Saturday, April 19, 2014

New Guidelines Say Lumpectomy Margins Can Be Small as Long as Tumor Has No Ink on It

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During lumpectomy, your surgeon’s goal is to take out all the breast cancer, plus a rim of normal tissue around it. This is to be sure all the cancer has been removed.
The tumor and surrounding tissue is rolled in a special ink so that the outer edges, or margin, are clearly visible under a microscope.
During or after surgery, a pathologist looks at the tissue that’s been removed to make sure there are no cancer cells in the margin. A clear, negative, or clean margin means there are no cancer cells at the outer edge of tissue that was removed. A positive margin means that cancer cells come right out to the edge of the removed tissue and have ink on them. In some cases, a pathologist may classify the margins as close, which means that cancer cells are close to the edge of the healthy tissue, but not right at the edge and don’t have ink on them.
There has been some question about how wide a clear margin should be. Some doctors want 2 mm or more of normal tissue between the edge of the cancer and the outer edge of the removed tissue. Other doctors believe that 1 mm of healthy tissue is fine. Still other doctors think that a clear margin can be smaller than 1 mm.
Because of the controversy, about 25% of women who have lumpectomy have a re-excision, which is when a surgeon reopens the lumpectomy site to remove a larger margin of cancer-free tissue. More surgery usually means more discomfort and stress for a woman and can possibly lead to more complications or side effects.
To establish a standard for lumpectomy margins, the American Society for Radiation Oncology (ASTRO) and the Society of Surgical Oncology (SSO) reviewed a number of studies. The groups issued new guidelines saying that clear margins, no matter how small as long as there was no ink on the cancer tumor, should be the standard for lumpectomy surgery. The guidelines also say that wider margins don’t lower the risk of recurrence any more than narrower margins.
The guidelines were published online on Feb. 10, 2014 by three journals at the same time: the Journal of Clinical OncologyAnnals of Surgical Oncology, and International Journal of Radiation Oncology Biology*Physics. Read “Society of Surgical Oncology-American Society for Radiation Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Stages I and II Invasive Breast Cancer.”
The guidelines were based on a meta-analysis done by a panel of experts from both ASTRO and SSO. A meta-analysis is a study that combines and analyzes the results of many earlier studies. In this case, the results of more than 28,160 women in 33 studies published between 1965 and 2013 were reviewed. All the studies looked at women diagnosed with stage I or stage II breast cancer treated with lumpectomy and whole-breast radiation therapy.
The guidelines include several recommendations about margins after lumpectomy to remove early-stage breast cancer, including:
  • If there is ink on the invasive breast cancer tumor or DCIS that’s been removed, the risk of recurrence (the cancer coming back) in the same breast is doubled.
  • Clear margins offer the lowest risk of recurrence in the same breast; wider clear margins don’t reduce this risk any further.
  • Treatments after surgery (called adjuvant treatments by doctors), such as hormonal therapy, radiation therapy, and chemotherapy, reduce the risk of recurrence in the same breast. Still, even if a woman doesn’t get adjuvant treatments, there is no evidence that the clear margins need to be wider than no ink on the tumor.
  • Clear margins don’t need to be wider than no ink on the tumor no matter what the biological characteristics of the cancer are. So clear margin width is the same for a cancer that is hormone-receptor-positive and hormone-receptor-negative, for example.
  • The width of the clear margin shouldn’t affect which type of radiation therapy a woman receives.
  • Women younger than 40 who are diagnosed with early-stage breast cancer have a higher risk of recurrence in the same breast after lumpectomy and a higher risk of recurrence in the chest wall after mastectomy. There is no evidence that a wider margin reduces these risks.
The panel of experts who did the meta-analysis and wrote the guidelines hope that their recommendations will reduce the number of re-excision surgeries for women diagnosed with early-stage breast cancer who have lumpectomy.
“Based on the…panel’s extensive review of the literature, the vast majority of re-excisions are unnecessary because disease control in the breast is excellent for women with early-stage disease when radiation and hormonal therapy and/or chemotherapy are added to a woman’s treatment plan,” said Dr. Meena Moran, M.D., associate professor of therapeutic radiology at the Yale University School of Medicine and one of the leaders of the expert panel.
If you’ve been diagnosed with early-stage breast cancer, these guidelines are reassuring. You and your doctor will consider which type of surgery makes sense for you based on your unique situation. For many women, lumpectomy followed by radiation therapy is a good option and more attractive than mastectomy, both physically and emotionally. The meta-analysis the guidelines are based on offers peace of mind that you likely won’t need more surgery after lumpectomy if you have clear margins, no matter how small the clear margins are.
For more information on lumpectomy, including margins, visit the Breastcancer.org Lumpectomy pages.

