Chapter Three
Glimmers in the Darkness
Blut ist ein ganz besonderer Saft. (Blood is a very special juice.)
—GOETHE
In retrospect, it’s surprising what we didn’t know about our bodies, and how recently we didn’t know it. We had a pretty clear picture of the planets in the solar system and the composition of moon rocks before we had a working understanding of what was happening in our own bloodstreams.
The study of immune biology started with the microscope, and a mess of cells strained out of the blood by a biologist’s porcelain filter. The ones that were red were recognized as the blood cells that shuttle oxygen through the body. The cells that weren’t red were called “white,” in the sense that non-red wine is called white. These white blood cells are also called leukocytes. (The Greek root for “white” is leuk and for “cell” is cyt.) The term still refers to any cell that’s part of the immune system.
Immune cells were originally assumed to all be the same. It would take more than a simple microscope, however, to reveal that our bloodstream in fact contains an exotic ecosystem of specialized players bound in an elegant and potent web of personal defense.
The first aspect of immune response to be grasped by nineteenth-century biologists was the oldest and most primitive, a 500-million-year-old personal defense system we call the “innate” immune system.1
The innate immune system is charismatic and deceptively straightforward. It also happens to have cells big enough to be seen wiggling and eating under the microscope. That includes amoeba-like cells adept at squeezing between body cells and patrolling our perimeter (inside and out, we have a surface larger than a doubles tennis court), looking for what shouldn’t be there and killing it.
These cells include small blobby smart patrollers called dendritic cells (remember them for later) and similar but larger blobby characters called macrophages (literally, “big eaters”). Among their other jobs, these serve as the garbagemen of the immune system. Mostly what they eat are retired body cells—normal cells that have hit their expiration date and politely self-destructed. They also eat bad guys.
Macrophages have an innate ability to recognize simple invaders. These foreign, or non-self cells, are recognizable as foreign because they look different—that is, the fingerprint of chemical arrangements of proteins on their surfaces is different. Macrophages look for anything they recognize as foreign, then grab and gobble it.
These cells also end up saving little pieces of the invader cells they kill, creating a show-and-tell for the rest of the immune system. (We’ve also recently discovered that some innate immune cells are more than just simple eaters and killers—they seem to be the brains of the larger immune system.)
Innate immune cells are tuned to recognize the usual suspects—the bacteria, viruses, fungi, and parasites that evolved right alongside us and account for most of what needs defending against.
Where there’s one invader there are probably more, so the cells of the innate immune system can also call for local reinforcements. The call for help is chemical, in the form of the hormone-like proteins called cytokines. Many cytokines are like a distress beacon, with limited range and longevity, to prevent overreaction. There are many different flavors of cytokines, conveying many different messages. Each begins a complex choreography of chain-reaction defense responses within the body.
The result is a surprisingly sophisticated chemical communication that can call for more blood supply and tell the small blood vesicles (capillaries) to become more leaky, so fluid and reinforcements can flood in between the gaps (what we know as inflammation), and even stimulate the local nerves to send out extra ouch! signals (so you pay more attention to the problem—and maybe remember not to do it again).
That’s what an immune system looks like for nearly all life on earth. It works fine for recognizing and killing the usual suspects of disease, providing a rough and ready response effective enough to mop up most invading threats in just a few days.
But more recently evolved critters on the tree of life—vertebrates with jaws, like us—also have an additional type of immune army, one capable of adapting to meet new challengers. This is the “adaptive” immune system, and it is able to face, fight, and remember unusual suspects: invaders that the body has never encountered before.
The major players of this adaptive immune system are two distinct types of cells that travel our bloodstream, with distinct tools of defense.2 These are the B and T cells.
Diseases evolve and adapt. Nature invents new ones all the time. The B and T cells are part of a system that adapts to counter them. In terms of attacking cancer specifically, it’s the T cells we care about. But both B and T cells play a role in the cancer immunotherapy story.
Vaccines are the most successful form of immunotherapy, one we’ve been familiar with for hundreds of years. Their biological mechanism is dependent on the adaptive immune system.
Vaccines train the cells of the immune system on a harmless sample of a disease that it might encounter later. The introduction allows the immune system to build up forces against anything that looks like that sample. Then later, if the live disease does show up, an immune army will be waiting for it.3
Both B and T cells are involved with creating immunity. B cells were discovered first, so they get first billing.
Before these immune cells migrate into our bloodstream, they mature from stem cells in the marrow of our bones. B cells4 have a unique method of defending us against the stuff that causes disease. They don’t kill disease cells directly. Rather, they are factories that spit out antibodies—sticky, Y-shaped molecules that grab and hold on to foreign or non-self cells, and mark them for death.
Antibodies were originally called antitoxins, because they were assumed to be the stuff in blood that neutralized toxins—little customized antidotes that matched the poisonous molecules of disease like a lock to a key, canceling them out one by one.
B cells (and T cells) need to be ready to recognize anything that is non-self. This is possible because non-self, foreign, or diseased cells look different from normal body cells, at least to the discerning immune system. The difference is superficial—the outside of the cell is different. Foreign or sick cells have foreign proteins on their surface. The molecular marking is a distinctive bad cell fingerprint. These telltale fingerprint arrangements of foreign proteins on the surface of non-self cells are called antigens.
B cells create antibodies capable of recognizing the antigen fingerprints for even unknowable threats through an ingenious random genetic mix-and-match process that allows for 100 million different antibody variations. This variety is enough to ensure that at least one will match up with one of the many millions of possible protein arrangements of a foreign antigen. Every B cell makes antibodies to fit a randomly assigned antigen type. It’s something like a lottery ticket approach to recognizing random strangers. Every potential combination is covered by one or another of the B cells. It really only takes one antibody recognizing a foreign antigen to kick off the immune response.
