Main The Breakthrough: Immunotherapy and the Race to Cure Cancer

The Breakthrough: Immunotherapy and the Race to Cure Cancer

The 2018 Nobel Prize was awarded to researchers who helped answer one of medicine's most confounding questions: Why do we know whenever we get a cold or a flu because of the immune defense symptoms, but need a test to know when we have cancer?
The answer is what many are calling cancer's "penicillin moment," a revolutionary discovery in our understanding of cancer and how to beat it.
In THE BREAKTHROUGH, Graeber guides readers through the revolutionary scientific research bringing immunotherapy out of the realm of the miraculous and into the forefront of twenty-first-century medical science. As advances in the fields of cancer research and the human immune system continue to fuel a therapeutic arms race among biotech and pharmaceutical research centers around the world, the next step-harnessing the wealth of new information to create modern and more effective patient therapies-is unfolding at an unprecedented pace, rapidly redefining our relationship with this all-too-human disease.
Groundbreaking, riveting, and expertly told, THE BREAKTHROUGH is the story of the game-changing scientific discoveries that unleash our natural ability to recognize and defeat cancer, as told through the experiences of the patients, physicians, and cancer immunotherapy researchers who are on the front lines. This is the incredible true story of the race to find a cure, a dispatch from the life-changing world of modern oncological science, and a brave new chapter in medical history.
Categories: Medicine\\Oncology
Year: 2018
Edition: 1st
Publisher: Twelve - Hachette Book Group
Language: english
Pages: 275
ISBN 10: 1455568503
File: PDF, 5.05 MB
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Copyright
Some names and other identifying details have been changed to protect the
privacy of the individuals involved.
Copyright © 2018 by Charles Graeber
Cover design by Christopher Lin. Cover image copyright © by Getty Images.
Cover copyright © 2018 by Hachette Book Group, Inc.
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First Edition: November 2018
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ISBNs: 978-1-4555-6850-5 (hardcover), 978-1-4555-6849-9 (ebook)
E3-20180915-JV-NF

Contents
Cover
Title Page
Copyright
Dedication
Preface
Introduction
Chapter One: Patient 101006 JDS
Chapter Two: A Simple Idea
Chapter Three: Glimmers in the Darkness
Chapter Four: Eureka, Texas
Chapter Five: The Three E’s
Chapter Six: Tempting Fate
Chapter Seven: The Chimera
Chapter Eight: After the Gold Rush
Chapter Nine: It’s Time
Photos
Acknowledgments
About the Author
Also by Charles Graeber
Appendix A: Types of Immunotherapies Now and Upcoming

Appendix B: The Breakthrough, in Brief
Appendix C: A Brief Anecdotal History of Disease, Civilization, and the
Quest for Immunity
Further Reading
Notes
Newsletters

For Diann Waterbury Graeber
My mother and our survivor

Preface
It seemed to me then, and still does, that some such built-in
immunologic mechanism ought to exist for natural defense against
cancer in humans.
—LEWIS THOMAS, 1982
Cancer is alive. It’s a normal cell, mutated and changed, and it continues to
change in the body.
Unfortunately, a cancer drug does not mutate or change.
A drug may poison or starve the cancer for a time, but whatever cancer
cells remain will continue to mutate. It only takes one. The drug dances with
cancer, but cancer dances away.
As a result, these types of drugs are unlikely to ever truly cure cancer.
But we have killers in our bodies, and scouts and soldiers, a dynamic
network of cells more nimble than any cancer. This is our immune system, a
living defense as old as life itself.
This system mutates. It adapts. It learns and remembers and matches an
innovating disease step for step.
It’s our best tool to cure cancer.
And we have finally discovered how to unleash it.
This is the breakthrough.

Introduction
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 1896.1 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 0.00001 percent cell kills us.2

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.
In December 2015 the second of these checkpoint inhibitors3 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-year-old president’s miraculous recovery4 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.5 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.

Chapter One

Patient 101006 JDS
Scientific theories… begin as imaginative constructions. They begin, if
you like, as stories, and the purpose of the critical or rectifying
episode in scientific reasoning is precisely to find out whether or not
these stories are stories about real life.
—PETER MEDAWAR, PLUTO’S REPUBLIC

Jeff Schwartz’s story begins in 2011, when researchers had discovered some
of the secret handshakes cancer uses to trick our defender immune cells.
Newly invented treatments blocked that handshake and unleashed the
defenses in our blood. These drugs were available in trials, but not everybody
knew about them.
Many cancer doctors were unaware of the new developments that might
save their patients’ lives. Others refused to accept that such a breakthrough
was possible. That refusal denied their patients the option to try it. It
sometimes still does. It’s why Jeff Schwartz was willing to share his story.

Jeff Schwartz knows he was one of the lucky ones. His father died from lung
cancer in the ’90s after increasingly ugly attempts to beat it—the usual
protocols of cut, poison, and burn; surgery, chemo, and radiation. Just before
the spring of 2011, Jeff was diagnosed with cancer too, kidney, stage 4.
So Jeff considers himself lucky, or blessed, or—he doesn’t really like to
put too fine a point on it, you know? It wasn’t because he had some sort of
influence or special knowledge or anything of the sort. What separated Jeff

from the hundreds of thousands of people who died of the same disease
during the same time was that he happened to live in California and happened
to walk through the right door at the right time. That’s changed the way Jeff
thinks about life and living. Now he hopes his story might reach someone
else so they don’t have to be lucky.
I met with Jeff in his room on the forty-third floor of a hotel in midtown
Manhattan. Jeff looks a little like a more biker version of Billy Joel postbooze and post–Christie Brinkley. He was dressed in jeans and a blue Izod
shirt that hid the hard edges of the titanium cage that prevents his spine from
collapsing. Surgeons had implanted it there, like he was Wolverine, after
tumors had eaten away his spinal architecture. He told me about the cage. He
pointed out the scars. These were facts, that was all, part of the story he was
telling.
Jeff Schwartz had been a kid in Rockaway, Queens, who went through the
public school system and drove a cab while he earned a degree in accounting
and economics. His first job was at the mortgage desk of Lehman Brothers,
his next at a Japanese bank run by Harvard MBAs. Neither was a good fit.
Jeff was a music guy. He played guitar “pretty good,” he says; it was his
secret identity, the other thing you tell people at parties when they ask what
you do: “I’m an accountant, but really _______.” And maybe for good
measure Jeff might talk about any of the hundred-plus Grateful Dead shows
he’d seen, or how he’d been given Allman Brothers tickets for his bar
mitzvah, or show you the first two measures of John Coltrane’s “A Love
Supreme” tattooed around his left ankle like a musical mandala. Nights after
the trading floor closed he’d head to the East Village to mix boards at CBGB
and the Mudd Club for Talking Heads, Blondie, and Richard Hell and the
Voidoids—he’s especially proud of assisting in the recording of Blank
Generation. Maybe he wasn’t cool, he says, but he was on the scene.
His passion transitioned to his career because of baseball. He’d done a
favor for a guy, and the guy thanked him with a pair of expensive tickets. Jeff
had been a diehard Yankees fan his whole life. These were Mets tickets, great
seats, really wrong team. So Jeff gave the tickets to a friend, who invited
another friend and, long story short, that friend made him a job offer to be a
junior guy with his company, a financial firm for clients in the music
business. Jeff would come on as the young guy to help with the young talent.
His first client was a new girl act, Joan Jett. That worked out for a few years,

exciting times, and eventually he opened his own shop and moved out to
Malibu.1 His wife was a record company exec, they had a kid, they had a
Lexus. He had an eye for talent and made 5 percent of what he made his
clients,2 and when one of his acts blew up, like Ke$ha or the Lumineers or
Imagine Dragons, Jeff made good. But the real perk was his access. Stopping
by their live shows was the coolest counterbalance to careful spreadsheets
and checked math.
He admired the musicians, dug the music. But his value lay in the
practical side. Music is a profession, though many musicians fail to realize it
until it’s too late. “Most acts are one-hit wonders, guys smoking pot in their
dorm room, they come up with a song that happens to be pretty good and
then, that’s it,” Jeff says. “I tell my acts: If you don’t want to be serious then
you’re wasting everyone’s time. Yeah, be a rock star, but this is how you’re
going to buy your house. It’s going to be your retirement account. It’s how
you’ll probably meet your wife or your husband. It’s more than lifestyle, it’s
your life.” As far as he was concerned, the song you wish you wrote? It isn’t
“Yesterday.” It’s “Tie a Yellow Ribbon ’round the Ole Oak Tree.” They’re
both about remembering, but only one made a billion in Muzak covers
alone.3
Jeff helped with the contracts, advised on royalty deals. There were
writing fees and pennies from records or plays on streaming media, iTunes,
Pandora, Spotify—the music world was changing fast in the early 2000s, and
you had to watch every stream. The more digital the music got the more free
it got, and the more it served as advertisement for the payoff of an
international tour. Sending an act off was like christening a new trade ship
after years of building. It could make or break, and Jeff wanted to be there.
And so in February 2011 he was in Portland, Oregon, watching the
roadies set up for the first night of Ke$ha’s new tour and wondering if maybe
he was pushing himself too hard. The 2011 “Get $leazy” tour—the dollar
sign in place of the S being Ke$ha’s trademark—had packed shows
scheduled across the Americas, Europe, Australia, and Japan. Jeff had taken
Ke$ha on when she was a kid playing club dates. She’d blown up when
Rihanna had signed her to open on her world tour, and now, at twenty-three
years old, she was positioned to leave port and capitalize on the zeitgeist,
with Jeff on deck to help steer the finances.