Have a Question about Breast Cancer, Diet and Exercise? Join us on May 7 and 8

Have a Question about Breast Cancer, Diet and Exercise? Join us on May 7 and 8

LigibelCancerConnect and Dana-Farber Cancer Institute Present: Ask the Expert with Dr. Ligibel
CancerConnect has partnered with Dana-Farber to provide you with the opportunity to engage with a breast cancer expert, Jennifer A. Ligibel, MD, of the Susan F. Smith Center for Women’s Cancers at Dana-Farber. OnMay 7 and 8, 2014, Dr. Ligibel will guest-moderate on CancerConnect for a question-and-answer session on “Breast Cancer, Diet and Exercise.” CancerConnect is a safe and private online support community for cancer patients and caregivers.
Dr. Ligibel has authored several papers on the role of lifestyle factors and breast cancer, including a recent study on the impact of exercise on reducing drug-related joint pain. She is also an assistant professor of medicine at Harvard Medical School. Click here for Dr. Ligibel’s bio.
Join the Conversation and Get Your Breast Cancer Questions Answered
To submit your question for Dr. Ligibel:
  • Use this form to pre-submit your questions until Monday, May 5, or
  • Submit your question directly in the CancerConnect Breast Cancer Community until
    May 8 at 5 p.m. EST.
The Q&A session with Dr. Ligibel will be posted on CancerConnect on May 7-8, and can be accessed here. Thank you for your participation.

Saturday, April 5, 2014

Cancer treatment: The killer within

The immune system can be a powerful weapon against cancer — but researchers are still grappling with how to control it.

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Illustration by Brendan Monroe
The first tumour was a small melanoma on the left side of attorney Mark Gorman's neck. Doctors removed it, and assured him that the cancer was gone.
But eight years later, in 1998, a physician felt Gorman's abdomen during a routine physical examination, arched an eyebrow, and asked if he had become a heavy drinker. The melanoma had spread to Gorman's liver, seeding an inoperable beast of a tumour that wrapped around the inferior vena cava carrying blood to his heart.
People with advanced melanoma typically live for just six to ten months after diagnosis. But Gorman, then 49, had little patience for the doctors advising him to get his affairs in order. When his sister told him about a drug called interleukin-2 (IL-2) that was being used together with chemotherapy against melanoma at a hospital in Colorado, he travelled from his home in Silver Spring, Maryland, to give it a try.
IL-2 is a protein produced by white blood cells called T cells during an immune response. Taking high doses of it sends T cells into overdrive, making them more likely to recognize and attack cancer cells. Gorman was treated, and remains cancer-free 15 years later. “Some doctors say my immune system is really smart,” he says. “I just know I'm lucky.”
The drug that saved Gorman's life was the first treatment approved by the US Food and Drug Administration (FDA) to fire up the immune system's response to cancer — a technique known as immunotherapy. After that 1992 approval, researchers and pharmaceutical companies spent years trying to develop new immunotherapies that could produce success stories like Gorman's. But those attempts failed to live up to their promise in the clinic, leading to decades of frustration.

