ANAHEIM, CA (UroToday.com) - Dr. Michael O’Donnell, University of Iowa presented “How Immunology Research Drives Treatment of Bladder Cancer” in the session “Target Selection in Renal Cell Carcinoma and Bladder Cancer”.

Dr. O’Donnell started by citing the some history relating to immunotherapy and cancer. He stated that in 1891 Coley fist injected cancers with bacterial toxins and saw tumor shrinkage. In 1929 Pearl noted that lower cancer rates in tuberculosis patients by autopsy series. In 1976 Morales used intravesical BCG in bladder cancer patients. Use of BGC resulted in decreased tumor cells in cytology specimens, but more neutrophils, suggesting an immune response. Cytokine production of interleukins is central to the immune response. T cells are stimulated to the bladder after BCG therapy and are present for months thereafter. Interferon-gamma (IFN-gamma) is upregulated and participates in cellular immunity. IFN-gamma is always the last cytokine to come up and may be influenced by more proximal cytokines in the pathway. IL-10 knockout experiments showed that IFN-gamma is critical to the response. IFN-gamma production is from BCG-stimulated human peripheral blood mononuclearcytes. Cox-2 inhibitors or indocin also inhibit IFN-gamma expression. BCG + IFN-gamma accentuates a type I cytokine response, suggesting that IFN-gamma may suppress IL-10. Response to BCG was increased if IFN-gamma was added. In fact, adding IFN-gamma and decreasing BCG maintains effectiveness.

TRAIL, an apoptosis inducing ligand was found to have higher urine levels in BCG responders vs. non-responders. TRAIL is strongly associated with neutrophils and is increased by IFN-gamma and alpha. BCG promoted cleavage of soluble TRAIL: from neutrophils and a Phase II trial using BCG + IFN-alpha. However, for those who have failed BCG twice, there does not seem to be benefit using the BCG-IFN-alpha. Other trials underway include adenoviral cytokine gene therapy and new gene polymorphisms that affect BCG anti-tumor response are being identified. Useful markers of BCG response are needed to help stratify patients and the basis for BCG failure needs to be better identified. This is an exciting area of research that will improve outcomes for patients in the future.

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Written by Christopher P. Evans, MD, a Contributing Editor with UroToday.

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