http://www.houstonchronicle.com/new...ncer-5379769.php?t=4febde41c5b05374ef#/0This scientist just might cure cancer
Texan Jim Allison's breakthroughs in immunotherapy have brought him a raft of awards, and thankful patients
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M.D. Anderson researcher Jim Allison's work on cancer immunotherapy earned him the 2014 Breakthrough Prize in Life Sciences, and $3 million.
Decked out in black tie, Jim Allison stood on the red carpet in Silicon Valley. It was unfamiliar territory for the small-town boy from South Texas who had become a scientist and spent his research career on what many considered a lost cause, the study of the immune system's cancer-fighting potential.
But he always believed that's where the action would be, and now here was Facebook CEO Mark Zuckerberg saying Allison's breakthrough "will change lives for generations to come." For that, late-night television host Conan O'Brien handed him the 2014 Breakthrough Prize in Life Sciences award, which includes a $3 million check.
Allison had become a rock star.
There had been something fiercely independent in him since high school, where he battled teachers over creationism.
There had been an extraordinary run of cancer deaths in his family, not least his 45-year-old mom, which convinced him that there had to be better treatment than radiation and chemotherapy.
And there had been that wild, creative streak that once led to him blowing a harmonica with country music legend Willie Nelson.
Whatever the source of his genius, Allison, chairman of immunology at the University of Texas M.D. Anderson Cancer Center, is credited today 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.
Allison did it - made the discovery, then translated it into a drug - in a climate that wasn't exactly welcoming.
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.
Bearded and scraggly haired, the 65-year-old Allison insists he never set out to cure cancer. Rather, he describes his motivation as "the selfish desire to be the first person on the planet to know something."
"It can be hard to go against the system," says Allison, "but sometimes you have to do it for progress to be made."
Six months before his red carpet moment in Mountain View, Calif., Allison found himself arriving late to Chicago's famed Arie Crown Theater, site of an immunotherapy session at the American Society of Clinical Oncology's 49th annual meeting.
For years, he'd been going to such gatherings. Historically, they'd been sparsely attended, the result of a series of flops that changed the idea of enlisting the immune system to fight cancer from the field's Holy Grail to a forgotten stepchild.
But here were 4,000 doctors who'd come from around the world to hear how the immune system was saving the lives of patients whose cancers historically meant a death sentence. They had come because of a flash of brilliance by Allison that deciphered which molecules on the surface of T cells function as catalysts - and which one functions as the brake.
Allison grew up in a town, Alice, that provided the ideal stage for his first clash with the Establishment. Its high school didn't teach evolution.
The son of a country doctor who had hoped Allison would follow in his footsteps, he was advanced enough as a student to chafe at the idea of a science curriculum influenced by religious-minded teachers. Even then, he recalls, he knew evolution is to biology as Newton is to physics. How could a biology class omit its most basic tenet?
So Allison did what any future maverick scientist would do: He refused to take the class.
Ultimately, a compromise was reached that would allow Allison, then a senior, to satisfy the requirement by taking UT-Austin's freshman biology course by correspondence.
A rebel was born.
Allison's childhood in Alice, an agricultural and oil center 40 miles west of Corpus Christi, was otherwise quiet, a classic rural Texas existence of the 1950s and early '60s.
Descended from a long line of Texans and the youngest of three brothers, he was bookish, outdoorsy, an Eagle Scout and straight-A student who loved dissecting frogs.
Still, it was a youth not without tragedy. He was 11 years old when his mother died.
She'd been seriously sick with lymphoma for some time, but he had no idea how seriously when his father called him to her bedside, stopping him from heading to the local swimming pool with some buddies. She died as he held her hand.
Allison remembers walking out of the house and wandering aimlessly, trying to comprehend things. No one ever told him much about his mother's illness, certainly not that she had cancer. That only came later.
The family cancers would keep coming. He lost an uncle to melanoma, another to lung cancer. Years later, his brother would die of prostate cancer, a cousin of ovarian cancer.
It was all a motivating force, he says, but emphasizes he never considered curing cancer his purpose.
"If I had, I'd never have found the immune system's brake," says Allison, who was diagnosed with prostate cancer and successfully treated by prostatectomy in 2005.
"Because of my family history, I always had in the back of my mind that if my research uncovered something that might help, I'd make the leap," he says. "But I always knew the key was figuring out how things work, finding the right button to push."
The hardest thing to accept was that his breakthrough didn't come soon enough to save his brother, who had ignored joint pain, only to learn it was advanced prostate cancer. He made it eight years, but by the end, in 2005, he was comatose from the morphine.
Allison was at his brother's side, too, when he died, holding his hand.
At 16, Allison graduated from high school and went to UT, where he quickly lost interest in going on to medical school, soured, first, by all the memorization it would require, then by the realization that doctors have an inordinate amount of responsibility.
