The Breakthrough

Charles Graeber


The good physician treats the disease; the great physician treats the patient who has the disease.
— Sir William Osler, 1849–1919

Until very recently we’ve had three main methods for treating cancer. We’ve had surgery for at least three thousand years. We added radiation therapy in 1896. Then in 1946, chemical warfare research led to the use of a mustard gas derivative to kill cancer cells. Those poisons were the foundation for chemotherapy.

These “cut, burn, and poison” techniques are currently estimated to be able to cure cancer in about half of the people who develop the disease. And that’s remarkable, a true medical accomplishment. But that leaves the other half of cancer patients. Last year, in the United States alone, that translated to nearly six hundred thousand people who died of the disease.

The fight was never fair. We’ve been pitting simple drugs against creative mutating versions of our own cells, trying to kill the bad ones while sparing the good ones and making ourselves sick in the process. And we’ve been doing that for a very long time.

But now we have added a new and very different approach— one that doesn’t act directly on cancer, but on the immune system.

Our immune system has evolved over 500 million years into a personalized and effective natural defense against disease. It is a complex biology with a seemingly simple mission: to find and destroy anything that’s not supposed to be in our bodies. Cells of the immune system are on constant patrol, hundreds of millions of them circulating throughout the body, slipping in and out of organs, searching out and destroying invaders that make us sick and body cells that have become infected, mutated, or defective—cells like cancer.

Which raises the question: Why doesn’t the immune system fight cancer already?

The answer is, it does, or tries to. But cancer uses tricks to hide from the immune system, shut down our defenses, and avoid the fight. We don’t stand a chance, unless we change the rules.

Cancer immunotherapy is the approach that works to defeat the tricks, unmask cancer, unleash the immune system, and restart the battle. It differs fundamentally from the other approaches we have to cancer, because it does not act upon cancer at all, not directly. Instead it unlocks the killer cells in our own natural immune system and allows them to do the job they were made for.


Cancer is us. It’s the mistake that works. Cells in the body regularly go rogue, their chromosomes knocked out by particles of sunlight or toxins, mutated by viruses or genetics, age, or sheer randomness. Most of these mutations are fatal to the cell, but a few survive and divide.

99.9999 percent of the time, the immune system successfully recognizes these mutant cells and kills them. The problem is that rogue 0.0001 percent cell, the one that the immune system doesn’t recognize as an invader and does not kill. Instead, eventually, that 0.0001 percent cell kills us.


Cancer is different. It does not announce itself like the flu or any other disease, or even a splinter. It doesn’t seem to sound an alarm in the house of the body, or provoke an immune response, or show symptoms of immune battle: no fever or inflammation or swollen lymph glands, not even a sniffle. Instead, the tumor is suddenly discovered, an unwelcome guest that has been growing and spreading out, sometimes for years. Often by then it is too late.

To many cancer researchers, this apparent lack of immune response to cancer meant that the goal of helping an immune response to cancer was futile—because there was nothing to help. Cancer was assumed to be too much a part of our selves to be noticed as “non-self.” The very concept of cancer immunotherapy seemed fundamentally flawed.

But throughout history, physicians had recorded rare cases of patients whose cancers apparently cured themselves. In a prescientific age these “spontaneous remissions” were seen as the work of magic or miracle; in fact, they are the work of an awakened immune system. For more than a hundred years researchers tried and failed to replicate those miracles through medicine, to vaccinate or spark an immune response to cancer similar to those against other formerly devastating diseases like polio, smallpox, or the flu. There were glimmers of hope, but no reliable treatments. By the year 2000, cancer immunologists had cured cancer in mice hundreds of times, but could not consistently translate those results to people. Most scientists believed they never would.

That changed radically and recently. Even for physicians, this change was invisible until it was at the doorstep. One of our best modern writers on the subject of cancer, Dr. Siddhartha Mukherjee, does not even mention cancer immunotherapy in his nonetheless excellent Pulitzer Prize–winning biography of the disease, The Emperor of All Maladies. That book was published in 2010, only five months before the first of the new- generation immunotherapeutic cancer drugs received FDA approval.

