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This article was published in December 2008 as part of the special ASH anniversary brochure, 50 Years in Hematology: Research That Revolutionized Patient Care.

The development of the drug rituximab as a therapy for B-cell lymphoma (a type of cancer affecting cells of the immune system) provides an excellent illustration of how great improvements in patient care were made through the discovery of a therapy that destroys cancer cells without harming other cells in the body.

Prior to 1975, rapid progress had been made in the use of chemotherapy for the treatment of lymphoma. Increasingly intense regimens, however, increased toxicity while making only incremental improvements in patient survival. Consequently, investigators were looking for a new approach, and it was clear that antibodies (proteins made by the immune system) might provide the clues  needed to diagnose and treat cancer. Antibodies are one way the immune system recognizes and destroys foreign invaders. Cancer cells are not foreign, since they are part of our own body, but they often exhibit alien features that could make them appear foreign. The main hurdles for making antibodies in a lab to fight cancer were figuring out how to find the right antibodies and how to make them in sufficient quantities with adequate purity. The first problem was solved by cloning the cells of the immune system responsible for making antibodies. The second problem was solved by making those cells "immortal" - in other words, most cells die in culture after several months, but these immortal cells continue to grow and divide indefinitely.

With these obstacles overcome, scientists set out to find targets against which to direct the antibodies. In order to make this approach clinically useful, a key objective was to destroy cancer cells without damaging normal cells. The first target that was chosen was a specific protein present on lymphoma tumor cells, but not on normal cells, termed an "idiotype." Each lymphoma tumor has its own unique idiotype; therefore, it was necessary to make a different antibody for each patient. In 1981, the first patient was treated with one of these "anti-idiotypic antibodies," and, amazingly, the tumor melted away without significant side effects. Motivated by this dramatic result, researchers treated 50 more patients with custom-made antibodies, and many of them are alive and well more than 20 years later.

However, this customized approach was circumvented by the discovery of rituximab, an antibody that recognizes CD20, a target shared by malignant lymphoma cells from almost all patients, but also found on normal, immune B cells. Rituximab proved to be effective in treating B-cell lymphoma, and the elimination of normal B cells was surprisingly not harmful. Because rituximab does not affect other normal cells in the body, it can be combined with other therapies. Today, rituximab is part of the regular treatment for almost all patients with B-cell lymphoma, and it has prolonged the lives of many of them.

The next surprising discovery was that rituximab could treat non-cancerous diseases caused by overactive B cells of the immune system. Rituximab has been used to treat rheumatoid arthritis, multiple sclerosis, and a growing list of non-cancerous conditions.

This is a success story that shows that new discoveries in the laboratory can lead to new treatments in the clinic. It represents a combination of scientific intuition, luck, and hard work by many individuals and organizations. From the scientists who made the original discoveries to the clinical investigators, investors, and patients who were willing to take the risk of trying something new, to the regulatory agencies that recognized that novel approaches to treatment deserved flexibility in evaluation, many possible roadblocks that could have prevented this successful therapy were overcome. Today, we must ask how many other potential new therapies are out there and how we can be creative enough to bring them forward.