by Matt Richtel
On November 16, 2011, Jason walked into a small square outpatient meeting room, eight feet on each side, with a round table in the middle. He was greeted by Andrea Maikovich-Fong, a psychologist specializing in counseling people with cancer. When Jason walked in, he didn’t look or act like a guy who was sick. He wore sunglasses, and not long after meeting Maikovich-Fong, he started playing air guitar and singing a rock song.
“He was very much alive,” she recalled of the moment. “I don’t think I’d have known he had cancer.”
He was ready to take on the beast.
To prep him for transplant, Jason was given drugs that spurred growth of his stem cells and caused them to leave the bone marrow and flow into the bloodstream. That way, they could be harvested. Then it was time for BEAM.
Jason began the high-dose chemotherapy to eliminate the last of the cancer and immune function on November 21, 2011. Eight days later, after a “day of rest,” he was infused with new stem cells.
At this moment, his body’s immune system was laid waste, as were virtually all of his rapidly dividing cells: His gut had gaping holes, his skin could not heal, his thick hair was falling out in clumps, and his smile was nonexistent. He’d lost the optimism.
“He wore a zip-up hoodie. He was sitting there, completely hunched over,” said Maikovich-Fong. “The room was all dark, and he looked like this shadow sitting there. He looked up with his eyes and not with his chin, and he said, ‘This is terrible.’
“He was a completely different person than when I first met him. It was a pretty striking image if you wandered into that room.”
He got out of the hospital a month later. By January 2012, Jason had learned that the BEAM and transplant appeared to have worked. Jason now was in possession of the immune system of a veritable newborn. Dr. Brunvand describes the patient with new stem cells as “like when your kids were in elementary school and brought home every virus.” Jason’s immune system needed time to relearn. He received antiviral medications so, as Dr. Brunvand put it, “a cold sore wouldn’t turn into pneumonia,” and they beefed up his microbiome with a yogurt diet—“we try to protect them and regrow the good bacteria in their gut.”
Typically, the plan was to let the patient heal and then reimmunize him, as a pediatrician might a child. But Jason wasn’t typical because of the fact that he’d initially relapsed so quickly, and in the same area where the cancer initially presented. “Jason had the highest relapse risk that you could imagine,” Dr. Brunvand said.
So Dr. Brunvand talked to Jason about trying to cement the victory by enrolling him in a clinical trial for brentuximab vedotin. The drug is noteworthy for how it takes advantage of several of the crucial discoveries made by the immune system pioneers.
Brentuximab is a monoclonal antibody therapy, its existence drawing from the powerful discovery in the 1970s of isolating and copying individual proteins. In this case, researchers had discovered that B cells with the Hodgkin’s malignancy express an antigen called CD30. Brentuximab was armed with an antibody to seek and destroy that antigen. Targeted therapy is another way to think about it.
One interesting bit of medical industry trivia arises here as well. When you see a drug with mab on the end, you now know it stands for monoclonal antibody.
However, just because a drug is targeted and is more precise than chemotherapy doesn’t mean it is without its own side effects. Brentuximab’s possible side effects include extreme fatigue, diarrhea, blood in the urine, mouth sores—the list goes on.
Jason, consulting with Beth, decided to go for it. This, he was told, would eradicate whatever Hodgkin’s tried to rear its head again.
One reason for Jason’s decision is that he had tremendous faith in Dr. Brunvand. Plus, Jason felt a real connection to his oncologist, someone who, like Jason, had a great sense of humor and a thirst for adventure and risk. Unafraid of a fight.
43
Shepherd of Death
June 8, 1990, was a sunny day with a lenticular cloud over the Alaskan peak of Denali, then officially known as Mount McKinley. Dr. Brunvand stood at a camp at 14,300 feet above sea level, getting ready to summit the tallest mountain in North America.
The top of Denali is 20,320 feet above sea level, with mercurial weather and unique challenges. A few months prior to this 1990 climb, temperatures had hit a record low of −57 degrees, bolstering Denali’s reputation as the coldest mountain on earth. The ascent from base camp, at 18,000 feet, is actually greater than Everest’s 12,000-foot vertical gain.
