Albert Lasker
Clinical Medical Research Award

To understand the achievements of this year's Lasker Clinical Medical Research awardees, it is important to consider the vital role the immune system plays in protecting us from infection. The immune system must constantly distinguish our own cells from those of the viruses and bacteria to which we are exposed. Its critical role has been demonstrated by the devastating infections experienced by children born without an intact immune system, by patients whose immune function has been destroyed by diseases such as AIDS, or when a cancer patient's immune cells are damaged as a result of the side effects of chemotherapy. Thus, the complex immune system we have evolved plays a vital role in maintaining our health and survival. Harnessing its power to prevent disease through vaccination is one of the most important medical advances of the last century.

One price which we pay for having an immune system that can protect us from infectious organisms is that it will occasionally suffer errors in the ability to distinguish between our own cells and those of invading microbes. The chances are small during any single infection that such an error will occur. However, when this risk is summed over a lifetime of exposures, there is an increasing chance that an individual will suffer the consequences of the immune system's mistaken attack on our own tissues. Such disorders are collectively known as autoimmune diseases. Although in most instances these diseases do not have the acute consequences of a heart attack, stroke, or cancer, they are a major cause of chronic illness and disability. One of the most prevalent autoimmune diseases is rheumatoid arthritis, a disease in which the body's immune system attacks the joints. Rheumatoid arthritis afflicts approximately one percent of the population. It affects women more frequently than men, and its incidence is relatively constant throughout the world, independent of geographic location, race, and socio-economic status. The disease is insidious in onset, the joints involved can vary, and symptoms often wax and wane, making the diagnosis difficult to establish in its early stages. However, once established, rheumatoid arthritis is a chronic and progressive illness, spreading like a wildfire through each of the joints. By the time most patients are diagnosed, the complications of chronic inflammation are so destructive that a vicious cycle of inflammatory joint damage followed by further activation of the immune system results in an endless spiral of disease.

Over the last 50 years, physicians have made little progress in improving the treatment of chronic autoimmune diseases such as rheumatoid arthritis. Although anti-inflammatory treatments such as aspirin can decrease the patient's symptoms, they do nothing to halt the progressive nature of the disorder. Steroids can suppress the chronic pain syndrome associated with these autoimmune diseases, but do little to alter the natural progression of the disease and are associated with significant long-term side effects. Until recently the greatest hope of intervening in the disease came with treatments using cancer chemotherapeutic agents that are used to destroy the immune cells causing the inflammation. Unfortunately, the use of these drugs involves all the complications associated with cancer treatments.

Beginning in the early 1980s, immune cells were discovered to release molecules, termed cytokines, which served to control the immune response. Investigation of the properties of these cytokines led to the clinical introduction of blood cell recovery factors such as erythropoietin for the treatment of anemia and the use of interferons in the treatment of cancer. To date, over 100 of these cytokines have been discovered, many with overlapping functions. Immunologists have rationalized the existence of so many cytokines because, as we have learned in this age of terrorism, the best defenses have multiple redundant back-ups built into the system.

At the time that Ravinder Maini and Mark Feldmann began the work for which they are being recognized today, it was clear that the joints of rheumatoid arthritis patients were a conflagration of these inflammatory molecules, the properties of any one of which is enough to induce an inflammatory response that would destroy the joints of the afflicted patients. This led to the "conventional wisdom" that autoimmune diseases could not be treated by blocking the actions of any single cytokine.

At this juncture, it is important for me to point out that Mark Feldmann and Ravinder Maini are not conventional characters. Mark Feldmann is Australian by birth and his desire to work at the interface of medicine and science led him, after medical school and residency, to return to school where he earned a Ph.D. in immunology at the University of Melbourne studying with Gus Nossal, one of Australia's preeminent scientists. Upon graduation, instilled with a burning desire to prove himself, Mark moved his family halfway across the world to London to take up a position in clinical immunology. It was in London that he met Ravinder Maini. In Maini, Feldmann found a kindred spirit. "Tiny," as Maini is known to his friends, had grown up to his current impressive stature in East Africa. During his childhood in Africa, Maini learned from his father the satisfaction of a life dedicated to the service of others. His father had served as mayor of Kampala during the troubled time preceding Ugandan independence and was recognized for his service in that part of the world by being knighted by Queen Elizabeth in 1957. It was with the desire to make a contribution to the world as his father had, that Tiny began his secondary education in England. However, during his undergraduate days in Cambridge, his interest turned to medicine. At the time he met Feldmann, Maini was working as a consultant rheumatologist at the Arthritis Research Campaign's Kennedy Institute of Rheumatology in London.

From the beginning, Feldmann and Maini shared the belief that the damage caused during an autoimmune disease resulted from the incendiary properties of cytokines that immune cells produce. They also believed that there existed a "spark" that initiated the inflammation during the early phases of the disease. With this underlying hypothesis they began a systematic study of the role each cytokine played in the inflammation observed in biopsy samples from the damaged joints of patients with rheumatoid arthritis. In less than two years, they found their "spark," TNF or tumor necrosis factor, a cytokine so named because it was capable of damaging even the most malignant cell.

The idea that a single cytokine was responsible for the initiation and maintenance of joint destruction in rheumatoid arthritis was viewed by most immunologists with skepticism. Furthermore, most argued that even if Feldmann and Maini were right, there didn't seem to be a way to use this information to develop a treatment. However, an experiment of nature showed the way. Another autoimmune disease, myasthenia gravis, in which patients suffer progressive muscle weakness, was found to be caused by antibodies that blocked the actions of the secreted molecules that normally transmit information from the nerves to the muscles. These observations raised the possibility that one type of immune molecule, an antibody, could be used to block the action of another, a cytokine.

To test this hypothesis, Feldmann and Maini obtained an antibody against TNF and initiated a clinical trial in 20 patients with long-standing rheumatoid arthritis that had failed to respond to existing disease-modifying drugs. The results from the onset were astonishing. All 20 patients responded to the treatment and many experienced almost a complete reversal of their swollen joints six weeks after the start of therapy. Drs. Maini and Feldmann went on to organize large, randomized trials to demonstrate the efficacy of TNF antibody in the treatment of chronic rheumatoid arthritis. Not only did these trials demonstrate a dramatic reduction in symptomatology, but over half the patients had improvement in the destructive joint changes they had already undergone, something no other therapy had ever accomplished. Based on the success of these clinical trials, these agents have been approved for therapy in both Europe and the United States. Today, over 300,000 patients have been treated with some form of anti-TNF blocking activity for the treatment of rheumatoid arthritis. This number is currently only limited by the pharmaceutical industry's ability to produce the drugs. More recently, clinical trials have demonstrated the efficacy of TNF blockade in the treatment of other autoimmune diseases including Crohn's disease, an autoimmune disease which destroys the intestines; ankylosing spondylitis, an autoimmune disease that attacks the spine; and psoriasis, an autoimmune disease of the skin. This remarkable story, from inception to clinical approval, took only a decade.

The results of Maini and Feldmann's work have demonstrated that not only is TNF the "spark" that ignites the inflammatory destruction of the joints in rheumatoid arthritis, but it is also responsible for what keeps the inflammatory fire smoldering between the acute episodes of the disease. Furthermore, the brilliant use of one of the immune system's own defenses to treat an autoimmune disease has demonstrated that Maini and Feldman are modern day medical firefighters: Their use of the antibodies to treat rheumatoid arthritis is truly an example of "fighting fire with fire."