That first class of cancer immunotherapy drugs would be called “checkpoint inhibitors.” They came from the breakthrough discovery of specific tricks, or “checkpoints,” that cancer uses like a secret handshake, telling the immune system, Don’t attack. The new drugs inhibited those checkpoints and blocked cancer’s secret handshake. They also won their discoverers the Nobel Prize in Medicine.

In December 2015 the second of these checkpoint inhibitors was used to unleash the immune system of former president Jimmy Carter. An aggressive cancer had spread through his body and he wasn’t expected to survive; instead, his immune cells cleared the cancer from his liver and brain. The news of the ninety-one-yea-rold president’s miraculous recovery surprised everyone, including the former president himself. For many people, “that Jimmy Carter drug” was the first and only thing they’d heard about cancer immunotherapy.

But the breakthrough isn’t any one treatment or drug; it’s a series of scientific discoveries that have expanded our understanding of ourselves and this disease and redefined what is possible. It has changed options and outcomes for cancer patients, and opened the door to a rich and uncharted field of medical and scientific exploration.

These discoveries validated an approach to beating cancer that is conceptually different from the traditional options of cut, burn, or poison, an approach that treats the patient rather than the disease. For the first time in our age-old war with cancer, we understood what we were fighting, how cancer was cheating in that fight, and how we might finally win. Some call this our generation’s moon shot. Even oncologists, a cautious bunch, are using the C word: cure.

Hype can be dangerous, just as false hope can be cruel. There’s a natural tendency to invest too much hope in a new science, especially one that promises to turn the tables on a disease that has, in some way, touched every person’s life. Nevertheless, these aren’t overhyped theories or anecdotal wonder cures, but proven medicines based on solid data. Immunotherapy has gone from being a dream to a science.

Right now there are only handful of immunotherapies available. Less than half of all cancer patients have been shown to respond to these drugs. Many who do respond profoundly, with remissions measured not in extra weeks or months of life, but in lifetimes. Such transformative, durable responses are the unique promise of the cancer immunotherapeutic approach, and part of what makes it attractive to patients, but it’s important to note that that promise is different from a guarantee for any one outcome for any individual patient. We still have work to do to widen the circle of responders and truly find a cure. But the door is open now, and we’ve only just begun.

Several of the immunotherapists I interviewed compared the discovery of these first cancer immunotherapy drugs to that of penicillin. As a drug, penicillin immediately cut infection rates, cured some bacterial diseases, and saved millions of lives. But as a scientific breakthrough, it redefined the possible and opened a fertile new frontier for generations of pharmaceutical researchers. Nearly one hundred years after the discovery of that one simple drug, antibiotics are an entire class of medicines with a global impact so profound that we take it for granted. Invisible terrors that plagued and poisoned mankind for millennia are now casually vanquished at a drive-through pharmacy.

The discoveries of how cancer tricks and hides from the immune system were immunotherapy’s penicillin moment. The approval of the first checkpoint- inhibiting drug that regularly and profoundly changed outcomes for cancer patients redefined the direction of scientific inquiry. That’s now kicked off a gold rush in research and investment and drug development. Seven years after the approval of that first solitary checkpoint inhibitor there are reportedly 940 “new” cancer immunotherapeutic drugs being tested in the clinic by more than a half million cancer patients in 3,042 clinical trials, with another 1,064 new drugs in the labs in preclinical phase. Those numbers are dwarfed by the number of trials testing the synergetic effectiveness of immunotherapy combinations. The research is advancing so rapidly that several drug manufacturers have successive generations of drugs stacked up in the clinical trial pipeline like planes waiting for clearance at LaGuardia, requiring new FDA “fast track” and “breakthrough” designations to speed them through the approval process to cancer patients who don’t have time to wait. Major advances in cancer usually come in roughly fifty-year increments; cancer immunotherapy has already made a generational leap, seemingly overnight. Describing what is coming next, many scientists smile and use words like “tsunami” and “tidal wave.” The pace of progress is rare in the history of modern medicine, unprecedented in our history with cancer. We have an opportunity to fundamentally redefine our relationship with a disease that for too long has defined us.

This is the story of the geniuses, skeptics, and true believers, and most especially the patients who spent their lives, and the many more who lost them, helping refine and verify this hopeful new science. It’s a journey through where we are, how we got here, and a glimpse of the road ahead, told through some of those who experienced it firsthand, and some who made it possible.

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The Breakthrough Charles Graeber