http://www.sfchronicle.com/health/article/Jim-Allison-confronts-cancer-critics-with-5405290.php
"......Allison, chairman of immunology at the University of Texas M.D. Anderson Cancer Center, is credited with one of the most important breakthroughs in cancer history, the discovery that finally frees the immune system to attack tumors - a dramatic departure from the existing models of treating the disease......
The achievement has recently won Allison a raft of awards that M.D. Anderson President Dr. Ron DePinho thinks will culminate in the Nobel Prize. "By creating this brilliant approach that treats the immune system rather than the tumor, Jim Allison opened a completely new avenue for treating cancers that's the most exciting and promising area of cancer research today," DePinho says......
By then, the mid-'70s, Allison already was keenly aware of cancer immunotherapy's checkered history.
It was all the rage for a time, but when early mice experiments didn't show benefits, immunotherapy fell out of favor.
"It had such a bad rap," Allison says. "People would say to me, 'Don't do tumor immunology, it'll ruin your reputation.' "
In the ensuing years, cancer immunotherapy made some strides, but they were frequently undermined by hype, sometimes by the scientists themselves. Allison believed none of them really knew what they were doing. He set out to be the one who did......
Allison was most interested in T cells, the immune system's little-understood soldiers that "do all the killing."
He wondered what about cancer disarms them. Why do they so efficiently attack virus-infected cells but not get the necessary signals to attack tumors?
In the next decade, Allison's work laid important basic science groundwork. He identified, first, the T cells' ignition switch, a receptor that has to recognize proteins on tumor cells, then the gas pedal, a co-stimulatory molecule necessary to activate the T cells. They would provide key insights that helped facilitate the big discovery still to come......
Numerous immunology labs were looking for molecular signals to rally T cells into action, and nothing looked so promising as CTLA-4. A newly discovered protein that protrudes from T cells' surface, CTLA-4 turned out to resemble the structure of the "gas pedal" Allison described, so it seemed logical that it was an activation signal.
But when he tried binding molecules with CTLA-4 as he had done with the "gas pedal" protein, he got an opposite effect: It inhibited T-cell proliferation. Could it be a brake, not a gas pedal?
So while most everyone else was looking for evidence that CTLA-4 turned on the immune system, Allison designed a study based on the novel hypothesis that CTLA-4 turned it off: He implanted mice with cancer cells and treated some with an antibody that blocked CTLA-4 - in essence, taking the brake off the immune system.
Allison was astounded by the initial data his research fellow showed him at the end of November 1995: While all the untreated mice had died, 90 percent of the cancers of the treated mice had disappeared. Allison wanted to reproduce the results immediately, but there was a problem: His fellow was headed off to a European vacation, and Berkeley would soon be closing for Christmas.......
Allison took the measurements every other day during December and, for a short while, the results were the source of despair. All the tumors were continuing to grow. But at about the third week, things began to change. In half of the mice, the cancers first stopped growing, then started shrinking, then disappeared.
In March 1996, the journal Science published Allison's research: Blocking CTLA-4 enhances antitumor responses......
He took the finding and determined to apply it to cancer. He developed an antibody that worked great in mice, but for two years couldn't find a company to fashion a human version. Most were still gun-shy about cancer immunotherapy because of the field's past failures, and most were still convinced that the future of cancer treatment involved molecular targets on tumors, not the immune system itself.
Finally, a small New Jersey company named Medarex took the plunge, sublicensing the patent and manufacturing a drug called ipilimumab (ippy for short), the first of a new class of drugs called immune checkpoint inhibitors. The company would ultimately be acquired by Bristol-Myers Squibb for $2.4 billion.
Ippy was tested, successfully, in human patients for the first time in 2001, but results from its first large-scale trial weren't good. There was little impact at 12 weeks, the point at which chemotherapy is assessed, so it was declared a failure. It took a second large trial for ippy's prospects to gain momentum, after clinicians noticed some tumors that were unaffected at 12 weeks had shrunk; years later, some patients were thriving.
It turns out that the immune system sometimes took time to rev up, but once it did, its effects last, unlike other cancer therapies......"