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Heidi Ledford talks about cancer treatments that use the body’s own immune system
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Now the tide seems to be turning. Clinical-trial successes in the past five years suggest that a new generation of approaches has potential against several forms of cancer that resist conventional treatments. Some analysts predict that in the next ten years, immunotherapies will be used for 60% of people with advanced cancer, and will comprise a US$35-billion market. “It is kind of crazy,” says Cary Pfeffer, chief executive of Jounce Therapeutics, a company specializing in cancer immunotherapy in Cambridge, Massachusetts. “This field has become so crowded. It's frenzied.”
But the sobering experience with earlier drugs has made many researchers and clinicians cautious. Despite its potential for miracles, IL-2 produces complete remission in only around 6% of people with melanoma. The treatment kills as many as 2% of recipients. Researchers are now racing to find ways to boost the number of patients who respond to immunotherapy and to reduce the dangerous side effects. “The good news — and the bad news — is that the immune system is incredibly powerful,” says Robert Tepper, chief medical officer at Jounce.

Checkmate

Cancer immunotherapy was born in 1891, when a New York surgeon named William Coley began injecting bacteria into patients' tumours in the hope of triggering an immune response to the infection that would also attack the tumour. Physicians before him had noted mysterious and rare cancer remissions following infections, and Coley was eager to harness that therapeutic power.
It would not be so simple. Tumours wield many defences against the immune system's most powerful cancer-fighting weapon: T cells that hunt out and eliminate problem cells. Cancer cells disguise themselves and make it difficult for T cells to find them. Tumours also fend off immune attack by expressing proteins that suppress T cells in the surrounding environment.
For decades, researchers chased the possibility of a vaccine that would alert the immune system to cancer cells. But those efforts have largely failed: the only FDA-approved therapeutic cancer vaccine is a complicated and costly therapy for prostate cancer. Whether it provides a significant benefit to patients is a matter of debate.
The field turned a corner in 2011, when the FDA approved a new kind of immunotherapeutic drug. Yervoy (ipilimumab) binds to and blocks a 'checkpoint' protein called CTLA-4, which normally acts as a brake on the immune system by preventing T-cell activation. Checkpoint proteins keep the cells in check so that they do not attack normal tissue. When Yervoy releases the brake, T cells are free to destroy tumours.
Like IL-2, Yervoy can bring long-lasting responses. Some participants in the original trials have been in remission for 13 years, says James Allison, a cancer immunologist at the University of Texas MD Anderson Cancer Center in Houston. But those clinical cures occur in just a small fraction — about 8% — of patients. And although Yervoy can rouse T cells to battle against cancer, sometimes the cells attack healthy tissue, too. Of the 540 people who took Yervoy in the largest trial, up to 15% experienced serious side effects and seven died of immune-related events. Some oncologists prefer to steer clear of the drug, says Suzanne Topalian, a melanoma researcher at Johns Hopkins University School of Medicine in Baltimore, Maryland.
Still, the promising aspects of Yervoy established the potential of checkpoint inhibitors — drugs that block checkpoint proteins — and that has prompted researchers to look at other potential target proteins. By the time Yervoy was approved, some investigators had begun to focus on PD-1, a checkpoint protein that some cancers use to deactivate the phalanx of T cells that surrounds the tumour.
Because PD-1 interacts directly with cancer cells, unlike CTLA-4, its inhibitors have the potential to be more potent and less toxic. Early clinical trials suggest that this is the case. A leading PD-1 inhibitor — nivolumab, made by New York's Bristol-Myers Squibb — shrinks tumours in 28% of people with advanced melanoma. The FDA is expected to issue a decision on whether to approve it by early 2015, if not sooner.
Hopes are high that, although there are some side effects, the new drugs will be less toxic than Yervoy. Some people notice no problems at all. “Many patients say, 'Doc, are you even giving me anything?'” says Antoni Ribas, a melanoma specialist at the University of California, Los Angeles, who has participated in trials of PD-1 inhibitors. “Then the tumours start disappearing, and they know.”
Researchers want to push immunotherapies even further. “We wish response rates were higher than what we currently have,” says Michael Postow, an oncologist and cancer researcher at Memorial Sloan Kettering Cancer Center in New York. Inhibitors of other checkpoint proteins are trickling into clinical testing and clinicians may one day match patients with the inhibitors most likely to act on the proteins expressed by their own cancer cells.
For other patients, the challenge may be in attracting T cells to the tumour in the first place. PD-1 inhibitors do not accomplish this — they simply remove the shackles from T cells already amassed at the tumour's edge, says Daniel Chen, head of immunotherapy development at Genentech in South San Francisco, California, a subsidiary of the Swiss pharmaceutical giant Roche. “Some patients just seem to have no existing immune response to start with,” he adds. “So then we need to add something that will generate that response.”