Just ahead of Dr. Brunvand’s group of eight climbers was a Japanese team of seven climbers. They were on the mountain’s West Rib, and they were in trouble. One of the Japanese climbers was suffering pulmonary and cerebral edema. Death lurked. On June 10, a message from the Park Service reached Dr. Brunvand’s group asking them to help the Japanese climbers, now stuck at 19,600 feet.
Dr. Brunvand and three others ascended in whiteout conditions to intercept three disoriented Japanese climbers, reaching them just below Denali Pass at 18,000 feet. The four mountaineers forged onward and encountered two more Japanese climbers at around 19,000 feet, a thousand vertical feet from the summit. One was a physician. The other Japanese climber was the one who had been sick with cerebral edema. He was now dead. Dr. Brunvand and two of his fellow climbers placed the body in a tarp fashioned into a toboggan and dragged it to Denali Pass, where the body was stored until a larger group could move it farther down.
In the end, Dr. Brunvand found himself attempting a rescue of someone at tremendous health risk, getting to the person too late, and winding up as death’s shepherd. This sounds a lot like the job description of an oncologist.
Dr. Brunvand had grown up in Denver, his father a wide-eyed entrepreneur who had a bit of Jason in him. His father, for instance, owned a car wash in 1968; half the crew that worked there were Vietnam vets and the other half were veterans of the “summer of love.” Little Mark Brunvand worked there too, sometimes running the car wash himself. This was not his calling, however. That would be medicine.
In 1985, he finished his medical residency and began a fellowship in immunology under Dr. Anthony Fauci at the NIH, eventually spending three years in Dr. Fauci’s laboratory of immune regulation (small world!). Then it was off to Seattle, where Dr. Brunvand started working with cancer patients. He faced a crossroads of whether to pursue research or continue to treat patients in a clinic. This can be a tough choice for many doctors initially drawn to research, which can be seen as a particularly noble job and thus can be ego-gratifying. The top thinkers in medicine, people sometimes say, do research and treat patients. But that’s just what people say, and it’s simply false; doctors, like lawyers or writers or businesspeople, have particular tasks they are drawn to and that they do well.
When Dr. Brunvand thought about why he preferred to deal with patients, despite the intense suffering it entailed, he came down to a simple answer. “I could connect to them.”
He felt that he understood what it was like to deal with difficult circumstances and loss. Dr. Brunvand had found himself—his voice in this world. It was true to him, the person who liked to connect and to feel connected, and it was an authentically heroic one. He loved the challenge of fighting on behalf of patients, but more than that, he loved “coaching” patients to deal with heinous malignancies on their own terms. On his wall at home hangs a picture and a letter written by a little girl (I’ve copied it here, spelling warts and all).
Dear Santa,
I have been a verry good girl this year. I have a lot of things I want this year
Hear are some: 1. Poo-chi. 2. Wove love. 3. Super Soft Kelly doll. 4. Super Poo-chi. 5. CD-Bah Hah men. 6. Tekno.
Love, Katie
Katie wrote a second note too, also on Dr. Brunvand’s wall. It reads:
Dear Santa,
Never mind all I want for Christmas is for mommy to get better and thats all.
Love, Katie
Katie’s mommy did not get well.
“She died,” Dr. Brunvand said.
Dr. Brunvand is both a highly cerebral oncologist and someone who owns the fact he has insecurities. He developed coping mechanisms, including humor and another trait essential to his authentic self, namely tenacity. On his high school ski team, he made himself run until he vomited or passed out, proof to himself he had trained hard. He took the cancer fight personally. “Once the decision was made to fight,” he wrote, he would “try every ethical, medically sound method to win.
“If I was found to have ‘cheated’ against cancer, I was not going to jail but to Stockholm.”
But it was the nature of the beast for an oncologist: Dr. Brunvand often came up short. He sometimes wondered if that was just his job, to fight and fight and fight, to play the martyr. The more desperate the cause, the more he dug in.
He was determined to save Jason, feeling like Jason was part brother, part son, a true fellow traveler.
