Allison’s mentors discouraged him from pursuing research on T-cells. “Tumor immunology had such a bad reputation,” he told me when we met in December at his laboratory at Sloan-Kettering, which overlooks the East River. Allison, who is sixty-three years old, is a thickset man with a stubbly beard and a gravel voice. “Many people thought that the immune system didn’t play any role in cancer.” Treatments like interferon and interleukin-2 had led scientists on a roller coaster of hype followed by disappointment. Immune therapy was also tainted by popular claims that following a certain diet or reordering your mind could be natural immune-boosting ways to cause tumors to disappear, with none of the miserable side effects of chemotherapy and radiation.

But Allison started looking at how the immune system fights disease, using mice as study models, and capitalized on a critical discovery: T-cells require two signals to attack a target effectively. The first signal, he said, was “like the ignition switch,” and the second “like the gas pedal.” When working against a microbe, both signals were operative. But, in the presence of cancer, “T-cells don’t get those signals to attack,” he explained. Allison started to wonder what it would take to reliably activate the immune system against cancer.

In 1987, researchers in France discovered a protein called cytotoxic T-lymphocyte antigen-4, or CTLA-4, which protruded from the T-cell’s surface. “There was a real race among a number of labs to figure out its function,” Allison recalled. A scientist at Bristol-Myers Squibb, using results from his lab, contended that CTLA-4 increased the activity of T-cells and the immune system. But Allison and Jeffrey Bluestone, an immunologist, obtained results from independent experiments that contradicted that conclusion. Allison and Bluestone believed that CTLA-4 actually acted as a brake on the T-cells, and Allison thought that it might be keeping the immune system from attacking tumors. “Jeff and I were kind of in the wilderness for a while,” Allison said. “Before this, people just thought that T-cells died on their own.” He speculated that treatments designed to activate the immune system might have failed because the treatments were actually stimulating CTLA-4. As Allison put it, “We ought to free the immune system, so it can attack tumor cells.”

Allison’s postdoctoral researchers implanted cancer cells under the skin of mice, some of which were then treated with an antibody that blocked CTLA-4. After several weeks, the cancers disappeared. One of the researchers showed Allison the data in early December, 1995. Allison was astounded. The lab was about to go on Christmas break, but he wanted to repeat the experiment immediately. “I told the researcher that he should inject the tumors into a new group of mice, and have a control group that didn’t get the antibody. And I’d measure the tumors myself,” Allison recalled. “So it was really a blinded experiment, because I didn’t know what was what.” A week later, Allison measured the cancers. “The tumors were still growing, and I’m starting to despair. And then, in half of the mice, the tumors just seemed to stop, but in the other half of the group they kept going. And then the ones in which it stopped, the cancer started disappearing and just went away.” Allison added, “It immediately confirmed our original assumption that this could be good for any kind of cancer.”

For two years, as Allison continued his experiments on mice, he approached pharmaceutical and biotech companies for help in developing the treatment for patients, but he was repeatedly turned away: “People were skeptical of immunology and immune therapy. They would say, ‘Oh, anybody can treat cancer in mice.’ Sometimes they’d say, ‘You think you can treat cancer by just removing this negative signal on a T-cell?’ ”

Allison also learned that Bristol-Myers Squibb had filed for a patent asserting that CTLA-4 stimulated T-cell growth. “If that was the case, you would never, ever think about injecting an antibody that blocked CTLA-4 into a cancer patient, because it would make things worse,” he said. “People were scared of putting that into a patient.” But Allison persisted, telling industry executives that Bristol-Myers Squibb was wrong. Finally, he persuaded a small company called Medarex to invest in the approach.

Among its first trials on humans, in 2001, Medarex included patients with malignant melanoma, because it was one of the few cancers that had occasionally responded to immune-based treatments like interferon or interleukin-2. In pilot studies, patients were treated with the antibody to CTLA-4, and, as in mice, the cancers continued to grow for some weeks, before a few of the tumors shrank. In 2004, Bristol-Myers Squibb formed a partnership with Medarex to collaborate on the drug. A subsequent trial showed scant impact after twelve weeks. Many of the tumors got bigger, and in some patients new lesions appeared. Pfizer was also testing an antibody to CTLA-4, and concluded that it was a failure; the trial was stopped early.

