JAMES ALLISON, MD

Affiliation: Chair of the Department of Immunology, the Vivian L. Smith Distinguished Chair in Immunology, Director of the Parker Institute for Cancer Research, and Executive Director of the Immunotherapy Platform at The University of Texas MD Anderson Cancer Center.

Making It All Worthwhile: “As soon as we met, she [Sharon -Belvin, a patient with advanced melanoma successfully treated with ipilimumab] began to cry and so did I. Standing right there was the reason I’d gotten into cancer research, but it never really hit me until that moment.”

Musical Memory: At the 2017 Austin City Limits concert, Dr. Allison got the chance to play harmonica with Willie Nelson and his band. “He played for about 3 hours, and I got up with my harp and played a song or two with him.”

Best Advice: “You should always do quality work and keep in mind that society is what makes it possible for us to have all this fun in the lab. At some point, you need to think about how you can repay that debt.”

For this installment in the Living a Full Life series of articles, guest editor Jame Abraham, MD, interviewed immunology pioneer James Allison, PhD, Chair of the Department of Immunology, the Vivian L. Smith Distinguished Chair in Immunology, Director of the Parker Institute for Cancer Research, and Executive Director of the Immunotherapy Platform at The University of Texas MD Anderson Cancer Center.

James Allison, PhD, was born and reared in Alice, Texas, a small city wedged in the southern portion of the state known for sprawling cattle yards and later on its oil fields. The youngest of three brothers, Dr. Allison’s father was a country doctor who, in Dr. Allison’s words, “Sometimes got paid in tamales. But he strongly encouraged me to go into science and medicine.”

Early on, Dr. Allison’s intellectual precocity and fierce independence from dogma caught both the attention and ire of the high school’s conservative establishment. After some rough patches, butting heads with the orthodoxy of the day, Dr. Allison officially entered the world of science in his senior year of high school through a correspondence course in biology offered by The University of Texas. It was the beginning of a career in research that eventually led to his trailblazing work in immunology, which has transformed cancer treatment.

Dr. Allison is also an accomplished harmonica player, so well regarded, in fact, that on several occasions he has shared the stage with fellow Texan, country western icon Willie Nelson. At the 2017 Austin City Limits concert, Willie brought Dr. Allison up onto the stage, where he delivered a harmonica solo for 60,000 avid country and blues music fans.

The Dark Ages of Immunotherapy

Immunotherapy’s origins reach back to the 1890s, when William Coley attempted to harness the body’s immune system by injecting streptococcus into patients’ tumors. Immunotherapy took a hiatus from mainstream medical research until the theory of cancer immunosurveillance was introduced in 1957. However, meaningful work in immunotherapy languished among the research community except for the few visionaries, such as Dr. Allison.

Dr. Abraham asked Dr. Allison to briefly describe his introduction into the nascent field. “Back in the late 1960s, when I was a graduate student majoring in biochemistry at The University of Texas at Austin, I took a course in immunology, which I found to be fascinating. Honestly, it was like the Dark Ages in the field back then. I had a professor who told me there were these recently discovered cells called T cells, and he said he didn’t even know if they existed or not, which gives you a sense of when my introduction to immunology occurred. All we knew was that T cells went around the body looking for pathogens to attack, and they did it without hurting the healthy cells, which really intrigued me.”

The biggest challenge in immunotherapy now is figuring out why an immune drug works in some patients and not in others; to do that we need to go back to basic science.

— JAMES ALLISON, PhD

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He continued: “When I got my first faculty job, I dropped everything and moved into immunology. I knew there was a T-cell antigen receptor, and that was about it. But by then, there was a cadre of researchers working in the field, and we began to make progress in understanding that the antigen receptor was a kind of molecular switch, but it became clear it was much more complicated than that.”