Here’s how that works:
There are an estimated 3 billion B cells riding around in your bloodstream, each covered with sticky antibodies designed to match up with the antigens of diseases it will probably never meet, and which may not even exist.5 B cells spend most of their short lives floating around until they happen to get lucky and come across the corresponding unique antigen of a pathogen (such as an unfamiliar bacteria, virus, fungus, or parasite).
If the antigen they encounter happens to match up exactly with the unique antigen receptors of a particular B cell’s antibodies (which stud the B cell surface like cloves on a Christmas ham), that B cell snaps into action, producing clones of itself, identical daughter cells all born with the same “right” antibody.
In twelve hours, that B cell can make twenty thousand cloned copies of itself, and the process continues for a week. Each new-made member of the B cell clone army also becomes a new factory, producing just that antibody against that disease cell.
Now it’s time to attack. The antibodies on the B cell surface fly out like sticky guided missiles at a rate of two thousand per second. Each of these antibody missiles has only one target: the unique non-self antigens on those foreign cells. They can see nothing else. The antibodies find and stick, accumulating on their target like burrs on a dog. Not only does this trip up the disease cell, it also acts like a blinking neon sign that catches the attention of the wandering blob-like macrophages, drawing them toward a free foreign meal. The antibodies are sticky to the macrophages too. They bind them to their dinner. They also seem to stimulate the appetites of “nature’s little garbagemen” (a process known as opsonizing, from the German word that means “prepare for eating”). The foreign invader cell gets stuck, then gobbled.
It’s a fantastically elegant and sophisticated defense that ramps up a response to a new disease in about a week. When the threat is over, most of the B cell army dies off, but a small regiment sticks around, remembering what happened, ready to snap back into action if the threat shows up again.
That’s called immunity.
B and T cells look nearly identical under an optical microscope (part of the reason that, for most of the twentieth century, there was no such thing as a T cell). Just like B cells, T cells recognize a foreign antigen and ramp up a clone army to attack it. But T cells recognize and kill sick cells in a totally different manner.
Eventually it became clear to biologists that all those white blood cells that looked so similar under the microscope didn’t look exactly the same, or function in the exact same way. By the 1950s it had been observed that some of the small lymphocytes (immune cells) also traveled differently through the human body.
B cells were known to originate in the bone marrow, travel the bloodstream for a while, and die. But some of these B-like cells seemed to take an extra side trip into a mysterious butterfly-shaped gland located just behind the sternum in humans, called the thymus; more of these cells were observed pouring back out of the thymus into the bloodstream. Even stranger, more came out than went in. Their numbers were sufficient to replenish the whole stock of B cells four times over, and yet, the overall number of lymphocytes in the body seemed to remain constant. So where did they go? The mystery of the disappearing lymphocytes was only cracked in 1968, when an experiment was able to follow them and find that the odd B-like cells that dumped into the bloodstream from the thymus were the same ones that later cycled back through the thymus. And many that went in never returned. It was as if they were being made, recycled, and perhaps modified in this strange gland.6
Experiments demonstrated that lymphocytes that cycled through the thymus were in fact very different from the familiar B cells. These cells seemed uniquely responsible for very specific aspects of immune response, such as organ rejection after surgical transplant.
The biological model that had all lymphocytes as B cells originating in the bone marrow didn’t match the new observations. Which begged the question: Was there a different type of lymphocyte, one that came from the thymus instead? A white blood cell involved with adaptive immunity that wasn’t a B cell? And if so, what should they call this thymus-born cell?
It was a surprisingly contentious question. When a young researcher named J.F.A.P. Miller proposed to his colleagues at a 1968 immunology conference that perhaps they should consider that there were two distinct types of lymphocytes—B cells from bone marrow that made antibodies, and T cells from the thymus that somehow worked differently—he was publicly reminded that B and T are the first and last letters of bullshit.7
But, of course, Miller was right, and by 1970 it was generally accepted that these T cell lymphocytes, or “T cells,” were different from the B cells that made antibodies.
It would be another five years before the picture was further complicated—or clarified, depending on your perspective—by the important realization that there were also several distinct types of T cells.
Immunologists distinguished two of the main ones with typical flair as “CD8” and “CD4,” but they’re better known as killers and helpers.8 Killer T cells are the single-minded bruisers of the immune team, while helper T cells serve as a sort of quarterback for that team, “helping” coordinate the larger immune defense game plan by broadcasting a complex array of chemical signals, or cytokines.9
Finally, the bigger immune picture was starting to make sense. The T cells had been a missing piece. Their discovery provided a workable explanation for most of what had been observed about our reaction to illness and disease.
It goes like this.
The cells of the innate immune system respond quickly to familiar invaders, the usual suspects. Usually they are sufficient to do the job. Sometimes they just hold off the invaders while calling for reinforcements. But sometimes the invaders are unfamiliar, and an adaptive response is necessary.
Meanwhile, the B and T cells of the adaptive immune system have started ramping up a response by making billions of copies of themselves, a clone army of the version of the lucky cell that happened to recognize the foreign antigen. That takes five to seven days.
Sometimes the defense is tag-team. The B cell antibodies gum up bad guys such as bacteria and viruses that make their way past the skin and mucosa layers of the epidermis and into the bloodstream, something like Spider-Man webbing up villains, so they can be collected later. They bag and tag. Then the macrophages gobble them.
But the B cells can’t always stop all invaders in time. Sometimes the agents of disease get in, overwhelm the defenses, and infect a body cell.
Viruses inject body cells with their virus DNA. Once that’s inside the cell, it’s too late for the B cell to stop it with antibodies. Eventually, that infected body cell will become a factory for more viruses, cranking out reinforcements for the disease. To prevent that and safeguard the body, that infected cell needs to be killed.
