The compound, AE37, is designed to stimulate an immune response against the tumor-causing gene HER-2/neu, which occurs in a significant percentage of patients with breast cancer as well as other cancers. A robust immune response against HER-2/neu has the potential to destroy tumor cells even at sites in the body distant from the primary tumor.

There are two main distinguishing features of the current trial. The first is that it focuses on developing a specific immune response against a target critical to the growth of tumor cells (HER-2/neu) rather than simply providing non-specific immune stimulation. This is much less likely to produce undesirable side effects than non-specific forms of immunotherapy.

Secondly, AE37 works through a portion of the immune system, represented by the T helper cells, that has been largely overlooked up to now in developing cancer immunotherapy strategies. In recent years, both pre-clinical and clinical studies have shown that stimulation of helper T cells is crucial for generating a robust, long-lasting and effective immune response.

The compound being examined, AE37, is composed of a small piece of the HER-2/neu protein coupled to a portion of the MHC class II-associated invariant chain (Ii protein) shown to greatly enhance stimulation of T helper cells. The discoveries that led to AE37 are based on the work of Dr. Robert Humphreys, founder of Antigen Express, who was first to identify both MHC class II molecules and their role in stimulating T helper cells as well as a portion of the Ii protein capable of dramatically increasing the response of T helper cells to specific antigenic epitopes.

In addition to establishing the safety of AE37, the current trial will establish both the level and longevity of specific T cell stimulation induced by AE37.

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The new findings also have implications for disorders such as flesh-eating staph infections and drug-resistant bacterial infections that are difficult to treat. The researchers note that in these cases, it might be possible to develop an inhibitor of IKKa that boosts the inflammatory response to better fight these infections. However, such an inhibitor should have a short half-life, so that its potential devastating effect can be properly terminated.

The Karin lab, which has made several of the past discoveries involving IKKb ™s pro-inflammatory role, has also studied IKKa over the years, but they have identified roles unrelated to the primary inflammatory response. For example, in 2001, the investigators determined that IKKa was essential for formation of the skin ™s outer layer.* In a follow-up study, the team found clues that IKKa may be more involved in the immune response than they previously thought, but its role still appeared limited.** The current study is the first, however, to specifically show the novel mechanisms used by the protein to control the duration of an inflammatory response.

The study was funded by the National Institutes of Health. The co-first authors were Toby Lawrence, Ph.D., and Magali Bebien, Ph.D., post-doctoral fellows in the Laboratory of Gene Regulation and Signal Transduction, UCSD Department of Pharmacology. Currently, Lawrence is an assistant professor and member of the Faculty of Medicine, Imperial College London. Additional authors were George Liu, Ph.D., UCSD Division of Pediatric Infectious Diseases, UCSD School of Medicine; and Victor Nizet, M.D., associate professor of pediatrics, UCSD School of Medicine.

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