Jeff didn’t need to show up, but his presence there was a personal
reminder to his talent. He was looking after their investment, and that
investment was themselves. They should do the same. He really couldn’t
avoid opening night, no matter how he felt. Which was too bad, because Jeff
was feeling like crap.
He was always a little sick these days, a little weak, more than the usual
morning stiffness—and the general ache now lasted all day. That came with
hitting fifty, he knew that, the way his hair had gone white and thinned at the
top. He’d adapted, wore it cut short with a white goatee. Late nights and
discomfort were part of the rock-and-roll soul swap, same as the inevitable
weight gain of late drive-through meals and no exercise. At least there was an
upside—between the pain and the nausea, he was losing weight. He hurt, but
he looked good. When he hit 180 pounds, he was happy to recognize his old
silhouette in the hotel mirrors. But the weight kept dropping and he felt
something else, a dread he couldn’t put his finger on.
Ke$ha, decked out in a rhinestone-studded leotard and laser-shooting
sunglasses, ducked into the spotlight. Jeff felt cold. There was a pain in his
side, or his belly, or his back—somewhere in the middle there. He wasn’t
feeling any better as Ke$ha came back out in a star-spangled getup and
fishnets to sing her hit, “Fuck Him He’s a DJ.” Jeff found a seat and watched
the backup dancers and the band, professional musicians whose costumes
were described as a cross between “Mad Max and prehistoric birds.” It was
nearly midnight when Ke$ha finally performed a lap dance on an audience
member duct-taped to a chair. An extra in a giant penis costume pogoed
around the couple in a choreographed number.
Jeff checked his watch. The encore was thundering. Thank you, Portland,
Oregon, and good night. Maybe, Jeff thought, he needed to just go lie down.
But the pain he’d felt had been at a different level, and it didn’t go away.
Ke$ha’s buses headed off to the next stop on the tour. Jeff stayed behind and
quietly drove himself to the hospital.
A doctor looked him over. A phlebotomist took his blood. They ran the
numbers, brought him back in, asked him to sit down. He remembers the
doctor telling him that the first thing that stood out was his hemoglobin
count. It was staggeringly low. With numbers like that, his blood didn’t have
the means to transport oxygen to his muscles or his brain. That was probably
what accounted for his exhaustion. But what accounted for the low

hemoglobin? It might be cancer.
That suspicion led Jeff to the Angeles Clinic on LA’s Wilshire Boulevard
—PET scans, the usual round of tests—and on President’s Day weekend Jeff
was told: kidney cancer, stage 4. He didn’t know about stages, but he did
know there wasn’t a stage 5.
He also didn’t know, and in the moment of shock wouldn’t have cared,
that he was one of about sixty-three thousand people in the United States to
get a diagnosis of kidney cancer that year. Of those, a far smaller percentage
would get a diagnosis for the rare and specific cancer Jeff had. It was, in the
language of cancer specialists, an especially “interesting” type of cancer, a
particularly aggressive variety called sarcomatoid renal cell carcinoma.
“The doctors tell you, don’t go online when you get your diagnosis,” Jeff
says. There’s no good that can come from trusting everything put up on the
internet to interpret your fate. “But of course, that’s exactly what you do.”
He got as far as his car. He took out his phone and looked. The numbers,
at first, looked—not bad, really. The five-year survival numbers, the standard
numbers given for cancer at that point, were nearly 74 percent. That’s a
passing grade, a majority, Jeff remembers thinking.
But then, reading further, he saw that the good number depended on other
factors. The most important was how early you caught the disease.
The kidneys sit in the lower back, two filtering masses about the size of
fists on either side of the spine, right about where you might hold someone to
slow-dance at a junior high prom. They’re complex filters, composed of
millions of tiny, capsule-shaped glomerular filters that sort out what the body
needs from what it must discard. But like a demolition worker clearing out
asbestos from a condemned building, those glomeruli are heavily exposed to
all the concentrated toxins that come through the body. They are more likely
to undergo DNA mutation as a result of that exposure, just as exposed skin
catches more UV radiation and is more subject to the mutations that facilitate
melanoma.
The survival rates Jeff was looking at were when you caught it early—
when it was just in the kidney and the tumor was no larger than seven
centimeters.
The United States doesn’t like metric measures, so it tends to translate
them to nuts and fruits, and sometimes eggs and vegetables, to describe
tumor size. For a five-centimeter, stage 1 tumor, the American Cancer

Society site uses a lime. Stage 2 is a lemon, or a small orange, still localized
as a mass within the kidney. Stage 3 means the tumor has started to spread
within the kidney. The growing, spreading cancer—a peanut, a walnut, or an
orange—if it’s stage 3, is still contained within the kidney area, so it can be
more readily targeted by conventional cancer therapies—specifically surgery
and radiation.
Since most of us have two kidneys, and can survive on one healthy
functioning one, cutting out one whole kidney—what they call a radical
surgery—is a common approach. But Jeff’s diagnosis was stage 4. That
meant the tumors had entered the bloodstream and moved elsewhere, and
possibly everywhere.
No matter where those mutated renal cells moved—they could fill the
lung, lodge in and take over the liver—they would always be called “renal
cancer.” (This naming system, as anachronistic as describing tumors in terms
of fruits, changed because of cancer immunotherapy in 2017, itself a
breakthrough.) And so when those mutated renal cells started colonizing his
spine, Jeff’s cancer was “kidney cancer,” stage 4. And on the tiny screen of
his flip phone, stage 4 kidney cancer looked really bad. The five-year
survival rate hung at a guttering 5.2 percent, and it had been about 5.2 percent
since the 1970s. The last new scientific advance for treating kidney cancer
had been made thirty years ago. There isn’t any way to put a positive spin on
that. You just close your phone, sit in your car, and wait until you’re calm
enough to drive.
There really isn’t a good time to get a diagnosis like that, Jeff knew. Jeff
was busy—but everyone is too busy for this sort of thing, and once he went
through the usual reactions he realized that too. But hey, come on. He was
really busy. His business was booming, his acts needed him, and he now had
two little kids—one three years old, the other just a year. He wasn’t going to
stop working, he wouldn’t make a big thing of it. He told only those clients
who really needed to know, who’d need to make professional decisions. He
told Ke$ha he was sick, didn’t say how sick. That seemed OK. Mostly, he
decided to just keep moving forward.
Next, Jeff was referred to the larger affiliate hospital, the mothership, to
see their kidney specialist. Maybe it was Jeff’s mood, but this doctor, he
decided, was “a fucking prick.”
Let’s call him Dr. K. He had looked at the numbers. Stage 4 kidney cancer

was pretty much a death sentence, especially in this rare agressive form, but
there was always a chance. Dr. K started Jeff on a drug called Sutent. As the
label promised, Sutent gave Jeff the usual symptoms of extreme nausea, lack
of appetite, and daily dry heaves.
Meanwhile, his PET scans had come back. The cancer in his right kidney
was now working its way up his spinal column, tumors leapfrogging each
other like kids grabbing a bat handle for dibs. They scheduled surgery to look
at that, and when the surgeons opened him up they found that the tumors had
eaten into the bone. Fists of dense tissue fissured the central supporting
column of his body and nervous system, and knuckled perilously into the
wiring of his spinal cord. The structure was brittle and laced with a
progressive disease; soon the tumors would either engulf and seize his spinal
nerves, or his increasingly fragile vertebrae would fail under his weight like
the collapsing World Trade Center towers, or maybe both.
It was moving fast, and either scenario would leave Jeff a quadriplegic at
best. They needed to immediately secure the structure. The cancer was
inscrutable, incurable, and complicated, but this was concrete physical work
that a surgeon could do with a knife. Chunks of his spine needed to be cut out
and titanium rods screwed in their place. It would give Jeff a Frankenstein
posture, and he would have to live with a constant hum of background pain
from the raw nerves—compressed by his collapsing vertebrae, permanently
pinned to the titanium infrastructure like guitar strings hard against a fret
board—but at least it kept him from being paralyzed. It was the deal to make.
A month later they operated again, and finally took out the diseased kidney.
It was hard, the surgeries and the pain were extreme, but “I never stopped
working,” Jeff said. “I tried to hide it from everyone.” He still got up in the
morning, showered and shaved and dressed, cinched his belt tight to keep his
pants from falling off his hip bones, got in his Lexus, and headed toward the
freeway as he’d always done. Going to work.
“But I never went to the office.” Instead, he’d pull off somewhere south of
Malibu, go through the McDonald’s drive-through to get an Egg McMuffin,
and force it down before he even pulled back out to the road. Then he’d drive
up and down the Pacific Highway taking calls on his car phone. “Every once
in a while, I’d pull over, put the phone on mute, throw up out the window,
and get back to the call,” he said. The McMuffins helped; they were soft, and
much better than the dry heaves.

He had two doctors: Dr. K, his kidney specialist; and the surgeon, Dr. Z.
Jeff saw Dr. K for the sutent, and met with his surgeon a few weeks later for
the follow-up. Both doctors had seen the same scans but gave him different
messages. “The surgeon told me not to bother with the chemo anymore,” Jeff
says. “He thought I should just give up trying to beat this thing and try and
enjoy the little time I had left, without the side effects.” Dr. K was upset that
the surgeon was telling his patient to ignore his prescribed treatment.
As far as Jeff was concerned, it wasn’t that Dr. K disagreed with the
surgeon’s prognosis; he, too, thought Jeff was going to die. It was that the
doctor was getting paid for every chemo treatment Jeff underwent, and Dr. K
wanted to keep collecting the fee for the treatments, as long as Jeff was alive
enough to take them.
Finally, in September, Dr. K gave him a final prognosis. “He told me that
I was going to have six months, tops,” Jeff said. In retrospect, it’s surprising
he was given that long. Jeff’s weight had dropped to 148 pounds, and
increasingly more and more of that was tumor.
“The guy told me to go get my financial affairs in order,” Jeff says. “He
was awful—no bedside manner, no compassion.” The way Jeff read it, “They
were done with me. They’d given up.”
Jeff believes it was a matter of the doctors at the hospital having nothing
left to bill for, that was how he saw it. Maybe that’s just how he thinks as a
manager and accountant; maybe it’s more than that. Doctors are just people.
While the best of them are very good at aspects of their jobs, and some of
them are good at several aspects, it’s rare to find one who can act as both an
expert physician for a patient’s physical body and a philosopher-priest for a
human mind contemplating its own death. These are also the desperate
thoughts of a desperately ill man raging against the tyranny of mortality, as
presented by a series of guys in white coats. It’s a tough go, however you
look at it. Bad news isn’t easy on anyone.
Either way, the medical professionals, the ones who knew more about
what was laying waste to his body than Jeff himself could comprehend, had
nothing more to offer. They saw no option but to give up. And so, the logical
thing for Jeff to do was to follow the experts’ lead and give up too.4
His referring physician at the Angeles Clinic, Dr. Peter Boasberg, had
another idea. There was a clinical study. Maybe, possibly, he could get Jeff

on this study. “Maybe” sounded pretty good at that point. The drug being
tested didn’t attack the tumors; rather, it attacked the tumors’ ability to shut
down the natural immune response against them. It was called a checkpoint
inhibitor. Already, there was a theory among researchers working with this
drug that it was most effective in generating a strong immune response
against tumors that had a high degree of mutation. That might include kidney
cancer—cancer like Jeff’s.

