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Precision Medicine: What Is Cancer, Really? Scientists overview here.

The men and women who are trying to bring down cancer are starting to join forces rather than work alone. Together, they are winning a few of the battles against the world’s fiercest disease. For this unprecedented special report, we visited elite cancer research centers around the country to find out where we are in the war.

I. Precision Medicine: What Is Cancer, Really?

When you visit St. Jude Children’s Research Hospital in Memphis, Tennessee, you expect to feel devastated. It starts in the waiting room. Oh, here we go with the little red wagons, you think, observing the cattle herd of them rounded up by the entrance to the Patient Care Center. Oh, here we go with the crayon drawings of needles. The itch begins at the back of your throat, and you start blinking very fast and mentally researching how much money you could donate without starving. Near a row of arcade games, a preteen curls his face into his mother’s shoulder while she strokes his head. Oh, here we go.

But the more time you spend at St. Jude, the more that feeling is replaced with wonder. In a cruel world you’ve found a free hospital for children, started by a Hollywood entertainer as a shrine to the patron saint of lost causes. There is no other place like this. Corporations that have nothing to do with cancer—nothing to do with medicine, even—have donated vast sums of money just to be a part of it. There’s a Chili’s Care Center. The cafeteria is named for Kay Jewelers.

Scott Newman’s office is in the Brooks Brothers Computational Biology Center, where a team of researchers is applying computer science and mathematics to the question of why cancer happens to children. Like many computer people, Newman is very smart and a little quiet and doesn’t always exactly meet your eyes when he speaks to you. He works on St. Jude’s Genomes for Kids project, which invites newly diagnosed patients to have both their healthy and tumor cells genetically sequenced so researchers can poke around.

“Have you seen a circle plot before?” Newman asks, pulling out a diagram of the genes in a child’s cancer. “If I got a tattoo, it would be one of these.” Around the outside of the circle plot is something that looks like a colorful bar code. Inside, a series of city skylines. Through the center are colored arcs like those nail-and-string art projects students make in high school geometry class. The diagram represents everything that has gone wrong within a child’s cells to cause cancer. It’s beautiful.

A Genetic Disaster: This circular visualization shows real gene mutations found in 3,000 pediatric cancers at St. Jude Children’s Research Hospital. Genes with sequence mutations are labeled in blue; those with structural variations are in red; and those

“These are the genes in this particular tumor that have been hit,” Newman says in a Yorkshire accent that emphasizes the t at the end of the word hit in a quietly violent way. “And that’s just one type of thing that’s going on. Chromosomes get gained or lost in cancer. This one has gained that one, that one, that one, that one,” he taps the page over and over. “And then there are structural rearrangements where little bits of genome get switched around.” He points to the arcs sweeping across the page. “There are no clearly defined rules.”

It’s not like you don’t have cancer and then one day you just do. Cancer—or, really, cancers, because cancer is not a single disease—happens when glitches in genes cause cells to grow out of control until they overtake the body, like a kudzu plant. Genes develop glitches all the time: There are roughly twenty thousand genes in the human body, any of which can get misspelled or chopped up. Bits can be inserted or deleted. Whole copies of genes can appear and disappear, or combine to form mutants. The circle plot Newman has shown me is not even the worst the body can do. He whips out another one, a snarl of lines and blocks and colors. This one would not make a good tattoo.

“As a tumor becomes cancerous and grows, it can accumulate many thousands of genetic mutations. When we do whole genome sequencing, we see all of them,” Newman says. To whittle down the complexity, he applies algorithms that pop out gene mutations most likely to be cancer-related, based on a database of all the mutations researchers have already found. Then, a genome analyst manually determines whether each specific change the algorithm found seems likely to cause problems. Finally, the department brings its list of potentially important changes to a committee of St. Jude’s top scientists to discuss and assign a triage score. The mutations that seem most likely to be important get investigated first.

