When James Allison was a young man, his mother died of cancer. He also lost two uncles to cancer and witnessed how chemotherapy's nausea, pain, and fatigue afflicted them before they passed. He became a biologist in part because he believed there "must be a better way" to treat cancer patients.
Allison is getting closer to fulfilling that aspiration in more ways than one. Using knowledge gleaned from decades of his and others' research about the immune system, he has developed a drug that is now being tested for its ability to treat different late-stage cancers. Also, as the newly installed director of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center, he facilitates new approaches to cancer care.
The journey from basic research to a possible new treatment for cancer has been years in the making. During that time, Allison has investigated how the immune system defends the body from pathogens and cancer, focusing on T cells, a class of immune cells that provide some of the protection. Along the way he uncovered key and previously unknown mechanisms about T cell behavior. With that knowledge, he has been able to manipulate the T cell system to make new therapies.
Bacteria and viruses, as well as cancer cells, differ from our body's healthy cells, and elicit an immune response. The body recognizes microbes as unfamiliar because they have foreign proteins on their surface, and then employs the immune system to demolish them. Likewise, the body sees cancer cells as different because they have unusual proteins on their surface, and also destroys them. But the body's surveillance system can fail, allowing tumors to develop.
Allison investigates how T cells respond to alien proteins, which are technically called antigens. In 1982, at the University of Texas at Austin, Allison identified the T cell antigen receptor (TCR), which allows T cells to recognize an unusual protein on the surface of another cell. Employing the automobile as an analogy, Allison dubbed the TCR an "ignition switch," because it turns T cells on, but doesn't do much else. Each T cell has a different "switch," allowing it to respond to different antigens presented to it.
But besides recognizing an antigen, T cells need to be galvanized to act. In 1988, at the University of California, Berkeley, Allison demonstrated that the molecule CD28 is the "gas pedal" a T cell needs for activation. First, CD28 connects with specific molecules on the surface of antigen-bearing cells. The interaction then causes the T cell to divide and create an army of cells ready to kill cells with that antigen.
Something, though, has to stop T cells from proliferating and acting indefinitely. In 1995, Allison, still at Berkeley, found the "brake" on the T cell, called CTLA-4, or cytotoxic T lymphocyte–associated antigen-4. Under normal conditions, CTLA-4 stops activated T cells from their killing of antigen-presenting cells. When Allison deleted the molecule in mice, the animals' T cells kept dividing uncontrollably.
After finding CTLA-4, Allison hypothesized that the immune system may fail to detect tumor cells because "the brake" prevents T cells from eradicating them. So shutting the brake off and allowing T cells to remain activated could stimulate cancer cell killing, he surmised. To test his theory, Allison made a molecule that negated the brake's function: a monoclonal antibody to CTLA-4. When he injected the antibody in mice with different cancers, the least aggressive tumors cleared away, he found in 1996. Combining the antibody with other treatments was even more effective.
Allison collaborated with a biotech company to develop an antibody to human CTLA-4 and conduct clinical trials in a variety of types of cancer. More than 4,000 people have been treated with this antibody, ipilimumab, and objective responses have been observed in advanced skin, renal, lung, prostate, and ovarian cancer. The results of a large randomized phase III trial of ipilimumab in metastatic melanoma was reported in June 2010. The research showed a remarkable survival benefit to patients receiving the antibody, with 25 percent alive 4 years after treatment. This is exciting because ipilimumab is the first drug ever to show survival benefit in patients with melanoma.
Allison continues to study CTLA-4 and other aspects of T cell biology to find steps in the system that could be targets for new treatments. Reflecting on his career, Allison said being a scientist is great fun. "I have always enjoyed the sense of discovery in research, of being the first person to know something," he said. But, he added, he always balanced the joy of doing research with a commitment to use his results to help save people's lives.