"As a scientist you make mistakes all the time - that's how you learn," says Allison. "But a physician has to be right all the time. I prefer the scientist's life - get an idea, devise an experiment, learn if it checks out. You only have to be right sometimes."
After completing his undergraduate studies and Ph.D. at UT, Allison went to Scripps Clinic and Research Foundation near San Diego for his postdoctoral fellowship.
Some of his most lasting memories there didn't involve science.
Allison describes himself as "always kind of doodling on the harmonica," but it was during those postdoc nights that he became more serious. For a couple of years he played regularly with Clay Blaker and the Texas Honky Tonk Band, whose front man would go on to write songs recorded by George Strait.
The stars aligned for his stint with Willie Nelson. He'd wangled an invitation to a party Nelson's label threw to celebrate the "Red Headed Stranger" album going platinum and, when Nelson asked Allison if he knew anywhere he could pick some music the next night, Allison didn't hesitate to volunteer it was Talent Night at the Stingaree bar where he played.
Allison would join Nelson on stage there for "Blue Eyes Crying in the Rain."
For all his love of music, Allison had no illusions. Asked by Blaker to accompany the band when it left southern California to play Texas clubs, Allison opted to keep his day job.
He returned to Texas a year after completing his Scripps Clinic fellowship. He showed up at M.D. Anderson's new science campus in Smithville, asked for a job and - easy as that - procured a biochemist job. He was the center's sixth hire.
By then, the mid-'70s, Allison already was keenly aware of cancer immunotherapy's checkered history.
It was all the rage for a time - some prominent scientists proposed in the '60s that one purpose of the immune system is to protect against cancer - but when early mice experiments didn't show benefits, immunotherapy fell out of favor.
"It had such a bad rap," says Allison. "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 felt that none of them really knew what they were doing. He set out to be the one who did.
Allison had free rein at Smithville to study the immune system, then in its research infancy.
He'd become fascinated following an undergraduate experiment he conducted that showed mice cured of leukemia had acquired an immune response that rejected his attempts to inject new tumors; he'd become even more interested as he learned of the immune system's complexity, the communication and coordination it calls upon to recognize and eliminate any pathogen, all without causing damage to healthy tissue.
Allison was most interested in T cells, the immune system's little-understood soldiers that "do all the killing."
Allison 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.
In that time, the University of California-Berkeley came recruiting. It was no easy decision for Allison, who loved his laid-back life - weekends watching his favorite Texas music acts in Austin, weekdays able to hike and canoe on land he'd bought within walking distance of work.
He dithered for two years, but finally decided it was time to make the move. It took a former adviser telling him if he passed the job up, he'd put up his feet 10 years later thinking he could have been a contender.
The heavyweight bout would come sooner than expected.
By the '90s, the race was on.
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 which 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.
Impatient, Allison instructed the fellow to inject tumors into a new bunch of mice, including a control group that didn't get the antibody. He'd come in during the break and monitor the mice himself, unaware which was the control group and which got the treatment, a truly blinded study.
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 anti-tumor responses.
"Everyone thought I was crazy," says Allison.
Uncowed, 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.
Sharon Belvin burst into tears in September 2006 when she was introduced to Allison.
Now employed at New York City's Memorial Sloan Kettering Cancer Center - he'd left Berkeley in 2004 so he could work closely with doctors and make sure his discovery wasn't mishandled - Allison had stopped by the office of Dr. Jedd Wolchok, his clinical partner. There was Belvin, the first patient he'd ever met who had received his drug.
She'd been diagnosed, at 22, with Stage 4 melanoma, words she says are "impossible to hear and not think 'death'." In the next year, when nothing stopped the spread of Belvin's cancer from her chest and lungs to her brain, Wolchok offered her ippy. Desperate, she jumped at the chance.
Infused through a vein every three weeks over three months, ippy quickly shrank Belvin's tumors and had her walking again. A year later, the day Wolchok summoned Allison, she'd just gotten the news that she was in remission.
It wasn't just Belvin who got teary-eyed. Her husband and Allison choked up, too. After a moment, all embraced in a group hug.
"That's the reason you do this work," says Allison, still moved by the memory. "It's not about the awards, it's about the difference made in people's lives."
Eight years later, Belvin, 32, and Allison remain in touch, typically bumping into each other once or twice a year at cancer advocacy functions. "What can I say?" says Belvin. "He gave me back a life."
It would take 10 years of trials involving 6,500 patients, but in 2011 the Food and Drug Administration finally approved ippy - brand name Yervoy - for the skin melanoma. No previous treatment ever made a meaningful dent in the advanced disease's five-year death rate of more than 95 percent, but the latest statistics show nearly a quarter of all melanoma patients treated with ippy live at least three years, after which point none die of the disease.
For a time, Allison loved living on Manhattan's Upper East Side, enjoying Central Park and the Metropolitan Museum of Art. But the charm eventually wore off.
"I'm not a New Yorker," he says.