If a virus does make it into a normal body cell and infects it, that cell changes. It starts expressing different proteins on its surface; it looks different, foreign.
It’s up to the T cells to recognize those new foreign antigens of a self cell gone wrong and to kill that cell, up close and personal. Recognizing a sick body cell, locking in on the telltale foreign antigen, and killing that sick cell are the T cell’s specialty.
After the attackers are defeated, most of the immune clone army dies off, but a few remain and remember. If that attacker shows up again, it won’t take a week to clone up a new army and mount a defense. The body is ready.
And that is immunity.
This wasn’t a complete picture (and of course it’s far more sophisticated and interesting, and still being discovered—an entire exotic coral reef ecosystem that is described here as a goldfish bowl). But for scientists trying to figure out how the immune system did its thing, this new B and T cell model matched what they were seeing in almost every disease—with one horrible, glaring exception.
Cancer was different. It was a sick body cell, no longer a self cell. But it wasn’t infected—it was mutated. It was a disease that T cells didn’t seem to recognize.
Most scientists believed the reason was that cancer cells were too similar to normal self cells for the immune system to recognize as foreign. That belief about the immune system and cancer was held by most cancer researchers, most oncologists, and most immunologists, and it corresponded pretty neatly to most observations about the disease. The immune system didn’t attack it. You didn’t feel sick until the cancer’s unchecked growth crowded out your vital organs. Until then, there were none of the usual symptoms of fighting off a bug—no fever, no inflammation, not even a runny nose. That was the rule, and there were no exceptions.
Which meant the idea that you could help the immune system do its natural job and recognize and kill cancer cells was one that would never work.
The scientific consensus on this point was fairly complete, and tough to argue against. Cancer vaccines failed. Patients noticed tumors in the mirror before the immune system seemed to.
Even those who believed, intellectually, that the immune system recognized and killed most mutations of self cells, before those mutated cells ever had a chance to become something we’d call cancer, also conceded that “there is little ground for optimism about cancer”10 and “the greatest trouble with the idea of immunosurveillance is that it cannot be shown to exist in experimental animals.”11
There was no data or proof otherwise.
But there were stories.
Through the ages, historians and physicians marveled at these “spontaneous remissions” of cancer,12 such as the miraculous cure of the thirteenth-century Christian saint Peregrin,13 later canonized as the patron saint of the disease. These stories or observations seemed like miracles or magic, but to a handful of scientists lucky enough to witness them firsthand, these sudden complete cancer cures were seductive and begged for scientific explanation.
In 1891, William Coley had Fred Stein.
In 1968, Dr. Steven Rosenberg had James D’Angelo.14
The first hope of therapeutic success comes with the observation of the efficiency of unaided Nature to accomplish cure… These cases, rare though they be, are the sun of our hope.
—ALFRED PEARCE GOULD, “THE BRADSHAW LECTURE ON CANCER,” 1910
One summer day in 1968, a sixty-three-year-old Korean War vet walked into the West Roxbury, Massachusetts, VA hospital emergency room complaining of severe belly pain. Dr. Steven Rosenberg was the twenty-eight-year-old surgical resident charged with handling whatever came through the door. At first, James D’Angelo presented as just another stubbled vet needing a routine gallbladder operation, but during his medical examination Rosenberg discovered that his patient had a massive scar across his abdomen and an inexplicable medical history.
Twelve years earlier James D’Angelo had been at same hospital with stomach cancer. His surgeons cut out a tumor the size of an orange, only to find smaller nodules like buckshot throughout his liver and abdomen—a death sentence in 1957, as it was in 1968. D’Angelo’s grim prognosis had been made worse by a raging postop bacterial infection. Finally D’Angelo was sent home with 60 percent of his stomach gone—a four-bottles-a-week, two-packs-a-day, stage 4 cancer patient with no expectation of surviving the year.15 And yet here he was on Rosenberg’s examination table twelve years later, very much alive.
Rosenberg asked the VA pathologist to pull D’Angelo’s old biopsy slides from storage. The diagnosis had been correct—D’Angelo had presented with stomach cancer, an especially aggressive and deadly variety.
Was the cancer still in there, growing slowly, in nonvital organs? Since D’Angelo needed his gallbladder removed, the young surgeon could look for himself. He found nothing in the abdominal wall, and felt nothing in the soft, yielding mass of D’Angelo’s liver. “A tumor is easy to identify by touch; it is tough, dense, unyielding, unlike the texture of normal tissues. It seems alien even,” he would write later.16 Twelve years before, according to the detailed surgical notes, the liver had contained several large, dense tumors. Now there were none, and none hiding in any of the other organs either. Rosenberg repeated the examination from scratch. But the cancer was gone.
“This man had a virulent and untreatable cancer that should have killed him quickly,” he wrote. “He had received no treatment whatsoever for his disease from us or anyone else. And he had been cured.”17 D’Angelo had beaten his own cancer. There was only one possibility. It had to have been his immune system that had done it.
Which, Rosenberg noted, was exactly what the immune system was supposed to do.18 Immune cells distinguish cells that belong in the body (self cells) from cells that don’t belong (foreign, or nonself, cells.) If the immune system overreacts, that’s an allergy. If it misidentifies normal self cells and attacks them, that’s autoimmune disease. And that was bad. Cancer was supposedly too similar to a normal self cell to be recognized by the immune system; Rosenberg covered that in his years getting an MD and a PhD. But something about D’Angelo suggested otherwise. He didn’t have an autoimmune disease, but his immune system had somehow noticed the cancer and had beaten it. There was no other explanation.