Better together

The key to attracting T cells is to create an 'inflamed' tumour using combinations of therapies, says Postow. Yervoy and PD-1 inhibitors are already in clinical trials with each other and a range of other treatments intended to alert T cells to the cancer. Radiation, for example, breaks open cancer cells and releases antigens, molecules that can trigger immune responses. In another approach, researchers alert a patient's immune system with experimental cancer vaccines containing proteins that are overexpressed by tumour cells. “The future is clearly combination therapy,” says Anthony Marucci, chief executive of Celldex Therapeutics in Hampton, New Jersey.
“The good news — and the bad news — is that the immune system is in credibly powerful.”
Eventually, checkpoint inhibitors could also be combined with a form of immunotherapy called adoptive T-cell transfer. This is a personalized treatment in which physicians isolate T cells from patients and select those that react to cancer. They then multiply the T cells and stimulate them with molecules such as IL-2 before injecting them back into the bloodstream. Trials of this method led by tumour immunologist Steven Rosenberg at the National Cancer Institute in Bethesda, Maryland, have shrunk tumours in more than half of people with advanced melanoma receiving the treatment, with 20% experiencing complete remission.
A newer form of T-cell transfer promises to broaden its reach to other cancers, by engineering extracted T cells to express an artificial tumour-targeting receptor called a chimaeric antigen receptor (see 'Immune boost'). A trial using T cells engineered to target B cells wiped out cancer in 14 of 16 people with acute leukaemia (M. L. Davila et al. Sci. Transl. Med. 6, 224ra25; 2014).
But technical challenges have limited the spread of T-cell transfer therapies. Only a handful of academic medical centres have performed the procedure so far. “After our initial results, we were besieged with melanoma patients,” says Rosenberg. “We couldn't possibly treat all the patients sent to us.”
Since those early days, researchers have simplified and standardized protocols. That, plus the remarkable results in leukaemia, has lured industry investors. Novartis, based in Basel, Switzerland, has bought a facility in New Jersey to process T cells extracted from patients around the United States. The facility will be key to the company's plans to expand its clinical trials to more sites this year. Smaller firms are following suit. In early 2015, Kite Pharmaceuticals in Santa Monica, California, hopes to launch a multicentre trial of adoptive T-cell transfer in a form of lymphoma that kills around 37% of patients within five years of diagnosis.

