Chapter Four

Eureka, Texas

Chance favors the prepared mind.

—LOUIS PASTEUR

The one who finally found the something was a hard living, harmonica-playing Texan who wasn’t even really researching cancer.

Jim Allison looks like something between Jerry Garcia and Ben Franklin, and he’s a bit of both: a musician and scientist who sugars his impatience and raw intelligence with beer twang and humor. More than anything, he is a curious and careful observer who doesn’t seem to give a damn about much else—a basic science researcher happy to be wrong ninety-nine times to be right once.

Allison outgrew his hometown of Alice, Texas,¹ in high school, after he was forced to turn to correspondence classes for an advanced biology class that dared mention Charles Darwin. That class was in Austin, home of Texas’s best public university and its most happening music scene. The combo suited Jim Allison perfectly, and after high school he moved there for good, seventeen years old and bound to be a country doctor, as his dad was.

The stretch between 1965 and 1973 was a good time to be young and musical in Austin.² Jim played the blues harp, well enough that he was in demand. He’d play honky-tonks in town, or play for Lone Stars in Luckenbach, where the new breed of outlaw country players like Willie Nelson and Waylon Jennings roamed the earth.³ That was fun; premed meanwhile felt like memorization for nothing.

In 1965 he switched to biochemistry, and traded memorization for a biochem lab, working with enzymes for his PhD. The enzymes he was studying happened to break down a chemical that fueled a type of mouse leukemia.⁴ As a biochemistry PhD candidate, Allison was supposed to figure out the biochemistry of how those enzymes worked.⁵ But he was also curious about what had happened to the tumors.

“So I was reading all this immunology stuff in the library,” Allison says.⁶ In the experiment, the enzyme eventually robbed the tumor of all its fuel, and the tumor went necrotic and “disappeared”—just another dead cell mass to be cleaned out by the macrophages and dendritic cells. But from his reading Allison knew those blobby aomeba-like cells weren’t all garbagemen; they had recently been discovered to also be frontline reporters, carrying updates on the constant battle against disease. Those updates were contained in the dead and diseased cells they gobbled into short protein fragments—the distinctive antigens of the disease pieces. Macrophages (and dendritic cells) were first on the scene, everywhere, embedded. When they found something interesting they brought pieces of the non-self proteins they’d gobbled back to the lymph nodes to show them around. (Lymph nodes are like Rick’s in Casablanca. Good guys, bad guys, reporters and soldiers, macrophages, dendritic cells, T and B cells, and even diseased cells, everyone goes to Rick’s.)⁷ That’s how B and T cells found their antigen, and activated.

What the macrophages were doing with the dead tumor tissue in his mice gave Allison a thought: That’s sorta how a vaccine works, right? A vaccine introduced the immune system to a dead (inoculated) form of a disease so that the immune system could prepare a response against that disease—build up a clone army of T cells specific to it, so that even an invading force of that disease would be evenly met. And wasn’t that what he’d done, by killing a tumor that macrophages cleaned out? Weren’t dead tumor cells, gobbled and presented by macrophages, something like a vaccine? So, he wondered—did that mean his experiment had, in a roundabout way, vaccinated his mice against this specific form of blood cancer? Were they now “immune” to this cancer?

“Just for the hell of it, I was setting up another experiment, and I decided that since I had these mice that were cured—who were just sitting there, eating—I would inject them with the tumor again, but not treat them with the enzyme this time, and see what happened.” This wasn’t the experiment—he hadn’t asked permission, he didn’t write a protocol, nothing. He simply shot from the hip. And what happened was—nothing. “They didn’t get tumors,” Allison says. “I went back and injected them with ten times as much and they still didn’t get tumors. I injected them with another five times more, and they still didn’t get tumors! Something was happening here, something amazing!”

As a casual one-off, the experiment hadn’t proved anything (“People talked about doing it in humans, you know, just taking your own tumor and mashing it up somehow and injecting it back, but it doesn’t really work that easily”), but it had provided Allison his first glimpse of the mystery and potential of the immune system. It was the most interesting thing he had seen. Now, he wanted to study that, first in a postdoctoral position at the Scripps Institute in San Diego,⁸ and then at a little lab MD Anderson Cancer Center was opening near the town of Smithville, Texas, “an economic stimulus thing from the governor,” Allison says, on donated land and with state money.

