way we want, what are all the different ways we’d want to put it into different animal models?’ ”
Allison had a target in mind. By that time, it was clear that T cells could recognize tumors—Hewitt had been wrong—but before they could fully react against them, something caused the T cells to abort their attack. Allison hypothesized that tumors had evolved to activate CTLA-4, essentially stopping T cells from seeing their target as hostile. If Allison could insert an antibody to inhibit CTLA-4—the brick under the brake—then maybe tumors would be unable to halt the T cell. Allison devised a plan to inject Krummel’s antibody into tumor-stricken mice and assigned the experiment to a postdoc in his lab named Dana Leach. When Leach showed Allison the initial results in late November 1994, Allison was speechless. “I thought we would slow the tumors down, but we completely cured the mice,” Allison remembers.
Allison insisted on repeating the experiment immediately, this time in a blind study with a control group. Leach injected the mice, but Berkeley was letting out for winter break, and only Allison remained in the lab to observe the results. For the first two weeks, the tumors in all the mice grew, and Allison thought that perhaps Leach had bungled the initial experiment. But then the tumors in half of the mice—the treated animals—began to regress dramatically.
It would be hard to overstate the magnitude of these results. By showing that T cells could eradicate tumors so effectively, Allison’s team had made a breakthrough that would alter the fields of immunology and cancer treatment. And the potential impact wasn’t lost on them. When Krummel showed that CTLA-4 was a braking mechanism, it was a triumph of basic science, advancing our understanding of how T cells function. Everyone in the lab felt good and sipped a little champagne—though the fact that Bluestone’s group had published first tempered the celebration. Allison realized that these new tumor results were much bigger. “We didn’t talk about that outside the lab for several months,” Allison said.
In March 1996 the journal Science published “Enhancement of Antitumor Immunity by CTLA-4 Blockade,” a paper written by Allison, Krummel, and Leach. It is only three pages long, but the results speak for themselves: by injecting a CTLA-4 antibody into mice, Allison’s team had turned the immune system against cancer. Not long after Allison saw the mouse tumors evaporating, he’d realized what his next step needed to be. He couldn’t just publish a paper. He and UC-Berkeley needed a patent on the CTLA-4 antibody and its biological process. “With that, we could go out and convince companies, ‘You can make a drug based on this.’ ”
Allison likes to tell a story from his time at the research facility in Smithville when Ernestine Glossbrenner, his eighth-grade algebra teacher, who had gone on to become Alice’s state representative, asked if he would testify in front of the House Committee on Public Education at the state capitol. It was 1981, and a newly elected representative from Longview named Mike Martin had introduced a bill to mandate the teaching of “creation science” alongside the theory of evolution in public schools. Glossbrenner thought Allison, a veteran of the Darwin wars, might have something to say about it.
“This guy was an absolute nutcase,” Allison remembers. “The discourse was him saying, ‘Well, if you put out a Ford and leave it there, it don’t turn into a Cadillac.’ ”
Allison’s default mode of speech is unhurried and a little gruff, but when he gets going on the right subject, he flies into arias of excitement. Speaking on the House floor about the cretins who would force creationism down the throats of Texas schoolchildren, Allison plainly had a ball. Allison lampooned men like Martin, who claimed evolution was controversial and only a theory. “While the theory of gravity is still controversial, apples do indeed fall down,” he roared. He extolled the virtues of Darwin’s discoveries. “Evolution enjoys almost universal acceptance among scientists . . . because it has been supported by observation and experimentation in the one hundred and twenty years since it was originally described!” And he skewered so-called creation science as an “archaic, inferior, and false view.” But Allison made his strongest and most surprising claim against Martin’s bill when he argued that evolution could help create a better future.
