First Monoclonal Cancer Therapeutic

NHL occurs when B-cells, the cells that produce antibodies, begin to grow abnormally. The B-cells (or, more rarely, T-cells) divide too rapidly and grow out of control. Tumors result when too much tissue is formed.  Because the lymphatic system is distributed throughout the body, the cancer cells may spread to other organs including the liver, spleen or the bone marrow.

The new compound, called Rituxan or  rituximab, is a genetically-engineered monoclonal antibody that targets a receptor called CD20 found on some B-cells. The Rituxan antibody marks the B-cells for destruction by the immune system, after which new B-cells are generated by stem cells. Stem-cells and B-cells bearing antibodies are spared by Rituxan, since they lack the CD20 antigen.

Graphic: Step involved in making monoclonal antibodies

In a clinical trial conducted at 31 U.S. medical centers, 166 patients with NHL who had failed to respond to conventional treatment with radiation and chemotherapy received a series of four infusions of Rituxan. About half of the patients saw their tumors shrink by at least half, while six percent had a complete remission of disease.

"Rituxan represents an important turning point in the treatment of lymphoma," said Myron Czuczman, M.D., Assistant Professor of Medicine, Roswell Park Cancer Institute, Buffalo, New York, and a key investigator. "Although it is not a cure, we finally have a cancer agent that can be effective with less serious side effects than with conventional chemotherapy. Treatment can also be completed in 22 days, unlike the typical four- to six-month chemotherapy regimens. This is exciting news, especially for elderly patients and relapsed patients who have failed at least one standard treatment regimen."

Rituxan will initially be used to treat patients with low-grade NHL who have failed conventional chemotherapy and radiation treatments. The new agent offers a number of potential advantages over current treatments. First, it may work when all else has failed. Some patients fail to respond to standard therapies, and others may develop resistance to treatment. Rituxan is also considerably less toxic than chemotherapeutic agents or radiation, causing none of the hair loss, nausea and life-threatening complications these agents can cause. Conventional treatments also may cause sterility and are sometimes associated with the development of other types of cancers.

As an added advantage, Rituxan can be administered on an outpatient basis, sparing patients the inconvenience and discomfort (and cost) of a hospital stay. While chemotherapy and radiation treatments may require lengthy hospitalization, Rituxan is administered as four infusions over a 22-day period.

Rituxan is a specific type of drug known as a chimeric monoclonal antibody. Chimeric antibodies take their name from the chimera, a mythical beast with the head of a lion, the body of a goat and the tail of a dragon. The Rituxan chimera is a hybrid of antibodies from both human and murine (mouse) sources. The CD20 antigen is injected into a mouse, encouraging the production of antibodies. Antibody producing cells are then isolated from the spleen of the animal. These are then combined with immortal cells called myeloma cells. This results in a cell line that will go on producing the antibody indefinitely. Further genetic engineering removes the elements of the mouse cell that would normally produce an immune (allergic) reaction  if injected into a human.

Early monoclonal antibody-based therapies for cancer were plagued with a host of problems. In the early experiments, allergic reactions to the foreign (mouse) part of  experimental antibodies, called HAMA (human anti-mouse antibody) limited their usefulness and preventing them from being used more than once. The developers of Rituxan overcame this problem by removing the antigenic part of the mouse portion of the chimeric antibody.

Lymphomas are cancers involving the lymphatic system, the network of glands and vessels that circulate lymph throughout the body. Lymph is a clear, colorless, watery fluid that contains the white  blood cells that form the basis of the immune system. Tumors may form on lymph nodes, small,  bean-shaped organs found throughout the lymph system, specifically around the neck, under the arms, in the groin and abdomen.

Non-Hodgkin's lymphoma, also called B-cell lymphoma, is the most common type of lymphoma. It is the sixth most common type of cancer in the US. Each year, some 54,000 new cases are diagnosed each year and more than 24,000 die from the disease. The overall incidence of NHL has increased more than 80% since the 1970s, a fact that is attributed to the AIDS epidemic and the aging population. One-half of NHL patients have low-grade or follicular lymphoma. A portion of these patients will have multiple relapses and may be eligible for Rituxan therapy.