“It was pretty weird,” Allison says. “It was in the middle of an eighteen-acre state park,⁹ and they’d just set up some lab buildings and hired six faculty members to go out there. We were supposed to study carcinogenesis [how cancer starts]. I didn’t know anything about that.” But he had picked up some immunological techniques that helped those experiments work. Meanwhile, Allison says, MD Anderson sort of forgot about them.¹⁰ “So they pretty much left us alone.” This was Allison’s kind of place—for now, anyway. His colleagues were bright, enthusiastic scientists his own age—the oldest were in their thirties—who kept beer in the lab, worked late, helped each other with their experiments, and pooled intellectual resources.

The setup was sweetened by a total lack of teaching or administrative responsibilities, a Norton Commando 850 motorcycle, and enough NIH and NCI grants to pursue what Allison was really interested in—the study of a recently recognized lymphocyte, the T cell.

“It was a fantastic time in science because immunology had just been this poorly understood field,” he says. “I mean, everybody knew we had an immune system, because there were vaccines. But nobody knew much about the details of anything.”

One of the things nobody knew was how a T cell recognized a sick cell in the first place. Allison read every academic paper he could on the topic, then read the papers cited in them. “At first, I’d think, I’m an idiot, I can’t understand this. Then, I thought, No, they’re idiots—they don’t understand what they’re talking about!”

There were plenty of theories about how a T cell recognized antigens.¹¹ One prevailing theory was that each T cell had a unique type of receptor (a specific arrangement of proteins that extended from the T cell surface) that “saw” a specific antigen expressed by a sick cell, homing in and fitting something like a key into a lock. That was a reasonable theory, but nobody had actually found one of the receptors. If they existed, there should be a lot of them, scattered among all the yet uncounted proteins that stuck from the T cell surface (there are so many that new ones are given numbers, like newly identified stars).¹² Those “receptor” proteins would be molecules built in some sort of double chain-like configuration. Several labs were quite convinced that it would look just like it did on B cells. Which, Allison thought, was stupid.

“People from Harvard and Johns Hopkins, and Yale, and from Stanford were already claiming they had a molecule that was the T cell receptor,” Allison remembers. “Most of them, because B cells make antibodies, figured that in T cells the receptor had to be an antibody-like thing, too.”¹³

Whatever it looked like, if you could find it, in theory you could manipulate it. Control the T cell receptor and you might control what the immune system’s killing machine targeted. The result could have massive implications for humanity, and make a massive name for whoever found it.

Allison believed that T cells weren’t just a version of B cells, not just killer-B’s. If T cells existed (they did) and were different from B cells (they were), then those differences were the point. The molecular structure of the receptor that allowed T cells to “see” their specific antigen target was one of the key points of differentiation from B cell receptors; it would look different, because it worked differently, and did a different job.

The idea came in a flash while he sat in the back row of a lecture on the topic, listening to a visiting Ivy League academic. Suddenly, it seemed so obvious: if he could find a way to compare B cells and T cells, devise a lab experiment that put one against the other and let their redundant surface proteins cancel each other out, the receptor should be the molecule that didn’t cancel out. Essentially, he was looking for a needle in a haystack, and his idea was to set fire to the haystack and sift the ashes. Whatever was left would be the needle he was looking for.

He hurried to the lab and got to work. “It was a success, the very first time,” he says. “So, now I’ve got a thing that’s on T cells but not on B cells, not on any other cells ¹⁴—so, that’s gotta be the T cell receptor!” He showed the receptor was a two-chain structure—an alpha and a beta chain, and he wrote it up in a paper.

Allison was hoping to be published by one of the leading peer-reviewed research journals.¹⁵ But nobody at Cell or Nature or any of the A-list peer-reviewed journals was willing to publish the findings of this junior academic from Smithville, Texas. “Finally, I ended up publishing the results in a new journal called the Journal of Immunology.” It wasn’t Science or the New England Journal of Medicine, but it was in print, and in the world.¹⁶

“At the end of the paper, I said, ‘This might be the cell antigen receptor, and here are the reasons why I think that it is the T cell antigen receptor,’ and I just listed it out, all the reasons.” It was a bold announcement regarding the biggest topic in immunology. “And nobody noticed it,” Allison says. “Except in one lab.”