This was Dr. Rosenberg’s Coley moment, and it would lead to a lifelong obsession. Something that wasn’t a miracle had cured this man’s cancer.
“Assuming his immune system had destroyed his cancer,” Rosenberg wrote, “could the immune system of other people be made to do the same?” D’Angelo’s bloodstream seemed to carry the mysterious material of immunity, “not only the white blood cells, but many of the substances that combine to mount an immune response.” Was it possible, Rosenberg began to wonder, to transfer those immune response elements to another patient?
What Rosenberg did next would be unthinkable today, but both patients involved were agreeable, and Rosenberg was singularly, surgically focused on results, and as quickly as possible. He searched the hospital records and found another patient with stomach cancer and of the same blood type as D’Angelo. When he explained his plan to D’Angelo, Rosenberg remembers, he laughed. “He had gone through a lot worse without helping anybody. He’d be glad to try and he hoped to hell it worked.” The patient with terminal stomach cancer hoped more than that. The thin, wheezing skeleton in the bathrobe had once been a gambling man. “He smiled wryly and joked that he had spent his life playing long shots and they had never come in for him yet, and he figured he was due,” Rosenberg remembered. If another man’s blood might cure him, he was willing to roll the dice.
It didn’t work; the transfused blood did no magic, and the patient soon succumbed to his cancer. Rosenberg’s experiment had been a failure. Still, he did not doubt what he had seen.
“Something began to burn in me,” he wrote, “something that has never gone out.”
July 1, 1974, the day after he finished his surgical residency, Rosenberg became the chief of surgery at the National Cancer Institute in Bethesda, Maryland, with a staff of nearly one hundred and a lab he would now dedicate to replicating the immune-based cancer cure he’d witnessed in 1968.19
Rosenberg wasn’t the only researcher focused on nailing down an immunologically based treatment for cancer. But few pushed as hard or accomplished as much as Rosenberg did during those years, and, significantly, nobody else had the nearly blank-check funding from Congress, which helped draw some of the greatest scientific talent from around the globe. For the coming decades, NCI labs at the National Institute of Health would help keep the field of cancer immunotherapy alive and moving forward. What kept its chief surgeon alive and moving forward seemed to be a healthy ego, burned coffee, and a single-minded focus on curing cancer. At thirty-four years old, this ambitious Bronx-born child of Polish Holocaust survivors was impatient to make his name and change the world. He was going to beat cancer, it was a seven-day-a-week thing, there was no other way. And he was certain that it all hinged on helping immune cells to recognize tumor antigens.
At the time, the scientific consensus was that this was a misguided and futile pursuit, but Rosenberg was one of those who believed the mechanism was already there in the body, waiting to be awakened. As a physician, he had seen patients with compromised immune systems develop cancer at greater rates than those with normal immune systems. As a transplant surgeon, he had seen cancer—probably only a few cells riding invisibly along on a donated kidney—bloom suddenly in the immunosuppressed organ recipient, only to be quashed again when the immune system was restored. He had seen the horrors of graft-versus-host disease, when a patient’s immune system rejected a transplanted organ because it seemed foreign. It was a terrible thing, but it showed the power of the immune system. That power, against cancer, would be wonderful.
Other labs around the world were also trying to ignite that wonderful response. Several20 were pursuing a Coley-like 21 approach to immunotherapy. One involved injecting tumors with a tuberculosis-related bacterium called BCG22 in hopes that the toxins would spark a broad immune response to the foreign bacterial proteins that might flare into an attack on the tumor itself. It had had some success.
That approach didn’t much appeal to Rosenberg. He considered toxins and BCG to be a “broad” and “blunt” approach, an immune “Hail Mary” with “little real intellectual rationale.” His idea was to focus specifically on targeting tumor antigens, through a mechanism based on the latest scientific understanding of T cell lymphocytes.
When Rosenberg started in medicine the immunology textbooks didn’t even have the word lymphocyte. Now they understood that there were two types, B cells, which made the antibodies, and T cells. T’s were the immune cells that recognized the unfamiliar proteins on the cells of donor organs, leading to organ rejection and graft-versus-host disease. If the T cell could distinguish one human from another, surely they could distinguish a healthy self cell from its cancerous mutant cousin.
Some mouse studies had suggested that T cells might be able to recognize antigens on cancer cells; Rosenberg chose to believe them.23 He also believed studies that showed those T cells could be transferred to another mouse surgically implanted with the exact same tumor, killing cancer in one as it did in the other.
Six years earlier, Rosenberg had tried to repeat that experiment at the Roxbury VA hospital using human beings instead of mice. It had failed, terribly. But he still believed in the principle.
Rosenberg believed that D’Angelo had T cells that recognized the antigens of his stomach cancer, much like an immune system that had been inoculated by some cancer vaccine. They apparently didn’t do the same job when transfused to another patient, but then those two patients did not have the exact same tumor, with the exact same antigen fingerprints. But what if he could grow T cells specific to a patient’s tumor?
At the National Institutes of Health National Cancer Institute, he and his colleagues now attempted to do exactly that, using pigs.24 It was laborious work, Rosenberg would recall—the procedure required “hoisting them up onto an operating table, anesthetizing and intubating them, scrubbing down exactly as we would for any operation under antiseptic conditions.” The surgeons would then place small slivers of tumor samples taken from a human patient into the intestinal lining of these pigs.
After several weeks, the pigs had developed an immune response against the foreign human cancer cell antigens, and built up a clone army of T cells, billions of cells, all specific to recognizing those tumor antigens and killing those tumors. Then Rosenberg’s team would harvest the pig’s spleen and the lymph nodes closest to the implanted tumor, where the T cell army was concentrated, take them back to the lab, and extract the lymphocytes in strainers. The first test patient was a twenty-four-year-old woman from Pennsylvania25 with an aggressive cancer and no better options. Even the amputation of her leg had not stopped the spread of her disease.