44
Trials, Personal and Clinical
In May 2012, Jason added a new drug to his regimen, an antidepressant called citalopram, or Celexa. Said Dr. Brunvand: “If you have multiply recurrent Hodgkin’s lymphoma and you are not depressed, you are not paying attention.”
Jason had, for the moment, shaken the malignant B cells. But the process of fighting, even for a born fighter, ultimately takes its toll. Each month, it seemed, there was a growth in the list of drugs that he had to take to counteract or compensate for some other treatment. He told me he considered this regimen to be a kind of tether on his freedom. But the truth is, he probably was feeling anxious and depressed for all the reasons we know about: He sought balance even as he struggled with sleep, self-doubt, and fear, and he desperately wanted to be his old confident, athletic early-adolescent self, before the constant threat of death changed his sense of the possible.
That year, 2012, saw the science of immunotherapy continue to grow by baby steps and, at times, leaps. These developments crowned a century of learning about the immune system and were the seeds of Jason’s miracle. But the progress that had been made was largely unknown to most or little regarded by all but a handful of scientists and oncologists, and probably some in the investment community.
For instance, a study began on September 26, 2012, to determine the effectiveness of Yervoy, or ipilimumab, in combination with a new immunotherapy drug called nivolumab on patients with advanced liver cancer. It looked at safety and effectiveness, comparing the impact of the drug on these cancer patients who had hepatitis B and hepatitis C.
A phase II clinical trial had begun in April at MD Anderson in Texas to explore the effectiveness and safety of the combination of these drugs in fighting uveal melanoma, an eye cancer.
In May, Bristol-Myers Squibb launched a phase I clinical trial aimed at studying the impact of nivolumab on patients with blood cancers, non-Hodgkin’s lymphoma and Hodgkin’s lymphoma. In phase I, the primary question was whether the drug is safe. The trial was not scheduled for completion until 2020. By Jason’s standards, that was a long way off.
Meanwhile, these were just a handful of a growing number of trials for a growing number of immunotherapy drugs.
Some stories blow the mind, like one written later that year by my colleague Denise Grady, an extremely insightful and deft writer with whom Andrew Pollack and I would eventually team up to write about immunotherapy for the Times. Denise’s story was about a girl named Emma Whitehead, who had been six years old in May 2012 and suffered from late-stage leukemia, and after two failed chemotherapies was, as Denise wrote, “out of options.” She was going to die.
Understandably, faced with death, Emma and her parents embraced a highly experimental treatment, one that stood on the shoulders of not just cancer research but of HIV research too. Millions of the girl’s T cells were removed from her body. Then a new gene was inserted into the T cells. The inserted gene came from disabled HIV. Why? Because HIV is very good at attacking B cells; that’s what makes it so dangerous.
But in the case of Emma, her B cells had grown malignant. That critical piece of her immune system, now a deadly force eating up her body from the inside, needed to be killed off by a portion of the immune system that remained healthy.
The new, altered T cells were injected back into the girl. They went to work. Specifically, Denise wrote, the T cells used HIV’s once-deadly targeting mechanism to seek out a protein called CD19 on the surface of B cells. Think of these T cells as guided missiles programmed to find and destroy a very specific site on B cells. The catch is that the T cells weren’t differentiating healthy from malignant B cells. It killed all of them.
With her B cells under massive attack, her defense system went, to use a nonclinical term, berserk.
What was happening, Denise wrote, was a cytokine storm. Denise’s evocative story explained that the girl’s temperature spiked to 105 and “she wound up on a ventilator, unconscious and swollen almost beyond recognition, surrounded by friends and family who had come to say goodbye.”
Steroids, which as you now know are used to tamp down an immune response, failed. The doctor overseeing the pioneering effort, himself an immunotherapy legend who shares the same status as innovators like Jim Allison, had one last idea. The girl was given a drug normally used to treat rheumatoid arthritis.
“Within hours,” Denise wrote, “Emma began to stabilize. She woke up a week later, on May 2, the day she turned seven; the intensive-care staff sang ‘Happy Birthday.’”