That lab was headed by eminent biologist Philippa “Pippa” Marrack at UCLA San Diego. Her lab (shared with her husband, Dr. John Kappler) hadn’t identified the T cell receptor yet, but they had a scientific technique that could verify if Allison’s results were correct. Dr. Marrack reproduced Allison’s experiment and got an exact hit on the protein Allison had identified—and only on that protein. It was a shock, especially coming out of a lab Marrack had never heard of. Allison said she called and told him she was organizing a Gordon Conference—elite, closed-door gatherings something like the Davos of science. She invited him to present at the meeting; Allison had a sense he was being invited into the big leagues.

The Gordon meeting helped put the brash young scientist on the academic map, and won him an appointment as a visiting professor at Stanford University. Now that the T cell antigen receptor (TCR) had been identified, and its two-chain molecular structure had been described, the race was on for the greater prize: the blueprints for those proteins, as encoded in genes in the T cell DNA.

“At that point, people had just figured out how you could work with DNA and clone genes, so now, everybody was trying to clone this [T-Cell receptor protein] gene,” Allison says. “It had been the holy grail of immunology for twenty, twenty-five years, and nobody had solved it. Everybody was scrambling, man, it got ugly. I mean, everybody realized there was a Nobel Prize at the end of it.”

That August, Stanford immunologist Dr. Mark Davis made an unscheduled speech at the big tri-annual immunology world congress in Japan, announcing that his lab had located the gene for the T cell receptor beta chain in mice. The following year he published the confirming details in the prestigious British journal Nature, back-to-back with a paper by renowned Canadian geneticist and biological researcher Dr. Tak Mak, who had successfully identified the T cell receptor beta chain gene in humans. That left the gene for the other half of the T cell receptor, the alpha chain. Davis, along with his collaborator and wife, Dr. Yueh-Hsiu Chien, were in the audience when that achievement was announced during a slide presentation by MIT immunologist Susumu Tonegawa.¹⁷ Davis had shared his lab’s gene-cloning technique with Tonegawa a few years earlier; now he felt like he was paying the price. On the plane ride home, Chien told her husband she recognized the slide of the barcode-like “fingerprint” Tonegawa had announced as coding the alpha chain. Davis smelled opportunity. They rushed back to their lab, pushed around-the-clock research into the gene Tonegawa’s slide seemed to have identified, and put a written paper on the subject onto a 7 p.m. DHL flight to London, where it was hand-delivered to the editor’s desk at Nature. Tonegawa’s own paper on the alpha chain gene arrived at the same desk days later.

While both articles, with nearly identical titles and announcing the same discovery, were published back-to-back in the November 1984 issue,¹⁸ technically the Davis and Chien paper had hit the desk first, giving them the honor and the citation in biology textbooks forever.¹⁹ Two years later, Susumu Tonegawa would be awarded the 1987 Nobel Prize in Medicine, citing his earlier groundbreaking work on B cell genes. To date, nobody has received a Nobel for the T cell receptor gene. Afterward, Tonegawa left immunology to study the molecular basis of what and how we remember, and what and how we forget.

“Anyway, we cloned a lot of stuff,” Allison says. “But none of it was right. At the end of it, I was invited to give a seminar at [University of California,] Berkeley. It was kind of controversial because I hadn’t been at the big labs. I hadn’t been at Harvard. I lacked the pedigree of most faculty at places like Berkeley.” Which was why it blew his mind two weeks later when Berkeley offered him a full-time job,²⁰ covered by a massive grant from the Howard Hughes Medical Institute. Allison would have a lab and postdoc salaries, and he could research whatever he wanted. He didn’t need to teach, and the money might last forever with no strings. His only obligation would be to go to the HHMI headquarters every three years and give a twenty-five-minute talk in front of fifty of the top scientists in the world and present his work on T cells.²¹

Allison’s work at Berkeley would have the benefit of a far better understanding of T cells than when he had first started fixating on them a decade before. Now it was widely accepted that there were different kinds of T cells, with different specialties for coordinating an immune response against disease. Some “helped” immune response by sending out chemical instructions, via cytokines, like a quarterback calling plays. Others, the killer T cells, killed infected cells one-on-one—usually by chemically instructing those cells to commit suicide. The processes above, and more, were set in motion only when a T cell was “activated.” Activation is the beginning of the adaptive immune response to disease; until then, the T cells are just floating around and waiting. So what activated T cells? What made them start mobilizing against disease?

“We thought that the T cell antigen receptor was the ignition switch,” Allison says. That was the natural assumption.