All decisions about the study parameters fell to Dr. Dan Chen, MD, PhD, an
oncologist immunologist who was also the cancer immunotherapy
development team leader at Genentech, the company that made the
experimental drug. Patients that might qualify for the study were presented to
him in blind applications—each reduced to a code name of letters and
numbers and the specifics of their medical history. Jeff Schwartz was now
patient applicant 101006 JDS.
Originally the drug study had been designed to look at the drug’s
effectiveness against solid tumors. It had been expanded to include
melanoma, bladder, kidney, and several others. Did Jeff qualify for such a
study? On paper, the answer wasn’t obvious.
If Chen was looking for reasons to exclude someone, he could definitely
find justification to rule out patient 101006 JDS, but that didn’t make it the
right decision. The study qualifications were advertised in terms of what
types of cancers qualified. That description did not specifically mention the
rare form of kidney cancer on patient 101006 JDS’s paperwork—but it was
kidney cancer, and Chen strongly suspected that 101006 JDS’s rare cancer
had many similarities to the cancers they believed would be responsive to
their immunotherapy candidate, a new checkpoint inhibitor. On the negative
side, this rare and aggressive cancer was now rooted deep in the bone, which
the immune system has a difficult time infiltrating, but this patient fit the
profile and, Chen suspected, might benefit from the experimental drug. If it
was already approved and readily available, Dr. Chen would have put him
right on it and hope it helped, as nothing else had. But in 2011 this
immunotherapy was not yet an option in an oncologist’s toolbox. The only
way for a cancer patient to access this drug was through the experimental

trial.
Which made patient 101006 JDS an especially tough call. Chen knew the
usual course of a stage 4 kidney cancer prognosis. As a physician and a
compassionate human being, he wanted to say, look, if 101006 JDS’s disease
qualified, he was in. But as a scientist and department leader in charge of a
massive phase study, there was a problem. Based on the paperwork, patient
101006 JDS was probably too unhealthy for a physically rigorous trial; he
might jeopardize the whole study. There was no computer algorithm, no chart
or slide rule for making this decision. Chen had to balance out the factors and
weigh them with his head and his gut.

Jeff didn’t know how to play the odds on this one, how hard he should hope
or how he should proceed with the next phase of his life. On the one hand,
there was no guarantee he would be able to start the new experimental drug
trial for the immunotherapy, and he should prepare for that. But on the other,
if he did beat the odds and get a green light, he’d need to be available to
accept on the spot. To do that, he couldn’t be on any other cancer treatment.
That meant he’d have to stop the chemotherapy and wait. The chemo had
been making him feel terrible, and it hadn’t stopped his tumors from
growing, but it was the only treatment offered. There was no telling how
quickly his cancer would progress if he wasn’t actively poisoning it with the
chemicals. It was possible that the chemo was slowing down his decline and
buying him a few extra precious days or weeks with his family. Quitting that
possibility on the slim chance that he might start something else, something
experimental, that might work, and might not—that was a perilous trade-off.
It felt like holding your breath to avoid breathing in poison.

Years later, Dan Chen still remembers everything about patient 101006 JDS
—his profile as a potential study participant, his response, even his coded
patient identity number, straight off the top of his head. As a scientist testing
his first immunotherapy drug, Chen wouldn’t quickly forget his first
responder. 101006 JDS turned out to be, as Chen says, “a special, special

case.” Part of what made him special was the fact that, even knowing how it
turned out, one could still make the case that from a data collection
perspective, patient 101006 JDS shouldn’t have been allowed onto any kind
of medical study at all.
“My initial reaction upon seeing him—it was all just on paper at that
point, but it was, ‘Are you kidding me? Why are you sending me patients like
this?’” The study Dan was running was a phase 1, meaning the first in
humans, and his team had something of a fire under their ass to make this
thing go. They’d started late in the immunotherapy game, despite the number
of cancer immunologists who were then like secret sleeper cells within
Genentech, and when they’d convinced the larger company to change the
course of their research and allow them to head into this unproven direction
for their drug development they were already years back, building a new drug
program from scratch.
Before he’d joined Genentech, Chen had been working with cancer
immunotherapy both in his lab at Stanford and with his patients at the
Stanford University Cancer Center. Those early approaches hadn’t worked
against cancer. But despite the failures of the various vaccines they had tried,
and the uneven and sometimes disturbing effects of giving patients doses of
strong immune stimulants like interleukin-2 and interferon, the researchers
had seen glimmers of hope. Chen and other cancer immunology believers had
seen them in their rare but real positive responders, and in those reported by a
handful of other labs around the world. Most oncologists—most scientists—
dismissed cancer immunology as a dead end, peopled by quacks and true
believers who confused hope for good science. But Chen believed, as the
handful of others who were still in the immunotherapy field believed, that
there was something more to these positive responses than misinterpreted
anecdotes.* This drug study might help prove that.
Was patient 101006 JDS going to help the study? Chen wasn’t so sure.
“He had a lot of disease. The disease was in bad places, including the bones,
which is harder for cancer immunotherapies to treat,” Chen remembers.
Worse, his “performance status” was horrible.
Performance status means: “What’s your day look like? Are you up and
about? Or are you unable to get out of bed because you’re puking all day, and
can’t eat?” Chen and other oncologists used performance status to predict

how a patient was going to fare—whether in a clinical trial or with a
traditional cancer therapy. It’s a more rigorous variation of: How you doing?
And 101006 JDS wasn’t doing well.
“If you can’t get out of bed, if you can’t move, your outcomes are
generally horrible,” Chen says. “Sometimes you have patients that are
declining like this—” He puts his hand out, tilted like a graph nosediving.
“You generally can’t reverse those patients. So putting people who are on a
downward course on your trial is not a great way to figure out if your drug is
safe.”
And that was the point of this phase 1 trial—to gauge the safety of a
potential new drug by testing it in low doses. If it failed here, it failed. If that
test was going to mean anything, it needed to be the truest possible reflection
of the safety of the drug. From this perspective, patient 101006 JDS wasn’t
exactly who you were dreaming of. Patients who were too weak and sick
would fail the test no matter what you gave them—and that failure would be
ascribed to the drug, not to the patient. It wasn’t just Jeff who would suffer, it
was the entire study and, by extension, an entire generation of patients.
If the “How you doing?” test was somewhat subjective, the main criteria
of entering the study were standardized and empirical. “We had a laboratory
value that you had to meet,” Chen explains. These values had been provided
to all the primary investigators who would be running the study; their patients
needed to meet or exceed those values in order to even be considered.
101006 JDS’s lab values were bad. His albumen, his white blood cell
count, was “not good.” Those values were a particularly negative indicator
for a potential immunotherapy drug study candidate.
“First of all, you need to have the white blood cells,” Chen says. “You
need to have the T cells. We didn’t know much about the drug at that point in
time, but if you don’t have the T cells in the first place, then why would we
be trying to give you a drug that’s going to react with the T cells?” That was
the most important number in the trial, and Jeff was below that number value.
“There was no way.”
Two months off the chemo, Jeff was sicker than ever—too sick to meet
the eligibility requirements for the Angeles Clinic study.5 Thus began a backand-forth, with Jeff’s doctors—Chen’s primary investigators on the study—in
the middle.

“They had protocols,” Jeff says. “My hemoglobin had to be at a certain
level. They drew my blood; I said, ‘Draw it again.’” Maybe Jeff’s levels were
fluctuating, “so they’d try drawing it at different times of the day,” he says. “I
was eating broccoli like crazy, every day, just trying to get the numbers up.”
“I know they were really trying anything they could,” Chen says. “There
had also been an old observation that showed that rubbing the earlobes
pushed out white cells—a real phenomenon, studied at Johns Hopkins, called
something like ‘earlobe lymphocytosis.’” So they tried rubbing his earlobes.
Jeff rubbed them at night or in the car, rubbed them right before they drew
blood. That didn’t get his number up high enough, either.
In November Jeff’s oncologist at Angeles, Dr. Boasberg, had to break the
news. He wasn’t going to qualify for the study. “And I knew that was a death
sentence,” Jeff said. He wasn’t ready to give up, but he couldn’t simply will
his immune system into health. “They offered to put me on a different drug
trial,” he said. It wasn’t an immunotherapy, and Jeff had already gone the
chemo route. It hadn’t worked, and it made him feel like shit, and he maybe
only had a few months anyway. Was he really willing to feel like that again?
Absolutely, if there was a chance it would help him, that was his attitude.
He hadn’t tried this particular drug, so at least he could try to think of this as
plan B. But maybe, Jeff worried, it wasn’t really a plan at all—it was simply
something to do, the medical equivalent of busywork for the doomed.
You try to put a good face on it, to go along, be a good patient, to not look
at the couldas and wouldas. Cancer is full of those—lung cancer clinics filled
with smokers who quit—and the important thing to Jeff was to keep moving
forward. But it was tough not to see that two roads were diverging here, not
to recognize that plan B was the wrong fork. The thing that his doctor wanted
for him, the thing he thought might possibly help him—Jeff couldn’t get.
This other study was clearly an afterthought—but maybe busywork was what
he needed. Maybe it would help him. Definitely Jeff wasn’t seeing any other
choice that didn’t amount to giving up and making peace with his fate.
The only problem was, Jeff wasn’t feeling peaceful. He kept glancing
over his shoulder at the other path. Now, it was Jeff who had the tough
decision: starting the study on offer meant giving up on some miraculous
possibility of entering the checkpoint inhibitor study, but this bus was
leaving, too. If he waited, he’d be left at the crossroads, stuck with nothing.
And nothing, he’d already been told, meant entering hospice.