On November 15, 1977, with approval from the NCI clinical research committee, Rosenberg’s team injected 5 cc’s of T cells they had previously generated specifically against a sliver of one of her tumors implanted in one of their pigs. She tolerated that test dose, so they proceeded to give her more, ultimately infusing the woman with some 5 billion cells in an hour. This time she developed a high fever and hives, but soon stabilized. The team was hopeful the reaction meant an immune response against the cancer would result, but when she returned several weeks later, her CAT scan showed that the cancer was growing unchecked. The treatment had done no good. It was a crushing failure two years in the making.
While one NCI lab had been busy with pigs, three other research scientists26 also at the National Cancer Institute27 published a paper outlining an experiment with an unexpected outcome. The researchers had been studying cancer of human blood and bone marrow—leukemia. They’d tried to grow cultures of the disease in the lab, but when they checked the vats, they discovered that they’d accidentally grown a large batch of healthy human T cells instead.
Follow-up investigation suggested that the happy accident had been triggered by a chemical messenger, or cytokine, made by immune cells. The cytokine seemed to act as growth serum for T cells, so they called it “T-Cell Growth Factor”; eventually it would become famous as interleukin-2, or IL-2.28 For a T cell–focused investigator, IL-2 seemed to be exactly the fertilizer he needed.
If tumor cells did have antigens a human T cell could recognize, they should be able to target and kill it, like any other sick or non-self cell. Something was preventing that from happening. Rosenberg’s lab didn’t know what that something was—nobody did—but they wondered if maybe they could overwhelm that resistance with a tsunami of T cells.
We all have about 300 billion T cells circulating through our bodies, each of them a lottery ticket randomly tuned to every possible antigen-recognizing combo. While that might sound like an enormous number, keep in mind that only those T cells that recognize the antigen fingerprint of an infected or a sick cell activate. And there’s no way for the immune system to predict what that antigen fingerprint might be. As a result, those 300 billion combinations need to account for—and potentially match up with—every possible antigen that nature might throw at us. That means that in this antigen lottery, of those 300 billion possible combinations, at most only a few dozen T cells have the same winning ticket—the exact right receptor capable of recognizing any one antigen, should it happen to show up.
But what if you boosted the odds by boosting the number of T cells? Surely one of the 300 billion T cells had the winning receptor that happened to match the tumor antigens. Ideally, a researcher would figure out which one matched, make a billion copies with the interleukin-2 fertilizer, and infuse them back into the patient. At the very least, if she could induce all of those 300 billion T cells to replicate, she’d end up with even more versions of all the possible combinations—including more copies of the one that happened to match the tumor antigen. Instead of twelve winning tickets, she’d have twelve million.
Rosenberg met with the authors of the IL-2 research. Then, on September 26, 1977, he tried it in his own lab, following the borrowed recipe for making IL-2 from mice. His lab added the powerful potion to a culture of ten thousand T cells. When they checked five days later, the mass had swelled to 1.2 million cells.
More was good, but were they still killers? And were any of them killers that could recognize and kill cancer? And would they be killers not just in a test tube, but in a living animal—a barrier that had stumped many hopeful immunotherapies over the years? And finally, the ultimate barrier: Would all that translate to humans?
Those questions would consume the next years of the many talented young scientists who passed through these government-funded laboratories. The work was slowed considerably by the difficulty of getting sufficient quantities of IL-2, a time-consuming process that was far harder on the mice than the researchers. By the early 1980s that dynamic changed, with the advent of new technology in genetic engineering and molecular biology. For the first time, researchers could manipulate the DNA blueprints of bacteria, inserting genes that turned them into living chemical factories. A number of biotech companies jumped into the race to use recombinant DNA to produce wonder drugs. IL-2 was an afterthought; at the time, the goal was to mass produce a cytokine called interferon.
Like most science stories, the story of interferon starts with a mysterious observation: monkeys infected by virus A (in this case, the Rift Valley fever virus) were afterward resistant to infection by virus B (in this case, the yellow fever virus).
The concept of inoculation and vaccines had long been familiar, but what was observed in these monkeys in 1937 was something new. This wasn’t inoculation, as the two viruses did not appear to be related to each other. Some different sort of biological mechanism seemed to be at work. Follow-up experiments showed that the mysterious phenomenon extended beyond these monkeys or these viruses specifically. In various cells, and all manner of animals, exposure to one virus (usually a weak, nonfatal sort) somehow interfered with the ability of a second, potentially fatal virus to infect the host cell.
Viruses are essentially just genetic material in a tiny crystal syringe. They cannot reproduce on their own; instead, they inject their genetic payload into a host cell. The virus’s genetic blueprints reprogram that cell’s genetic machinery to stop making proteins that help the host and to start producing virus parts instead. Somehow, the experiment suggested, prior exposure to a virus interfered with that master plan, the way a large radio tower crowds out smaller stations on the dial. They called the phenomenon “interference.”
Throughout the 1940s and 1950s, the search for the essence of viral interference was the most intriguing quest in biology, drawing a generation of young scientists to its study. If this “interferon” existed as a hormone-like liquid, it was hoped, it might hold the power to vanquish disease.
That hormone-like liquid was finally described in 1957 by researchers Alick Isaacs and Jean Lindenmann, as found in the membranes of chicken cells they’d cleverly infected with a flu virus.29 The resulting clear, powerful syrup turned out to be a previously unseen type of protein—one of three major classes of cytokines produced by animal cells in response to viral attack and, in some cases, the presence of a tumor.
