By Clifton Leaf
October 1, 2018

The 2018 Nobel Prize in Physiology or Medicine was awarded today to James P. Allison and Tasuku Honjo for groundbreaking discoveries that have led to a genuine revolution in cancer therapy—techniques that harness the human immune system to fight this family of diseases. It is a damn good choice.

To understand why, it helps to consider one of the central and enduring mysteries of cancer: It’s a pathology that comes from within. The disruption and destruction of healthy tissue by malignant cells is a homegrown terror, a proliferation of biological anarchists that were born and bred and ultimately corrupted within the human organism. It is not, like so many of the diseases we think of when we think of “disease,” a threat from outside the body—a raging infection like influenza, pneumonia, TB, or Ebola.

That quality of “selfness”—that eerie likeness in façade, in many ways, between invader and invaded—has arguably been the single largest impediment to treating and preventing cancer.

But the story is a lot more complicated than that. That’s because, in spite of this ability to blend in with the normal, cancer cells are often caught and killed by our remarkably vigilant immune system, which manages to recognize certain key markers, or antigens, on their cell surfaces that identify them as not-quite-right.

So why, you ask, are cancer cells “often” caught, but not caught all the time? Why do immune sentries often—and even routinely—find and destroy these bioterrorists, but sometimes fail with deadly consequence?

That’s where Allison and Honjo come in.

For much of the past century and longer, research scientists and clinical experimenters focused their efforts on trying to rev up the immune systems of cancer patients, believing that that’s where the failure lay. As Allison told me in an on-stage interview two years ago: “In the early days, people just tried to turn [the immune system] on, to pour more gas in it, to push harder on the pedal—without really knowing how it worked. What really broke it open was we realized there’s more than just turning it on. There’s actually a very complex system of off-switches, brakes, to keep it from killing you—because it will if it’s unrestrained. We found a way to do that temporarily, to unleash it to attack cancer cells.”

As it turns out, cancer can trip up the body’s bodyguards in a number of ways—but one particularly insidious trick is to send out signals to immune system regulators to hold back on an attack. In short, they induce the guards to look the other way.

When Jim Allison suggested that hypothesis, the mandarins of the cancer research establishment scoffed—or worse, ignored him. Still, he pressed on. Working out of the University of California, Berkeley, in the 1990s, Allison (who’s now at Houston’s MD Anderson Cancer Center and a seminal force within an exciting collaboration called the Parker Institute for Cancer Immunotherapy), figured out how one such “off” switch, or “immune checkpoint,” known as CTLA-4, could be flipped to preempt an attack by immune defenders called T cells.

What’s more, he went on to develop a molecule that could release this emergency brake, allowing the T cells to, at last, seek and destroy their quarry. (Read Erika Fry’s terrific 2014 feature story on this in Fortune.)

Working in parallel at Kyoto University in Japan, Honjo helped elucidate how a different immune checkpoint, called PD-1, put the brakes on T cells. (You can read the press release for the Nobel Prize announcement here.)

Many dozens of anti-cancer therapies have been developed targeting PD-1 and a related molecules in the same pathway. So far, as I’ve written, such therapies have led to spectacular and unprecedented remissions in a subset of patients with certain types of advanced cancer, but have fallen far short of that goal in most patients. The treatments have also come, in some cases, with serious side effects and complications.

But the hope is, the age of cancer immunotherapy is just beginning and we are finding more and more clues to this puzzle every day.

You can thank scientists like Jim Allison and Tasuku Honjo for that.

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