It took thirteen years and cost $2.7 billion to sequence the first genome, which was completed in 2003. Today, it costs $1,000 and takes less than a week. Over the last two decades, as researchers like Newman have uncovered more and more of the individual genetic malfunctions that cause cancer, teams of researchers have begun to tinker with those mutations, trying to reverse the chaos they cause. (The first big success in precision medicine was Gleevec, a drug that treats leukemias that are positive for a common structural rearrangement called the Philadelphia chromosome. Its launch in 2001 was revolutionary.) Today, there are eleven genes that can be targeted with hyperspecific cancer therapies, and at least thirty more being studied. At Memorial Sloan Kettering Cancer Center in New York City, 30 to 40 percent of incoming patients now qualify for precision medicine studies.

Charles Mullighan,a tall, serious Australian who also works at St. Jude, is perhaps the ideal person to illustrate how difficult it will be to cure cancer using precision medicine. After patients’ cancer cells are sequenced, and the wonky mutations identified, Mullighan’s lab replicates those mutations in mice, then calls St. Jude’s chemical library to track down molecules—some of them approved medicines from all over the world, others compounds that can illuminate the biology of tumors—to see if any might help.

New York: Britta Weigelt and Jorge Reis-Filho use police forensics techniques to repair old tumor samples at Memorial Sloan Kettering so the samples can be genetically profiled.

If Mullighan is lucky, one of the compounds he finds will benefit the mice, and he’ll have the opportunity to test it in humans. Then he’ll hope there are no unexpected side effects, and that the cancer won’t develop resistance, which it often does when you futz with genetics. There are about twenty subtypes of the leukemia Mullighan studies, and that leukemia is one of a hundred different subtypes of cancer. This is the kind of precision required in precision cancer treatment—even if Mullighan succeeds in identifying a treatment that works as well as Gleevec, with the help of an entire, well-funded hospital, it still will work for only a tiny proportion of patients.

Cancer is not an ordinary disease. Cancer is the disease—a phenomenon that contains the whole of genetics and biology and human life in a single cell. It will take an army of researchers to defeat it.

Luckily, we’ve got one.

Interlude

“I used to do this job out in L.A.,” says the attendant at the Hertz counter at Houston’s George Bush Intercontinental Airport. “There, everyone is going on vacation. They’re going to the beaach or Disneyland or Hollywood or wherever.

“Because of MD Anderson, I see more cancer patients here. They’re so skinny. When they come through this counter, they’re leaning on someone’s arm. They can’t drive themselves. You think, there is no way this person will survive. And then they’re back in three weeks, and in six months, and a year. I’m sure I miss some, who don’t come through anymore because they’ve died. But the rest? They come back.”

II. Checkpoint Inhibitor Therapy: You Have the Power Within You!

On a bookshelf in Jim Allison’s office at MD Anderson Cancer Center in Houston (and on the floor surrounding it) are so many awards that some still sit in the boxes they came in. The Lasker-DeBakey Clinical Medical Research Award looks like the Winged Victory statue in the Louvre. The Breakthrough Prize in Life Sciences, whose benefactors include Sergey Brin, Anne Wojcicki, and Mark Zuckerberg, came with $3 million.

“I gotta tidy that up sometime,” Allison says.

Allison has just returned to the office from back surgery that fused his L3, L4, and L5 vertebrae, which has slightly diminished his Texas rambunctiousness. Even on painkillers, though, he can explain the work that many of his contemporaries believe will earn him the Nobel Prize: He figured out how to turn the immune system against tumors.

“One day, the miracles won’t be miracles at all. They’ll just be what happens.”

Allison is a basic scientist. He has a Ph.D., rather than an M.D., and works primarily with cells and molecules rather than patients. When T-cells, the most powerful “killer cells” in the immune system, became better understood in the late 1960s, Allison became fascinated with them. He wanted to know how it was possible that a cell roaming around your body knew to kill infected cells but not healthy ones. In the mid-1990s, both Allison’s lab and the lab of Jeffrey Bluestone at the University of Chicago noticed that a molecule called CTLA-4 acted as a brake on T-cells, preventing them from wildly attacking the body’s own cells, as they do in autoimmune diseases.