Meanwhile at Genentech’s San Francisco campus, Dan Chen had a problem.
A number of them, really. One was a problem every oncologist had, the
burden of the job. Cancer treatment is generally not a good-news field. To be
a good doctor and researcher, you had to accept the fact of mortality and the
terrible outcomes from the disease, even while working actively, often
fruitlessly, against them, every day.
Part of what he had to accept regarded the fate of potential patient 101006
JDS. He looked bad on paper, but he’d been wavering near the line long
enough that, even behind the coded identity, his case had become personal.
Dan hoped for a good outcome for this guy—he knew it was a man at this
point—but he also hoped for good outcomes for his drug, and for cancer
patients in general.
“And now we’re coming up on the Christmas holiday, and everything is
going to shut down,” Chen says. There would be a break at the company,
short breaks maybe for some physicians, and the patients themselves might
choose to go see far-flung friends and family, some of them for the last time.
It’s what happens. That meant that the race to get this drug developed, tested,
and to patients and the marketplace was about to suffer a major delay. “So I
had to face the fact that if we don’t fill out this cohort before the holiday, we
delay this whole trial,” Chen says. And that would have a ripple effect, and
potentially serious consequences. The other patients couldn’t start until the
cohort was filled. And no patients could get the drug, or have reason to
believe it was worth getting, until the drug passed through clinical trials and,
best case, expedited FDA approval. That one empty spot in his cohort had
become a stop sign.
If patient 1001006 JDS was ever going to be considered, it was now or
never.

Jeff Schwartz was scheduled to begin the plan B clinical drug study on
December 17. He remembers the morning, the car, the highway. The drive to
the Wilshire Boulevard clinic was like a gallows march, dead man driving.

The windows of his Lexus were shut tight against the Los Angeles air; his
heater was cranked up to eighty degrees, just to keep him from shivering too
hard to drive.
“I didn’t tell anybody, but—that was awful,” Jeff says. “I’d sorta resigned
myself to it. I was going to keep fighting but…” Jeff stops. He hadn’t thought
further that day either, at least not about himself, because, as far as he was
concerned, he was done. The rest was about fiduciary responsibility. “Every
penny I made, I made sure my kids had savings,” he says. “I paid my leases
up front, not knowing if I’d be there to make the next payment. I didn’t get
spiritual from it, it didn’t change that, but death, the prospect of it, knowing
the end—” Jeff stops and considers the room for a moment. “Well, it changes
the way you think about things.”
Jeff drove through the gate. He parked, pulled himself out of the car,
checked in at the desk. There was the clipboard with the cheap pen. A nurse
came out, called his name. She waited, smiled, turned. He followed through
the doors and into a room, a comfortable chair. The overhead lighting was
bright. His name had been transcribed to an ID, then matched with an IV.
Studies have to be double-blind to avoid any bias or sentiment. For the sake
of science, the patient is stripped of his identity. Good for science, but hard
on us humans. The procedure would be: pull out the drip, check the numbers
on the drip against the bracelet on the patient, enter the numbers on the form,
hang the IV, unstop the stopcock. Patient 101006 JDS, formerly known as
Jeff, was ready. His sleeve was rolled up, a catheter needle was inserted and
taped. The drug would be useful, they’d discover later,6 for giving extra
months of life to some kidney cancer patients, but almost certainly not of any
use for patients like Jeff.

Five hundred miles north in San Francisco, Dan Chen was in his office as the
sun came up. At 7:30 his phone rang. The sudden noise startled him. The call
regarded patient 101006 JDS’s latest numbers. Maybe it was the ear rubbing,
Dan doesn’t know; maybe there’s a value for sheer will. Whatever it was, the
guy had popped over the line.
Maybe the numbers wouldn’t stay there, but they’d run the tests and he’d

passed. It was a cold line and he’d crossed it. That part wasn’t a judgment
call now, it was empirical. The next call, if Dan made it, would be to the
clinic: Can they put this guy on the trial?
Dan remembers the light. It bounced off the cold gray chop of the San
Francisco Bay and it did something to the room. He watched it, looked out
the window.
“It wasn’t just about this one guy,” Chen says. “The trial would affect far
more people. Was this guy just going to crash and burn?” Would he hurt the
trial and hurt those people? If he let this one in, was Chen doing the right
thing, or the wrong thing?
It all had to happen in a matter of minutes, the call with the numbers, his
decision, but something about the light—maybe he’d watched too many
movies but there was something of a Christmas miracle in it, that feeling you
get that time of year, maybe a kindness, even when kindness could be
misguided. Dan picked up the phone, called the clinic. The line was busy. He
put the phone down, checked the number, tried again. Same thing. Maybe
this was a sign? Maybe it was just a busy phone. He tried once more and got
through. He gave the patient number, said, “Let’s put him on.” There was a
pause and a noise, and a sort of panic. It sounded like somebody was running.

“So I’m sitting there,” Jeff said. “They had everything hooked up, that was it.
The bag was hanging, they just needed to finish the job. And a nurse came
running in and said, ‘Wait.’ Like there was something wrong with my blood
or something.”
Then the doctor came in. “They called,” he said. Apparently, Jeff’s
lymphocytes were up enough to fit into the protocol for the study.
“They said they were 1100 or something,” Jeff says. “I had the same
cancer as before, it wasn’t getting better, but my numbers were better.”
According to the blood work, his lymphocytes had finally showed up.
“Maybe there was some miracle, what happened—I don’t know.” What he
does know is they pulled the drip, unhooked the line from his vein. His
doctor had one final message from Dr. Chen. “He said the message was, ‘Tell
the patient Merry Christmas.’”

Three days later, on December 20, Jeff became patient twelve of the twelveperson study. He drove himself to the center. It was the first time the
clinicians administering the study had met their trial patient in person. He
was sicker than they had imagined. Sick enough that they called to make sure
this guy was really supposed to be there.
Jeff went through the same setup as before: the clipboard and the forms,
the stickers and the armband and the rolled-up sleeve and the needle. Except
this time, he was infused with the experimental checkpoint inhibitor
immunotherapy drug.
This was Jeff’s first experimental drug. They called it MPDL3280A. The
mad scientist notion of that, an experimental drug, that was exciting, but also
a bit frightening. MPDL3280A had worked in mouse models, but 90 percent
of all cancer drugs that work in mice fail in human trials. “I asked them,
‘Hey, this stuff you’re giving me—is this going to blow my head off?’ And
they say, ‘Fuck if we know.’ Because I’m the first one!”
It didn’t blow his head off. But it did do something. “Right away, I just
came back to life,” Jeff says. “It was weird.” Was it really working? Or was
that just in his head? He’d only gotten one dose, and a low dose—that was
one of the goals of a phase 1 trial, to find the “lowest effective dose” of a new
drug. That seemed like an unlikely scenario for an instant effect.
Jeff knew about the placebo effect, and he knew about the effect faith and
hope can have on a person’s health and even on their outcome. He did plenty
of that with his clients, talking them up; the power of belief was important
and real, but it didn’t cure cancer. He also realized that he’d been off the
chemo long enough that, no matter what, he was going to be less nauseous.
The next visit, two weeks later, they injected him again. And again, right
away, he was pretty sure he was feeling better. He’d always been working,
even while he was dying. Now he felt good enough to do things besides
work. Good enough to take his five-year-old son to SeaWorld that month.
“I’m there, I felt a pop in my hip—it was my hip bone. The cancer had
eaten right through it, it just popped right through the hip socket.” That did
nothing to help his performance status, so that was a setback. He had another
surgery, but it was just a surgery, rather than new cancer, one of his old
problems coming home to roost. You didn’t worry about the old problems;

you hoped to stop any new ones. His next appointment comes, Jeff gets
another infusion of the experimental drug. And this time, he doesn’t just
think, he’s sure he’s better now.
At home a few weeks later, his son asked him: “Dad, what happened?”
Jeff didn’t know what he meant, but his son told him—he didn’t think that his
father could lift him anymore. But here he was, throwing the boy up in the
air, watching him squeal with delight. Jeff hadn’t really thought about that,
but his son noticed. Something was improving. Then, the PET scans
confirmed it.
On March 15, 2012, Dan got an email update from the physician at the
trial clinic. The iffy patient they’d sent over, the one with significant fatigue,
pain from a retroperitoneal node, the one unable to work or lift his young
children—they wanted Chen to know. Patient 101006 JDS had been “recalled
to life.”

