Innovation

A new Texas icon: Nobel laureate James Allison, Ph.D., explains how his research led to new cancer therapy

The immunologist explains his fascination with T cells and details his own cancer survivorship story


By Cindy George | November 6, 2018

Through weeks of international acclaim, with highlights that included an early-morning phone call from Sweden and a homecoming parade through the halls of MD Anderson, James Allison, Ph.D., insisted that he never set out to find a new way to treat cancer.

As a basic scientist, Allison arrived at immunotherapy by way of T cells.

“I’ve always been interested in the immune system and, in particular, a very specific part of it called T cells. These are cells that, to me, are just amazing,” Allison said. “They go all through your body looking for infection or cancer, we know now, and respond to it by generating an army of similar soldiers who can attack … in a way that doesn’t harm normal cells. I’ve been intellectually challenged by the wonderful complexity of that.”

Allison was awarded the 2018 Nobel Prize in Physiology or Medicine jointly with Japanese immunologist Tasuku Honjo, M.D., Ph.D., for the discovery of cancer therapies that stimulate the immune system to attack tumor cells. Treatments developed from Allison’s work have extended the lives of thousands of people with advanced disease, though certain cancers have responded better to immunotherapy than others.

“A few cancers, like glioblastoma and pancreatic cancer, thus far, have not responded at all,” Allison said. “There’s a lot more hard work to be done.”

Both Allison, 70, and Honjo, 76, made discoveries that led to the development of “checkpoint inhibitors,” drugs infused into patients to block molecules that put the brakes on T cells. By releasing these brakes, the body’s own immune system is able to fight cancer.

Allison recognized that a protein on T cells called CTLA-4 stopped their ability to fight disease. By inhibiting that checkpoint—or releasing the brakes—he found that the T cells could be unleashed to attack tumors. Allison developed an antibody to block CTLA-4, which turned into the drug ipilimumab, now used to fight metastatic melanoma. Known commercially as Yervoy, the drug was approved in 2011 by the U.S. Food and Drug Administration (FDA) and has delivered unprecedented results.

Honjo, of Japan’s Kyoto University, also discovered a protein on immune cells that serves as a brake—the checkpoint molecule PD-1. In 2014, the FDA approved the drugs Keytruda and Opdivo, which inhibit PD-1 for the treatment of metastatic melanoma. In March 2015, Opdivo was approved for lung cancer treatment.

The fourth pillar

Now, Allison and his research collaborator and wife—MD Anderson oncologist Padmanee “Pam” Sharma, M.D., Ph.D.—plan to build on their accomplishments by using immunotherapy in tandem with traditional treatment to increase response rates in patients.

Allison said the melanoma data is especially encouraging. A study of almost 5,000 patients who had a single round of immunotherapy—four injections over three-week intervals—showed that 20 percent were alive 10 years after treatment. A combination of immunotherapy with a traditional treatment tripled 10-year survival to about 60 percent.

“The good news is that we know it can be done in some patients,” Allison said. “There’s a lot of optimism, but still a ways to go. That’s going to come from combining immunotherapy with conventional types of therapy.”

Though Allison has been mentioned as a contender for the Nobel for several years, he said he was shocked by an early-morning phone call on Oct. 1, 2018 from his son, Robert, an architect in Manhattan, telling him he had won the coveted prize. Allison and Sharma were in New York for an immunology meeting and, after the new laureate spoke to Nobel officials in Stockholm, the couple’s hotel room filled with friends and colleagues bearing champagne.

During a news conference later that day, Allison explained how his research has driven cancer treatment closer to a cure.

“After many years of resistance, I think the cancer field has begun to accept immunotherapy now as the fourth pillar—along with radiation, surgery and chemotherapy—of cancer therapy. … Immunotherapy can be used in combination with the other three. I think that what we are looking forward to is combinations in the future—not just of multiple checkpoints, but of checkpoints with radiation, checkpoints with chemotherapy, checkpoints with genetically targeted small molecule drugs. It’s not going to replace all those others, but it’s going to be part of the therapy that essentially all cancer patients are going to be receiving in five years or so—and they’re going to be curative in a lot of patients.”

Three bouts with cancer

Allison is a cancer patient himself.

