Targeting B Cells as Antigen-Presenting Cells for Improved Anti-Prostate Cancer DNA Vaccines
Abstract
Our group has been interested in developing vaccines as treatments for prostate cancer, using vaccines that train the immune system to recognize prostate cancer cells that express particular proteins. Sipuleucel-T and Prostvac? are examples of this kind of approach, and the approval of sipuleucel-T in 2010 demonstrates that these kinds of therapies can benefit patients with advanced prostate cancer. However, we have been focused on a simpler method of delivering a vaccine called a "DNA vaccine." This is an "off-the-shelf" approach that does not require custom manufacturing and does not use infectious agents. As such, this is a much less expensive and safer approach, and one that may be more feasibly combined with other therapies. In fact, the first vaccine that has entered trials to protect against the Zika virus is a DNA vaccine. We have been investigating DNA vaccines for over a decade in animal studies and early human clinical trials and have demonstrated that we can generate immune responses to tumors in patients and that tumors can respond. However, we and others have observed that these vaccines, while safe, are less immunologically potent than other kinds of vaccines. Thus, we have been exploring in the lab how we can increase their "immunogenicity." Work in other laboratories has shown that DNA vaccines are taken up by skin or muscle cells at the site of immunization, and these cells produce the protein encoded by the vaccine and deliver it to specialized "professional" cells called "dendritic cells" that prime the immune response. In recent studies, we asked what happens if dendritic cells or other professional cells take up DNA directly. We found, surprisingly, that most of the DNA taken up directly by these cells is degraded. However, one type of cell, called "B cells," can take up DNA and directly prime immune responses. If dendritic cells or other professional antigen-presenting cells were given DNA, they could not prime these immune responses. This was surprising, because most people associate B cells with production of antibodies, and not with starting immune responses. We then found that if we deliver DNA to B cells, and deliver these B cells as a vaccine, we generate a more potent immune response than by just delivering DNA as is typically done with vaccination. These findings suggest that the general approach of DNA immunization could be greatly improved by targeting B cells, and this is the focus of this proposal. In this proposal, we will evaluate two ways to delivery DNA to B cells, and we will study this in two mouse models of prostate cancer. One approach will be by directly taking B cells out of the mouse, "feeding" the DNA to these B cells, and delivering them back to mice with prostate tumors. In these studies, we will determine the best way to deliver these B cells, determine whether this can be further improved by blocking one mechanism of resistance to vaccination (called PD-1 blockade), and determine whether this is more effective in treating growing prostate tumors than our standard ways of giving DNA vaccines. In the second approach, we wish to determine whether we can target B cells directly in the mouse, without having to take B cells out first. We see this as a more feasible direction long term, and less costly, for human trials. We will study two different ways to deliver DNA to B cells, one in which we will complex the DNA with a portion of a protein (peptide) that can be taken up by B cells. In another approach, we will use small particles derived from cells that contain the DNA and also express a viral protein (gp350) that can be taken up by B cells. Both of these methods rely on recognition of a human protein only expressed on B cells called "CD21." For these studies, we will use a genetically engineered mouse that expresses this protein on mouse B cells as a best model to study what we might expect in human studies. In the final part of the proposal, we will
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710247
Entities
People
- Douglas McNeel
Organizations
- United States Army
- University of Wisconsin–Madison