"I Wanted to Figure Out How Things Work"
When James Allison, the new Chairman of the Immunology Program at the Sloan-Kettering Institute (SKI), was growing up in a small oil town in Texas, he was just like any other kid, with, as he explains, one exception: "I probably spent a bit more time with my chemistry set and a little less time on the football field."
By the time he reached eighth grade, he had decided that he was going to be either a scientist or professor. The scientific curriculum at the local schools left something to be desired, but fortunately for Dr. Allison, two of his teachers recommended him both for correspondence courses and for summer programs at the University of Texas, Austin.
"I wanted to figure out how things worked," says Dr. Allison. "That gradually evolved, in the somewhat egotistical way that affects many scientists, into the idea that I wanted to be the first person on the planet to know something before anyone else." He concluded that the best way to do this was through a career in basic science, which he began pursuing at the University of Texas, Austin, where he received his BS in Microbiology and his PhD in Biological Sciences.
But the desire to be a scientific pioneer was not the only motivation driving Dr. Allison early in his training. Coupled with his quest for knowledge, he also understood that there should be a responsibility to pay society back. "I tried to look at basic science and ask, 'How can this be used to make a difference with people?'" he explains. This led him to develop in interest in cancer research -- a subject of particular, personal relevance. "My mother and two of her brothers died of cancer. And I thought we could do better."
Dr. Allison has long had a particular interest in the field of immunology and its potential clinical applications, an interest dating back to a grad school project that involved the discovery of an enzyme which could cure leukemia in mice.
After receiving his doctoral degree and finishing a postdoctoral fellowship in the Department of Molecular Immunology at Scripps Clinic and Research Foundation, he accepted a faculty position at the University of Texas System Cancer Center. This was followed by a year as a visiting scholar at Stanford University School of Medicine, then a 20-year stint at the University of California, Berkeley, where he was a professor in the Division of Immunology and Director of the Cancer Research Laboratory.
Dr. Allison's research has focussed on the mechanisms that regulate the immunological responses of T lymphocytes, also known as T cells, with an emphasis on the development of strategies to manipulate those responses to develop novel tumor immunotherapy approaches.
The Complexity of the T cell
In the midst of many promising discoveries, it became apparent to Dr. Allison and other researchers working in the field that stimulation of T cell response was more complicated than originally thought. As Dr. Allison and others discovered, first the T cell uses a structure called the antigen receptor to recognize a foreign antigen in the system (created by infecting viruses or bacteria, or new antigens found in tumor cells). Using an automobile as an analogy, Dr. Allison likens this step to turning the key in the car's ignition. "The car is running, but it's not going anywhere."
Recognition is not enough. Dr. Allison explains: "A second signal is also required, which, in the car analogy, would be the foot on the gas pedal." This second signal occurs when a particular family of molecules called the B7 molecule engages a molecule known as CD28 found on the surface of the T cell. Only these molecules are capable of initiating T cell response.
The final part of the car analogy is the immune system's brake -- an immune-regulating molecule, whose function was discovered by Dr. Allison's lab, known as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 inhibits activated T cells in the immune system, preventing them from attacking the body's own tissues.
Promising Results
Dr. Allison theorized that if CTLA-4 could be blocked from carrying out its inhibitory functions, then the cancer-fighting activity of certain vaccines and the T cell response they trigger could be enhanced. This theory was proven in mouse models, when his lab identified and used an antibody that blocked CTLA-4. The antibody has been effective in mice against colon cancer, fibrosarcoma, melanoma, renal carcinoma, and prostate cancer, and it has shown early promise in early-stage clinical trials, treating patients with melanoma and ovarian cancer. In the mouse models, the only apparent side effect was the development of tissue-specific autoimmunity.
As a result of his work, Dr. Allison was appointed as an Investigator of the Howard Hughes Medical Institute. He was also elected to the National Academy of Sciences, which described his groundbreaking isolation of the T cell receptor protein as "one of the three most important findings in immunology in the last twenty years."
An Exciting Time and an Exciting Place
Having only recently arrived at Memorial Sloan-Kettering, his excitement for the Center is already obvious: "The overall quality of the science being done here and the leadership administering it are outstanding. It's an exciting time and an exciting place to be."
Dr. Allison has big plans for the Immunology Program at SKI. "My goal, initially, is to concentrate on bringing outstanding basic scientists here. Then, using the unique resources available, we want to bring the basic scientists together with the clinicians." He notes that the new research building, scheduled to open in 2006, will help to foster this interaction.
"I believe that the Immunology Program at Sloan-Kettering, in conjunction with our clinical counterparts at Memorial Sloan-Kettering, is positioned to translate basic research advances into treatment applications that can make a difference in people's lives," Dr. Allison says, his voice brimming with enthusiasm.
