Treatment of Prostate Cancer Using Targeted Radionuclide Therapy (TRT) with Tumor-Specific T-Cell Activation
Abstract
Prostate cancer is obviously an important health concern, and new treatments with few side effects are urgently needed. Dr. McNeel’s laboratory has been focused for over 20 years on the development of vaccines as treatments for prostate cancer. The goal of vaccines is to generate a specific type of immune cell, called a CD8+ T cell, which can directly kill tumor cells. They have been focused on one type of vaccine, called “DNA vaccines,” given their simplicity and safety. In the laboratory, they have studied a DNA vaccine that targets prostate cancer cells that make the androgen receptor (AR), the testosterone receptor, a protein that is critical to the growth and survival of prostate cancer. They have found that patients with prostate cancer can have low-level immune responses already to this protein, and that CD8+ T cells specific for the AR can kill prostate cancer cells. They have also found that mice engineered to develop prostate tumors develop CD8+ T cells that kill prostate cancer cells if they receive this DNA vaccine, and these animals live longer. The McNeel laboratory has started clinical trials using this same vaccine in patients with prostate cancer. In other clinical trials, they have found that combining another DNA vaccine with another drug, called a “PD-1 inhibitor,” produces greater effects than either treatment alone, including PSA declines and tumors shrinking after treatment. A clinical trial using a PD-1 inhibitor with the DNA vaccine targeting AR is planned to open before the end of 2018. The other primary investigator in this proposal, Dr. Weichert, has been studying molecules called alkylphosphocholines (APC), because they can be taken up very specifically by cancer cells. They have attached radioactive molecules to these APC and shown that, when these are injected into mice with tumors, they concentrate in the tumors. The APC can then be used to identify even small tumors using a scan that can pick up the radiation. Given at higher doses, these APC can also treat those tumors very specifically, since the radioactive molecule is concentrated in the tumor. They have started clinical trials using these APC as agents for detecting and treating many different kinds of tumors, including prostate cancer. In more recent work, they have made modifications to this APC molecule, such that different radioactive molecules can be more easily attached. We have found that this new generation of molecules is taken up by prostate tumors, including mouse prostate tumors that have been studied in Dr. McNeel’s laboratory. In the last year, our laboratories have started working together to see whether using APC labeled with radioactive molecules (called targeted radiotherapy [TRT]) can be used in combination with vaccines to more effectively treat prostate tumors. In early studies, we have found that TRT, when used at low doses that do not have much effect on the tumor directly, in combination with vaccine and a PD-1 inhibitor, did better than either treatment alone. We found that this low-dose TRT had effects on the immune cells within the tumor. We believe this combination can be further exploited by understanding what exactly TRT does to the immune cells in prostate tumors, whether this is affected by the radioactive molecule used, and by understanding the best timing to combine it with vaccination. These are the goals of the current project, using two different types of mice with prostate cancer, to answer these questions. We would highlight that both of our laboratories have extensive experience in each of these areas (immunology and radiation biology), but this project could not be reasonably performed by just one laboratory; this is a truly synergistic proposal. Our laboratories are literally within yards of each other, making it truly feasible to conduct the research we propose and be able to discuss findings and design new experiments very quickly. Each of our laboratories has also s
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910227
Entities
People
- Douglas McNeel
Organizations
- United States Army
- University of Wisconsin–Madison