Evolution was not only about dinosaurs and fossils and the development of apes and humans, Allison told the committee. It was “intimately involved in our understanding of how the immune system in the body learns to recognize what is self and what is nonself, what is a normal cell and what is a malignant cell, and even how to detect and eliminate that cancer cell from the body.” Evolution, Allison continued, would help us “devise strategies to manipulate the immune responses to eliminate diseases.” Fifteen years before the publication of the revelatory paper in Science, Allison was already trying to convince anyone who would listen that using the immune system to cure cancer wasn’t just possible, it was based on the most fundamental principles of our world. (Martin’s bill would fail, and he resigned from office amid a bizarre attempted assasination scandal and perjury charges.)
Allison’s testimony at the statehouse would prove good practice for what came after he unveiled his tumor findings to the world. As Allison made the rounds of biotech firms, trying to convince them to turn the CTLA-4 discovery into a drug, he was greeted with indifference. The past failures of immunotherapy were proving a serious impediment.
“The pitch was, ‘Hey, look, we’ve gotten this to work in mice. Let’s try some pilots to get this to work in humans,’ ” said Krummel, who accompanied Allison to some of the early meetings. “We weren’t exactly getting laughed at, but it was sort of, ‘Hey, that’s a nice result, but it’s never going to really do anything.’ ”
Even when Allison got a firm interested, the path was full of land mines. After presenting his tumor results at a conference in Southern California, he’d convinced Alan Korman, a scientist at a small Colorado-based biotech firm called NeXstar Pharmaceuticals, to take a chance on developing an anti-CTLA-4 cancer drug. But NeXstar’s development of the drug stalled, and both Allison and Korman grew frustrated. “It was clear that they weren’t going to be able to contribute, and I said, ‘Either try a new technology or give us the patent back, and they wouldn’t do either,’ ” Allison recalls. “I was really pissed.”
A new path appeared when Korman enlisted the help of Nils Lonberg, the scientific director of another small biotech firm, Medarex. Lonberg had experience with transgenic mice, which are genetically modified to have immune systems that mirror humans’, and these specimens would allow him to create a fully human anti-CTLA-4 antibody quickly. Korman, Lonberg, and Allison joined forces in February 1998, and soon, Medarex bought the license on Allison’s patent. In June 2000 ipilimumab entered its first phase I clinical trials. The plan was to try out the drug on prostate cancer and melanoma. Prostate cancer yielded some positive results, but nothing miraculous. The melanoma trial saw fewer patients respond to the treatment, but in Sharon’s case—in which tumors melted away within weeks—there was more than enough cause for hope.
“When we opened these trials, I had patients from all over the world volunteering for the studies,” Ribas told me. “Patients learned quickly that this was the only realistic chance they had of beating this disease long-term. When they wouldn’t qualify for the clinical trials, a few people would say, ‘You’re killing my wife,’ or my daughter, or my husband.”
But in truth, a cure was far from assured. Of the seventeen people who took ipilimumab in that first trial, Sharon was one of only three responders. And nasty side effects became apparent. In a minority of patients, releasing the brakes on T cells caused a host of symptoms, among them colitis and lung inflammation. Many patients needed to go on hormone therapy because the drug caused vital glands to malfunction. In early trials, several patients died, not of metastatic melanoma but of exposure to ipilimumab itself. Some clinicians said the drug was the most toxic they’d ever administered. At conferences and in journals, immunotherapy skeptics saw interleukin-2 all over again.
Allison wasn’t overseeing the trials—he’s not a medical doctor, after all, nor did he work for Medarex—but he realized that ipilimumab might very well fail without a concerted campaign on its behalf, and he threw himself into the fray. In 2004 Allison left Berkeley to take a position at New York City’s Memorial Sloan Kettering Cancer Center. The area was the epicenter of the push for ipilimumab: Medarex was ninety minutes away, in Princeton, New Jersey, and Memorial Sloan Kettering was performing many of the clinical trials. “I figured if I went there, I’d be able to have influence,” Allison said. “My plan was to be a nuisance. ”
Side effects weren’t ipilimumab’s only problem. As Medarex partnered with Bristol Myers Squibb on larger melanoma trials of ipilimumab, the drug’s efficacy was called into question. In the initial phase III trials, a patient would be considered to have responded to ipilimumab only if his or her overall tumor load shrank by 50 percent after twelve weeks. This was a standard chemotherapy endpoint, but it proved ill-suited to the new drug.