Allison’s mother died of lymphoma when he was a child and he has since lost two uncles and a brother to the disease. “Every time I found something new about how the immune system works, I would think, I wonder how this works on cancer?” he says. When the scientific world discovered that CTLA-4 was a brake, Allison alone wondered if it might be important in cancer treatment. He launched an experiment to see if blocking CTLA-4 would allow the immune system to attack cancer tumors in mice. Not only did the mice’s tumors disappear, the mice were thereafter immune to cancer of the same type.

Ipilimumab (“ipi” for short) was the name a small drug company called Medarex gave the compound it created to shut off CTLA-4 in humans. Early trials of the drug, designed just to show whether ipi was safe, succeeded so wildly that Bristol Myers Squibb bought Medarex for $2.4 billion. Ipilimumab (now marketed as Yervoy) became the first “checkpoint inhibitor”: It blocks one of the brakes, or checkpoints, the immune system has in place to prevent it from attacking healthy cells. Without the brakes the immune system can suddenly, incredibly, recognize cancer as the enemy.

“You see the picture of that woman over there?” Allison points over at his desk. Past his lumbar-support chair, the desk is covered in papers and awards and knickknacks and frames, including one containing a black card with the words “Never never never give up” printed on it. Finally, the photo reveals itself, on a little piece of blue card stock.

That’s the first patient I met,” Allison says. “She was about twenty-four years old. She had metastatic melanoma. It was in her brain, her lungs, her liver. She had failed everything. She had just graduated from college, just gotten married. They gave her a month.”

The woman, Sharon Belvin, enrolled in a phase-two trial of ipilimumab at Memorial Sloan Kettering, where Allison worked at the time. Today, Belvin is thirty-five, cancer- free, and the mother of two children. When Allison won the Lasker prize, in 2015, the committee flew Belvin to New York City with her husband and her parents to see him receive it. “She picked me up and started squeezing me,” Allison says. “I walked back to my lab and thought, Wow, I cure mice of tumors and all they do is bite me.” He adds, dryly, “Of course, we gave them the tumors in the first place.”

After ipi, Allison could have taken a break and waited for his Nobel, driving his Porsche Boxster with the license plate CTLA-4 around Houston and playing the occasional harmonica gig. (Allison, who grew up in rural Texas, has played since he was a teenager and once performed “Blue Eyes Crying in the Rain” onstage with Willie Nelson.) Instead, his focus has become one of two serious problems with immunotherapy: It only works for some people.

So far, the beneficiaries of immune checkpoint therapy appear to be those with cancer that develops after repeated genetic mutations—metastatic melanoma, non-small-cell lung cancer, and bladder cancer, for example. These are cancers that often result from bad habits like smoking and sun exposure. But even within these types of cancer, immune checkpoint therapies improve long-term survival in only about 20 to 25 percent of patients. In the rest the treatment fails, and researchers have no idea why.

Lately, Allison considers immune checkpoint therapy a “platform”—a menu of treatments that can be amended and combined to increase the percentage of people for whom it works. A newer drug called Keytruda that acts on a different immune checkpoint, PD-1, knocked former president Jimmy Carter’s metastatic melanoma into remission in 2015. Recent trials that blocked both PD-1 and CTLA-4 in combination improved long-term survival in 60 percent of melanoma patients. Now, doctors are combining checkpoint therapies with precision cancer drugs, or with radiation, or with chemotherapy. Allison refers to this as “one from column A, and one from column B.”

The thing about checkpoint inhibitor therapy that is so exciting—despite the circumscribed group of patients for whom it works, and despite sometimes mortal side effects from the immune system going buck-wild once the brakes come off—is the length of time it can potentially give people. Before therapies that exploited the immune system, response rates were measured in a few extra months of life. Checkpoint inhibitor therapy helps extremely sick people live for years. So what if it doesn’t work for everyone? Every cancer patient you can add to the success pile is essentially cured.

Jennifer Wargo and team remove lymph nodes from a melanoma patient.

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