The Wrong Switch

Dr. Allisonexplained that in the late 1980s, most immunologists were focused on the stimulatory response to drive antitumor response, but he was actually proposing the opposite: finding a way to block the “off” switch. “It was around this time that the work in cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) kicked off, which was pretty exciting and controversial, too. Up until then, the prevailing thought in immunology was that T cells simply died, but Jeff Bluestone, PhD [Professor of Metabolism and Endocrinology and Director of the Hormone Research Institute at the University of California, San Francisco] and I found the opposite: They had an off switch. At that point, I was still deeply interested in the fundamentals of the immune system, but it wouldn’t prove a far leap from research to developing a medical application,” said Dr. Allison.

A paradigm-changing development in immunotherapy was on the horizon, as Dr. Allison’s work with CTLA-4 in murine models showed dramatic results in curing tumors. In 2000, 14 patients with metastatic melanoma were accrued on a clinical trial in New York testing the new CTLA-4 antibody ipilimumab (Yervoy), a first-in-class checkpoint inhibitor. Not long into the trial, several patients saw their cancer regress.

Emotional Meeting

By 2004, Dr. Allison accepted a position at Memorial Sloan Kettering Cancer Center as Chair of the Immunology Department, largely to be closer aligned with the clinical trial. Laboratory research is a grueling and frustratingly iterative process, but the end goal is developing life-saving therapies for patients, such as ipilimumab. In 2006, Dr. Allison got to meet the results of his work, an event that still brings emotion to his voice.

“I’d started hanging around with clinicians at Memorial, one was Jedd Wolchok, who had a patient named Sharon Belvin with advanced melanoma that had metastasized to her liver, lungs, and brain. She was in her 20s, just got her degree and married, and was essentially headed for hospice before he put her on ipilimumab. One day Jedd asked me to come to the outpatient clinic; it was all kind of mysterious. By then Sharon had been tumor-free for a year and was there for her annual checkup with her husband and parents. As soon as we met, she began to cry and so did I. Standing right there was the reason I’d gotten into cancer research, but it never really hit me until that moment. Here was this drug I’d invented that wasn’t just a data point on a U.S. Food and Drug Administration application, it was actually keeping somebody alive who otherwise would have died.”

Treating Patients, Not Scans

Dr. Allisonand Sharon Belvin stayed in contact, and a year after their emotional meeting, she sent Dr. Allison a picture of her first baby. “That was about 13 years ago; now she has three children and runs in marathons. Sharon taught me one thing. There are a lot of people in our industry who have a fear of saying cancer and cure in the same sentence. That is understandably so, because you need to be careful about declaring someone cured. That said, if you’ve been cancer free for 5 or 8 years, and you’re told you have a chronic disease that might very well recur, it’s like you’re contently looking over your shoulder. At one point, Sharon just said, you know, I’m just going to live my life and not think about recurrence.”

Jim Allison on stage with The Checkpoints, a band composed of oncologists and cancer researchers—all with an interest in immunotherapy. Photo credit: Michael Hotel DGPh Germany.

Dr. Allison recalled a meeting during which he used the “cure” word for a person who was 10 years out. “Someone got up to the mic and said you can’t say cure because that means there’s not a tumor cell in the body, and many patients who have long-term responses with ipilimumab still have spots on CT scans. We can never say a person doesn’t have a cancer cell, but in regard to the spots on CT scans, many of them are just residual granulomas. Besides, I told him, we’re not treating a scan, we’re treating a person who has feelings.”

Dr. Allison bolstered his point by citing a 10-year follow-up of 5,000 patients, and more than 22% were still alive after their therapy had been stopped. “The point is, very few patients on ipilimumab who have been cancer-free for 3 years or more die of the disease. So I think it is completely appropriate to use the term cure. Sharon said that one of the reasons she cried so much when she met me was she thought I was going to tell her that her cancer had recurred.”

Lasker-DeBakey Award

In 2015,Dr. Allison was awarded the Lasker--DeBakey Clinical Medical Research Award for research and development that “have already benefited thousands of people with advanced melanoma, a disease that typically had a survival of less than a year. The therapy he conceived has delivered recoveries that last for a decade or more.” Unbeknown to Dr. Allison, the Lasker Committee had brought Sharon Belvin and her family as guest attendees to the award ceremony. “I almost lost it when Sharon was introduced. It was a real-life validation of all the work. I still keep in contact with Sharon,” said Dr. Allison.