“I am currently being treated for bladder cancer,” the scientist said. “I’m doing great. One of the benefits of working in a cancer center is that it was picked up early and I get the best treatment. It’s an old, crude [treatment] that’s been around since the ’60s. It’s called BCG treatment. It’s the use of bacteria in the bladder. They irritate it and that leads to an activation of the immune system. Nobody knows exactly how that particular one works even though it’s been around for 50 years now.”

BCG is a germ placed directly into the bladder through a catheter.

This is Allison’s third bout with cancer. The first occurred more than a decade ago.

“Pancreatic. It was caught early. I had surgery about 12 years ago. Then, a few years ago I had melanoma surgically removed from my nose,” he said.

Because Allison’s research is targeted to more advanced cancers, he personally has not benefited from the immunotherapy he helped pioneer.

“I have localized disease,” he explained. “These immunotherapies—the checkpoint blockades that I developed—start off as experimental therapies that treat the people that have no other alternative. … As with all drugs, the treatments with time are going to move earlier and earlier in the disease.”

Important questions

Allison was born in Alice, Texas, a small town 50 miles west of Corpus Christi. His father was a “country doctor” who helped inspire his son’s interest in basic science. Allison lost his mother to lymphoma when he was 10 and cancer also claimed two uncles. The budding scientist witnessed the ravages of radiation and chemotherapy at an early age.

As a young man, Allison grew interested in the role T cells played in the immune system. After finishing his bachelor’s degree in microbiology and a doctorate in biological sciences at The University of Texas at Austin, Allison first worked for MD Anderson at its science park in Smithville, Texas, where he began unraveling the mysteries of T cells from 1977 to 1984. He took a sabbatical to Stanford University to continue his research.

“He slept on my couch on and off for the next year. We got to be good friends,” said Lewis Lanier, Ph.D., now chair of the department of microbiology and immunology at the University of California, San Francisco. The pair had bonded a few years earlier during a week of extracurricular skiing and wine-drinking at a lymphoma conference.

“We started doing things scientifically together related to understanding the T cell receptor and we published some nice papers together during that time,” Lanier said, noting that Allison eventually jumped from Smithville to the University of California, Berkeley. “Then we got to be really close friends.”

Over the next two decades, Lanier and Allison collaborated professionally while celebrating holidays at each other’s homes. Their families vacationed together. During this period, Allison honed his love of the blues and country music as a harmonica player who performed with The CheckPoints, a band composed of immunologists and oncologists.

For years, Lanier has set his alarm to wake in the wee hours for the Nobel Prize announcement in medicine—and then gone back to sleep. This year, Lanier stayed wide-eyed and rang his longtime friend to offer congratulations.

“It’s so well deserved. There really would not be this new checkpoint blockade therapy without him,” Lanier said. “Jim always asked: ‘What is the important question to pursue?’ And then he’d go after that doggedly. He did that with the T cell receptor. He did that with what is known as co-stimulation—identifying the turbocharge for the second segment of T cells—and then when he had the idea of blocking the inhibitors of the T cells to apply that to cancer. Those were three huge questions that he managed to address.”

Driven to find the truth

Antoni Ribas, M.D., Ph.D., a professor of medicine at the University of California, Los Angeles (UCLA), met Allison in the mid-2000s after making a presentation at an American Society of Clinical Oncology meeting. Ribas had used a CTLA-4-blocking antibody in patients and was sharing the results.

“I told everyone that the person who invented this approach just walked in—Jim Allison,” Ribas said. “After that, we had a very close relationship. We talk on Saturday mornings about what we are doing. It wasn’t until I went to the celebration of his 70th birthday that Jim said that I was the first one to acknowledge his work in a medical oncology meeting. He said that many other people who were working on those antibodies acted as if they had invented them and there was nothing behind them.”

Ribas, an oncologist-researcher, had been reading Allison’s papers for years and trying to replicate his work.

“I emailed him at one point asking him for the mouse antibody. He didn’t answer, but a week later I received the antibody in the mail and I was able to experiment,” Ribas said.

The first human trials of ipilimumab took place in a private oncologist’s California office affiliated with UCLA. Ribas referred patients to the study. One of them, Sharon Vener, had several tumors that did not shrink with other treatments. She was the first patient whose cancer responded to ipilimumab. That was in 2001. Now in her mid 60s, Vener has survived cancer for 17 years thanks to Allison.

“His understanding of how the immune system is regulated led to the hypothesis that if you take away a brake, the immune system would attack some cancers. That has made a big change in the clinic and I have a bunch of patients who have benefited from that,” Ribas said.

