CD133-Targeted Natural Killer Cell Therapy for Aggressive Prostate Cancer
Abstract
Once prostate cancer (PCa) has escaped the confines of the gland and metastasized to other parts of the body, it is highly lethal. New therapies are urgently needed to combat the harm and suffering caused by this disease. Succinctly put, there is no cure for PCa, and outside-of-the-box strategies are needed to fight it. More attention is now being focused on harnessing the power of the patient’s own immune system to fight PCa. Several institutions are investigating transplanting immune cells that kill invading cancer cells to help give the patient’s immune system a boost. Cells known as T cells have been used for this type of therapy, primarily in blood cancers. Clinical trials have already initiated using chimeric antigen receptor T cells (CAR T-cells) in PCa. In this type of therapy, T-cells are engineered to specifically target a protein on the tumor cell surface using a homing device called a CAR. There are a number of problems associated with using T cell-based therapies. With all T cell therapies, T cells are harvested from a patient, grown in culture, manipulated for increased potency, and then returned to the same patient. T cells are patient-specific, meaning a healthy donor cannot provide T cells for a number of people. As a result, each T cell therapy is individualized and extremely expensive (~$475,000). T cells are also very long-lived and can end up attacking the patient’s healthy cells, resulting in undesirable side effects and even death. Another class of immune system cells that are potentially better than T cells for targeted therapy using CARs are natural killer cells (NK cells). NK cells are short-lived in the body and can kill tumor cells in a number of different ways. NK cells do not require donor matching in the same way that T cells do. This means that one person could, in theory, donate NK cells that could be used to treat a number of other people. This will cut down the cost of CAR NK cell therapies immensely compared to CAR T cell therapies. CAR NK cell-based therapies have never been investigated for the treatment of PCa. Thinking outside of the box, our goal is to make CAR NK cell therapies for aggressive PCa a reality. NK cells are readily abundant from a simple blood draw, but they are notoriously difficult to engineer, making it almost impossible to generate CAR NK cells. Using cutting-edge genome engineering technology, we have developed inexpensive methods to efficiently generate CAR NK cells from readily accessible NK cells isolated from the blood. To target our CAR NK cells, we recently identified a protein called CD133 that is overexpressed in men who have failed second-generation anti-androgen therapy (abiraterone or enzalutamide) and in the PCa of African-American men. In this proposal, we will generate CAR NK cells that selectively home to the tumors of both of these patient populations that have aggressive PCa, as demonstrated by poor overall survival. Our CD133-targeted CAR NK cells will be tested in cell lines and then in mouse models of human PCa. Additionally, we will perform nuclear imaging studies with our CAR NK cells to ensure that they do not localize to non-target tissues that may result in toxicity. Our intention is to bring a CD133-CAR NK cell therapy into the clinic within a few years of our first experiments. The University of Minnesota is a world leader at conducting NK cell clinical trials, and we have a production facility to generate clinical-grade CD133-CAR NK cells. The ability to effectively treat men in the clinic with aggressive PCa is a dire unmet need. We believe that our CD133-CAR NK cell therapeutic strategy will have a dramatic impact on prolonging the life expectancy of, or even curing, men with aggressive forms of PCa.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910243
Entities
People
- Aaron M LeBeau
Organizations
- United States Army
- University of Minnesota