Given the right conditions, the human immune system is capable of recognizing and killing cancer. And perhaps, eventually, an immune approach is the best way to get to a possible cure. And yet, for some reason, it hadn’t worked. For years, cancer immunologists were racing to figure out why.
The immune system, like cancer, is a nimble, adaptable, and evolving system. Cancer had already proven its ability to rebound from the most direct attacks by drugs or radiation, a confounding, unique capacity now known as “escape.” Even as a drug targeted cancer, that cancer mutated and evaded the attack. Whatever cells survived came roaring back, impervious to the old drugs. That mutational capacity defined cancer. But adaptability and mutation were also what defined immune response.
The immune system did a great job with most invaders to the bloodstream; it found sick cells and attacked and killed them. Cancer was a sick cell—a mutant cell in our own body that couldn’t stop growing. So why didn’t what happened with the common cold seem to happen with cancer? For decades, researchers had believed they were missing some pieces of the puzzle, the molecular keys that might allow the immune system to treat the diseases known as cancer in the same way that it treated other foreign pathogenic invaders, like viruses, bacteria, or even a splinter. Exactly why cancer seemed to receive a different immune response than other diseases, and exactly how it somehow evaded the complex web of traps and scouts, trackers and killers that patrolled the perimeter of our epidermis and floated invisibly in our bloodstreams, had been a subject of fierce debate. Most researchers believed that the immune system simply could not recognize cancer as a foreign (or “non-self”) cell, because it was too similar to normal, healthy “self” cells.
A handful of stubborn cancer immunologists disagreed. They believed something about cancer allowed it to evade—and trick—the immune system’s hunter and tracker cells. They were correct. Cancer uses these tricks to prevent its own destruction.
Only a few years earlier, that viewpoint was considered ridiculous by most cancer specialists, and perhaps hopeless, even by the few cancer immunologists still hanging on to the dream. But in 2011 some important new discoveries—breakthroughs in cancer research—finally identified some of the missing puzzle pieces that prevented the immune system from recognizing and attacking cancer. Much of this was good old-fashioned research that had nothing to do with cancer specifically.
Some of the mysteries of the immune system were finally teased out; the existence and role of the T cell as the serial-killing attacker of foreign cells was firmly established. The specific ignition switch for that immune response—a receptor on T cells that got “turned on,” or activated, by recognizing the unique protein fingerprints (or “antigens”) on sick or infected cells—had been identified, as was the mechanism of the amoeba-like dendritic cell, which was something of a frontline water boy of the immune system, presenting those antigens for the T cells to pick up and learn from. That communication gave a T cell its marching orders, like a wanted poster: it told the T cell what specific unique sick-cell surface proteins to look for, then sent the T cell off on a search-and-destroy mission. It was like a suspect’s description being broadcast to police via an all-points bulletin.
The discovery of the receptor of the T cell (T cell receptor, or TCR) in 1984 and its subsequent cloning had helped finally pin down the means by which the T cell interacted with its pathogen target. The receptor of the killer T cell was a physical thing that fit the antigen it was supposed to target and kill like a lock to a key. It’s through this lock and key, receptor and antigen interaction that the T cell is activated, and immune response against sick, or non-self, cells occurs.
But of course, because it’s the human immune system, it couldn’t be so simple. Researchers quickly realized that more than one key was required to initiate that immune response—something like how multiple keys are required to unlock a nuclear button or to open a safe deposit box. And for much the same reason.
The immune system is powerful and therefore dangerous. Proper triggering of immune response against pathogens is what keeps you healthy. But improper hair-trigger immune response against the self cells of your own body is autoimmune disease. This is a belt-and-suspenders approach to a life-or-death decision on a cellular level. If it wasn’t safe, you’d be sorry.
The code was truly cracked with the discovery of that second signal required to activate the T cell. But that discovery had come with a surprise.
They’d been looking for a second signal, another “go” button that would act as a sort of gas pedal for that T cell and start the whole cascade of reactions that we call immune response, which results in killing the bad guys. But instead of a gas pedal, what reseachers discovered was a brake.