Jeff understood how lucky he was, and he wanted to meet the people
responsible for what he had received. He had known that the global lead on
the study was a Dr. Chen, based somewhere in the biotech boxes in San
Francisco. He’d hoped to call in, maybe a conference with the team, just to
say thank you to the room.
“In July they told me there was a conference in LA, and that ‘Dr. Chen’
was going to be there. I’d always pictured this Dr. Chen, the mysterious Dr.
Chen—you know, I’m picturing some geek in wire-rimmed glasses
somewhere. I meet him and, here’s Mr. GQ.”
Jeff found Chen surprisingly charming and accommodating. Later, Chen
brought Jeff into the San Francisco offices, then down to the labs. There was
a sort of Willy Wonka feel to the whole thing. “This place, they’ve got a sign
reading E. COLI on one side, CHO on the other,” Jeff says. “I ask him, ‘What’s
“CHO”?’ He says it’s ‘Chinese Hamster Ovaries’! Then they bring me over
there to a big steel vat. He asks me, ‘Know what this is?’ I tell him, ‘It looks
like a brewery.’ Dan says, ‘Yeah, well, they’re brewing proteins.’”
Finally, Jeff was introduced to four researchers who had helped develop
the drug and build the protein.7 “I meet them, they know who I am, and so

they’re all crying,” Jeff says. “Because, these guys are geniuses, but they’re
all like idiot savants, they never leave the lab.” After all the work that had
gone into getting their immunotherapy drug ready, and after decades during
which immunotherapy drugs had failed to save patients, the sight of a healthy
man, returned from the brink of death by virtue of their efforts—it was a first.
“All these guys, I don’t know how they do it. They get rejected all day,
everything they do fails, people die. Can you imagine being these guys? Chen
is an oncologist, he does melanoma, all his patients, all these guys. Can you
imagine?”
Dan Chen had done something for him, something big. So Jeff wanted to
do something for Dan. “Chen doesn’t know me, not personally, he knows me
by my initials from the study. So, he doesn’t know I’m in music.” Jeff asks
Dan, who’s got a teenage daughter,8 “So, what’s her favorite band?” Chen
tells him it’s a band called Imagine Dragons. Jeff smiles as he recalls: “So,
next time the band is in San Francisco, I get her tickets, she goes backstage,
then she’s on the stage throwing out balloons—it’s great! She’s having the
time of her life. Dan says, ‘Thanks.’ I tell him, ‘Hey, thanks for keeping me
alive!’”

Jeff was feeling well enough now that it was almost life as usual. That
included going to his son’s weekend basketball games in the grade school
gym. “My wife’s with me, she says, ‘Look, you know who that is, across the
gym?’ I look and I can’t believe it—it’s K. Dr. Fucking K.
“So I march right over, I ask him, ‘You remember me?’ He says no. I tell
him, ‘Well, I’m the fucking prick you gave five months to live!’
“I saw him again six months later—our kids are the same age at the same
school, he’s going to see me, and I went up to him again. I told him—I just
had to say something. I had to tell him, ‘Look. A patient hangs on every
word. Every word. You told me you had nothing left, told me I had five
months to live, and my world was shattered.’”
Jeff also remembered what his other doctor had told him when he was
getting sicker and hadn’t found a clinical trial. Dr. Boasberg had seen the new
immunotherapy drug trials come through, he’d seen the transformative

effects, things they never imagined. And he knew how quickly the new drugs
were coming. “I might not get into the study now,” Jeff said. “But he told me,
‘Hang in there, because there are new drugs right around the corner.’”
In 2011, that was a rare and radical perspective. Not every oncologist was
aware of what was happening in cancer immunotherapy. At the time, the vast
majority still thought of the immune-based approach to treating cancer from
the bad old days of false promises and ineffective vaccines. Jeff was lucky
enough to have a physician connected to a place like the Angeles Clinic,
staffed with oncologists open to the potential of cancer immunotherapy and
geared toward clinical trials. Of course, he’d only gotten there because his
cancer failed to respond to anything else. In that sense, he wasn’t so lucky.
When Jeff was in his twenties, cancer was an old man’s disease, and he
didn’t much think of it. He was the kid filing out from some live show
downtown with his ears ringing as snowflakes slanted through the
streetlights. Not to get sentimental, but that trouble-free time really did seem
like yesterday, like in the song. He can still picture the snow landing like lace
on his black leather jacket, there and gone. He had all the time in the world.
“Just think of all the people who died, waiting,” Jeff said. “Just a little too
early, or the ones who just gave up because a doctor told them they were
done, that’s it.” That could have been him. It wasn’t. And why was that?
Jeff doesn’t know. But part of it has to do with luck, part with sheer will,
part with faith, or something like it. And part of the answer took place more
than one hundred years before, on the same downtown streets of Jeff’s youth,
where a New York surgeon chased a medical mystery into the immigrant
slums and returned with a recipe to cure cancer.

Chapter Two

A Simple Idea
The real voyage of discovery consists in seeking new landscapes, but
in having new eyes.
—MARCEL PROUST, 1923

In terms of modern Western medicine, the idea of using the body’s own
immune system to kill cancer traces back through the end of the nineteenth
century and a seventeen-year-old girl named Elizabeth Dashiell. “Bessie” was
the pretty and self-possessed daughter of a Midwestern minister’s widow.
She was also the very close pal of the only son and namesake of the founder
of Standard Oil, John D. Rockefeller Jr. There’s never any mention of
romance in their relationship—Rockefeller referred to her as a sort of sister or
soul mate—but their steady flow of letters and their habit of taking long
carriage rides along the Hudson River suggests the crushy intensity of youth,
which only intensified with their separation during the summer of 1890,
when Dashiell left New York for a cross-country train journey.1
She returned in late August complaining of only one small injury. Her
right hand had been caught in the seat lever of her Pullman rail car and was
now swollen and discolored.2 She couldn’t sleep with the pain. Finally,
Johnny Rock’s family suggested New York Hospital,3 where Bessie would
be examined by a twenty-eight-year-old bone specialist and surgeon freshly
released from Harvard Medical School, Dr. William Coley.4
Coley was a rising star in the surgery department, a skilled and caring
clinician with a youthful enthusiasm for new ideas, such as germ theory and
Joseph Lister’s latest advances for controlling infection through sterilization

techniques and vigorous handwashing.5 These modern notions rendered
surgery far more survivable for patients; they might have also put the young
surgeon in a state of heightened awareness of both the astonishing invisible
microbal world around him and the promise of further scientific advances on
the horizon. Coley considered that he had entered medicine “at the most
opportune time in a thousand years.”
The young surgical intern examined Bessie Dashiell’s hand.6 He noted a
slight swelling “half the size of an olive,” like an extra knuckle where her
metacarpal met the pinkie. He thumbed the mass; it did not move, but it was
tender, and the girl winced. Coley carefully palpated Bessie’s jawline and
armpits and found them unremarkable. Her lymph glands weren’t swollen.
That suggested that the problem wasn’t an infection; there was no immune
response.
As a bone specialist and a surgeon, Coley’s best guess was that her pain
and swelling resulted from inflammation of the sheath-like sac that covered
the bone of her little finger. To be certain, he needed to cut. Coley took his
scalpel and drew a line down the girl’s finger, parting flesh and membrane
down to the bone. He noted that he did not find the great reservoir of pus he
would expect from infection, and that the membrane was hard and gray. His
diagnosis was periostitis, a subacute bone ailment. Dr. William T. Bull—his
mentor and a legendary surgeon known as the Dapper Dan of the operating
theater—agreed, and the young woman was sent home to let time heal this
wound. But over the following weeks, Bessie Dashiell’s Pullman pinch
continued to worsen. And that didn’t make sense. If all the symptoms
resulted from the initial insult to the bone, they shouldn’t have been getting
worse.
Coley performed a second exploratory surgery on Dashiell, scraping more
of the tough gray matter from the bone. But the swelling and pain continued
to increase, and Dashiell began to lose sensation in one finger, then others.
Now the young surgeon had to consider a more dire diagnosis and yet another
surgery. This time Coley cut a slab of the gritty gray matter from Bessie’s
finger to be analyzed. A few days later, a report messengered from a New
York Cancer Hospital pathologist confirmed his suspicions: Under the
microscope, the “granular” gray stuff Coley had been scraping off Bessie
Dashiell’s bone was revealed as cancer. Specifically it was a sarcoma, and it

was spreading. What little feeling Bessie had left in her fingers now radiated
as pain. Coley prescribed morphine.
Sarcoma was a relatively rare form of cancer, a disease that affects the
connecting tissues of the body such as the tendons and joints and ligaments.
(It’s distinct from what is commonly called carcinoma, which affects
essentially everything else.) Treatment options for cancer, especially those of
the bone, were extremely limited in 1890.7 The only means the surgeon knew
to get rid of the cancer was to cut off the hand itself.
Coley hoped to cut beyond the clean margins of the disease, while leaving
the girl some useful length of arm. But the cancer had already spread. What
had started in her pinkie now proliferated grotesquely through the landscape
of her young body. Small buckshot-like nodes began to appear in one breast,
then in the other. Soon, they were in her liver, and Coley was able to feel a
large solid mass growing above the young girl’s womb; perversely, he
described it as being the size of “a child’s head.”8
Bessie Dashiell’s decline was shockingly rapid. By December the young
woman’s porcelain skin pushed out everywhere in hard lumps. Her liver was
enlarged, her heart was failing, and she was skeletally thin, surviving only on
brandy and opium. The frail, drug-addled creature was almost unrecognizable
as the pretty, plucky young woman who had walked into his offices only two
months before, fresh from a cross-country adventure. There was nothing for
the young surgeon to do but bear witness and provide the comfort of opiates.
Dashiell died at home on the morning of January 23, 1891; Coley was at her
bedside.
Coley would later admit that her death had been for him “quite a shock.”
Partly it was her youth, and his—he was new at the job, and only ten years
older than Dashiell. And partly it was the rapidity of this disease, and his
helpless flailing in the face of it. Perhaps his surgeries had even hastened the
disease by scraping it loose into her bloodstream. Maybe he had made her
suffering worse by trying to save her.
Despite his modern surgical refinements and degrees, Coley had offered
Bessie Dashiell little that wasn’t available in the blood-slick chairs of streetside barber surgeons or the numbing comforts of the barroom. He was
determined to find a better way. Technological advances were rapidly
ushering in the new century; each morning paper seemed to herald a stunning