The true target

Another big challenge for adoptive T-cell transfer is to broaden its reach by finding new molecular targets that will guide T cells to specific tumour types while sparing healthy cells. The approach works well in leukaemia and other cancers that affect B cells, another class of white blood cell, because researchers can engineer T cells to target a protein called CD19, which is found only on B cells. Although the treatment wipes out healthy B cells in addition to the cancerous ones, patients can tolerate that side effect relatively easily. But finding a similar target for solid tumours, which are less uniform than liquid tumours, has been difficult. “It's a major limiting step,” says Ribas. “We're all excited about CD19, but it's not clear what the next target will be.”
Researchers are mining growing databases of gene expression to find the best candidates. But firing up immune responses to specific proteins can be dangerous: a few years ago, four patients died in trials of T cells engineered to attack cells expressing a protein called MAGE-A3. This protein is expressed only in embryos and in some cancer cells in adults, so it seemed an ideal target. But researchers later learned that the T cells attacked similar proteins present in the heart and brain. “These T cells are professional killers,” says Arie Belldegrun, chief executive at Kite. “If their target is expressed even in minute quantities on normal cells, these super killers are going to find those cells and destroy them.”
In response to the deaths, ImmunoCore, an immunotherapy company based in Abingdon, UK, developed new bioinformatic methods to search for signs that any possible T-cell target could be expressed in normal tissue. The company also began to do its initial safety testing in three-dimensional cell cultures that better reflected the cells' natural environment. This approach has led to a collection of more than 20 potential targets for various cancers. Michel Sadelain, a cancer geneticist at Memorial Sloan Kettering, hopes to engineer T cells that target two proteins, both of which would have to be expressed on a cell for the T cells to destroy it. The idea, he says, is that the chance that a healthy cell will have both targets on its surface will be slim.
Finding more targets could help immunotherapy to reach more types of cancer. So far, researchers have focused on melanoma and kidney cancer because they responded best to immunotherapies in early trials, and are thought to be particularly visible to the immune system.
Rosenberg says he is working on 11 clinical trials testing adoptive T-cell therapies against a variety of cancers, including a particularly lethal and rare form called mesothelioma. The door to much wider applications for cancer immunotherapies opened in 2012, when results showed that the checkpoint inhibitor nivolumab shrank tumours in 18% of people with certain types of advanced lung cancer (S. L. Topalian et al. N. Engl. J. Med. 366, 2443–2454; 2012). Because lung cancer is one of the world's most prevalent forms of cancer, the results raised hopes that immunotherapy could make a sizeable dent in cancer deaths. “This was a cancer that we thought was not immunogenic,” says Ribas, who notes that both Yervoy and IL-2 failed to shrink lung-cancer tumours. “We thought immunotherapy wouldn't have a chance.”
Some cancers, including liver cancer, may still pose a challenge to immunotherapy approaches, says Lisa Butterfield, a cancer researcher at the University of Pittsburgh in Pennsylvania. The liver processes pathogens and antigens in the blood, and the immune system is carefully controlled there to avoid prompting reactions that would target an individual's normal cells. Breast, colorectal, pancreatic and ovarian cancers are also particularly adept at suppressing immune cells. Combination therapies may provide a way around these limitations, she says.
Combination therapies may also be the salvation of the cancer-vaccine concept. Although the vaccines tested thus far have fared poorly, they may work synergistically with other immunotherapies, says Willem Overwijk, a cancer researcher at MD Anderson.
After so many years of disappointing results, the growing excitement over immunotherapy has surprised many cancer researchers and families touched by the disease. Since his own remarkable recovery, Gorman has mourned again and again as friends he made at melanoma support groups succumbed. Then, a few years ago, he had a new experience: a close friend was given Yervoy, and went into full remission.
As for his own melanoma, Gorman goes for scans to look for new tumours every two years. In February, he noted that it might be time to schedule his next set of scans. But he wasn't sure — he had stopped fearing his cancer's return years ago. “I'm a cool cucumber now,” he says. “My immune system has it under control.”
Nature
 
508,
 
24–26
 
()
 