It was only after they’d identified the T cell receptor that they realized, nope, that wasn’t quite right, either.²² They could get the T cell receptor to “see” the foreign antigen of a sick cell; they bound like lock and key. But the antigen key wasn’t enough to turn on a T cell.²³ It wasn’t the “go” signal.

“When I learned that, I said, ‘Oh, wow, this is cool, T cells are even more complex,’ you know? It just added more to the puzzle. It made it more fun.”

If keying the T cell receptor with an antigen wasn’t the only signal needed to turn on a T cell, that meant there had to be another molecule, maybe several, required for costimulation.²⁴ Maybe the T cell required two signals—like the two keys for a safe deposit box, or how, when starting a car, you need to key the ignition and also press the gas pedal to make it go. But where was the T cell’s gas pedal?²⁵ Three short years later, they found it, another molecule on the T cell surface called CD28.²⁶ CD stands for “cluster of differentiation,” which is sort of like calling it “a thing that’s clearly different from the other similar things around it.”

CD28²⁷ was the second signal to turning on T cells. ²⁸ That was important, but, as Allison and other researchers quickly discovered, it also wasn’t that simple. Presenting the right antigen key to the T cell receptor and costimulating CD28 did start up the T cell, but when they did that in mice models, often the T cell just stalled out. It was as if they’d found the key to the ignition and the gas pedal, but a third signal was still necessary to make the T cell “go.” So now they went hunting for that.

One of Allison’s postdoctoral students, Matthew “Max” Krummel, compared the structure of the protein CD28 to other molecules, looking for something similar in a sort of computerized book of molecule mug shots—“the gene bank, that’s what we called it at the time,” Allison says. The idea was that if you found a molecule that looked similar, maybe it did similar things and was related. Krummel soon found another molecule with a close family resemblance to the part of CD28 that stuck out of the cell, the receptor part.²⁹ The molecule had recently been identified, named, and numbered.³⁰ It was the fourth cytotoxic (cell-killer) T-immune cell (lymphocyte) identified in the batch, so Pierre Goldstein, the researcher who’d found it, called it cytotoxic T-lymphocyte-associated protein #4—or CTLA-4 for short.³¹

Meanwhile, researchers Jeffrey Ledbetter and Peter Linsley were working on the same third signal problem at the Bristol-Myers Squibb research campus in Seattle. “Linsley made an antibody to block CTLA-4,” Allison recalls. The group published a paper concluding that CTLA-4 was a third “go” signal, another gas pedal on the T cell that had to be activated for immune response.³² Having another researcher beat them to making the antibody was disappointing, and especially disheartening to Krummel—he’d just spent three years working on the antibody as his intended thesis project—but Allison decided to proceed with more CTLA-4 experiments anyway. There was always more to learn. Besides, he wasn’t totally convinced that Linsley et al. had completely solved the T cell activation mystery.

“I knew there were two ways you can get something to go faster,” Allison says. “One is to press on the gas pedal. The other is to take off the brake.” Allison says Linsley’s group had only devised experiments consistent with CTLA-4 being another “go” signal, essentially a second CD-28. “I said, ‘Let’s do the experiments consistent with [CTLA-4] giving an “off” signal,’” Allison says. “Sure enough, that’s what we found out. CTLA-4 was an ‘off’ signal.”³³

Allison’s lab now had a fairly complete picture of the steps required for T cell activation against disease. First, the T cell needed to recognize the sick cell by its unique protein fingerprint; in other words, it needed to be presented with the antigen that matched its T cell receptor (TCR). Usually it was a dendritic cell or macrophage that did that presenting. Binding to that antigen was like turning the key in an automobile ignition. The other two signals (CD28 and CTLA-4) were like the gas pedal and the brake on that car. CTLA-4 was the brake—and it was the more powerful of the two. You could press both (and in experiments, Krummel found that was a crude way of controlling the activation rate), but if you floored both, the brake overruled the gas pedal, and the T cell wouldn’t go, regardless of everything else. Enough stimulation of CTLA-4, and immune response stalled out.

If all this sounds complicated, it’s because it is, on purpose. Allison’s lab had discovered an elaborate safety mechanism, an aspect of the larger framework of checks and balances that prevents the immune system from going into overdrive and attacking healthy body cells. Each safety is a sort of fuse that gets tripped if a trigger-happy T cell is programmed to target the wrong antigen, such as one on normal body cells. It was a way of repeatedly asking, Are you sure about this? before T cells turned into killing machines.

