Metabolic Reprogramming of CAR-Macrophages for Ovarian Cancer Immunotherapy
Abstract
Ovarian cancer treatment is an uphill battle in crucial need of new approaches and treatment options. Current treatments are often able to initially control ovarian cancer growth. However, most of the time, ovarian cancer will grow back and will become resistant to therapy. Many cancer types have benefited from immunotherapy, which is an approach that stimulates the immune system to attack and kill the tumor cells while leaving normal cells untouched, just as it would a virus or bacteria that had infected the body. Unfortunately, this type of treatment has not worked well for women with ovarian cancer. The long-term goal of this proposed work is to develop new treatment strategies and discover new treatment targets for all American women with ovarian cancer in order to improve quality of life and survival. One type of immunotherapy takes cells from the patient’s blood, activates those cells to target the tumor, and then gives those cells back to the patient through the blood stream. This kind of treatment has worked well for types of cancer that grow in the blood, but it has not worked well for patients with ovarian cancer. One roadblock for these activated cells is traveling through tissue to find the cancer. Recently, some studies have shown that a cell type called a macrophage can make it into ovarian tumors and are a safe therapy. We also now know that cells that are part of the immune system need certain metabolites, or nutrients, in order for the cells to function properly. In tumors, cancer cells take up those nutrients and prevent immune cells from gaining access to them, which results in the immune cells not functioning properly to target the tumor. Our hypothesis is that we can load macrophages with an important nutrient called succinate that will enhance the cell’s ability to fight ovarian cancer. Our proposal seeks to use a combination of human blood cells, ovarian cancer cell lines, and mouse models to understand how certain nutrients affect macrophage metabolism and how they may enhance tumor cell killing. As part of this proposal, we will use the Human Cell Therapy Lab (HCTL) at Mayo Clinic Arizona to produce these cells, called chimeric antigen receptor-macrophages (CAR-Ms). The rationale for the proposed research is that, once it is known whether succinate can successfully enhance the killing ability of CAR-Ms, we can use this information to develop novel therapies. Importantly, because we will use the HCTL we will have critical insight into how to generate a clinical grade therapy that we could use in phase 1 clinical trials to benefit women with ovarian cancer that may lack additional therapeutic options.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310328
Entities
People
- Marion Curtis
Organizations
- Mayo Clinic Scottsdale
- United States Army