Metabolic Remodeling of the Tumor Microenvironment to Improve the Efficacy of Immunotherapy
Abstract
Melanoma is a type of skin cancer that is deadly when it spreads to other areas in the body. Over the past few decades, the cases of melanoma have been increasing every year, especially in the military. In fact, studies have shown that melanoma is increasing at a much higher rate in the military than it is in the general population. This is likely because active duty personnel are often required to be outside for prolonged periods of time and are therefore exposed to more sunlight, which is a known risk factor for the development of melanoma. This project addresses two Fiscal Year 2017 Peer Reviewed Cancer Research Program Topic Areas, melanoma and immunotherapy, and the Military Relevance Focus Area that we address is gaps in cancer treatment. Immunotherapy activates the immune system to recognize and fight cancer cells and has revolutionized the way we treat many advanced cancers, including melanoma. One of the commonly used kinds of immunotherapy is called “anti-PD1.” PD-1 stands for programmed death receptor 1 and is found on the surface of a lot of cells in the immune system. Tumor cells have PD-L1 on their surface (which stands for programmed death ligand-1). When PD-L1 on the tumor cells binds to PD-1 on immune cells, it causes the immune cells to stop working properly, so they can’t fight the cancer. We now have medications that stop cancer cells from killing immune cells in this way, and when immune cells aren’t killed by the cancer, they’re supposed to be able to do their job. However, while many patients benefit from these treatments and live longer, a lot of patients don’t get better on these medications. The key problems are that (1) we don’t know why these drugs are successful at fighting the cancer in some people and not others and (2) we don’t know how to get these drugs to work in more people. T cells are a part of the immune system and are supposed to identify and destroy cancerous cells. To do this properly, they require an enormous amount of energy. Tumors grow with unrestrained metabolism and consume all of the nutrients and a lot of the oxygen in their environment, making it very challenging for T cells to do their job. We hypothesize that part of the reason that immunotherapy is not effective in all patients is because some tumors are more metabolically active than others, taking up a lot of the nutrients and oxygen, so that when T cells enter the tumor, they are nutrient and oxygen deficient and cannot function properly. We have recently shown that metformin, a drug typically used for diabetes treatment, may increase normal metabolism in the tumor, and that when used with immunotherapy, it shrinks tumors more than when immunotherapy is used alone. In this project, we will test if the combination of metformin with anti-PD1 immunotherapy is superior to anti-PD1 immunotherapy alone in improving metabolic abnormalities in the tumor. Importantly, these studies are expected to provide crucial data for the development of new strategies to improve clinical outcomes to immunotherapy treatment, so that more patients may benefit from these lifesaving therapies. We already have funding for a clinical trial that will be testing the combination of anti-PD1 with metformin, compared anti-PD1 alone, in patients with advanced stage melanoma. The anti-PD1 drug we are using is already approved by the Food and Drug Administration, but it has not been tested with metformin yet. In this project, which is based on the clinical trial, we will do a lot of testing on tumor tissue and blood from patients on the clinical trial. This will significantly add to our understanding metabolic abnormalities as key mechanisms of resistance to immunotherapy and how to overcome them. The full potential benefits of combining anti-PD1 with metformin to the subjects are not known and will be determined by these studies. The proposed research is designed so that we develop a better understanding of how to overcome
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810211
Entities
People
- Greg Delgoffe
Organizations
- United States Army
- University of Pittsburgh