Update: Today the pioneering work of James P. Allison is receiving the recognition it deserves: Science magazine in 2013 hailed immunotherapy as “Breakthrough of the Year” and Allison, now at the University of Texas M.D. Anderson Cancer Center, is the latest recipient of the Louisa Gross Horwitz prize—often a precursor to a Nobel.
The early 1990s were a heady time for immunology. Researchers had identified a “commander” molecule that launches the body’s white blood cells, called T cells, into battle against invaders such as viruses or bacteria.
Soon scientists were finding other molecular signals that helped rally the T cell troops. Hopes were high that drugs could be developed to treat autoimmune diseases and a range of other illnesses.
But in 1995, in his Berkeley lab, James Allison and then–graduate student Matthew Krummel discovered the exact opposite—that a kind of strongman pulls back T cells in the midst of battle. The uber-cop, a protein called CTLA-4 that attaches to T cells, effectively turns off the body’s killer cells. This, Allison figured, was the immune system’s way of preventing T cells from attacking the body’s own cells—the hallmark of autoimmune diseases. He had identified the immune system’s natural brake.
“Everybody thought I was crazy,” he says, his soft South Texas accent rising as if maybe he’s still a little ticked off.
It’s a scientist’s nightmare. You make a discovery that might change medicine. No one wants to hear about it.
“The hunt was on for proteins that turned on the immune system,” recalls Phil Greenberg, head of immunology at the Fred Hutchinson Cancer Research Center in Seattle. “People weren’t thinking about signals that inhibited it. It seems obvious now that if there are ‘turn-on’ signals that activate T cells, there would also be ‘turn-off’ signals, but there was no framework for it. Jim’s finding just didn’t fit the paradigm.”
But then, Allison didn’t either. He wasn’t looking for a way to rein in immune attacks. He wanted to release the immune system brake. He wanted the T cells to attack cancer.
Allison had a painful and very personal relationship with cancer. He was born in Texas in 1948 and raised in the small oil town of Alice. When he was 10, his mother died of lymphoma. Two of his uncles and one of his brothers later died of prostate cancer, and his other brother is living with it. Allison got prostate cancer, too, but it was caught early.
So when he recognized that CTLA-4 was acting as the brake on the immune system, he went looking for a company to develop and test a drug to counter it. At first, he got no action. Then he teamed up with a small company called Medarex (now owned by Bristol-Myers Squibb), which fairly quickly developed an antibody to the protein—a potential drug to block its action.
“There was definitely something that was very moving for Jim. He was very passionate about getting drug companies to develop this potential new strategy against cancer,” says Corey Goodman, a colleague of Allison’s at Berkeley in the ’80s and ’90s.
The sequence of events in the immune system is like tag-team wrestling but with lots of acronyms and abbreviations: The commander protein, known as CD28, binds to other proteins on the T cell’s surface, prompting the T cell to attack invading viruses or bacteria. To prevent T cells from attacking healthy cells, CTLA-4 blocks the action by getting to those proteins first. An anti-CTLA-4 drug would essentially block the blocker.
One disease that T cells don’t attack is cancer, because the immune system recognizes cancer as the body’s own cells. But if the new drug did its job, it would free up the immune system to identify and attack cancerous cells, even those that have resisted chemotherapy. “That’s the main point,” Allison says. “We’re not treating cancer, so we don’t have to worry about how the cancer cells are changing. We’re treating the immune system, and mutations in tumor cells just create new targets for the immune system.”
Medarex sought FDA approval for clinical trials of their anti-CTLA-4 drug against an incurable metastatic melanoma. In 2000, the FDA granted approval to launch clinical trials.
Cancer vaccine research, or cancer immunotherapy, has a long, sad history. In the 1960s, an important discovery showed that all cells, including cancer cells, carry proteins on their surface, called antigens. T cells can recognize them and latch on to the antigens of invading cells. This readies the T cell to receive its “attack” order from the commander molecule.
Each type of cancer has a different set of antigens, and cancer immunotherapy is about developing vaccines against specific types of tumors—like a flu shot against one strain of influenza. The vaccine is meant to provoke an immune system response, killing the targeted cells and permanently “educating” T cells to recognize that specific type of cancer if it reappears. But the strategy rarely worked, and by the time Allison first published his theory, cancer immunotherapy was out of favor.
Allison’s discovery, though, suggested a much more straightforward strategy. The new therapy, he believed, could blast any threatening target. It offered a kind of one-shot-fits-all approach against any kind of cancer, not just a single type.
When clinical trials got under full sail, however, Allison’s cancer strategy ran into another hurdle.
Chemotherapy efficacy is determined by how quickly and how much the poison shrinks tumors. If a total body CAT scan reveals no tumors after three months, the treatment is considered a complete success. If during the same period tumors have shrunk by more than 50 percent and no new tumors have appeared, the outcome is considered a partial response.
