IMMUNOTHERAPY

Immunotherapy is a disease treatment based upon the concept of triggering the body's own natural defenses to fight off the disease, usually by stimulating the immune system either locally or systemically.

Oncology represents one of the most actively researched areas of immunotherapy, and offers the promise of new therapies for cancer, based upon the idea of stimulating the patient's immune system to attack the malignant tumor cells that are responsible for the disease.

Since the immune system responds to the environmental factors it encounters on the basis of discrimination between self and non-self, many kinds of tumor cells that arise as a result of the onset of cancer are more or less tolerated by the patient's own immune system since the tumor cells are essentially the patient's own cells that are growing, dividing and spreading without proper regulatory control.

In spite of this fact however, many kinds of tumor cells display unusual antigens that are either innapropriate for the cell type and/or its environment, or are only normally present during the organisms' development (e.g. fetal antigens). Examples of such antigens include the glycosphingolipid GD2, a disialoganglioside that is normally only expressed at a significant level on the outer surface membranes of neuronal cells, where its exposure to the immune system is limited by the blood-brain barrier. GD2 is expressed on the surfaces of a wide range of tumor cells including neuroblastoma, medulloblastomas, astrocytomas, melanomas, small-cell lung cancer, osteosarcomas and other soft tissue sarcomas. GD2 is thus a convenient tumor-specific target for immunotherapies.

Other kinds of tumor cells display cell surface receptors that are rare or absent on the surfaces of healthy cells, and which are responsible for activating cellular signalling pathways that cause the unregulated growth and division of the tumor cell. Examples include ErbB2, a constitutively active cell surface receptor that is produced at abnormally high levels on the surface of breast cancer tumor cells.

Antibodies are a key component of the adaptive immune response, playing a central role in both in the recognition of foreign antigens and the stimulation of an immune response to them. It is not surprising therefore, that many immunotherapeutic approaches involve the use of antibodies. The advent of monoclonal antibody technology has made it possible to raise antibodies against specific antigens such as the unusual antigens that are presented on the surfaces of tumors.

Herceptin is an antibody against ErbB2 and was one of the first generation of immunotherapeutic treatments for breast cancer. Antibodies have also been developed for the immunotherapeutic treatment of other diseases such as rheumatoid arthritis. Remicaide for example, is an antibody against tumor necrosis factor, a naturally occurring protein in humans that is one of the major causes of the inflammation-related symptoms of rheumatoid arthritis.

The development and testing of second generation immunotherapies are already under way. While antibodies targeted to disease-causing antigens can be effective under certain circumstances, in many cases, their efficacy may be limited by other factors. In the case of cancer tumors for example, the microenvironment of many tumor types is immunosuppressive, allowing even those tumors that present unusual antigens to survive and flourish in spite of the immune response generated by the cancer patient, against his or her own tumor tissue. Certain members of a group of molecules known as cytokines, such as interleukin-2 also play a key role in modulating the immune response, and have been tried in conjunction with antibodies in order to generate an even more devastating immune response against the tumor. While the therapeutic administration of such cytokines may cause systemic inflammation resulting in serious side effects and toxicity, a new generation of chimeric molecules consisting of an immune-stimulatory cytokine attached to an antibody that targets the cytokine's activity to a specific environment such as a tumor, are able to generate a very effective yet localized immune response against the tumor tissue, destroying the cancer-causing cells without the unwanted side-effects.

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