Interferons (IFNs) were the first cytokine to be heralded—some would say hyped—as a potential magic bullet in the war against disease, including cancer, and they wouldn’t be the last.30 The first eyedropper-sized batches were painstakingly squeezed from white blood cells centrifuged from donations collected en masse by the Finnish Blood Bank and mashed through incrementally finer porcelain filters. The process was messy, but the result was, for a time, the most precious commodity on earth.
That changed with the invention of recombinant DNA technology. By 1980 scientists could manipulate the DNA blueprints of yeast cells well enough to begin pumping out interferon proteins like a brewery. Finally, researchers had sufficient supply to begin testing the reality of interferon against nearly four decades of hype, and hopes were perilously high for what Time magazine promised on its March 31, 1980, cover story was the “penicillin of Cancer.”
IFN would never quite live up to the pent-up enthusiasm. The research presented good science and provided important new biochemical insights31 and even a few practical medical applications. But ultimately what would be publicly remembered was how far it missed the “penicillin” mark as a magic bullet cure for the C word. In the end, hope for IFN had spiked and crashed in the course of a Time magazine news cycle, one more disappointingly premature cry of eureka in the troubled history of immunotherapy.
But in 1980, that disappointment was hardly imagined. The excitement over interferon had fueled a speculative boom in the handful of biotechs that could engineer and produce the valuable stuff, companies that soon searched for other scarce biochemicals to mass-produce. And at the time, nothing was more scarce, or potentially more important or lucrative, than the one the brilliant young post-docs in Steve Rosenberg’s lab were clamoring for: interleukin-2 (IL-2).
IL-2 is an incredibly powerful cytokine, effective even when diluted at a ratio of 1:400,000 (one part IL-2 to 400,000 parts inert solution). IL-2 also degrades quickly, preventing powerful and specific immune battle commands from echoing dangerously around the body after they’re no longer relevant. Its half-life of less than three minutes32 wasn’t nearly long enough to accomplish the job Rosenberg and his colleagues had in mind. To keep conducting experiments providing the immune cells with the growth signal, especially during the critical period following recognition of tumor antigen and activation, even more IL-2 would be required. That meant more lab hours, and many, many more mice. Finally, on June 12, 1983, the head researcher at a Stanford biotech spinoff called Cetus surprised Rosenberg as he was about to board a plane from a conference, handing him a test tube full of recombinant gene-made IL-2. Rosenberg secured the vial of the most precious stuff on earth in his jacket pocket. “I tried to hide my excitement,” he remembered. It’s difficult to imagine he was convincing as he cautiously boarded a plane with an amount of IL-2 that dwarfed all previous supply.
The vial survived the trip, facilitating experimental ventures into levels of T cell growth previously considered impossible; what was more, Rosenberg was promised, even greater amounts would soon be available. As production ramped up, those test tubes would become flasks, then buckets; researcher Paul Spiess later calculated that the unused drop of recombinant IL-2 wasted at the bottom of a test tube represented the amount of natural IL-2 that would have formerly required the sacrifice of 900 million mice.
“I had felt as if there was a powerful machine at my disposal, that its engine was ready to roar, but that I could not find the key to it,” Rosenberg later recalled. “I had wondered if IL-2 was that key. Now I would find out.”
As promised, his lab had taken a methodical approach to the experiments, all based on the yet-unproven premise that T cells could recognize the antigens of cancer cells in humans. They now had two main approaches to using the IL-2 to grow a T cell army that might overwhelm cancer. One approach was to remove a patient’s T cells, fertilize them with IL-2, then reinject that fortified T-cell army into the patient. Another approach was to feed IL-2 directly into the patient’s bloodstream to fuel and support any response their immune systems might naturally initiate.
At sufficient doses, both approaches worked in mice. But by November 1984 it was clear that, once again, what worked in mouse models didn’t translate to people.33
“Perhaps for the first time, at least part of me began to doubt the path that I had begun to follow,” Rosenberg would later allow. This was a rare confession of self-doubt from the hard-charging surgical chief, as well as a massive understatement of the human stakes and scope of his failure. Congress wanted results from the hundreds of millions it had spent on the war on cancer; Rosenberg was at a government lab, spending public money on pigs and mice and racking up a record of sixty-six consecutive “failures”—sixty-six human beings he’d gotten to know, tried to help, and failed to save trying one experimental approach then the other.
Finally, on November 29, 1984, desperate to make something work, he tried both approaches at once, and at double the previous dosage of this powerful cytokine.
His team injected a bolus of IL-2 fertilized T cells back into a woman named Linda Taylor, a former Navy brat and military attaché who’d suffered a relentless melanoma that was unresponsive to other treatment. It took nearly an hour to drip the mass of 3.4 billion cells into her arm. Then she was given large injections of IL-2 to sustain the immune action, over 40 million units daily, for six days.
Taylor responded to the combination treatment. Within a few weeks, the tumors began to get smaller and squishy—under the microscope they revealed necrotic tissue, dead tumor. By March of the following year, Taylor’s scans showed no cancer at all. “It had disappeared,” Rosenberg reported. It was working. He felt a new urgency to continue this combination technique, to “push harder,” with more patients.
The results of that larger study were mixed. The treatment still did not help most patients, and the side effects could range from debilitating to deadly. Rosenberg described how, for him and the staff, a visit with a responding patient was a special thrill quickly tempered by the patient in the next bed who was not responding to the treatment at all and was only closer to death from the side effects. They had no idea why a treatment that worked in some patients failed entirely in others. And so while the treatment provided data, and helped some patients, it didn’t definitively prove anything. The IL-2 treatment seemed to clear cancer in some patients. It definitely proved fatal to others. This outcome was emotionally and physically exhausting. Even some of those who survived both treatment and cancer suffered traumatic flashbacks for years afterward.