Proper triggering of immune response against pathogens is what keeps you healthy. However, pedal-to-the-metal immune response against self cells is autoimmune disease: multiple sclerosis, Crohn’s disease, some forms of diabetes, rheumatoid arthritis, lupus, and more than a hundred others. They happen often, even with this elaborate feedback system in place. And so the double-check, double-signal mechanism of T cell activation is only one of many redundancies and fail-safe feedback loops built into immune response. Those “checkpoints” on T cell actuation hadn’t been guessed at.³⁴ But now Allison’s lab, and, simultaneously, the lab of Jeff Bluestone at the University of Chicago, had found one of those checkpoints.³⁵ Bluestone was focused on ways of placing this new discovery in the context of organ transplants and diabetes, tamping down unwanted immune response. But Allison had a different idea where he’d like to stick it.

Biology was interesting, diseases weird and fascinating, immunology cool. But cancer, Allison admits, “pissed me off” personally.³⁶ He was just a kid when he lost his mom to it,³⁷ had held her hand as she went, not even knowing what the disease was or why she had burns, only knowing she was gone. He’d lose most of his family that way eventually, and though he’d never said it out loud, hadn’t even voiced it to himself, in the back of his mind cancer had always been the one potential, practical outcome of his otherwise pure scientific research. And now here he was, with another experiment in mind, and an intellectual path to an emotional destination.

“My lab always has been basic immunology, and half—or less, actually—tumor,” Allison said. “But I had a new postdoc [Dana Leach] who had done some tumor stuff. In late summer, I wrote the experiment out. I said, ‘I want you to give some mice tumors and then inject them with this [CTLA-4 blocking] antibody. Give others tumors but no anti-CTLA-4, and let’s see what happens.’” In November, the postdoc came back with the results: The mice that got anti-CTLA-4 had been cured of cancer. The tumors had disappeared. In the mice that didn’t have CTLA-4 blocked, the tumors kept growing.

Allison was stunned—this wasn’t what experimental data looked like. “According to the data, it was a ‘perfect’ experiment, 100 percent alive versus 100 percent dead. Jesus, I mean, I was expecting—something. But this was 100 percent. Either we’d just cured cancer, or we’d really screwed up.”

He needed to do it over again. “We had to—it was Thanksgiving, and these experiments take a couple of months.” But Allison says his postdoc wasn’t going to give up his European trip over Christmas break, not for a bunch of mice.

Allison told him to just set up the experiment again. “Right now, inject all the mice, then go do whatever you’re going to do.” To ensure that his observations were as unbiased as possible, he told the postdoc to label the cages A, B, C, D. “I’ll measure the mice. Don’t tell me anything,” he said. Allison would do the grunt work and check the results for each, but until it was over, he wouldn’t know which group was which.

“It was really harrowing,” Allison remembers. He’d come in every day and see that the tumors in cage A seemed to be getting bigger. He’d measure each tumor with calipers and mark the results on his gridded paper, then move to cage B and find the same thing, mice with growing tumors. Same story in cage C and cage D. There were a lot of mice, a lot of numbers, and they were all on the same track. It was 100 percent failure.

Had his break-happy postdoc screwed up this experiment too? Allison felt he was moving backward. Finally, on Christmas Eve he was in the lab, staring at four cages of mice, all with steadily growing tumors. “I said, ‘Fuck—I’m not going to measure these anymore. I need to take a break from this.’”

He returned four days later to discover that the situation in the cages had changed dramatically. In two of the cages the mice tumors were now shrinking. In the other two cages the tumors continued to grow. When he unblinded the experiment’s cages, he was sure. It had taken time for the immune response to kick in, much like it does with a vaccination, but it had happened. Day by day, and surprisingly quickly, the trend continued; it was just as before—100 percent, a perfect experiment.

He hadn’t known where he was going with all of this experimentation, but now, suddenly, they had arrived. They’d figured out a biological mechanism that made sense of decades of confusing data. Tumors learned to exploit CTLA-4. In mouse models, this was how cancer shut down an immune response. It was evolution, cancer’s survival trick, or one of them. If Allison could block it in mice, maybe he could block it in people. The breakthrough wasn’t what was in the cages; it was the new view of the world the data revealed. It doesn’t usually happen in science like it does in the movies, the eureka moment, a new understanding in an instant. But this was it. EUREKA! T cells could recognize cancer, cancer used tricks to stifle a complete T cell response, and you could block that.

What else was possible? That question, and the hope it engendered—that was what mattered. And that was the breakthrough.