From Allison’s first mouse trials onward, it was apparent that patients responding to checkpoint inhibitors would look different from patients responding to chemotherapy. In the mice, some tumors had actually grown before eventually receding, and even Sharon, the model ipilimumab patient, had a recurrence of lung lesions a year after her nearly instantaneous recovery. Sharon, like the mice, likely experienced what is now known as “pseudo-progression.” Tumors grew not because the disease was progressing but because the immune system was hyperactive. But before this concept had been widely accepted, it threatened to derail the entire checkpoint-inhibitor field.
“Those twelve-week scans showed absolute, undeniable growth of tumors, yet the patients felt better, and they would sometimes have regression six weeks later,” Jedd Wolchok, a Memorial Sloan Kettering oncologist who led several of the trials, told me. “We argued that there should be a different sort of endpoint: overall survival. It required the trials to be open for much longer, and it cost much more money to do a trial like that, but it was really the gold standard.”
Pfizer had been pursuing its own anti-CTLA-4 drug, and upon seeing poor tumor progression results, it abandoned development in April 2008. But Bristol Myers Squibb, which would eventually purchase Medarex, agreed to change the endpoint of a key phase III trial to overall survival, and the decision paid off. The results were presented at the American Society of Clinical Oncology’s annual conference in June 2010. Just 11 percent of the patients met the tumor-shrinkage criteria, but the drug improved median overall survival—the point at which half of the patients remain alive—from a little over six months for the control group to ten months for the ipilimumab-dosed group. This wasn’t just an incremental improvement. Many of those who survived past ten months experienced more-robust results: about 22 percent of the ipilimumab patients were alive three years after treatment. The FDA approved the drug in March 2011.
“That trial represented two really important milestones,” Wolchok told me. “One was that it showed that there could be an intervention that improved overall survival in melanoma”—no treatment had ever done that before—“and second, it showed that there was an immunotherapy that could improve overall survival in a large, randomized international phase III trial. It validated our field for the first time.”
Some of the most prominent skeptics of immunotherapy had already started coming around. This had become clear to Allison in June 2005, when, in the midst of the ipilimumab trials—with the drug’s fate and that of the entire immunotherapy field far from certain—Allison was invited to speak at a major cancer conference at New York’s Cold Spring Harbor Laboratory. The mecca of molecular biology, Cold Spring Harbor is the longtime home of James Watson, the brilliant and unabashedly thorny co-discoverer of the DNA double helix. The conference’s organizers had given Allison an opening-night speaking slot, sharing the bill with some of the war on cancer’s most decorated veterans: Dennis Slamon, Mina Bissell, and Allison’s boss at Memorial Sloan Kettering, the Nobel laureate Harold Varmus. Allison was excited, but he went into the night with more than a little trepidation. He realized that not only was he the sole immunologist scheduled to speak, he was the only immunologist who had been invited to attend.
