The immuno man

Back in 1977, James Allison arrived at MD Anderson's Science Park in Smithville, Texas, with an itch to discover something new. It was the music-loving, harmonica-playing scientist's first faculty position, and he was happy to be near Austin, his favorite city.

There was no way of knowing then, but Allison's initial research on the immune system at MD Anderson laid the groundwork for his return in 2012 as the father of immune checkpoint blockade — an entirely new way of treating cancer that’s yielding unprecedented results.

Thanks to his clinical collaborators, he's been fortunate enough to meet some of those saved by his drug, ipilimumab (Yervoy®), the first ever to improve survival for patients with advanced melanoma. According to American Cancer Society predictions, the disease will kill more than 9,700 people in the U.S. in 2014.

One of the most dramatic stories belongs to an original phase I clinical trial patient in Los Angeles.

"The patient just wanted to live long enough to see her teenage sons graduate from high school," says Allison, chair of Immunology. "That was 14 years ago. She's lived to see them go to college, go to graduate school, start their own families and get established in their careers …" His voice trails off and his eyes mist. "I get emotional talking about them. That's what it’s all about."

The basic science behind success

"Jim has great scientific intuition and he's stubborn — or maybe persistent is a better word. He tells you exactly what he thinks," Patrick Hwu, M.D., says of Allison, who goes by Jim.

"He had the vision to see the research through to a paradigm changing treatment strategy," adds Hwu, chair of Melanoma Medical Oncology, who's both a scientific and musical collaborator of Allison. "I truly appreciate what he's done for my patients."

Follow-up studies show an unprecedented 22% of late-stage melanoma patients treated in ipilimumab clinical trials survived for at least four years. Meanwhile, checkpoint blockade is being extended to treat other cancers, and the journal Science named cancer immunotherapy its 2013 Breakthrough of the Year.

Allison lost his mother to lymphoma when he was 11 years old and a brother later on to prostate cancer, a disease he himself has survived.

"My family has suffered greatly from the ravages of cancer, so cancer treatment has always been in the back of my mind," he says.

"But I didn't set out to develop a cancer treatment. If I had, I probably would have missed something important because the target we found isn’t on tumors, it's on T cells," Allison says. "Checkpoint blockade emerged as a cancer therapy only because we first uncovered the basic science and biology of T cells, the immune system's primary attack cells. It's a classic example of how understanding basic science can lead to new disease treatments."

Allison's return to MD Anderson in November of 2012 came with a $10 million recruitment grant from the Cancer Prevention and Research Institute of Texas and an MD Anderson commitment of $30 million to develop an immunotherapy program that Allison says is unmatched in its scientific and clinical capabilities.

"Immunotherapy is the most exciting and promising area of cancer research today, and its potential is just beginning to be realized," says MD Anderson President Ron DePinho, M.D. "We’re proud to have Jim leading our efforts to expand and hone this approach as executive director of MD Anderson's Moon Shots Program immunotherapy platform." Allison, who's encountered a lot of immunotherapy naysayers over the years, acknowledges DePinho's commitment to advancing the treatment.

"Ron is the first cancer center leader to say 'we're really getting into this big,'" he says. "I wouldn’t be here without him."

First stop: Science Park in Smithville

Almost 40 years ago, fresh from a post-doctoral fellowship at the prestigious Scripps Clinic and Research Foundation in La Jolla, Calif., Allison was looking for his first job as a scientist.

A friend in Houston tipped him off to a new MD Anderson program in Smithville, a research center that studies cancer causes. Importantly for Allison, Smithville is just southeast of Austin.

“I grew up in Alice, which is a very small town in South Texas,” Allison says. “Summer science programs at The University of Texas-Austin, starting in middle school and continuing through high school, were fun, inspiring and a lifeline to intellectual life.”

At 16, he enrolled at UT-Austin and ultimately earned a doctorate in biological sciences. Along the way, he soaked up the city’s academic energy and music scene.

In La Jolla, he had played harmonica in a band and once finagled his way into a platinum-record celebration for fellow Texan Willie Nelson. When Nelson asked afterward where he might go pick and play that night, Allison gave him and two other musicians a ride to his regular haunt, The Stingaree.

“A friend of mine was singing ‘Blue Eyes Crying in the Rain’ when we arrived. He just about gagged.Willie sang that song later and I got to play harmonica,” he recalls.

That part of his California stay was fun, but “I loved Austin and wanted to get back,” Allison says.

So he packed his car, drove to Smithville and inquired about a job. He became the sixth person hired at the Science Park, an assistant professor in Biochemistry. His initial research involved using components of the immune system — antibodies — to understand liver cancer.

But Allison was intrigued by the immune system itself; dating back to mouse studies he conducted as an undergraduate.

“The complexity and versatility of the immune response fascinated me,” he says.

The T cell ignition switch

"Ellen Richie, my friend and colleague from graduate school, was having a lot of fun studying T cells,” he recalls. “She urged me to get into them, which recently had been discovered and were poorly understood.”

