image courtesy of Memorial Sloan Kettering Cancer Center

Message to Immune Cells: Sic ’Em!

Researcher’s longtime efforts to drive T cells to attack tumors hits pay dirt.

A Texan straight-shooter and lifelong Willie Nelson fan, Jim Allison doesn’t back down or mince words. And his fight against cancer is personal. “I saw my uncles, my mother, and my brother undergo cancer therapies that were not only unsuccessful but quite grotesque,” he says. “I always had the feeling that you could go through the immune system to kill tumor cells instead of cutting them out or burning them.” His tenacity in following that instinct may soon be changing patients’ lives.

Allison was sitting front and center at a presentation at the 2010 meeting of the American Society of Clinical Oncology (ASCO) to witness a clinical researcher report that the fruit of his labor—the drug ipilimumab—was the first immune-altering therapy to extend the lives of patients with stage III and stage IV melanoma. Although Allison was not directly involved with the multisite study, the drug was a product of his research and he’d been following the trial.

Like others, Allison had suspected that melanoma patients might benefit from the drug, because melanoma tumors are infiltrated with T cells, which respond to immunotherapy.

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“I was aware of the data and had met many patients who had benefited from treatment, but there had been a couple of false starts,” says Allison, an immunologist and HHMI investigator at Memorial Sloan Kettering Cancer Center (MSKCC) in New York. “So when that report was presented it finally hit me—it really does work.”

The story of ipilimumab began in Allison’s former lab at the University of California, Berkeley. There he worked to activate the body’s protective T cells so they could do a better job fighting cancer. After he discovered the T cell receptor, which the cells use to identify invaders, Allison looked for ways to drive T cells to attack.

In 1993, he found that a molecule called CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) puts the brakes on an attack by inhibiting T cell activation. CTLA-4 is important because it prevents the body from damaging its own tissues. But Allison wondered if it was also stifling a response to cancer. If he could disable CTLA-4, he thought, perhaps activated T cells might go after tumor cells unimpeded.

The idea of treating disease by manipulating the immune response—immunotherapy—stood on shaky ground with scientists in academia and drug companies alike. Although some experiments suggested that immunotherapy might help treat disease, others found it ineffective. Worse yet, knocking out genes for inhibitors like CTLA-4 in mice led to autoimmune diseases.

Allison, however, found that blocking CTLA-4 function, as opposed to ablating the gene entirely, did not cause lethal autoimmunity. He pushed hard to convince the pharmaceutical company Medarex, later acquired by Bristol-Myers Squibb, to create antibodies that block CTLA-4 in people. Ipilimumab is the result.

Still, the road was long. Allison’s heart sank during the holiday season in 1995 when mice with tumors consisting of transplanted colorectal cancer cells were given CTLA-4 blockers, and fared no better than those left untreated. His hope rose again shortly after Christmas, however, when the tumors started shrinking and then disappeared altogether. “I had never seen anything like it,” Allison remembers. “I was convinced it would work in people.”

Allison recalled that time lag between treatment and effect when he learned of results from early clinical trials of a CTLA-4 drug. While the therapy worked for some patients within the first 12 weeks of treatment, others responded later, often after the tumors had progressed. “When I heard this, it reminded me of the mice and the fact that tumors first grew prior to shrinking,” says Allison. “I thought, this is exactly what you should expect.”

Clinicians of course hope for a timely response to chemotherapy. Allison worried that rapid efficacy might be an impossible requirement for immunotherapy to meet, since T cells must detect cancer cell debris, multiply, and then trigger attack before the tumors will shrink. A few years ago, thanks to steady rallying by Allison and many clinical colleagues, the criteria for immunological trials changed so that patients were given more time to respond to drugs.

In the trial presented at ASCO, the benefit of ipilimumab began to show after four months. A total of 676 patients with stage III or IV melanoma received ipilimumab alone, ipilimumab with an anticancer vaccine (gp100, which targets a protein on the melanoma’s cell surface), or the vaccine alone. Patients taking ipilimumab alone or ipilimumab with the vaccine lived an average 10.1 and 10 months, respectively; those given only the vaccine lived an average 6.4 months.

The advantage of ipilimumab became more notable over time. At one year, 46 percent of patients taking ipilimumab were alive compared with 25 percent of those receiving the vaccine only. The study was published June 5, 2010, in an online edition of the New England Journal of Medicine.

“Look at the survivors at the tail of the curve,” urges Allison referring to the lines in a graph representing overall survival of stage III and IV cancer patients taking ipilimumab. “People who are alive at two years are alive after four years—usually, no one survives that long.”

“I’ve been in the field [of immunotherapy] for a long time and I’ve seen the waves of enthusiasm followed by disappointment,” says Lloyd Old, a cancer immunologist at MSKCC. “But Jim’s research on CTLA-4 has led to a discovery of the first magnitude.”

Although 60 percent of study participants given the drug experienced autoimmunity issues such as colitis or diarrhea, the symptoms usually resolved within two weeks of corticosteroid treatments.

In late June, Bristol-Myers Squibb applied to the FDA for regulatory approval of ipilimumab. If approved, it could be the second cancer immunotherapy available. The drug is also being tested in Phase III trials for hormone refractory prostate cancer and Phase II trials for lung cancer.

For an approach so heavily scrutinized in its early days, Allison was wise to trust the data and carry on. At MSKCC since 2004, he’s sticking to his guns, digging ever deeper into the immunological frontier.

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Memorial Sloan Kettering Cancer Center