“I thought, ‘Shit, these guys are going to kill me and cook me and eat me,’ ” Allison said. “Some friend had warned me, ‘So-and-so, he hates tumor immunology.’ These were very prominent cancer researchers that were just outspoken. And when I got there to speak, they were all in the front row scowling at me—Jim Watson, Chuck Sherr, very smart people. I thought, ‘If I don’t do it right, I’m going to blow this whole thing.’ ”
By then Allison could recite in his sleep the cancer establishment’s rap against immunotherapy: The whole field was hocus-pocus, they said, just a rung above snake oil. Immunologists took credit for a few miraculous cures that they couldn’t explain, then shrugged off low response rates and fuzzy science as inevitable steps on the road to progress. Allison came with a plan to circumvent this line of attack. Instead of leading off his talk with stories of miracle cures or bragging about the promising data from clinical trials, he focused first on the biology of checkpoint inhibitors—on fundamental science. Allison walked the scientists through what amounted to his life’s work—T cell activation, co-stimulation, the role of the CTLA-4 molecule, and the dramatic changes in the immune system that came from using checkpoint inhibitors. “Then I said, ‘If it works this way, then here’s a way you can treat cancer, and so we tried it, and here’s what happened,’ ” Allison said. “After I gave the talk, Jim Watson came up to me and said, ‘Well, Jim, you’ve almost made me believe that the immune system can do something about cancer.’ ”
The twentieth floor of the T. Boone Pickens Academic Tower offers a dramatic view of the Texas Medical Center, a sprawling city of hospitals, clinics, research buildings, office towers, and parking garages within the famously sprawling city of Houston. The center is home to 54 nonprofit institutions, including medical schools affiliated with UT, Texas A&M, and Baylor. It has more than 50 million developed square feet, making it the biggest medical complex in the world. And its signature institution is MD Anderson, which since its creation by the Texas Legislature, in 1941, has grown into the world’s largest and perhaps most renowned cancer hospital.
“At MD Anderson, our network of sister institutions reaches one third of the earth’s population,” said president Ronald A. DePinho as we both stared out the window at the expanse below. “This is Texas’s gift to the world.”
An early-summer rain was pelting the city, but as we stood in his corner office, DePinho was in a gung ho mood. Wearing a state of Texas pin and a stars-and-stripes tie, in an office decorated with pictures of him smiling next to George H. W. Bush, Bill and Hillary Clinton, and Jimmy Carter, DePinho could have been mistaken for a head of state, and as he made clear, that’s more or less what he is.
“The stats are approximately twenty-one thousand individuals, singular focus on cancer, multidisciplinary culture of patient care and research,” DePinho continued. “We publish ten papers per day; our research budget is over $800 million. We have the world’s largest cancer clinical trials engine. All of that infrastructure allows us to take advantage of the new capabilities.”
Immunotherapy is at the center of these new capabilities, and DePinho’s full-on embrace of it is a sign of how much the institutional perception of the field has shifted. DePinho told me that he’d once viewed immunotherapy as “more phenomenology than really rigorous science.” Now he’s chosen to make immunotherapy a centerpiece of his administration. When DePinho had arrived at MD Anderson, in 2011, one of his first orders of business was launching the Moon Shots Program, a series of intensive research efforts that seek to “make a giant leap” for patients by quickly and drastically reducing mortality in thirteen common cancers. Every one of those research efforts has an immunotherapy component. And when DePinho began to poach star talent from other institutions—another key plank of his leadership—Allison was his first target.
By the time the potential of checkpoint inhibitors was becoming clear, in the late aughts, Allison was already a highly respected scientist. But in the four years since his arrival in Houston, in late 2012, he has become one of the cancer world’s biggest stars. In addition to his post at MD Anderson, he is the director of the scientific advisory council of the Cancer Research Institute, the leader of Sean Parker’s Immunotherapy Dream Team, and a member of vice president Joe Biden’s blue-ribbon panel on cancer. He has also received nearly every prestigious award for which he is eligible, including the $1.3 million Tang Prize, funded by Taiwanese entrepreneur Samuel Yin, and the $3 million Breakthrough Prize in Life Sciences, backed by Mark Zuckerberg, Sergey Brin, and other Silicon Valley luminaries.(Allison now drives both a Tesla and a Porsche Boxster with the vanity license plate “CTLA-4.”)