Dr. John Mendelsohn, then president of M.D. Anderson, began wooing him to Houston, promising that the famed cancer hospital could provide an even larger platform for Allison's work. When Mendelsohn retired in 2011 without making a formal offer and was replaced by DePinho current president, Allison wondered whether the moment had passed. He couldn't help remembering how DePinho, a decade earlier, goaded him during a taxi ride to a meeting in Italy that immunotherapy would never work.
But even before taking office, DePinho pushed hard to pick up the recruitment, telling Alison that it was imperative to engage the immune system to beat cancer, making immunotherapy a linchpin of M.D. Anderson's "Moon Shots" initiative to cure some of the most deadly tumors.
Allison accepted in late 2012, a year after the Cancer Prevention and Research Institute of Texas approved a $10 million grant for his recruitment. M.D. Anderson invested $30 million more to bolster its immunotherapy research capabilities, which enables Allison to design trials across a variety of tumor types, using ippy by itself or combining it - with other checkpoint inhibitors and with chemotherapy or targeted therapy. It also provides Allison access to freshly removed tumors, which he can analyze to gauge ippy's effect and understand how it works, as he did with mice.
Allison says he has no plans to retire, despite old friends asking him "what the hell he's doing still working."
Allison is clearly enjoying the good life. He tools around in a Porsche convertible, whose vanity license plate bears the characters CTLA4. He says he might buy a sailboat.
But in other ways, he remains a child of the '60s. He once suggested the FDA place an "h" at the front of "ippy." The shaggy-haired harmonica player - a bouncer at a music joint once assumed he was part of Willie Nelson's band - still surfaces regularly, only now he plays with a band made up of other M.D. Anderson doctors.
"I'm a king bee, baby," Allison sings in his gravelly voice. He stops, wails on his harmonica, then finishes the lyric, "buzzin' around your hive."
The blues classic is an Allison signature song, which he played at Chicago's House of Blues a couple nights after the ASCO immunotherapy presentation. That was his national band, called the Checkpoints, after his big discovery. He also plays in the Checkmates, a new band of M.D. Anderson doctors.
Allison's harmonica style has been described as "from the gut," a characterization he says is a euphemism for the fact he can't read music. Self-taught, he once started a book on reading music, but got bored playing the scales and never finished.
These days Allison never finds himself bored. When not in his lab, he is wildly in demand on the lecture circuit, traveling constantly to evangelize about cancer immunotherapy's promise.
The speaking engagements come not just because of Allison's drug but because his discovery blasted open the door for cancer immunotherapy. Scientists have since discovered eight other immune system brakes and developed a few corresponding pharmaceuticals now in clinical trials, one of which combined with Yervoy in the trial presented at the ASCO meeting to bring advanced melanoma patients' 1�-year survival rate to 80 percent. The National Institutes of Health in 2011 began funding a network of 27 centers' immunotherapy trials. Every major pharmaceutical company is investing heavily.
Because the target is the immune system rather than the tumor, immune checkpoint drugs are expected to work on all sorts of cancers. Besides melanoma, Allison's drug and the others in clinical trials already have had success against cancers of the lungs, colon, kidney, breasts, ovaries, pancreas and prostate.
"There's a sense of paradigms shifting," Science magazine wrote in an article that declared cancer immunotherapy the Breakthrough of the Year for 2013. "Immunotherapy marks an entirely different way of treating cancer - by targeting the immune system, not the tumor itself. Oncologists, a grounded-in-reality bunch, say a corner has been turned and we won't be going back."
For all the excitement, there are still questions about ippy. Researchers have no idea why it benefits some people but not others. Because releasing the brake facilitates an all-out attack by the immune system, it can cause serious side effects - colitis, skin rashes, impaired pituitary function - that must be managed.
And the drug's price is $130,000, an amount Allison calls obscene.
Still, years of skepticism about immunotherapy have finally faded. Allison notes that even James Watson, Nobel Prize-winning co-discoverer of DNA's structure and one-time immunotherapy skeptic, recently told him, "This is going to do it."
Through the years with Dr. James Allison From Texas to California to New York and back to the Lone Star State, Dr. James Allison has been at the forefront of the use of immunotherapy in cancer treatment for the past 40 years:
1970s
Allison, who grew up in South Texas, lands a job with M.D. Anderson in Smithville after completing his postdoctoral fellowship near San Diego.
1980s
Allison's work with T cells lays important basic science groundwork toward his later discoveries. The University of California at Berkeley recruits Allison.
1990s
Allison explores the hypothesis that the protein CTLA-4 turns the immune system off, not on. In March 1996, the journal Science publishes his research.
2000s
Allison applies his finding to cancer treatment, which eventually has patients thriving years later. He moves to Sloan Kettering in New York in 2004.
2010s
Allison is lured back to Texas in 2012, taking a job as part of M.D. Anderson's "Moon Shots" initiative to cure some of cancer's most deadly tumors.
Todd Ackerman
Todd Ackerman
Medical Reporter
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