Allison always pursues big ideas, but he knows there is more to life than work.

“He is driven to find the truth of things,” Ribas said. “Some people think the goal of their life is to write an article in Nature or Science or The New England Journal of Medicine. His motivation is to write about something important that may change how we treat cancer.”

At the same time, Ribas added, Allison “is a fun guy. He is somebody who enjoys life and has a lot of interests.”

With the band

Phil Greenberg, M.D., head of the immunology program at Fred Hutchinson Cancer Research Center in Seattle, became friends with Allison 40 years ago during their post doc days in San Diego.

Once, during a conference in Maui, Hawaii, Allison noticed a black-tie benefit in a newspaper headlined by Willie Nelson, with whom the future laureate had jammed in Texas. The scientists decided to “crash the event” in their jeans, Greenberg said. Both have long hair and when they pulled up in a rented Ford Mustang convertible, the valets assumed they were with the band and escorted them into the affair.

“It was an open bar, so we kind of hung out. The show hadn’t started,” Greenberg said. As attendees moved to tables, they did too—then enjoyed a meal and the concert. “After the performance, Willie came out. He had a drink with us and took a picture with us. … It was a really fun time.”

Big leaps

In a Dec. 10 ceremony in Sweden, James Allison and Tasuku Honjo will each receive a Nobel medal and diploma. The scientists will also share a $1 million prize.

Allison is the first Nobel laureate for MD Anderson, where he is a professor and chair of the department of immunology. He is the executive director of the Immunotherapy Platform, which is part of MD Anderson’s Moon Shots Program—an ambitious effort to more rapidly reduce cancer deaths and suffering by developing advances in prevention, early detection and treatment based on scientific discoveries. In addition, Allison holds the Vivian L. Smith Distinguished Chair in Immunology and serves as deputy director of the David H. Koch Center for Applied Research of Genitourinary Cancers in the department of genitourinary medical oncology.

“The miracles actually come out of deep science and understand- ing how it works,” Allison explained, following a parade in his honor when he returned to MD Anderson a few days after winning the Nobel. “Our work on this molecule, CTLA-4, had nothing to do with cancer—it had to do with understanding how T cells work. And once we figured it out, then I was able to say: ‘Oh, maybe we could do this’ and take it to the clinic.”

After technology billionaire Sean Parker invested $250 million in 2016 to form the Parker Institute for Cancer Immunotherapy—a research collaboration between six leading academic research institutions in the United States—Allison, Lanier and Ribas were selected to direct the Parker centers on their respective campuses.

In mid-October, Allison was asked to offer advice to young scientists during an online chat hosted by STAT news. His thoughtful response articulated the philosophy of his steady, four-decade pursuit.

“Follow your heart. Find something you’re really interested in. Do absolutely the best you can at your science without a whole lot of regard for potential translation—that can come later,” he wrote. “When you really understand something, then you can think about how it’ll be applied. Don’t start with trying to solve a particular issue of medicine; you’re unlikely to find any great leaps or findings. The big leaps come from understanding fundamental mechanisms in detail.”

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WHAT IS IMMUNOTHERAPY?

Immunotherapy is a type of treatment that trains the immune system to attack cancer. Immune system cells—including T cells (so-called because they develop in a small organ called the thymus gland) and antigen-presenting cells (APCs)—defend and protect the body. APCs patrol the body and T cells are the soldiers of the immune system. When an APC finds something suspicious, it sends a signal to a T cell to multiply and attack the suspicious cells.

But if T cells don’t stop multiplying, they can damage healthy cells, so a safety switch in the T cell, called a checkpoint, prevents this. Because cancer is so complex, though, T cells are switched off before their work fighting cancer is done. Checkpoint inhibitor drugs, the most common type of immunotherapy, can prevent T cells from being switched off. This allows T cells to fight cancer. Immunotherapy also helps the immune system remember so the T cells can quickly target the cancer if it returns.

WHAT CONTRIBUTION TO IMMUNOTHERAPY EARNED JAMES ALLISON A NOBEL?

Allison blocked a protein on T cells that acts as a brake, thus freeing T cells to attack cancer. Specifically, Allison developed an antibody to block the checkpoint protein CTLA-4. His work led to the devel- opment of the first immune checkpoint inhibitor drug, ipilimumab, known commercially as Yervoy.

Source: The University of Texas MD Anderson Cancer Center




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