Allison’s return home has come with other perks and honors as well. UT System chancellor William McRaven named Allison his 2015 Texan of the Year. More thrillingly, Allison scored an invitation to play onstage with Willie Nelson. The two men, in fact, had crossed paths onstage once before. As a postdoc, in La Jolla in 1975, Allison had crashed a party celebrating the album Red Headed Stranger, introduced himself to Nelson, and ended up leading the singer and his band to an open-mic night, where Allison sat in on harmonica. Forty years later, Nelson’s longtime harmonica player, Mickey Raphael, read an article in the Dallas Morning News about Allison, and he was touched by the scientist’s work. “I lost my girlfriend to ovarian cancer,” Raphael told me. “I know the drill. I spent a lot of time in hospice with her. I got off the road and was with her to the end.” Raphael felt that a guy like Allison who was trying to defeat cancer deserved a special reward, so he figured “maybe I’ll do a reverse Make-A-Wish.”
One night, Allison showed me an iPhone video of the performance from earlier this year, at the Redneck Country Club, in suburban Houston, and he beamed as he watched the footage. He’s onstage standing next to Ray Wylie Hubbard, bopping around as Nelson sings “Roll Me Up and Smoke Me When I Die.” Then Raphael cues up “Dr. Jim,” and Allison whips out his harmonica and starts to wail. “I’m very kinetic—I’m used to playing the blues,” Allison explained. “When I went out and started playing those blues riffs, Willie said, ‘Whoa, that’s not Mickey!’ ” (Raphael’s appraisal of Allison’s performance: “He could play.”)
The official story of Allison’s return to Texas is that both MD Anderson and the state—through the Cancer Prevention and Research Institute of Texas—invested heavily in his recruitment, dedicating more than $50 million to bolster the cancer hospital’s immunotherapy research capacity. “Beyond those specific investments, Jim saw the comprehensive commitment to fully translate his brilliant ideas into lifesaving clinical trials, and so it was the obvious choice for us to have him and for him to be here,” DePinho said. But it didn’t take long for me to realize that this wasn’t the only reason Allison had come home. “Well, it wasn’t all scientific,” he admitted sheepishly.
A few hours after I’d visited DePinho in his office, Allison and I were walking through the third level of South Campus Research Building 1, where we were about to begin a tour of MD Anderson’s immunotherapy platform, a kind of meta-laboratory where tumor tissue from dozens of immunotherapy clinical trials is studied in exhaustive detail. Then, seemingly out of nowhere, a woman in a white lab coat popped into the hall in front of us, waved, and called out, “Mind if I steal him for a minute?” Allison dutifully lumbered off in her direction.
The woman was Padmanee Sharma, an M.D./Ph.D. who’s the scientific director of the immunotherapy platform, a professor of genitourinary medical oncology and immunology, and also, since 2013, Allison’s wife. (Both were previously married.) Several people in the halls of MD Anderson, upon learning that I was writing about Allison, mentioned that the pair was “an unusual couple,” and they are—gloriously so. Sharma is 46—slim, energetic, and as much fun as her husband—a Guyanese immigrant who spent her teen years as a latchkey kid in Queens, New York; gave birth to three daughters before she turned 30; and pioneered a new approach to studying the effect of immunotherapy drugs on tumors before she had her first faculty appointment, at MD Anderson, in 2004. Sharma met Allison in 2005, when she asked him for a letter of recommendation to help secure a grant to fund her immunotherapy research; they started dating, and he proposed to her not long after. Sharma turned him down.
“It wasn’t my idea of how to make my career,” she said. But that wasn’t a final no. They continued seeing each other when they could. By the time Allison arrived in Houston, Sharma was a full professor with tenure, and she no longer felt she’d be forever known as Mrs. James P. Allison.
“Of course, Jim had another wonderful statement that helped,” Sharma told me. “He was like, ‘Seriously, Pam, nobody can stand either one of us, so we better get married. Who else is going to talk T cells with you all day?’ ” (Allison’s take on their pairing, as he looked at a photo of the two of them in formal dress: “Beauty and the beast.”)