The brake, called CTLA-4, was useful for self cells preventing a T cell from an autoimmune attack. Allison discovered that cancer had hijacked that brake signal. The brake wasn’t a key—it was a safety switch. CTLA-4 was a checkpoint. Cancer used it to shut down T cell activation before it ever began. By developing a drug (an antibody) that bound to and blocked the brake, they prevented the tumor cell from trying to use it. They kept cancer’s foot off the brake of the immune system.
That breakthrough discovery inspired researchers to rethink and look harder for other checkpoints, and maybe other brakes. Blocking CTLA-4 worked, the way blocking the brake on a car prevented it from being pressed. But, to continue the car analogy, driving without brakes wasn’t entirely safe, either. It worked, but the brake was a safety to control against autoimmunity.
For patients whose immune systems were not particularly responsive and who had tumors with obvious mutations that made them clear targets for an awakened immune system, there had been some remarkable results—tumors that melted away, terminal cancer that disappeared and never came back. For other patients, however, it was like driving in a car without brakes. Especially for patients with hair-trigger immune systems, blocking CTLA-4 could be a ride from hell. And if those patients had cancers that were difficult for T cells to pick up on, that hell ride was too hard on the body, and not hard enough on the cancer. Like a fever that rages too high, it hurt faster than it helped.
But the proof of concept inspired researchers to consider other, more recently discovered cell receptors on the T cell. These, they hoped, would be more specific, awakening the immune response in a more intimate way, when the T cell was up close and personal to a tumor cell, and only in that up close environment.
Such a checkpoint inhibitor, if it existed, might have less severe side effects and better specifically targeted anticancer effects. And a potential second checkpoint inhibitor had been identified, another antigen on the T cell surface they called “PD-1.” In some cancers, the tumors were discovered to have a complementary protein on their surfaces that fit into PD-1 like the other side of a handshake. The thing that fits a receptor is called a “ligand,” so on the tumor side, they called it PD-Ligand 1, or PD-L1 for almost short. Tests in the dish and mouse models had led researchers to suspect that PD-1/PD-L1 was in fact a more precise and localized secret handshake between cells, which allowed cancer cells to convince T cells not to kill them. Normally, this was a handshake between killer T cells and body cells; cancer cells had successfully adopted this trick to stay alive. The hope was that if researchers could find a way to block that handshake, or checkpoint, they could block the trick, and the immune cell could kill cancer. Those “checkpoint inhibitor” drugs would be anti-PD-1, blocking the handshake on the T cell side, and anti-PD-L1, blocking it on the tumor side.
CTLA-4 cracked open the door; PD-1 blasted it wide. Suddenly years of failed experiments in cancer immunotherapy could be explained by the simple fact that they’d been trying to drive the immune system with the hand brake on. And for the first time, they suspected they might know how to turn it off.
They didn’t believe it would work for all patients, or in all cancers. They didn’t even know if it would be enough to make a difference. But the strong suspicion was that for some patients, simply removing the hand brake on the immune system, and allowing it to recognize the cancer as the non-self pathogen that it really was, might help make the other therapies they were using more effective. And, they suspected, for some patients, simply unleashing the immune system to do its job would be enough to destroy cancer.
This was the proving time, and an exciting period for immunologists who had spent careers looking for a missing piece to the immune puzzle. The first generation of checkpoint inhibitor drugs, the anti-CTLA-4 drugs, were already in the process of phase 2 trials. They were being tested in people—not just in phase 1 tests to see if they were safe, but now to see if they were effective. Despite some early hope, those trials were now having some significant problems. Two major pharmaceutical companies were testing their versions of these checkpoint inhibitors independently. The results had been discouraging enough that one of them had abandoned the trials, at an expense of millions of dollars and many years of work. The fate of the other was still uncertain, but the results thus far wouldn’t pass FDA muster. The jury was still out on whether checkpoint inhibitors would just end up being another overhyped chapter in the history of immunotherapy, another approach that worked in mice and failed in humans, like the cancer vaccines.
Regardless, the new discovery of CTLA-4 had put other pieces of the immune puzzle in motion, including amped-up research and clinical trials on the other, newer checkpoint inhibitors. The stars among them are the anti-PD-1 drugs targeting the T cell side of the programmed cell death (PD) secret handshake, and anti-PD-L1, which blocked the tumor side.
These drugs would turn out to be game change for several types of cancer.