Richie, today a professor in Molecular Carcinogenesis at Smithville, is an expert on the development of T cells and the thymus — an organ right behind the sternum where these white blood cells mature.

“Somehow, something I said raised his interest in T cells, but I don’t recall specifics,” Richie says. “I’m really glad that it did, though, because he revolutionized the field.

“From his earliest days, he was always on the cutting edge,” she says. “He was never shy or put off by common wisdom or existing methods, challenging them when he found evidence to the contrary. He’s persistent — he definitely doesn’t give up.“

The big mystery of the time was the T cell antigen receptor. Nobody had any idea what it was,” Richie says. “The intellectual challenge that presented itself appealed to Jim.”

T cells seemed to function in a way that required them to recognize an antigen — a distinctive piece of a virus or bacterium, for example — to become activated and attack the invader. Research to identify a T cell antigen receptor had been so plagued by lack of conclusive proof that some scientists thought it might not exist at all, that T cells worked by some other mechanism.

Allison recalls a graduate-level immunology textbook that closed with some advice for budding immunology researchers: “Don’t try to find the T cell antigen receptor because it’s ruined more careers and wasted more time than any other single thing.

“So we tore that page out and stuck it to the wall in our lab because we figured we already had it, or at least an antibody to it.”

In a 1982 paper in the Journal of Immunology, Allison and colleagues identified an antibody that bound only to a specific type of lymphoma cell. Its specificity was a surprise — it didn’t connect with any other lymphoma cell line or with normal spleen, thymus, lymph node or bone marrow tissue.

Intrigued, they tapped their biochemistry expertise to determine the underlying protein structure on the lymphoma cell surface that held the antigen. Then they looked for similar proteins on the surfaces of other types of cells, finding them only on T cells and their precursor cells, but not on the better-known immune system B cells or in the bone marrow.

Their findings suggested that the protein complex made up a T cell-specific surface structure with both constant and variable regions, ideal for acting as the versatile, longsought T cell antigen receptor.

After publication, the young scientist was invited to a Gordon Conference on immunology, an elite meeting of the leading researchers in the field. A major paper in Cell soon confirmed what Allison’s team had suggested.

“The T cell antigen receptor is the ignition switch of the immune response,” Allison explains. But it wasn’t enough to fully ignite immunity by itself.

CD28: The gas pedal

The next step was to identify the genes responsible for the T cell antigen receptor, and, at the time, MD Anderson simply wasn’t equipped for such research. Allison took a visiting professorship at Stanford in the lab of Irv Weisman, a leading scientist who once gave a speech at MD Anderson that had set Allison’s mind abuzz with research possibilities.

As it happened, other scientists beat them to the genes. While in the Bay Area, Allison gave an invited talk at the University of California, Berkeley, and made a strong impression. He was soon recruited to lead the immunology department there.

Leaving MD Anderson in 1984 was difficult.

“Smithville was wonderful for several reasons,” Allison recalls. “I had no administrative duties, I didn’t teach, I just did science all of the time. Had a great team, good support and a few National Institutes of Health grants.

“I owned a house and 18 acres in the Lost Pines area close enough to walk through the woods every day to work (the Science Park is located within Buescher State Park) and had a house in Austin.”

At Berkeley, Allison turned his attention to a molecule on the surface of T cells called CD28. By then, researchers knew that an antigen presented to a T cell was not enough to activate it, and CD28 seemed like a good candidate as a co-stimulatory molecule.

In a study published in Nature, Allison and his colleagues showed that CD28 is cross-linked to the antigen receptor and, when activated, sparks an immune response, much like a gas pedal applied after ignition moves a car.

CTLA-4: The brakes

French scientists identified another T cell surface protein they named Cytotoxic T-Lymphocyte Antigen 4, or CTLA-4. Because it greatly resembled CD28 and was activated by the same binding molecules, the initial thought was that CTLA-4 was another co-stimulator.

Allison’s research, and additional work done by Jeff Bluestone, Ph.D., then at the University of Chicago, indicated otherwise. In July 1994, they presented data at another Gordon Conference showing CTLA-4 inhibited immune responses. Subsequently, they published papers demonstrating that effect in mice.

“CTLA-4 is cross-wired with the antigen receptor and CD28, so the brake is activated at the same time to help ensure that the immune response doesn’t go on and on, destroying healthy cells,” Allison says.

For decades, research had shown that activated T cells often penetrate tumors, indicating an activated immune response, but one insufficient to overcome the cancer. It occurred to Allison that the CTLA-4 checkpoint might be shutting down those immune responses and that blocking it might free T cells to more effectively find and kill cancer.

A mouse experiment in 1995 using an antibody against CTLA-4 worked so well that Allison wanted to repeat it immediately. He didn’t know which mice, all with colon cancer, had been treated with the antibody to block CTLA-4. All developed tumors, but by the third week, distinct differences developed. For some, tumor growth slowed, then stopped and the tumors went away completely, while others progressed rapidly.

When the experiment was unblinded after six weeks, nine of the 10 treated mice were fine, all of the untreated had died. These results were repeated in a variety of cancers, including melanoma. 

