Next-Generation Human Prostate Cancer Cocultures to Optimize Autologous Chimeric Antigen Receptor T-Cell Immunotherapy
Abstract
Treatment approaches called immunotherapies that redirect the human immune system to attack cancer are revolutionizing cancer medicine. A promising strategy is chimeric antigen receptor (CAR) T cell therapy, where killer cells of the immune system named T cells are collected from a patient, engineered in the laboratory to seek and destroy cancer cells, expanded into an army, and delivered back to the patient to wage war against their cancer. For prostate cancer, a CAR T cell therapy that targets a cancer protein called prostate stem cell antigen (PSCA) is entering clinical trials. CAR T cell therapy has been successful for the treatment of certain blood cancers but has not been as effective for solid tumors. A major reason for this is that solid tumors like prostate cancer contain physical barriers and other cell types within the microenvironment of the tumor that block the ability of CAR T cells to seek and destroy cancer cells. Unfortunately, current models to test CAR T cells in the laboratory do not adequately account for these cell types in human tumors. We believe that a strategy to overcome this limitation is to test human CAR T cells in live slices of human cancer tissues maintained for a few days in culture dishes. The live cancer slices retain the cells and the tissue organization found in the original tumor, providing an opportunity to examine how CAR T cells interact within solid tumors. In this proposal, a new system combining human prostate cancer tissue slices with human PSCA-CAR T cells will be developed to study and improve the ability of PSCA-CAR T cells to kill prostate cancer. First, we will establish the conditions to maintain live tissue slices from human prostate cancer specimens in the laboratory. Second, matched PSCA-CAR T cells and prostate cancer tissue slices processed from the same patients will be mixed together in a culture dish to carefully examine how well the PSCA-CAR T cells invade into the tissue and kill cancer cells. Lastly, we will use this system to test whether the addition of new therapies that affect the microenvironment of the tumor may improve the ability of PSCA-CAR T cells to infiltrate and eliminate prostate cancer. We believe that our studies may contribute a model system that will allow other prostate cancer researchers to more faithfully test immunotherapies, including CAR T cells, for prostate cancer in the laboratory. This system also has the potential to inform the design of rational clinical trials of immunotherapies in combination with CAR T cells for men with advanced prostate cancer. We believe that combining immunotherapies that affect the microenvironment of the tumor may unleash the potential of PSCA-CAR T cell therapy to eradicate prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910758
Entities
People
- John K Lee
Organizations
- Fred Hutchinson Cancer Center
- United States Army