The immunotherapy platform is the core of Allison and Sharma’s research, and it is dedicated to a simple question: Why don’t more people respond to immunotherapy? Ipilimumab significantly reduces cancer cells in about 20 percent of stage-4 melanoma patients, a remarkable improvement from past treatments but far short of a universal cure. Two second-generation checkpoint inhibitors that block another “brake” known as PD-1 have increased this response rate to 50 percent, and trials combining ipilimumab and anti-PD-1 drugs have improved survival rates further. But we’re still a long way from turning metastatic melanoma into pneumonia, and that particular malignancy has been considered the most susceptible to an immune response. There are now four FDA-approved checkpoint inhibitors: Bristol Myers Squibb’s Opdivo, Merck’s “Jimmy Carter drug” Keytruda, Genentech’s Tecentriq, and ipilimumab, which is marketed under the name Yervoy by Bristol Myers Squibb. In addition to being approved for metastatic melanoma, the drugs have gotten the green light to treat non–small cell lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin’s lymphoma. These and other checkpoint inhibitors are currently in trials for a host of other malignant diseases, among them brain cancer, breast cancer, ovarian cancer, and prostate cancer.
In all of these cancers, and with all of these drugs, the final results remain uncertain, a fact underscored in August when Opdivo unexpectedly failed to meet its endpoint in a lung cancer trial, and Bristol Myers Squibb plummeted $20 billion in market value in a single day. It’s possible that checkpoint inhibitors could become the standard-of-care treatment in the majority of metastatic cancers—the fourth pillar transforming into the very foundation of cancer therapy. It’s also possible that the development of checkpoint inhibitors could stall out close to the current levels of effectiveness, with science unable to push survival rates much higher. These are widely celebrated drugs, but when immunotherapy researchers drop their marbles off the observation deck of the Empire State Building, the majority of those marbles still fall to the ground. The question now is, How can you make more of them stay floating in midair?
By the time Allison returned to the immunotherapy platform, I was already in the middle of a tour with two of his colleagues, Jorge Blando and Luis Vence. As we walked through the lab, Blando showed me a machine that cuts tumor tissue (taken from immunotherapy patients) into tiny slices—“like a ham,” Vence added—allowing scientists to see the location of biomarkers on the treated cells and ascertain whether there are patterns common to patients who respond to the treatment and those who don’t. Vence performs a similar analysis, but instead of slicing tumor tissue, he places it in a giant metal box called a Helios machine, then blasts it with a plasma torch that is as hot as the surface of the sun.
“It’ll measure forty things,” Allison, now standing next to us, said of the machine. “The idea is that the computer then will reassemble that in forty dimensions of data.”
I looked puzzled at what this meant. So did Allison.
“I really can’t even figure out what that’s going to look like. It’s very new—we’re a beta-test site.”
But this technology isn’t merely serving an academic interest. It’s being used to address what Allison sees as a potential obstacle to the immunotherapy revolution. “After taking so long to get the clinic to understand the science, now the clinic is way beyond the science,” Allison said, meaning doctors are testing out new drugs and new combinations of drugs without anyone understanding—Allison very much included—exactly what they do to the human body. Such experimentation is an inevitable part of medicine, of course. When lives are at stake, you go with what works, not with what you can explain in an elite journal. But, Allison believes, an everything-and-the-kitchen-sink approach that dispenses with scientific research could very quickly return immunotherapy to its phenomenological past. In the short run, you might see a few more miracle cures (and more patients with debilitating side effects). In the long run, Allison told me, “if you don’t do the fundamental science, then you’re going to ensure that everything is incremental—you’re going to ensure that things are done in baby steps. You’re not going to have the really big thing.”
When Allison talks about his work, he likes to be bold. He doesn’t shy away from the word “cure.” But he can be pragmatic about his role too. “As much as I say we shouldn’t be satisfied with moving the median, if you move over survival just another six months, then maybe another trial opens up with a new drug or a new combination that does better,” he said. He may not work in the cancer ward, but he’s not a fantasist. He knows that until the next major advance comes along, immunotherapy remains more often a form of triage than a miracle elixir.