By these criteria, the new therapy didn’t work. But, Allison explains, the drug was treating the immune system, not the cancer, so it needed time to get a response. And sure enough, under the drug’s regimen, many of the patients lived for record lengths of time. Most patients gained four months. Some lived—and still live—four, five, even ten years after the treatment. No other drug had proven as effective.
“I met a woman last week who was in the very first clinical trials around 1999,” Allison says. “She’s been melanoma-free for more than 10 years. It’s really gratifying.”
The real measure of success in clinical trials, Allison says, is the survival curve. In previous clinical trials for this melanoma, it was a pretty sharp downward trend, no matter what the drug. But the survival curve in the new trials looks quite different. It has a “tail.” Some patients are beating the cancer.
The latest statistics show that about 23 percent of patients who receive the drug live at least five years longer, and some, like the woman Allison spoke with, are still going strong after ten years. Strikingly, only a small fraction of those patients are totally cancer free. The immune system must be controlling the cancer—like a chronic disease instead of a fatal one, Allison says. The new drug is training the immune system.
“We’re trying to find out what makes those 23 percent different than the others, so we can get it up to 50 percent, 100 percent,” he says. One theory is that the disease in the other patients was more advanced and the immune system did not have enough time to do its job.
It took 15 years—clinical trials involving 6,500 patients—before the drug was finally available to treat melanoma. In 2011, Bristol-Myers Squibb (owner of Medarex) received FDA approval to market the drug, ipilimumab, sold under the name Yervoy.
“I almost diiiied waiting for these clinical trials to end,” Allison says in that drawn-out South Texas way. Behind his specs, the eyes look a little weary, but the round, almost cherubic face shows a kind of innocence—an inability, still, to understand how a promising strategy could take so long to get to patients.
Approval for Yervoy came not long after another cancer immunotherapy drug, sold as Provenge, was approved to treat a type of prostate cancer. These are the first two cancer immunotherapy drugs to ever gain FDA approval. Yervoy is now being tested in clinical trials against lung, prostate, and other types of cancer.
Treatment with Yervoy involves four infusions, three weeks apart. Because the T cells are being unleashed, Yervoy can sometimes provoke severe, even fatal autoimmune reactions such as colitis, hepatitis, and nerve problems. But, according to Allison, clinicians have learned to quickly recognize and treat the most serious of them.
One key advantage of Allison’s strategy is that T cells usually don’t “launch” unless other types of immune soldiers have already identified threatening cells—reducing the likelihood that normal cells will suffer a T cell blast.
Allison’s breakthrough opened the way for other cancer immunotherapy strategies. Dozens of clinical trials now are working their way through the system, using different types of antibody drugs to stimulate the immune system. Allison and most cancer immunologists now favor a double-whammy approach: chemo to kill most of the cancer, and immune treatment to kill the drug-resistant holdouts.
The National Academy of Sciences has called Allison’s insight one of the most important discoveries in the field of immunology in the past 20 years.
Back in the 1990s, a University of Chicago research team zeroed in on CTLA-4 about the same time Allison did. Immunologist Jeffrey Bluestone, leader of the Chicago team and now Executive Vice Chancellor and Provost at UCSF, focused his research on efforts to turn down immune responses that trigger autoimmune diseases, rather than to ramp up the response to attack cancer. “Jim’s research was essential in revitalizing cancer immunotherapy,” Bluestone says.
His work, adds Greenberg of the Hutchinson Center, “made it absolutely clear that, with appropriate strategies, the patient’s own immune system can be harnessed as a way to treat their cancer.”
Allison is of course not an outlier any more. He was elected to the National Academy of Sciences in 1997, its Institute of Medicine in 2007, and in 2011 was named co-chair of the Scientific Advisory Council of the prestigious Cancer Research Institute (he had been codirector since 2006).
His intense focus on getting treatments to patients prompted a move in 2004 to the Memorial Sloan-Kettering Cancer Center in Manhattan, where he could collaborate more closely with oncologists leading clinical trials. He heads a lab there, supported in part by the Howard Hughes Medical Institute.
At Berkeley, Allison and his wife, Malinda, and son, Robert, lived in a large house in the hills and sailed on the Bay. Now it’s a Manhattan apartment and a miniature radio-controlled boat on the Central Park Lake.
The University of California licensed the patent for the anti-CTLA-4 drug to Medarex and Bristol-Myers Squibb. Per UC policy, Allison and his research team shared a third of the proceeds, with his department and Berkeley each getting a third. Most likely, he netted a fair amount of cash. It’s a crude question to ask, but it is worth a shot, anyway.
Let’s just say you got some millions from the drug. What would you want to do with it?
Pause. “Well, I might get a car.”
You live in Manhattan. Where would you go?
“To the airport. Last month I was in Nice, Boston, New Jersey, Lausanne. I’m going to Stockholm next week.”
He’s hugely sought after these days—a big daddy in cancer immunotherapy.
With major medical discoveries, widespread acceptance of his insights, and finally, patients gaining many years of life, how does the ride from Alice to Austin to Berkeley to Manhattan look in the rearview mirror?
“What a long strange trip it’s been.”