CTLA-4 had turned out to be what would be called a “checkpoint” on T cell activation, a built-in kill switch poking from the T cell surface, installed by Mother Nature to prevent the body’s cell killer from running wild. Allison had discovered it had been hijacked by cancer to shut down (or “down-regulate”) an immune response against it.

Allison’s lab had made an antibody that found and fit to the CTLA-4 receptor like a key broken off in a lock. It blocked that checkpoint, so cancer couldn’t use it. Some biologists compare the action of this checkpoint inhibitor to wedging a brick underneath the brake pedal of a running car.

Checkpoint inhibition differed from previous attempts at a successful cancer immunotherapy that sought to induce, ramp up, or “boost” an immune response to cancer. Instead, blocking the checkpoint prevented cancer from shutting down the natural immune response against it.

For decades, researchers had been looking for something to explain why they couldn’t make an immunotherapy that worked reliably against cancer. Many assumed that the problem was that T cells couldn’t really recognize tumor antigens—which meant that the problem with cancer immunotherapy was that it was futile to begin with. Work in Allison’s lab suggested a different scenario. The T cell could see cancer, but the CTLA-4 receptor acted like a brake, a checkpoint that stopped immune response. Blocking or inhibiting that checkpoint with an antibody might be the missing puzzle piece cancer immunologists had been searching for.³⁸

Allison’s lab³⁹ now had antibodies that blocked the CTLA-4 receptor in T cells. They believed they could block cancer cells before cancer got a chance to shut down T cell activation; in theory, this was a potential drug that might help cancer patients. In order to realize that potential, to even know if it worked, it would need to be tested. And in order to test it at scale, it would first need to be manufactured. But Allison couldn’t find a pharmaceutical company that was interested.

One problem was that it was 1996 and he wasn’t hawking the sort of drug most pharma manufacturers were equipped to make. The easiest, the most common kind, were small molecules. They’re relatively simple to assemble in quantity, and the manufacturing process is far more straightforward than that required for the large antibody Jim Allison had for blocking CTLA-4. Most cancer drugs were small-molecule drugs. They didn’t cure cancer, but they attacked it, for a while. “That was what was driving pharma then,” Krummel says. “And it would be for the next fifteen years.”

The other problem was that, while anti-CTLA-4 was a cancer drug, it was one that represented a treatment philosophy that acted not on cancer but on the immune system, unleashing it so it could do its work.

It was, in other words, a cancer immunotherapy. And cancer immunotherapies had heretofore proven to be a risky bet. Manufacturing, testing, marketing, and distributing such a drug (or any drug) would take many millions of dollars and many years. It was a bigger risk than most companies were willing or could afford to take, especially for an approach to cancer most oncologists distrusted.

And as Allison now also discovered, he had a third problem. In the years between when CTLA-4 was first discovered and Allison’s and Bluestone’s labs figured out how it worked and what it did, a provisional patent had been filed by the pharmaceutical giant Bristol-Myers Squibb. Their patent preceded Allison’s as a stake in the ground, but it was based on a misunderstanding of how CTLA-4 worked.

The BMS patent had CTLA-4 as a gas pedal. It claimed their antibody would bind to CTLA-4 as an agonist, revving up the T cell. Allison and Bluestone’s breakthrough realization was that CTLA-4 was in fact a brake pedal, down-regulating immune activation. Allison’s unique patent was for an antibody that blocked that brake, as a drug for use against cancer. Allison had been right, Bristol-Myers Squibb had it wrong. Allison and his postdocs would eventually prevail. But in the meantime, a conflicting claim against a billion-dollar corporation didn’t help their sales pitch any.

“There was all this excitement, and then it was like radio silence,” says Krummel. “You could hear the bees in the orchards.”

It took two years of travel and talk before they finally found a home, with a small New Jersey–based pharma company created by a team of immunologists from Dartmouth Medical School.⁴⁰ Medarex wasn’t big, they didn’t have the deep pockets of a Bristol-Myers Squibb or a Roche, but they did have a mouse genetically engineered to make human antibodies (rather than mouse antibodies).⁴¹ With Allison’s intellectual property, their mice would become living pharmaceutical factories, capable of producing anti-CTLA-4 in quantities sufficient for the first-in-human clinical trials. It might even become a cancer drug, and help people. But that maybe was still fifteen years away. Far more likely was that they’d end up curing cancer in mice, one more time.