The drug he identified to do that, called Yervoy, went on sale in 2011 to treat metastatic skin cancer. In lucky patients, it causes otherwise fatal tumors to melt away. By last year, worldwide sales of Yervoy and two newer drugs had reached $6 billion a year, and the medications had been given to more than 100,000 people. This transformative new class of immunotherapy agents, known as checkpoint inhibitors, is acknowledged to be the most important advance against cancer since chemotherapy.

Allison, who is 68, is an unimposing man, with a slight Texas drawl and a stringy mane of white hair. He still finds it hard not to cry when he meets cancer survivors saved by his discovery. But I had gone to talk to him about unfinished business. That is because for every miracle cure, for every Jimmy Carter or 22-year-old melanoma patient pulled back from death, there are many more people who, for reasons that no one understands, can’t be saved. Of all patients dying from all types of cancer in America this year, only one in 12 would be expected to benefit from any immunotherapy drug. Some even argue that direct-to-consumer marketing, including a Super Bowl ad, has created dangerous expectations. Patients cashing in their last chance will, more likely than not, find themselves among the large majority for whom drugs like Allison’s don’t yet work.

Allison has known about the shortcomings longer than anyone. He says they dampen any sense of triumph and shadow him at award banquets. Sometimes, he stays awake at night. “About 22 percent of melanoma patients that get a single round of treatment with Yervoy are alive 10 years later,” he said after receiving a Lasker Award in 2015, and then added solemnly: “We got to get that up, and we got to do it in more kinds of cancer.”

James Allison with his wife and scientific partner, Padmanee Sharma.

At MD Anderson I was introduced to what Allison calls the “platform.” It is a large-scale effort to determine why the immune system at times acts like the perfect weapon but in other cases fails to kick into action. Sharma, a Guyanese immigrant and practicing cancer doctor, oversees the collection of tumor samples from 100 of Anderson’s 165 cancer trials that involve immunotherapy. The tissue is then scrutinized by her lab and Allison’s for clues to how the battle is proceeding. “What is the immune response doing that leads to tumor rejection? What is the immune response doing that it stops rejecting the tumor and [it] starts growing again?” Sharma asks. “Those are big questions that we still need to understand.”

The answers can’t come too soon for some. The pharmaceutical industry and research institutions are in the midst of a pell-mell sprint into thousands of clinical trials based on new immunotherapy agents. As of October, by one tally, more than 166,736 patients were being sought to fill slots in studies of drugs involving a single protein, called PD-1. The overall number of immunotherapy trials probably tops 3,000, says Jeff Bluestone, an immunologist at the University of California, San Francisco, who also serves as president and CEO of the Parker Institute for Cancer Immunotherapy.

But a growing number of researchers fret that the flood of clinical trials is uncoördinated, redundant, and potentially counterproductive. That is because in many cases, the basic science remains little understood. “This is not sustainable,” Ira Mellman, the keynote speaker at the annual meeting of the Society for Immunotherapy of Cancer, told his colleagues when he took the stage last fall. Mellman, a vice president at the biotech behemoth Genentech, put up a byzantine diagram, consisting of concentric circles crammed with small type. The visually overwhelming slide showed trials under way to test immune-boosting therapeutics. His industry, he said, is “[throwing] plates of pasta against the wall, and hoping that something is going to stick.”

Mellman told me that while Allison hadn’t invented immunotherapy, his drug had been the one that clarified its potential. Now, he says, Allison’s is one of the “few serious efforts” to better understand the mechanisms by which the immune system is killing cancers and the reasons why, too often, it is still not seeing them. “We would have a much better shot at doing what’s best for patients, doing best for science, if we understand mechanisms,” he told me. “You can just wildly try different things and hope that something works, or you can go back and try again and understand the basis of all of this. Until we know that, we’re not going to really understand why some respond and some don’t.”

Checkpoint discovery

Cancer is personal for Allison. At 10, he held the hand of his mother, Constance, in tiny Alice, Texas, and wondered at the burn marks up and down her neck. He had not expected her to die. Only later did he learn that the marks were from radiation, and that cancer had killed her. By the time he was 15, cancer had consumed two of his uncles.

When Allison first began to chart a scientific career, he says, he recoiled from cancer. Back then, it seemed, there were few real clues. And immunology, the field he had picked, had a particular reputation for serving up fool’s gold when it came to the disease. “I couldn’t get any purchase on it,” he recalls. “I wasn’t going to go crashing into something until I knew how it worked.”

At that time, in the 1970s, T cells—those tiny assassins that allow the body to fight off infections—had only recently been discovered. Allison was fascinated to learn there were molecular-level sentinels that patrolled the human body looking for trouble—that “if they see something wrong, they just deal with it.” He thought: “What could be cooler than that?”

In the late 1980s, James Allison began studying the molecular basis of T-cell behavior.

The existence of such immune cells did raise an obvious question: if T cells were designed to protect the body by killing infected and diseased cells, how was it that cancer managed to elude them? By then, there were hints that sometimes tumors did in fact succumb. In the 19th century surgeons had inoculated cancer patients with heat-killed bacteria, with inconsistent results. In 1980, a Time magazine cover spotlighted a scientific frenzy around a molecule called interferon, which sends the immune system into overdrive. But the treatment was indiscriminate, as likely to harm a person as heal. “It was crazy, because people were doing things and they didn’t understand how they worked,” Allison remembers. “People just said: ‘Oh, well. It causes T cells to grow. So we put tons of it into people.”’