“I thought, ‘we need to get this to people as soon as we can,’ ” Allison says.

The slow road to drug approval

Translating Allison’s antibody against CTLA-4 into the clinic was a frustrating grind, so his legendary persistence became crucial. He shopped it to 12 companies over two years, none of which were interested.

Some were intimidated that Bristol-Myers Squibb had a patent on another antibody to CTLA-4. Others scoffed at yet another immunotherapy idea — a field plagued by earlier therapies that didn’t come close to living up to their hype.

Finally, a small company licensed the patent and tried unsuccessfully to make a small-molecule drug to block the brakes rather than use an antibody to CTLA-4 that he and colleague Alan Korman had made. The project stagnated.

“It got pretty ugly. I tried to get it back,” Allison says. 

In 1998, a small biotech called Medarex bought the drug rights and made the human antibody to CTLA-4. An early clinical trial was deemed a failure after tumors didn’t shrink by three months of treatment — the usual clinical-trial standard for new chemotherapy — and in some patients, tumors appeared to grow. 

Fortunately, physicians involved in the clinical trial noted that many of the patients showed tumor shrinkage later than three months and continued to live well beyond the expected survival period for late-stage melanoma. As it turned out, immune responses in those patients were sometimes slow to get started. 

Bristol-Myers bought Medarex in 2009 for $2.4 billion and advanced ipilimumab through clinical trials, culminating in a successful phase III study that finally led to FDA approval in 2011. In the meantime, Allison had moved to Memorial Sloan Kettering in New York in 2004 to head its immunology efforts and work with clinicians conducting clinical trials there.

Improving overall survival

Eight other immune checkpoint or costimulatory molecules have been identified, and drugs to block the PD-1 checkpoint currently are advancing through clinical trials.

When the FDA approved ipilimumab for metastatic melanoma, it cited the traditional measure of success: an increase of four months in the median overall survival (the point where half of treated patients remain alive) of treated patients. 

But that’s not what has oncologists excited about the drug and the checkpoint blockade approach. When ipilimumab works, it works for a long time — complete remission or disease so tamped down that life returns to normal for patients who once faced certain death from the disease. This is an uncommon result not just for metastatic melanoma, but for any type of solid tumor that has spread to other organs.

“Long-term follow-up, so far, indicates that once a patient survives for three years, if they die after that, it’s from something other than melanoma,” Allison says.

One of the important mysteries that has yet to be solved is why the drug doesn’t work for more patients. Testing new combinations is an exciting area, as are discovering new checkpoints and co-stimulatory molecules, as well as developing drugs to address them. Research at MD Anderson addresses all of these.

Five pharmaceutical companies have signed collaborative agreements with MD Anderson’s immunotherapy platform to develop new drugs.

Allison points out that one of MD Anderson’s strengths is the ability to conduct innovative clinical trials that include the measurement of scientific endpoints.

These protocols, developed by Padmanee Sharma, M.D., Ph.D., associate professor in Genitourinary Medical Oncology, allow patients to consent to presurgical treatment with an immunotherapy. This permits in-depth analysis of the molecular effect of the drug after the tumor is removed.

This approach allowed Sharma to discover that activation of a protein called ICOS increases ipilimumab’s effectiveness.The details of this co-stimulatory molecule and its effect were then worked out in a mouse model. ICOS activation to improve treatment now is being explored by Jounce Therapeutics, a company co-founded by Allison and Sharma.

“Immunotherapy for cancer is really just beginning,” Allison says. “As we learn more and develop immunotherapy drug combinations,we can start thinking about curing cancer in many patients. MD Anderson is a center of immunotherapy excellence that will grow, improve and contribute significantly to that cause.”

A lifelong hunger for knowledge

Knowledge has been its own reward for Allison, going back to childhood.

“I’ve always wanted to know how things work. My father was a doctor in Alice, Texas, so I had a pretty good look at what it’s like to be a physician. As a doctor, you can’t make mistakes,” says Allison.

“The scientist’s job is to generate and test hypotheses, which are wrong most of the time, otherwise the answer would be obvious. So you go back and do another experiment,” Allison says. “Scientists only need to be right some of the time — preferably about something important.”

Allison has been right often enough about important things that honors have been pouring in — including seven major awards since April 2013.

Prestigious awards given to Allison recently:

• The Economist’s 2013 Innovation Award for Bioscience
• The Breakthrough Prize in Life Sciences, which recognizes researchers whose work extends human life and is worth $3 million
• The 2014 Canada Gairdner International Award, which recognizes seminal medical discoveries
• The 2014 Szent-Györgyi Prize for Progress in Cancer Research from the National Foundation for Cancer Research
• The inaugural AACR-CRI Lloyd J. Old Award in Cancer Immunology from the American Association for Cancer Research and the Cancer Research Institute. It’s named in honor          of Old, an immunology trailblazer.
• Elected as a fellow of the American Association for Cancer Research Academy 
• 2014 Tang Prize for Biopharmaceutical Science