Modulation of PD-1 Expression in Combination with Anti-Prostate Tumor DNA Vaccines
Abstract
Sipuleucel-T (Provenge?), a prostate tumor-directed vaccine, was approved by the Food and Drug Administration (FDA) in 2010 based on evidence from clinical trials that patients with advanced metastatic prostate cancer who received it lived longer than those who didn t. This finding shows that anti-tumor vaccines can have a role in the treatment of prostate cancer and can do so with minimal side effects, but we should improve on this approach and develop directed immune-based therapies with even greater effect. Our group has been interested in developing vaccines as treatments for prostate cancer, and we have been particularly focused on a simple method of delivering a vaccine called a DNA vaccine. This is an "off-the-shelf" approach, as opposed to the Provenge? approach that requires custom manufacturing of a vaccine for individual patients. As such, this is a much less expensive approach, and one that may be more easily combined with other therapies. We have been investigating DNA vaccines for over a decade in animal studies and early human clinical trials. In some of our recent studies in mice, we found that efforts to produce a more potent vaccine had the opposite effect. That is, when we immunized animals without tumors, we found that a more potent vaccine generated more CD8+ immune cells, cells with tumor killing ability, as we expected. When we immunized animals with tumors, however, these cells became inactive and were worse at controlling tumor growth than cells generated with our "less optimal" vaccine. We found that this was due to the increased expression of a molecule on the CD8+ cells called "PD-1" with the "optimized" vaccine. When PD-1 binds PD-L1 on the tumor cell, the CD8+ cell can be inactivated. When we used the "optimized" vaccine in combination with an antibody that blocked this PD-1 molecule, however, we found that the immune function was restored, and that some tumors were completely eradicated. This is a direction we wish to explore in a human trial, and in fact we are planning to conduct a trial combining a DNA vaccine with a PD-1 blocking antibody in patients with prostate cancer. In this proposal, however, we would like to dissect this mechanism further, because we think there may be ways to further improve the efficacy of vaccines than just using this combination therapy with PD-1 directed antibodies. Specifically, we have also recently found that T cells do not necessarily increase the expression of PD-1 when they become activated. Therefore, we should be able to figure out a way to activate the CD8+ cells we want with a vaccine without increasing the PD-1 at all. We will explore this mechanism and ways to interfere with PD-1 expression using mouse models in the first two aims of this grant. In the last aim, we will use what we have learned from these studies in other prostate cancer mouse models to see if they can be combined with DNA vaccines to produce a greater anti-prostate tumor effect. We believe our results will be directly applicable to patients with prostate cancer. As acknowledged above, we are currently in the process of designing a clinical trial combining a DNA vaccine with a PD-1 inhibitor that will evaluate the efficacy of this combination for patients with prostate cancer that has metastasized. A PD-1 blocking antibody was just recently approved by the FDA for the treatment of melanoma; however, to date this antibody and a similar antibody have not shown significant effects when used alone for patients with prostate cancer. We believe that combining these therapies will improve the efficacy of both. That study, while funded by another grant mechanism, could be changed based on early findings from our results here, and that could take place over 1-2 years. Alternatively, the results in our studies could suggest novel directions that we could explore in separate human trials over the next 2-4 years. We are committed to using scientific knowledge gained i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510492
Entities
People
- Douglas McNeel
Organizations
- United States Army
- University of Wisconsin–Madison