doi:10.1038/508024a

http://www.nature.com/news/cancer-treatment-the-killer-within-1.14955

The scientist who just might cure cancer

The scientist who just might cure cancer

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'd 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'd been something fiercely independent in him since high school, where he battled creationist teachers.
There'd been an extraordinary run of cancer deaths in his family, not least his 45-year-old mom, that convinced him there had to be better treatment than radiation and chemotherapy.
And there'd been that wild, creative streak that once led to him blowing a harmonica with Willie Nelson.
Whatever the source of his genius, Allison, chairman of immunology at 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 for a time wasn't exactly welcoming.
The achievement has recently earned Allison the Economist magazine's 2013 Innovations Award in Bioscience; the National Foundation for Cancer Research's 2014 Szent-Györgyi Prize for Progress in Cancer Research; and just last week, Canada's Gairdner International Award. On Monday, he will be presented the American Association for Cancer Research's G.H.A. Clowes Memorial Award for outstanding recent accomplishments in basic cancer research.
M.D. Anderson President Dr. Ronald DePinho thinks Allison's work will ultimately win 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 all cancers that's the most exciting and promising area of cancer research today," DePinho says.
Bearded and scraggly haired, Allison, 65, 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, preferably something important."
"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 at the scholarly conference. Historically, they'd been sparsely attended.
A series of high-profile flops and disappointments had been responsible for that. Long a Holy Grail of cancer research, the idea of enlisting the immune system to fight cancer over time became a forgotten stepchild, seemingly forever out of reach. But this session promised to be different. It concerned the tangible progress flowing from Allison's breakthrough.
Allison and Dr. Patrick Hwu, an M.D. Anderson colleague, barely had to set foot in the theater's lobby to know cancer immunotherapy's moment had arrived. Faced with standing-room-only crowds on the floor level, they scrambled for the best remaining seats in the nosebleed section, where they gazed out on 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.
"Wow," Allison said to Hwu, taking in the view. "This is amazing."
The doctors 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.

James Allison grew up in a town, Alice, that furnished the ideal stage for his first clash with the Establishment. Its high school didn't teach evolution.
The son of a country doctor who'd hoped he'd follow in his footsteps, Allison was an advanced enough 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 fundamental tenet?
So Allison did what any future maverick scientist would do: He refused to take the class.
Fortunately for Allison, his father was on the school board. A compromise was reached to allow him, then a senior, to satisfy the requirement by taking the University of Texas-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 '50s and early '60s. Descendant of a long line of Texans and 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 when his father called him to her bedside, stopping him from heading to the local swimming pool with some buddies, that this would be the last time. 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. None, he says, were pretty.
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. But I always knew the key was figuring out how things work, finding the right button to push."
The hardest thing was that his breakthrough didn't come soon enough to save his brother. He'd ignored significant joint pain, only to ultimately learn it was advanced prostate cancer. He made it eight years, but by the end, 2005, he was comatose from the morphine.
Allison was at his bedside, 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, or there are consequences to the patient. I prefer the scientist's life – get an idea, devise an experiment, learn if it checks out or not. 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 his post-doc nights in mid-'70s southern California that he became more serious, more skilled. For a couple of years he played regularly with Clay Blaker and the Texas Honky Tonk Band, the front man of which would go on to write half a dozen 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.
That night Allison picked up Nelson, his drummer and bass player in his Volkswagen bus and, after Nelson took the stage, Allison joined him for Blue Eyes Crying in the Rain. Over the years, Allison bumped into Nelson a few times and each time he'd remind him of the night.
"He'd say, 'I remember it like it was yesterday," then add, 'What's your name again?' " laughs Allison.
For all his love of music, though, 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 post-doc. He showed up at M.D. Anderson's new science campus in Smithville, asked for a job and, easy as that, procured a biochemist position. He was the institution's sixth hire.
By then, the mid-'70s, Allison already was keenly aware of cancer immunotherapy's checkered history.
In the 1890s, a New York doctor claimed several successes inoculating cancer patients with cultures of microbes, an idea that came to him after he discovered one seemingly terminal patient's tumor had shrunk to nothing after her immune system fought off a strep infection. But his results couldn't be reliably reproduced and the approach never took off.
Cancer immunotherapy resurfaced In the 1960s, when some prominent scientists proposed that one reason people have an immune system is to protect against cancer. The idea was all the rage for a time, but when early mice experiments didn't show benefits, it fell out of favor.
"Tumor immunology 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 was struck that nobody really knew what they were doing. He set out to be the scientist 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 little-understood immune system soldiers that "do all the killing." What about cancer disarms them, Allison wondered. 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, 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 the life he was leading – weekends watching his favorite Texas music acts in Austin, weekdays able to hike and canoe on 18 wooded acres of land he'd bought within walking distance of the Smithville campus. He dithered for two years, before finally deciding as much fun as he was having, 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 a protein, CTLA-4, newly discovered by a team of French researchers. CTLA-4, which protrudes from T cells' surface, turned out to resemble the structure of the "gas pedal" Allison described so it seemed logical it was an activation signal.
But when Allison tried binding molecules with CTLA-4 like he'd 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 of them 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. In Allison's mind, a follow-up experiment to reproduce the results needed to be done immediately, but there was a problem: his assistant was headed off to a European vacation, and Berkeley would soon be closing for Christmas.
Allison didn't want to wait until the school break was over. He instructed the student to inject tumors into a new bunch of mice, including a control group that didn't get the antibody, before he left for vacation. Allison would come in during the break and monitor the mice himself, unaware which was the control group and which group 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, Allison 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 still gun-shy about cancer immunotherapy because of the field's past failures, most still convinced 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 so good. There was little impact at 12 weeks, the point at which chemotherapy is typically 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 or even larger 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. Clinicians says that's immunotherapy's great advantage – its long-term retention once it recognizes a foe.

