Understanding the Immune Biology of Checkpoint Inhibitors to Develop New Strategies for Therapy

This proposal deals with the development of novel treatment strategies for the deadliest of all skin cancers, melanoma. The disease is generally caused by excessive ultraviolet light (sun) exposure. Once the tumor cells have spread from the skin to other organs, there is only a approximately equal to 15 percent chance of surviving more than five years. This may change because in the last five years seven new treatments have been approved by the Food and Drug Administration, each improving survival of patients and/or their well-being. The clinical and scientific evidence clearly points to the potential for further improvements in treatment outcome, mainly by combining different drugs. The core of the proposal is a clinical trial for the treatment of advanced melanoma, in which two newly-approved drugs are tested in combination when compared to the stronger drug alone. Now we need to extract as much information as possible from the trial by monitoring the blood and tumor before and during treatment and, in case the patients become resistant and progress with disease, after therapy. Ideally, we want to combine the stimulation of the immune system with new inhibitors that block MAPK signaling pathways in the cancer cells, but the initial studies done by others had to be stopped due to toxicities from the treatment. While we can progress in developing new strategies inpatients, we need to advance faster. Therefore, we want to do all initial treatment work in experimental animals. To date, this has been difficult because the animal models do not faithfully reflect the human disease and, if they do, important components such as the immune(defense) system are missing. We have now developed two novel models of cancer, in which mice bear the human cancer cells but at the same time have a human immune system that is developed from blood stem cells. One model uses immune stem cells from newborns and the other uses stem cells from the same patients we have obtained tumors from.