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.
Jason and immunotherapy were headed for a date.