Months after the end of the Bristol-Myers Squibb study, however, several of the clinicians involved, including Jedd Wolchok, of Memorial Sloan-Kettering, and Stephen Hodi, of the Dana-Farber Cancer Institute, in Boston, realized that the tumors had either stopped growing or begun to shrink. Wolchok and his colleagues prevailed upon Bristol-Myers Squibb to include over-all survival rates of patients after several years. (Because the established criteria for judging the effectiveness of chemotherapy drugs are based on the first months of treatment, the trial had been considered a failure.) “It was pretty courageous,” Allison said, “because it would take a long time to finish the study.” In June, 2010, the results were presented at the annual meeting of the American Society of Clinical Oncology. Although the drug had extended the patients’ lives a median of only four months, nearly a quarter of the patients were alive two years into the trial. Their predicted survival had been seven months. “This is a drug unlike any other drug you know,” Allison said. “You are not treating the cancer—you are treating the immune system. And it was the first drug of any type to show a survival benefit in advanced-melanoma patients in a randomized trial.”

Allison’s results astounded cancer specialists. Nature published a review in December, 2011, and noted that the antibody to CTLA-4 “provides realistic hope for melanoma patients, particularly those with late stage disease who otherwise had little chance of survival. More broadly, it provides clear clinical validation for cancer immunotherapy in general.” I asked Harold Varmus why Allison had had success where other researchers in immunotherapy had failed. “We need to understand what we do,” he said. “Jim made things understandable.”

“You’ve got to be careful about using the word ‘cured,’ because some patients have residual tumors,” Allison said. “But it doesn’t matter, because their cancers are not growing. And, in others, tumors just pop up and then go away. So it’s become something of a chronic condition,” rather than a death sentence. Allison moved to Sloan-Kettering to be closer to the clinical trials conducted by Wolchok and others. “I just wanted to be the advocate who is keeping it in everybody’s face,” he said.

In the fall of 2003, Sharon Belvin was a twenty-two-year-old student teacher with plans to marry the following June. She ran between four and five miles a day, and began to notice that her chest hurt after her morning workout. The student health service thought that she might have viral bronchitis, picked up from the children in her class. But her symptoms did not improve, and she was given other diagnoses, including asthma and pneumonia. Before long, she found it uncomfortable even to walk. On a visit to her mother, Belvin saw the family physician, who found a lump on her clavicle. A biopsy showed that she had metastatic melanoma. “It shocked me,” Belvin told me. “I was never a sunbather. And I never had any lesions on my skin.” A week before her wedding, she completed her evaluation. A body scan “lit up like a Christmas tree,” she recalled. “I ended up having chemotherapy on Monday, Tuesday, and Wednesday, and got married on Saturday.” During four months of therapy, the tumors shrank a bit. Then they began to grow again. An MRI showed that the melanoma had spread to her brain. Belvin went to Sloan-Kettering, where the brain tumor was treated with radiation. After recovering from the procedure, she received interleukin-2, to stimulate her T-cells. The therapy caused such a severe reaction that “my skin peeled off over my body,” Belvin said. “I was so violently ill, I don’t remember half of what happened.” Worse yet, the treatment failed to stop the cancer’s growth. “The doctor told me, ‘If you are going to take a vacation, you’d better do it now.’ ” Belvin and her husband went on a Caribbean cruise.

When she got back, Belvin returned to the hospital and had twelve litres of fluid drained from her chest. Then Wolchok offered Belvin treatment with the antibody to CTLA-4, which was still an experimental therapy. “By that point, I had told my husband, ‘If this doesn’t work, I don’t know how much more I can take,’ ” she recalled. Wolchok gave her an informed-consent release that listed all the possible side effects. “It was pages and pages of this could happen to you and that could happen to you. I didn’t read one page. I just signed at the bottom and said, ‘Give it to me.’ ”