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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.