Kent Haffer remembers when his oncologist approached him with an unusual idea. It was 2013, and Haffer, a 55-year-old computer programmer living in St. Peters, Missouri, had been receiving treatment for advanced melanoma for eight years. His oncologist proposed that Haffer be part of a clinical trial, but not one involving hundreds of people. Instead, this study would have only one person in it: Haffer.
A one-person study is often called an N-of-1 trial (the N stands for “number”). Cancer researchers are increasingly looking at this investigational strategy to capitalize on the molecular information provided by genomic sequencing, in which cancer cell mutations are identified by analyzing a patient’s tumor. The idea is that the patient receives an experimental therapy targeted to those mutations and is monitored for disease progression and side effects while researchers collect data.
In Haffer’s case, that experimental therapy involved three doses of a cancer vaccine that he would receive every six weeks. His oncologist’s goal was twofold: One, he wanted the vaccine to help bolster Haffer’s immune system to prevent a recurrence of melanoma, which had been treated successfully in a traditional clinical trial. And two, he wanted to study Haffer’s response to the vaccine to see if it would be a valid approach in other patients.
A Rough Path To N-of-1
Haffer had already had a bumpy journey. He found a suspicious spot on his left calf and was later diagnosed with stage III melanoma in 2005. After the initial biopsy and surgery to excise the first tumor and lymph nodes in his left leg, he self-administered interferon injections to his abdomen three times a week for six months. Despite these efforts, the melanoma reappeared and spread. Additional cancerous spots showed up on his leg, and CT scans showed new tumors growing in his pelvis. Over the next several years, he had nine more surgeries to remove tumors, “sometimes seven or eight of them at a time,” he recalls. He also underwent isolated limb perfusion—in which high doses of chemotherapy are administered only to one limb and removed from the bloodstream before they can reach and damage internal organs. Still, scans showed that the disease had progressed to stage IV, spreading further into his pelvis. By 2008, his oncologist declared his disease unresectable.
In that same year, Haffer’s oncologist, Gerald Linette at the Washington University School of Medicine in St. Louis, enrolled him in a traditional phase III clinical trial of Yervoy (ipilimumab), a then-experimental treatment that helps the body’s immune system attack cancer cells. Haffer took 26 doses of the drug, stopping when his immune system became overstimulated and caused mild inflammation in his lungs. But he experienced a complete response: All detectable signs of tumors disappeared, and his scans remain clean nearly eight years later.
Linette says few patients respond so completely to immunotherapy, and he wanted to know what was different about Haffer. So in 2013, Linette approached him with another experimental treatment. Linette and his colleagues had developed a method of making a personalized cancer vaccine—Haffer calls it a “custom cocktail”—based on mutations in a patient’s own tumor cells and designed to give the T cells a boost. T cells are white blood cells, part of the body’s immune system, that help protect the body from infections and can be used to fight cancer. Unlike preventive vaccines for diseases like measles or shingles, which can protect healthy people from infection, therapeutic cancer vaccines aim to fortify the immune systems of people who already have cancer. Linette wanted to use the vaccine to probe and even strengthen the molecular mechanism that made Haffer’s immune system respond so well.
Many patients develop resistance to immunotherapy, and Linette wanted to counter that. “Based on our understanding of the human immune system, we thought that [Haffer’s] immunity against the tumor would also diminish over time,” says Linette, who believed the vaccine might help keep recurrence at bay and assist researchers to better understand how the immune system works against cancer.
Haffer didn’t hesitate. He told Linette, “Let’s do it.”
Pros and Cons Of N-of-1 Studies
Large phase III clinical trials provide evidence that the U.S. Food and Drug Administration (FDA) relies on in deciding whether to approve a drug for a specific patient population. But most trials report average responses, meaning, in theory, that no one in the trial may have experienced the reported outcome. Some patients taking the drug may survive longer; others may die sooner. It’s impossible for a large-scale clinical trial to predict how each individual cancer patient will respond to a given drug. Furthermore, researchers may stop studying a drug if not enough patients respond to it during a clinical trial—even though some might have benefited.
But in papers, panels and presentations, experts argue that individualized studies involving only one or a small number of patients may be a more insightful way to determine treatment—especially in some cancers, like those that are rare or treatment-resistant. A group of physicians and epidemiologists in Canada described the N-of-1 approach in a 1986 paper in the New England Journal of Medicine, outlining a design for studies on individuals. But Laurence Collette, a biostatistician with the European Organization for Research and Treatment of Cancer in Brussels, Belgium, says researchers still have a long road ahead of them to make N-of-1 studies robust and clinically applicable to a wide patient population. “It’s very experimental and not regarded as a statistically valid approach,” she cautions. She and other experts note that in order to be useful to a larger community, data from N-of-1 studies must be collected in a standardized fashion, anonymized and stored with other data.
In April 2015, biologist Nicholas Schork from the J. Craig Venter Institute in La Jolla, California, wrote in Nature that in many cases, N-of-1 studies are exactly the right tool for developing personalized therapy, in which a person’s treatment matches his disease. Schork noted that if N-of-1 studies are done properly—sticking close to guidelines like the ones proposed in 1986—their findings about a patient’s response to intervention could be as statistically valid as those from large, classical clinical trials.
Cancer researchers are increasingly calling attention to the need to formalize the N-of-1 trial. Done correctly, the approach has the potential to help a wider population than just the person at the center of the trial. Analyzing and sharing individuals’ data—about genetic mutations, diagnosis, treatment, response and survival—can help researchers better understand tumor biology and prescribe treatment based on the particular mutations that drive a person’s disease.
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