Understanding the Immune Biology of Checkpoint Inhibitors to Develop New Strategies for Therapy
Abstract
Scientific Objective and Rationale of the Project: 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 ~15% chance of surviving more than 5 years. This may change because in the last 5 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 in patients, 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. These models will allow us to investigate the mechanisms of tumor destruction (response) and tumor progression (resistance) by the drugs and also to develop novel rationale-guided combination therapies with a variety of drugs. Applicability of Research: Besides melanoma, other cancers are candidates for improvement of outcome including cancers of the lung, prostate, ovary, kidney, pancreas, and liver. This makes checkpoint inhibitors, including the ones used in this clinical trial, currently the most promising drugs in all of cancer. Melanoma has historically been at the frontline for the development of new drugs to stimulate the immune system. This proposal is designed to achieve the most benefits from the drugs and at the same time look to the future to improve current treatments. We are aiming for cures, or at least stable disease in a high number of patients and hope to achieve this goal during the next 4 years in 35% to 45% of melanoma patients. As we develop the studies that are proposed here with more experience in combining immune checkpoint inhibitors with signaling small molecule inhibitors, we are optimistic that the percentage of long-term survivors will even be higher. One of the two drugs, Nivolumab, is relatively well-tolerated, but the second drug, Ipilimumab, is toxic in approximately 20% of treated patients. Colleagues of ours are working on markers in all humans that would predict who will not benefit from Ipilumumab. Our studies will likely give us strong markers of who should be treated with the combination, and we can subsequently validate any findings by using our novel animal models. Those models may also provide information on potential toxicities in patients. Such information would greatly help us spare some patients from receiving treatments with unreasonable toxicities. We expect the study to be completed by the end of year 3 of the grant cycle and also expect that the study will provide inf
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610119
Entities
People
- Meenhard Herlyn
Organizations
- United States Army
- Wistar Institute