But Rosenberg maintained that the numbers were not uncommon for cancer trials. The patients in these experiments knew that while there were definitely risks inherent in the testing of an experimental medicine, the mortality rate for doing nothing was 100 percent. Still, some at the NCI wanted to cease the treatments. Rosenberg vowed he wouldn’t stop “until they make me.” Eventually, they did exactly that.
This was a dark time for Rosenberg, but he believed they needed to continue to test the possibilities of the therapy and announce the findings, good and bad. Further to that, the president of the National Cancer Institute, the pioneering chemotherapist Dr. Vincent T. DeVita,34 was under pressure from Congress to justify the millions spent on the war on cancer with some, or any, proof of success. That fall, the New England Journal of Medicine accepted a paper from Rosenberg et al. that cautiously reported the result from twenty-three patients. That paper was scheduled to be published in December 1985, but sent, under embargo, to health reporters a week early, so they might prepare. That, Rosenberg would later write, was a mistake.
Rosenberg’s scientific paper was beaten to the news stands by a feature story in Fortune magazine. The cover showed a photo of a test tube of medical-looking liquid labeled “Cetus Corps tumor-zapping interleukin-2.”
The cover line read: CANCER BREAKTHROUGH.
Rosenberg says that his reaction was apoplexy. “Cancer breakthrough,” he declared, was exactly the sort of hyperbole serious scientists wanted to avoid; the Fortune cover was irresponsible and misleading. Yes, a small minority of patients responded completely to the treatment, but they couldn’t predict who those patients would be, or why it worked in some patients and on some cancers, or why it failed in others. And some of the responders had relapsed fatally. “We had not cured cancer,” Rosenberg declared. “We had only detected a crack in its stone face.”
Nevertheless, between the Fortune cover and the NEJM “special issue” a week later, the breakthrough genie was out of the bottle. All the major networks ran the breakthrough story on the evening news. The next day it was on the front pages of the New York Times, the Los Angeles Times, USA Today, the Washington Post, the Chicago Tribune, and hundreds more papers around the world. Rosenberg agreed to a walk-through of the wards with Tom Brokaw, hoping to course correct the sensationalized Fortune cover, but that story had already set the “breakthrough” tone. The newsweeklies followed, with major coverage in Time magazine and with Dr. Steve Rosenberg smiling benevolently from the cover of Newsweek.
Now the NCI was being bombarded with interview requests from journalists, and hundreds of calls a day from cancer patients across the world. Switchboards at cancer centers across the country were soon being flooded by hopeful, desperate patients. Looking back at the hype, Rosenberg was confounded. He’d published the results of his work but never declared he’d made a breakthrough. Perhaps the media frenzy was because he was already a face on the nightly news: not only as chief of surgery at the NCI but also as the surgeon who had operated on President Ronald Reagan, and then bluntly told the nation on live TV what none of his press secretaries dared say: “The president has cancer.” That press conference and the backlash to his blunt honesty had surprised him. This was far worse.
“With an increasing sense of urgency, I tried to play down the expectations,” Rosenberg would write later. But Rosenberg lived for his work, and several of his colleagues felt that even as he tamped down the flames, he seemed to appreciate at least some of their heat and light; certainly, they illuminated the focus of his life’s work, and brought attention to it. In his interview with People magazine, in which he would feature as one of their “people of the year,” Rosenberg referred to his lab’s findings as “the biggest advance in cancer for 30 years.” Even as he rebuffed the breakthrough angle on his immunotherapy, he also sometimes referred to it as such, using the B word.
One Sunday morning, Rosenberg and DeVita set aside a few hours to appear on CBS’s Face the Nation. In conversation with the staff before the show taped, DeVita mentioned one of the patient deaths, a particularly difficult and personal episode that underscored the need to temper the sensational headlines. That death hadn’t been mentioned among any of the twenty-three patients Rosenberg had reported on for the NEJM, and it hadn’t been part of any previous news report. It was, in short, a scoop, and a few minutes later Lesley Stahl, the show’s host, popped in to say hello, asking in an offhand manner, was it true there had been an IL-2–related death?
Rosenberg had never spoken of the man, a patient named Gary Fowlke, publicly. He found the notion of “offering the press a running scorecard on patients” offensive, and didn’t believe the press understood how dangerous cancer treatments—any cancer treatments, and especially experimental ones—truly were. Daytime TV certainly wasn’t the place to publish scientific information. And yet, despite all that, it was also true—in all the coverage, he hadn’t mentioned that death or the horrifying side effects.35
Rosenberg says he decided to beat Stahl to the punch and bring up Mr. Fowlke’s death in the clinical trial before Stahl had a chance to ask about it. But the damage had been done. The sensational headlines around Rosenberg’s experimental results had given most of the world their first exposure to cancer immunotherapy. And as high as public hope had soared on that exposure, it now suddenly came crashing back to earth with a vengeance.
“There may be a balance scientists can reach in publicly discussing a scientific development—a balance between the public’s right to know and scientists’ fears that the public’s lack of expertise will lead to misunderstanding or unrealistic expectations,” Rosenberg would reflect later. “But in that case I failed to reach it.”
But the peaks and valleys of sensational coverage didn’t change the data, or the results Rosenberg’s lab had elicited from his cancer patients. And so, despite the uncertainty over the exact biological mechanism, on January 16, 1992, the FDA approved IL-2 for patients with advanced kidney cancer. It wasn’t a cure, or even a frontline, first-choice approach. But it was, Rosenberg proudly noted, the first approval in the United States of a treatment for cancer that acted solely through stimulating the patient’s immune system.36 Many researchers now believe that when combined with the newest cancer immunological advances such as checkpoint inhibitors, IL-2 may prove to be more important than even Rosenberg had then realized. But perhaps most important was the glimmer of proof the NCI labs had provided the world. Cancer immunotherapy could work, and in fact had. The underlying science was still poorly understood. Rosenberg’s methods and success rates proved very difficult to reproduce,37 and a great deal of basic immunological research was yet to be undertaken. But there it was, in black-and-white data, and in living patients as well. Rosenberg paraphrases Winston Churchill when assessing the impact of these IL-2 studies; it was neither the end nor the beginning, but rather, the end of the beginning of the cancer immunotherapy story.