new scientific advance. In the previous ten years Karl Benz had invented a
gasoline-powered engine, Charles Parsons had invented a steam turbine, and
George Eastman developed plastic photographic film. Less than a mile from
Coley’s medical offices, Nikola Tesla and Thomas Edison were in a furious
competition to build power stations capable of illuminating whole city
blocks. It felt as though the whole world would soon be lit and the shadows
of ignorance banished.
The records of everyone who had ever walked or limped or been carried
through the hospital’s doors were written in copperplate longhand in
oversized ledgers. Coley turned the heavy pages, scanning the progress notes
on every patient who had presented with a disease resembling Bessie
Dashiell’s. This was tedious work; the records ran chronologically, page after
page, book after book. By immersing himself in the collective experience of
cancer patients and their presentations, Coley thought, he might better
understand the fatal course of Bessie’s cancer. And if he was lucky, he might
find an exception to it.
Seven years deep in the patient logs, Coley’s attention caught on an
unusual case history. It belonged to a thirty-one-year-old patient named Fred
Stein, a German immigrant and house painter. He had arrived at New York
Hospital in the winter of 1885 with a disfiguring egg-sized mass bulging
from his left cheek near the neckline.9 This was far larger than the one Bessie
Dashiell had on her hand, but it was the same sarcoma.
Dr. William T. Bull, the head surgeon at New York Cancer Hospital, had
operated on Stein to remove the mass.10 When it came roaring back, Bull
operated again. Yet again it reappeared and grew until it was as big as a
man’s fist. Bull performed a total of five operations on the man over the
course of three years. It was impossible to remove all the tumor, and the case
was considered “helpless.” Skin grafts were attempted but were unsuccessful,
leaving an open wound, which soon became infected with erysipelas.
Erysipelas was the name given to an infection caused by bacterium known
as Streptococcus pyogenes, the bane of nineteenth-century hospitals. Under
the microscope the bacterium appeared as little chains, like a bead necklace
cut into small lengths.11 On the ward, carried by the wind or bedding, these
infection seeds infested open wounds and blossomed in the bloodstream.
Infected patients broke out in fiery red rashes that started at the face and neck

and spread rapidly, followed by raging fever, chills, inflammation, and,
usually, death.12
Erysipelas was the most deadly postop killer in the nineteenth-century
hospital and still ominously referred to as St. Anthony’s Fire, as it had been
since the Middle Ages.13 The name referred to the speed of the infection’s
spread, its burn-like symptoms, and the desperation of the infected, who
prayed for a miracle.
Fred Stein—deathly ill from an inoperable tumor, an open surgical wound
on his neck, and infected by erysipelas—was assumed to be doomed. Instead,
as the fire spread and Stein’s fever raged, his surgeons noted something
unusual. His tumor mass appeared to be melting away.
According to his hospital record, Stein survived the fever only to relapse
again a few days later. He continued recovering and relapsing. Each time he
slipped back into fever, his remaining tumor masses seemed to be withering
and shrinking. Four and a half months later both the infection and the cancer
were gone, and Stein walked out of the hospital. It was presumed that he had
returned home to the immigrant slums of New York’s Lower East Side, but
his address was never recorded in the hospital records. That had been seven
years earlier. What had become of Stein or his cancer since, nobody had
bothered to find out. The only evidence of his existence and “miraculous”
cure were the notes in the ledger.
Coley was intrigued. Here he had two patients that had presented with the
same disease and been treated by the same methodologies at the same
hospital, under the watch of the same physicians. And yet these patients had
experienced wildly different outcomes. Dashiell had done well in surgery but
died anyway. Stein had done poorly in surgery, become infected, and
survived. It was so counterintuitive, it was tempting to look for causality. Had
Stein survived because he’d become infected?
Either the observation on Stein was incorrect, or this incongruity offered a
glimpse of something not yet understood. The only way to know more was to
examine Fred Stein himself. And Fred Stein had last been seen walking out
the stone gates of New York Hospital seven years before. Now, he could be
anywhere, including underground. William Coley had landed upon a medical
adventure. It would prove to be his strong suit.
Like many of his late-nineteenth-century contemporaries, Coley believed

that the answer to the big questions of science were out there, somewhere,
waiting to be discovered. The thinking wasn’t so different from that of
contemporary scientists using supercomputers to mine new insights from
dumps of old data—except in the late nineteenth century, the answers were
more likely to be uncovered via machete or microscope. That same year,
radiation and X-rays had been discovered, and several new elements had
been attached to the periodic table.14 Fridtjof Nansen was attempting to reach
the North Pole. Sir Richard Burton was bringing back tales of sea-sized lakes
in the center of Africa. And now here was Coley, young and trained and
ready. Coley wasn’t one for the quiet sit-and-study routine of academic
research; he had a quest to undertake.
Coley was a Connecticut Yankee from an old New England family, but he
wasn’t a complete stranger to the newer faces of 1890s’ immigrant America.
While still a student he’d worked aboard a brigantine on the rough Atlantic
passage between the Azores and the wool mills of coastal Rhode Island and
Massachusetts, and his wards at New York Hospital treated the huddled
masses arriving from every corner of the globe. Many settled in the
tenements in Manhattan’s Lower East Side, a ghetto segregated from uptown
society by the hard line of Fourteenth Street, but just south of the hospital.
After putting in a shift, Coley (now the personal surgeon to Rockefeller)
took a hansom cab downtown, climbed out in his tailored English suit, and
started walking the streets made famous to uptown slum tourists by
photographer Jacob Riis’s 1890 book How the Other Half Lives. Coley
himself wrote little about his forays in search of Fred Stein, and so it’s
difficult to imagine whether it plays as comedy or drama. Probably it was
both. It took weeks of combing the tenements, walking up and down stairs,
knocking on doors, describing and gesturing. But finally, improbably, on a
second-floor landing, a door opened to his knock and William Coley found
himself face-to-face with the man himself.
A photograph of Fred Stein, provided in Coley’s published report in the
medical literature, shows a tall, gaunt man with the glandular severity of an
Old Testament hermit. His hair was black with high, chopped bangs like a kid
might do with safety scissors. High, polished cheekbones framed a goatee
that extended like a black curtain from nose to collar, years of growth pulled
and cut square. You must assume the mouth. Only the back of his hair was

long, a cascading mullet that only partially covered the puckered scars of
disease, surgery, and infection.
If Coley was surprised he did not say. The real surprise was that Stein was
not only alive but apparently enjoying excellent health. After some initial
awkwardness and comically pidgin German, the young doctor was able to
persuade Stein to return with him to New York Hospital to be examined by
his original physician, William T. Bull. Bull confirmed this was the same
Fred Stein on whose notes he had written the terminal prognosis and
discharge, dated 1885.
Something had changed Stein’s cancer, and with it his fate. The only
observable something between Stein’s failed cancer surgery and incredible
cancer remission was the bacterial infection. If that infection had somehow
cured a case of “undoubted sarcoma,” Coley wrote later, “… it seemed fair to
presume that the same benign action would be exerted in a similar case if
erysipelas could be artificially produced.”15
And Coley couldn’t wait to be the one to artificially produce it.

Coley’s observation was astute and important, but hardly unique.Physicians
had been describing spontaneous regressions of disease, including cancer, for
thousands of years. Many had been observed to be coincidental to, or perhaps
even in reaction to, the introduction of a new, different disease to the
patient’s system, including erysipelas. By the time Coley was making his
observations about Stein’s infection, such notions had become a regular
feature of anecdotal medical hypotheses. Only two years before, Anton
Chekhov, the Russian physician and playwright, had written about the
apparently well-known phenomenon to a friend.
“Cancer is not a microbe,” Chekhov began in an 1890 letter from Moscow
to his colleague Alexei Suvorin. “It is a tissue growing in the wrong place
and like a noxious weed smothering all the neighboring tissues… It was
observed long ago that with the development of erysipelas, the growth of
malignant tumors is temporarily checked.”16
Over two hundred years earlier, Friedrich Hoffmann, in his 1675 medical
treatise Opera Omnia—a modest work on the stated subject of literally

“everything”—noted that an outbreak of St. Anthony’s Fire had driven from
his patients the other diseases already in situ, much as fire clears a diseased
forest. French physicians Arsène-Hippolyte Vautier and S. L. Tanchou
claimed to have effected hundreds of successes against breast cancer by
means of infection induced by dressing their patient’s wounds in soiled
bandages worn previously by other infected patients. The sign that the
desired infection had taken hold was a “laudable pus” that flowed like human
sap from the wound.
Exceptional stories like these are found throughout medical history.17
And for hundreds of years they remained just that—stories, anecdotally
compelling and scientifically inexplicable. Nevertheless, they were enough to
provoke occasional speculation and experiment. The result was an often
ethically perilous version of mad scientist immunotherapy—human
experiments without systematic methods, accountability, or follow-up. Most
were performed on poor women—infecting breast cancer patients with
gangrene, or adding a hypodermic full of syphilis to the wombs of women
suffering from uterine cancer. (The latter was performed by a Belgian
physician in 1851 and justified by the dubious claim that prostitutes were not
known to suffer from uterine cancer.)18
In the 1890s these repeated medical observations of spontaneous
remission of cancer attracted renewed international scientific interest.19 In
fact, at the very moment that Coley was formulating a plan to intentionally
replicate Stein’s accidental erysipelas infections, a physician named Friedrich
Fehleisen had already begun.
Within a month of finding Stein, Coley had also found Fehleisen’s data in
a foreign medical journal. Fehleisen had identified the specific bacterium
strain that caused erysipelas, had injected this bacterium in five patients, and
was enthusiastic about the possibilities. Coley read this and was even more
convinced that it was just such a postoperative bacterial infection that had rid
Fred Stein of his terminal cancer. He apparently hadn’t gotten the subsequent
news that Fehleisen’s experiment had cost several of those patients their
lives, and Fehleisen his medical career.20) The only way to prove it was to
reproduce a similar effect in another willing and desperate patient. He found
exactly what he was looking for in an Italian immigrant we know only as
“Mr. Zola.”