Sharon Belvin burst into tears the September 2006 day 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 was cajoled into dropping what he was doing and stopping 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" even if her doctor was cagey enough not to give her a prognosis. Just the fact that she couldn't hold a conversation without gasping for air told her all she needed to know about the disease's progression. 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 shrunk Belvin's tumors and had her walking again. A year later, the day Wolchok summoned the man responsible for the life-saving drug, she'd just got the news she was in remission.
It wasn't just Belvin who got teary-eyed. Allison and her husband 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 ten years of trials, trials involving 6,500 patients, before the FDA gave approval and ippy was marketed as Yervoy. Allison still shakes his head at how long it took to get a life-saving drug available to patients.
"James had a nose for what would work and a stubbornness to stick to his guns and push it through," says Hwu, chairman of M.D. Anderson's department of melanoma medical oncology. "Without that, this approach wouldn't exist today."
Allison's drug was approved in 2011 by the U.S. Food and Drug Administration for the skin cancer melanoma, one of the nastiest of tumors. 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 who have received the drug live at least three years, after which point none die of the disease.

For a time, Allison loved the New York experience, living in a triplex on Manhattan's Upper East Side, enjoying Central Park and the Metropolitan Museum of Art. But the charm eventually wore off, so relentless was the pace.
"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 his work. When Mendolsohn retired in 2011 without a formal offer and was replaced by DePinho, M.D. Anderson's 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 Allison that it was imperative to engage the immune system to beat cancer, making immunotherapy a linchpin of M.D. Anderson's ambitious "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 an additional $30 million to bolster its immunotherapy research capabilities, which enables Allison to design clinical 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 the drug's effect and understand how it works, much like 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." Unable to imagine just sitting around, Allison says he wants to bring immunotherapy's benefits to more patients.
Still, after years of following his own path, 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 front of ippy upon learning that was his drug's name. 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 bands made up of scientists.
"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, one he played last June 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 harmonica for the Checkmates, a new band of M.D. Anderson doctors.
Hwu, who plays keyboards for both bands, describes Allison's harmonica style as "from the gut," a characterization the immunology chair says is really just a euphemism for the fact he can't read music. Allison, self-taught, says he once started a book on reading music, but couldn't stick with it, bored playing the scales.
These days Allison never finds himself bored. When not in his lab, he is wildly in demand on the lecture circuit, travelling constantly – Shanghai, Tokyo, Kyoto, Australia, St. Petersburg – 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 1/2-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 Yervoy. 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 have to be managed. And the drug price is an exorbitant $130,000, an amount Allison calls obscene.
Still, years of skepticism about cancer immunotherapy have now faded, scientists say. Allison notes that even James Watson, the Nobel Prize-winning co-discoverer of DNA's structure and one-time immunotherapy skeptic, recently told him, "'This is going to do it.'"