Those glimmers inspired a handful of talented young researchers to enter the field, and they sustained the handful that remained. For decades to come, the army of scientific talent that passed (and still passes) through the NCI laboratories would read like a who’s who of those leading advances in the cancer immunology field.
But for everyone else—the oncologists trained when Coley was a dirty word, the researchers who had been suspicious of the unreproducible results, and most especially the general public for whom Rosenberg had been the face, and interleukin-2 the promise, of salvation from an uncurable disease—it was a disaster. Cancer immunology became the science that cried “breakthrough” on the cover of Time once too often. Immunotherapy’s moment came and went, and the spotlight with it.
It was the 1990s, and DNA manipulation was the apparent future for potential cancer cures. Oncogenes, genes which, when mutated, increase the likelihood of a cell becoming cancer, had been identified, as had suppressor genes, which seemed to work against those destabilizing mutations, and researchers sought to target them. Soon these efforts were joined by targeted therapies and “inhibition pathways,”38 small molecules that targeted the metabolic means by which cancer created its blood supply or requisitioned the fuel it needed to grow and divide. These were cancer therapies that, like radiation, chemotherapy, and surgery, directly targeted the disease instead of acting upon the immune system. That made sense to people, and they worked, to a degree. The new scientific technology made those drugs easier and cheaper to make and more successful than before, adding weeks or months to cancer patients’ lives. They also made headlines, eclipsing immunotherapy research and outcompeting it for R&D funding. After the breakthrough, “bust” became the next immunotherapy story line.
“We search where there is light,” said Goethe. And the promise in cancer immunotherapy was still just an occasional flash in the darkness. For the best and brightest young scientists, cancer immunotherapy was explicitly a no-go zone as a career choice. Most of the generation graduating in the late ’80s and through the ’90s gravitated toward better-funded and more hopeful fields of scientific inquiry. Some went into developing new classes of chemotherapy, or radiation oncology. Many went into “pathway inhibition” science. And cancer doctors maintained the traditional cut, burn, and poison treatments they had been taught by the generation before them, the only weapons they could truly trust.
Basic but essential immunotherapy research was left to the handful of true believers, researchers still quietly chipping away, like Lloyd Old, Ralph Steinman, and others. Steve Rosenberg, meanwhile, had moved on from IL-2 to new targets and technologies, following Dr. Phil Greenberg’s lead in figuring new and better ways to grow up and transplant armies of T cells that could recognize and kill tumors.39 Though you wouldn’t have guessed it by looking at the nearly empty cancer immunotherapy presentations at the national cancer conferences, populated by the same faces, often from underfunded labs, year after year, there were still more avenues left to try for making a successful cancer immunotherapy. What most of those avenues had in common was the immune cells cancer immunologists still believed could recognize tumor antigens and kill cancer: T cells.40
But that raised the now familiar question: If T cells could recognize cancer antigens (they can), and if Greenberg and others had been able to grow and stimulate a T cell army that recognized tumor antigens and would attack cancer (they did), why didn’t cancer patients experience an immune response to cancer without such intervention? If the immune system could see and kill tumors, why didn’t it? Why did we have cancer at all?
There were two possible answers: either the immunotherapists were wrong, or something was still missing from the equation.
The questions were interesting. Dr. Rosenberg was more interested in pushing experiments theory into the clinic as quickly as possible, even if that meant outpacing the basic immunological research that might make sense of the results. But it was clear that something was missing, something undiscovered, like an unknown puzzle piece, that prevented T cells from getting “activated” against cancer, or shut them down before they could complete the job. This wasn’t an observation about the immune system or disease in general; that mysterious something seemed to happen only when the immune system interacted with cancer cells.
If you were a chemotherapy-trained oncologist or a molecular biologist, the idea of an elusive something sounded quaint, and not very scientific.41 Which meant cancer immunotherapy wasn’t a legitimate science. You believed, or you didn’t; it all came down to which studies you chose to believe, and how you decided to interpret them.
Immunotherapy cynics (constituting the vast majority of the people working with cancer, the immune system, or both) believed that the elusive “something” that kept cancer immunotherapy from working was called “reality”: Cancer and the immune system didn’t interact, they had nothing to say to each other, and the conversation could not be forced. Any anticancer effects of interferon or IL-2 or BCG were surely just the T cell recognizing an antigen from a virus that had infected a cell, and led to cancer. Nobody was arguing that T cells didn’t recognize virus-infected cells; they did. And some cancers were known to be more likely after infection by a virus (such as HPV).42 Here was a model that fit the fact pattern, shaved by Occam’s razor; Rosenberg, they maintained, had simply misinterpreted what he’d seen. The antigens of a cancer cell just weren’t non-self enough to be recognized as foreign by a T cell. If they were, one could make a successful cancer vaccine. And yet, no such vaccine then existed.
Cancer immunologists could argue about this all they wanted, they could point to the glimmers. But at the end of the day, they didn’t have the biology to back up their arguments. Really, there was only one successful counterargument that could be made: discover that certain something that explained the problem with cancer immunotherapy and allowed T cells to reliably recognize, target, and kill cancer cells. And in the race to do that, the most successful would be the ones who weren’t even trying.