In June Sharma invited me to come meet some of her patients so I could see what the effects of immunotherapy actually look like. A few weeks later, I arrived at the Mays Clinic, the home of MD Anderson’s genitourinary department, and found Sharma rushing purposefully but good-naturedly between examination rooms. There were sixteen kidney and bladder cancer patients on her schedule that day, all with stage-4 disease, and by the time I arrived, Sharma had already broken the news to two patients that they were failing to respond to treatment. “We had to talk about whether it was time for hospice,” she said. “They were going to decide whether to go on another trial or go home to their families.”
This was the awful reality of treating patients with advanced disease: eventually you had such talks with far more patients than ones you sent home with a clean bill of health. But that didn’t mean there weren’t moments to celebrate.
Sharma was eager for me to meet one of the few patients she’d been treating since the start of her career at MD Anderson, a retired Army lieutenant colonel named Michael Lee Lanning, who now spent much of his time writing military histories. Like Allison, Lanning was a small-town-Texas child of the fifties—he had grown up on a ranch near Sweetwater—and like Allison, he’d gotten out of Dodge as fast as he could. (For Lanning, that meant A&M and a platoon in Vietnam.) Lanning had been diagnosed with metastatic kidney cancer at age 59, and he’d been given such a poor prognosis by every doctor that he figured he might not make it to 60. But he refused to go home, and he’d come to Sharma looking for a sunnier forecast. Their first appointment was rough.
“He wanted someone to tell him ten years,” Sharma said.
“I said, ‘Give me something!’ ” Lanning replied.
“I told you the likelihood is that you would die of cancer. We didn’t have a therapy. I was giving the facts,” Sharma said.
“Very cold,” Lanning replied, shaking his head in jest. They were good friends now, and he liked needling her. “ ‘Cold bitch’ is what I said to my wife when I walked out. But you know what? She had to be. She tells people, ‘You’re dying,’ and that’s what she told me. She was very up front.”
That was more than a decade ago. In the intervening years, Lanning would take a succession of targeted chemotherapies, and his cancer would beat a retreat, only to come roaring back.
“I’ve gone through a lung removal. I had a brain tumor. I got down to one hundred and forty pounds; I couldn’t stand, I couldn’t keep food down, and everything I ate I couldn’t taste,” Lanning said. “I remember getting the brain tumor out, and once I could finally walk again, I would walk ten steps; the next day I did twenty, the next forty, and back up.”
Lanning had lived in Phoenix during the first years of his treatment with Sharma, and when he’d see local doctors to check up on his condition, it wasn’t unusual for them to give him “a bottle of codeine and the phone number for hospices.” But unwilling to resign himself to a terminal diagnosis, he kept coming back to Sharma.
Sometimes, Lanning felt, the treatment was worse than the cancer. After his first dose of chemotherapy, he ended up in the emergency room. “I’m not a tough guy, but I spent a lot of time with tough people—Airborne, Rangers, that type of thing—so I thought I was pretty tough until I took that medicine.” But even when they found chemotherapies that worked and were more tolerable, the drugs proved to be temporary fixes. Last year, Lanning’s tumors were once again advancing, and Sharma put him on a combination of ipilimumab and radiation. So far, Lanning’s tumors have remained stable.
“If it comes back, I don’t know,” Lanning said. “But when I got this, I was hoping I would make sixty. I’ll be seventy in September.”
“And we have more immunotherapies if this one doesn’t work, so we’re not done,” Sharma said.
“Is that right?” Lanning said. “Look, I don’t think people are going to jump up on the steps of MD Anderson and say, ‘They’ve cured cancer with this thing.’ In fact, I think that whole ‘Making Cancer History’ campaign at MD Anderson is mostly bullshit propaganda money-raising stuff anyway.”
But Lanning had gotten good news that day, and he was feeling a little less cynical than he liked to let on. “So far, this immunotherapy is a hell of a good scrip,” he said to Sharma. “Tell your husband thank you.”