By the time Mr. Zola stepped off his migrant ship to the New York docks, a
conspicuous morphine habit was the least of his problems; certainly it was his
only relief. Zola had presented to Coley’s hospital in March 1891 with a
recurrent sarcoma in his neck that a previous surgeon in his native Rome had
already operated on to remove.21 The cancer had soon grown back and
spread, and now another tumor “the size of a hen’s egg” in Zola’s throat
prevented him from speaking, eating, or even swallowing. He had a hacking
cough (likely the same cancer metastasized to his lung), and few options but
to present himself to the charity ward of New York Hospital, where he was
operated on by William Bull. Bull cut out a piece of the neck tumor, “about
the size of an orange,”22 but he couldn’t get it all without killing the man.
Bull concluded Zola to be a hopeless case; Coley estimated that Zola had at
best a few weeks left to live. Apparently, Zola believed it too. It’s difficult to
imagine any other circumstance under which he would have willingly
allowed himself to be infected by a deadly bacteria.
Erysipelas wasn’t a disease anyone would foster intentionally. It thrived in
the close quarters, poor ventilation, and inadequate bed linens of the poorer
sick wards. Though both William Bull and Zola consented to the experiment,
the risk was considered too great to conduct within their hospital. Zola would
be infected at home.23
Coley wasn’t a fastidious experimental data collector, but he was a welltrained physician, a gifted surgeon, and a keen observer. He was also
persistent and fairly lucky. Modern clinical trials of any drug have a
standardized protocol to ensure that they are reproducible and correlate
causes to effects. Coley basically winged it. His experiment was less a
clinical trial than the monkey-wrenching of an intuitive biological mechanic.
He wanted to cure Zola’s cancer, not write a paper. The papers would come
later.
And so, in the course of testing the bacterium on Zola, Coley switched
between two different bacterial strains prepared by two different sources,
which he administered in two different ways. At first, he made small cuts in
his patient and applied the bacterium, which he had grown on a gelatin,
directly into the incisions, but he soon found this method unsuitable and

abandoned it midexperiment. He then cultured other samples of the bacterium
in beef broth and injected anywhere from half a gram to two grams away
from the incisions, but neither of these did much more than to give Zola a
slight fever, a quickened pulse, and light chills—nothing like the symptoms
of the dreaded St. Anthony’s Fire Fred Stein had endured.
Finally, Coley determined that the problem might lie with the virulence of
his particular strain of bacteria, and he asked two colleagues from Columbia
University’s College of Physicians and Surgeons to mix up a stronger brew.
This he injected in large doses directly into Zola’s unhealed neck wound and
various other places on his skin. Within a few hours Zola’s body responded
with localized redness.24 Zola still couldn’t speak because of the tumor
blocking his throat, but he could wince and hold his aching head. The chills
and vomiting spoke for themselves, but at 101 degrees F, his fever was only
0.5 degrees higher than it had been using Coley’s first bacterial batch.
Still, Coley believed the treatment was working and continued plugging
away at his patient. After a month of steady injections, the tumors in Zola’s
neck and throat seemed “diminished”—sometimes “appreciably
diminished”—in size.25 That was good, but it wasn’t exactly the spontaneous
remission he’d read about with Stein. Undeterred, Coley determined to push
harder, and with stronger toxins.
That summer of 1891, Coley decided to forgo even a brief vacation to
remain in the city, injecting bacterial toxins into his patient. Meanwhile his
hospital colleague Farquhar Ferguson would be spending his holiday on a
miniature grand tour, sampling the culture of the European continent. Coley
asked Ferguson to bring back a souvenir; he wanted a bit of deadly infection,
fresh from Berlin.
As Debra Jan Bibel points out in her comprehensive 1988 book,
Milestones in Immunology: A Historical Exploration, our view of the world
is often shaped by the lenses through which we examine it. In the late
nineteenth century that biological view was defined by the literal lens of new
and powerful microscopes, and the startling bacterial world that technology
had suddenly rendered visible.
Suddenly, the factors responsible for illness, infection, and beer were
realized to be living creatures. Different types of bacteria, it was believed,
made different types of poison, or toxin; the body’s curative response was

with some sort of antitoxin (or, as it would be called later, an antibody) to
cancel it out.26*
In this bacterial age, Robert Koch was practically a household name.
Koch was a prodigious collector of deadly toxins, most famous for isolating
the deadly bacteria that caused anthrax in his Berlin laboratory. If anyone
could provide Coley with a whoppingly deadly dose of erysipelas, it would
be him.
Ferguson arrived back in New York at the beginning of October, his
unusual travel souvenir from Koch’s laboratory in carefully wrapped glass
vials. Koch hadn’t disappointed; his erysipelas sample had been collected
directly from a corpse only days before Ferguson’s visit. This was the good
stuff, potent and fresh. Coley wasted no time. On October 8, he traveled back
to Zola’s Lower East Side rooms, loaded up his syringe with five decigrams
of the new German bacterial toxin, and injected the toxin directly into the
tumor in Zola’s neck.
This was definitely the good stuff. Zola’s internal temperature started to
climb; within the hour it would hit 105 degrees F. Meanwhile the infection
boiling beneath Zola’s skin at the injection site darkened and spread across
his upper extremities like fire consuming paper.
Zola was pushing the boundaries of physical endurance, but by the second
day of fever, the sweating, trembling patient finally produced the results
Coley had been hoping for. Zola’s tumor seemed to be physically “breaking
down.” Soon it was melting down his neck like some horrible ice cream cone.
“A discharge of broken-down tumor tissues continued until the end of the
attack,” Coley wrote. At the end of two weeks, Coley reported, “the tumor of
the neck had disappeared.”
The tumor on Zola’s tonsil was still there, but it had shrunk enough that
Zola could eat again, and the patient “gained rapidly in flesh and strength.”
Soon Zola felt well enough to leave bed and get back to his business, which,
Coley noted in his final sentence on the man, included “a confirmed
morphine habit which he had contracted previous to the inoculations.”
Coley examined Zola two years later, and again after five years, and found
the man still in good health. (Soon after, he returned to his native Italy, where
he died, eight and a half years after his injection regimen, causes unknown.)
What Coley witnessed with Zola was not a typical reaction; in fact, the

success with that particular bacterial “toxin” has never been fully
explained.27 But something had happened, and that something wasn’t magic.
The gap between the observations of so-called spontaneous cancer
remission following infection and the scientific understanding of the
complex, microscopic, and yet-unguessed-at immune biology responsible for
it would be the bane of cancer immunotherapy researchers for a hundred
years. Here was a field where, time and again, experiment and observation
outpaced even the faintest understanding of the unimaginable complexities of
either the immune system or cancer. As a result, cancer immunotherapy
retained a certain naturalist’s air about it, a field of both science and stories—
observations of therapies that worked for some people and not others, results
that were confoundingly difficult to reproduce, immune responses that cured
cancer in a mouse or in a petri dish but did nothing for humans, all of it
scientifically mysterious. As Stephen S. Hall put it in his 1997 immunology
masterwork, A Commotion in the Blood, “The tyranny of the anecdote, the
boon and bane of immunotherapeutic interventions, had formally begun.”28

Zola had been a one-off, too unstandardized and uncertain to qualify as a
properly performed scientific study, or as proof of anything. Now Coley
attempted to reproduce his success, patient after patient, method after
method. By now, his work with deadly bacteria had moved him uptown to
106th Street and Central Park West and the ventilated gothic towers of the
New York Cancer Hospital29 (which would later be renamed General
Memorial Hospital; today we know the entity as Memorial Sloan Kettering
Cancer Center, or MSKCC). Coley tried direct injection; he tried rubbing the
bacteria in; he tried scarification techniques, combinations, and repetitions.
Over the course of three intense years, Coley gave repeat inoculations to
twelve patients presenting with a variety of cancers. He had more failures
than successes.30 He triggered the desired fever reaction31 in four of his
patients, and that plus a positive tumor response in another four (including
Zola). All of the patients who showed a response had sarcomas. Four of his
patients died, two as a result of the bacterial infection Coley had initiated.
Coley couldn’t predict who would react to the bacterial toxins or what dose to

give, or by extension, whom he might help and whom he might accidentally
kill. It was an intolerable situation, not to mention a dangerous and unethical
one. It endangered his own medical practice as much as it endangered his
patients.32
Infecting his patients with the live bacterium was too risky, but it wasn’t
the whole living microscopic animal he was after anyway, just the “toxic
products” that he believed destroyed tumors. Now Coley started working on a
plan for “isolating and using the active principle of the germ.”33
The idea was based on the serum-centric view of contemporary biologists,
and the fact that inoculating a patient with a dead or an inactive form of a
bacteria was the fundament of vaccination.
That summer, an especially deadly strain of the bacteria was grown in the
laboratory. The live bacteria were overheated and killed,34 then the broth was
strained through a porcelain filter to remove the dead bodies of the bacteria
themselves. The ruby-colored juice that flowed through the other end of the
filter was assumed to be just the “toxins” from the bacteria. This had to be the
stuff. Coley injected this new brew into a fresh group of terminal sarcoma
patients. The serum had some of the desired effect—light fever, rash, and
chills—but not enough.
Now Coley was in a bind. He needed to find the sweet spot between too
little toxin and too much. Once again, Coley got lucky. Just as he was asking
the question, a French medical journal happened to include a new study that
supplied the exact answer.35
The study showed that the erysipelas bacteria Coley was using became far
more virulent, and produced a far more powerful toxin, when cultured in the
same incubator together with another bacterium strain, called Bacillus
prodigiosus.36 With this recipe Coley hoped he’d finally found a compromise
between a deadly and an ineffective toxin. In fact, he’d stumbled onto the
perfect combination of bacterium, which produced a synergistic toxic effect.
As its name suggested, B. prodigiosus proved to be a very prodigious little
bacillus indeed, and produced a toxin with a unique effect on the human
immune system (ones that are being looked at today as cancer therapies,
some in clinical trials).37 Now he needed to find a subject on whom to test
his potent new bacterium-combo toxin.
Coley would finally get his chance in 1893, with a sixteen-year-old boy