The novel treatment worked. The little girl survived the side effects and joined the growing lore of immunotherapy.
But here’s the thing: If you pull back the lens, this wasn’t just a tale about cancer. The main character in the story was the immune system, its power to save and to destroy. Though on its surface this narrative seems to be about cancer, it actually weaves together the relationships among cancer, autoimmunity, and the most basic immune system functions, like fever and inflammation, gone awry.
In July 2012, Jason was in the middle of his brentuximab trial. He felt like he’d gone to hell. “Worse than you can imagine,” he would tell me. “Nothing you ever want to go through.”
Every twenty-one days, he’d return to Denver for another treatment, recover as quickly as he could force himself, and then get back to Vegas or the road, and his dreams. His casino-trinket business was doing reasonably well. The trinkets, small crystal animals like a pig or ornaments, would come stuffed with a card that could be redeemed at a particular casino for cash. The casino gave the promotions away to draw in new customers. Jason loved coming up with new trinket options, a train car for a casino in Colorado, and driving to casinos to convince management to sign up. He never could nail a Vegas casino, despite living there, and worked instead with smaller casinos in places like Mississippi and Colorado.
In 2012, he got a new business idea that came from an observation made by Beth. She was getting tons of Amazon packages on her doorstep and wondered if there were a way to keep them locked up or protected when she wasn’t home to accept them. Jason became enthralled. This was it! The next great idea, a functional and aesthetic lockbox on the porch to cater to the new economy!
Chemotherapy be damned. He went looking for prototypes everywhere—Home Depot, local hardware stores. He put a prototype, a box with a lock on it, on his mom’s doorstep in Denver. He went into remission. He was hobbled, but back.
On October 3, officials from the Food and Drug Administration met with officials from Bristol-Myers Squibb. That was the pharmaceutical giant that had, through one business maneuver and another, wound up acquiring the company and intellectual property that Nils Lonberg had pioneered. The subject of the meeting was how to put the new immunotherapy cancer drug nivolumab onto the fast track.
Fast-track designation is increasingly utilized as a way of pushing drugs to market when there are few, if any, alternatives for patients with fatal conditions. In this case, nivolumab was in late-stage trials to deal with melanoma, skin cancer, one
of the deadliest of the malignancies when it is not caught early and surgically removed. At the time, the survival rate for the small portion caught after the cancer had spread—become metastatic—was 16 percent.
The immune system was the crux of the problem. It was paralyzed by the cancer. This could involve two key braking systems that I’ve described: CTLA-4 and PD-1. The former, when activated, would dampen an immune system response. The latter, programmed death, would actually cause an immune cell to implode, in effect dampening the response.
Early clinical research was showing that nivolumab was helping turn off the brakes by turning off the programmed death response. It had been only seventy years since Jacques Miller discovered that the thymus, far from being vestigial, was the epicenter of T cell development, and now scientists were tinkering with the T cell on a molecular level. With significant success. A trial that began on December 21, 2012, and ran through most of 2013 involved 631 melanoma patients in fourteen countries, and found a response rate of 32 percent.
The FDA’s decision was not clear-cut, though. It had to consider a core question of side effects that happen when the immune system’s brakes are dulled—rash; cough; lung infection; colon, liver, and kidney damage; and cerebral edema, which is brain swelling. “The toxicity profile of nivolumab includes serious risks of autoimmune-mediated organ toxicity, which can be fatal and requires treatment with high-dose corticosteroids,” the FDA wrote in a paper summing up some of the issues.
As we’ve seen, taking off the brake can send the immune system roaring ahead, which can be dampened by steroids and in turn can so dampen the immune system that it becomes susceptible to infection.
Once more: Tinker with the immune system at your own risk.
But it sure beats dying. Besides, this was still very early on. There was much work to be done.
None of this was anywhere on Jason’s radar, or for that matter, on that of most people. Immunotherapy was being followed mostly by investors. They could see the potential for a series of drugs that for now were focused on a few cancers but eventually might be much more far-reaching, including that 10 percent of Hodgkin’s patients like Jason who had fallen through the cracks of traditional chemotherapy and radiation.