Challenge in Immunotherapy

Dr. Allisonnotedthat after decades of hard, and often controversial, research, immunology has finally taken its place alongside the other pillars of cancer therapy: surgery, chemotherapy, and radiotherapy. “Moving forward we’ll see some cancers that can be cured strictly by immunotherapy and others that will need a combination approach, matching an immune drug with a particular targeted chemotherapy or radiation therapy. The biggest challenge in immunotherapy now is figuring out why an immune drug works in some patients and not in others, or in some tumors and not in others; to do that we need to go back to basic science. That’s how it’s done; there’s no easy answer, just hard basic science,” he admitted.

Playing the Harp With Willie

Toward the end of their conversation, Dr. -Abraham asked the super busy scientist if he had any hobbies or passions that help him decompress. “I like to travel. I like good food and wine. When I was at Berkeley, I sailed quite a bit, usually with friends, some wine, cheese, and good conversation, tooling around San Francisco out by Treasure Island. I loved it. When I was in New York at Memorial Sloan Kettering, I’d compensate for the lack of sailing with a remote-controlled sailboat on the lake in Central Park,” Dr. Allison said with a laugh.

Then, of course, the harmonica came up, an instrument that Dr. Allison began playing as a young kid and went on to master. “When I was doing postdoc work in California, I hooked up with some ex-pat Texans who had a country western band. I like country western music, so I joined the band. We played twice a week. I never really made any money, but it was fun. They decided to go pro, went back to Texas, and started playing the dance circuit. That’s when I parted company and stuck with my day job as a research scientist.”

Dr. Allison has spent parts of about 25 years in Austin, Texas, which is a bubbling hub for an eclectic music scene. “I was there when Willie Nelson and Stevie Ray Vaughan were hot on the scene. I actually met Willie in California when I was a postdoc and he was getting a platinum record for his Red Headed Stranger album. A friend of mine was a cop who was providing private security for Willie’s private celebration party at some club, and he let me crash it. I got to talking with Willie about music, and he asked me where he could play, as he had a night off. He just wanted to play music. So the next night, I ended up taking Willie and his bass player to the club I played at for talent night. Well he just took over and played for about 3 hours. I got up with my harp and played a song or two,” said Dr. Allison.

When Willie Nelson’s harmonica player, Mickey -Raphael, saw a piece in the newspaper about Dr. Allison’s cancer research, he sent off an e-mail. “We got to be friends over e-mail, and one day out of the blue he contacted me saying the band was going to be playing for a few days at a place called The Redneck Country Club. He asked me to come down and play. So I joined them on stage and played a bunch of numbers. The highlight was playing ‘Roll Me Up and Smoke Me When I Die,’” said Dr. Allison.

Rewards of Taking a Chance

When askedif he had any advice for those entering the field of research, Dr. Allison replied: “All the work I did up to the point of clinical trials was funded by the National Institutes of Health or the National Cancer Institute, and to see the erratic and dwindling support these vital institutions receive is scaring bright students away from basic science. That said, I tell people it is hard and takes a special type of person to be a scientist. Your hypotheses are usually going to be proven wrong, and it takes perseverance. But the big jumps come from fundamental studies of first principles, so the rewards are huge if you take the chance.”

Best Advice Received

“Probably the best advice I received was from my PhD advisor. He simply stressed that you should always do quality work and keep in mind that society is what makes it possible for us to have all this fun in the lab. At some point, you need to think about how you can repay that debt.”

DISCLOSURE: Dr. Allison is a licensor of intellectual property and receives royalties from Bristol Myers-Squibb; is founder, a licensor of intellectual property, and scientific advisory board member of Jounce Therapeutics; is a licensor of intellectual property and receives royalties from Merck; is a founder and scientific advisory board member of Neon Therapeutics; and a scentific advisory board member of Kite Pharmaceuticals.