Thalidomide: From Villain to Cancer Fighter - Page 2

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Apr 30, 2004

3. Stimulation of the Immune System

A long-held dream of cancer researchers is to mobilize the body's immune system to destroy cancer cells. Unfortunately, cancer cells usually are very similar in appearance to normal cells, so the immune system does not recognize them as foreign. A key stage in the process is the activation of T-cells by so-called antigen presenting cells (macrophages). These macrophages routinely engulf cells, particles, and large molecules in their environment, break them down, and present fragments on their surfaces. It is up to the T-cells to determine if these fragments are foreign (antigenic), requiring mobilization of the immune system to destroy them. In order to be fully activated, the T-cell must bind to the fragment, and to a co-stimulatory molecule provided by the macrophage or by the T-cell. When cancer cells are involved, there is often a lack of binding of a co-stimulatory molecule, so they are not recognized by the T-cell. In 1998, researchers demonstrated that thalidomide could serve the role of a co-stimulatory molecule, thereby allowing recognition of cancer cells by the immune system. The effect of T-cell activation by thalidomide on the immune response to cancer is dependent on many factors, not least of which is the contrary effect of inhibition of TNF and interleukin by thalidomide.

Development of new drugs based on thalidomide

Chemists analyzed the thalidomide molecule, and synthesized a series of analogues or derivatives that are much more active then the parent molecule. These "second generation" drugs are known as Immunomodulatory Drugs (ImiDs) or Selective Cytokine Inhibitory Drugs (SelCIDs). Most likely, these drugs, or future derivatives of these drugs will be used in cancer therapy, rather than the basic thalidomide drug.

Clinical trials

Two ImiD drugs known as compounds CC-5013 and CC-4047 are currently either being tested in clinical trials, or recruitment of patients for clinical trials is underway. Emphasis is in the use of patients who have suffered relapses of cancers, and are refractory (unresponsive) to other treatments. The most advanced studies are with malignant myeloma, which has shown very promising results over several years. 4 This disease is a B-cell malignancy that is incurable at present. Since malignant melanoma is characterized by bone-marrow vascularization, the anti-angiogenic properties of ImiD are active in treatment. Reported studies with the use of ImiDs do not show the significant side effects of drowsiness, constipation, and nerve damage that is seen with the use of thalidomide. Trials are also underway against melanoma, myelodysplastic syndromes, glioma, prostate, lymphoma and other solid tumors. 2

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