whose belly seemed pregnant with an eggplant-sized sarcoma. John Ficken,
like most of Coley’s subjects, was a patient with nothing left to lose. The
massive tumor had invaded the wall of his abdomen, as well as his pelvis and
bladder; biopsy suggested that it was malignant.
Coley started Ficken off gently, with a low dose of his new toxins. When
Ficken didn’t respond he titrated up, first half a cc, then more, every couple
of days. Finally, the boy had the classic reaction Coley had witnessed with
his previous toxins—St. Anthony’s Fire.
The treatments started on January 24 and lasted ten weeks. By the time
Coley stopped the injections on May 13, the tumor mass had shrunk by 80
percent. A month later it was no longer visible to the naked eye, but it could
still be palpated. Coley sent the boy home a few weeks later. Ficken was
feeling well, looked normal, and, despite the loss of the tumor, had gained
weight.
Eventually, of course, Ficken died—suffering a heart attack on a subway
car outside Grand Central Station. At the time he was forty-seven years old.
Coley’s bacterial concoction—later patented as Coley’s Toxins—had cured
his cancer, at least for the additional thirty-one years of his lifetime.

Coley published in the usual medical journals, but excited as he was, or
perhaps impatient, in 1895 he wrote up his own volume on his sarcoma
treatment and brought it to the offices of the Trow Directory, Printing and
Bookbinding Company on East Twelfth Street. The volume was part
academic medical journal, part testimonial, and was the same dimension as a
religious pamphlet or museum guide. (The size is still a sort of unofficial
standard for some resident quick guides that fit perfectly into a pocket of a
medical resident’s white coat.)
“I am conscious that the treatment of inoperable tumors is a very trite
subject,” Coley began his treatise, “yet in consideration of the fact that
practically no advance has been made in this field since the disease was first
known, I am sure I need offer no apology if I can show that there has been
even a single step forward.”38
In fact, Coley was certain he’d made not a step but a leap.

“My results in thirty-five cases of inoperable tumors treated with the
toxins during the past three years, were reported in detail at the last meeting
of the American Surgical Association at Washington, May 31st, 1894,” Coley
wrote, “and will be only briefly referred to here.” At which point Coley
shared his proprietary recipe for the toxic home brew.
The recipe called for a pound of meat, lean and chopped and left
overnight in 1000 cc’s (about a quart) of water. In the morning, remove the
meat; the remains were the raw beginnings of a boullion broth. This meatwater should then be cloth filtered, boiled, and filtered again. Season with salt
and peptone (a partially digested protein, enzymatically broken down into
shorter amino acids so that it can be digested by simple bacteria; essentially
microbe chow). Another pass through the straining cloth and another boil will
result in a clear consommé. Finally add the deadly bacterium, and you’re
ready to serve mankind.

At least fifteen versions of Coley’s toxins were in use during Coley’s
lifetime. (Parke Davis manufactured the most widely used commercial
version; the Mayo Clinic made another for their patients, and continued well
after others had quit the field.) Coley had indeed invented a sometimes
effective cancer cure by intentional immunotherapy, not that he realized it as
such at the time.39 What Coley achieved could have been a breakthrough, if
the results had led to systematic further investigation of the phenomenon, and
a push into the basic science behind it. Instead, the opposite happened;
Coley’s results were a century ahead of any science that might make sense of
them, and they were largely construed as quackery.
Coley had theories about the agents at work. But he had no real
understanding of the immune system, or the nature of cancer, nor any inkling
of the genes, mutations, antigens, or any of the biology necessary to bridge
the gap between what he’d observed and something approaching bench
science. The mechanisms by which immune cells recognize disease had not
been discovered; not even the immune cells themselves had been discovered.
Nonetheless, over the course of the following forty years Coley continued to
treat hundreds of patients with his toxins.

More recent scientific assessments of the effectiveness of those treatments
vary—one by Coley’s daughter reviewed more than one thousand of Coley’s
patient records and reported finding some five hundred cases of remission; a
controlled study in the 1960s reported Zola-like results in twenty of ninetythree patients.40 The numbers vary wildly and much of the methodology is
questionable, but when reading all the academic analyses and reviewing the
more recent experimentation, the takeaway is always the same. Coley was no
quack.
Careful regulation of a patient’s fever—a laborious and personal process
—seemed key to his successes. That factor, and the enormous variability in
the exact formulations and strengths of the toxins available to other
physicians, made Coley’s results difficult to duplicate. But that doesn’t
change the general consensus that in Coley’s hands, his toxins did sometimes
work, and they sometimes worked well.41 And the reason they worked is
now believed to be that they somehow triggered an immune response, or
unleashed a previously blocked one.
But as a medicine, Coley’s Toxins would not last.42 Parke Davis stopped
production in 1952. By 1963, the Food and Drug Administration would no
longer acknowledge Coley’s Toxins as a proven cancer therapy.43 The fatal
blow to Coley’s vision of immunotherapy occurred two years later, when the
American Cancer Society put the fluids on its list of “Unproven Methods of
Cancer Management.” They might have well have called it “the quack list.”
Ten years later the ACS would reverse itself and remove Coley’s Toxins
from this list of shame, but the damage was done.44 The retraction garnered
less notice than the original infamy. His name, if it was known at all, was
associated with the absurd miracle medical claims of the gaslight era of
radiation gargles and patent medicines; whatever glimpse at the possible
interaction between the immune system and cancer he had provided now
seemed like a delusion or fraud.
Ideas can be powerful viral things that spread like a forest fire. They can
also be snuffed out like candles. It takes only a generation for an idea to be
forgotten. And a generation of researchers, scientists, and doctors went
through training hearing nothing about Coley or a successful if still
mysterious illustration of the potential of the immune system to be induced to
interact with and protect against cancer. For thirty years Coley and his

methods were virtually unknown to oncologists, and, as Hall writes, those
who did “lumped them together with such controversial therapies as
Krebiozen, laetrile, mistletoe and orgone boxes.”45 Good oncologists looked
to the more modern and promising scientific therapies like radiation and
chemotherapy. And when those physicians trained the next generation, they
taught them to do the same. If you were smart and science-minded and came
of age in the ’80s or ’90s, you weren’t trained to put stock in Coley.
Coley’s legacy might have died with him had it not been for the efforts of
his daughter, Helen. Helen Coley Nauts had traveled with her father on many
of his speaking engagements, had seen him rise to become a wealthy and
famous man, and had seen his fall. Nauts understood her father’s work even
as he had not, and in doing so she helped carry his ideas into the present
generation.
Near the end, Helen had watched her father at conferences fending off
attacks against both his data and his person. The most vigorous of those
attacks came from Memorial Sloan Kettering, the cancer center Coley had
helped establish, and where his approach to cancer had first been supplanted
by radiation therapy, which was viewed as more modern, with more
quantifiably scientific results. It also didn’t hurt that, although the radium
required to make radiation therapy was considered one of the scarcest
resources on earth, the chief benefactor of the hospital at the time was a mine
owner supplying Memorial and its charismatic and powerful president, Dr.
James Ewing, with as much as it needed. Memorial’s hoard of eight grams
was reported to include the original supplies of Marie Curie, and represented
most of the known radium supply on the planet.
Together, Ewing and Coley had turned Memorial into the world’s first
cancer research center.46 Now Ewing was Coley’s boss, and his leading
critic. He publicly denounced Coley’s Toxins as a fraud and a sales scheme.
Soon, every patient who came to Memorial with a bone complaint would get
a full dose of Ewing’s exclusive radiation therapy. The results, of course,
were disastrous. The mortality rate was 100 percent.
Coley requested a five-year trial of his toxin vaccine, as it was then
considered, in order to evaluate its effectiveness against bone cancers such as
sarcoma. Coley claimed to have no statistical data to prove that his treatment
was effective, but then, neither did the advocates of radiation therapy and

amputation. What Coley did have were survivors. The advocates of radiation
therapy had none.
Coley never did get his five-year trial; he died within a year of asking for
it. But his daughter never forgot it. In 1938 she went to the family country
estate in Sharon, Connecticut, and discovered all her father’s papers—some
fifteen thousand of them—bundled and stored in a barn at the edge of the
property. It wasn’t that Coley didn’t have data; he just didn’t have it
organized.
Working tirelessly (and funded in part by a small grant from Nelson
Rockefeller, the son and heir of her father’s patron and Bessie Dashiell’s soul
mate, John D. Rockefeller Jr.) Nauts organized her father’s heap of
observations, correspondence, and notes into something more organized and
academic. With a high school education but a lifetime of tutelage under a
master physician and thousands of hours of careful study, Nauts set out to
convince anyone who might listen that her father’s approach to “the use of
bacterial products in malignant disease” was, at the very least, worth a more
serious investigation.

William Coley had believed that the “toxins” from his bacteria acted as a sort
of poison against cancer—a natural chemotherapy. By the 1940s, following
the death of Ewing, Memorial had transitioned from being a “radium
hospital” to one that used chemical poisons—chemotherapy—as cancerkilling therapy. Nauts hoped to pursue her father’s work with the new
director of the hospital, the eminent physician Dr. Cornelius Rhoads. During
World War II he had served as the chief of research for the Chemical
Wartime Service of the US military forces, the same group that had
d