Prostate cancer is a significant global health concern for which new treatments are needed. The long-range goal of our research for nearly two decades has been to develop active immunotherapies, and tumor vaccines in particular, as treatments for prostate cancer. We have focused on DNA vaccines as a simple method, and one specifically aimed at generating tumor antigen-specific CD8 T cells. A major effort in our laboratory over the last several years has been to evaluate the tumor response to immunization and identify mechanisms of resistance to immunization. We have found that PD-1 or LAG-3 are upregulated after T cell activation with vaccination, and that even the transient expression of PD-1 or LAG-3 following antigen-specific T-cell activation is sufficient to allow them to be regulated in the immunosuppressive tumor environment, and this can be abrogated using concurrent blockade of PD-1 or LAG-3. We have recently demonstrated that this is true in humans as well, as delivery of a PD-1 blocking antibody (pembrolizumab) at the time of immunization with a DNA vaccine, rather than beginning weeks after immunization, elicited objective anti-prostate tumor responses. This forms the basis of the hypothesis underlying this proposal, namely that given the dynamic nature of the expression of PD-1 or LAG-3 following anti-tumor immunization, blockade of the transient upregulation of regulatory T cell markers (including PD-1 and/or LAG-3) using either antibody blockade or using TLR agonists that reduce expression of these regulatory receptors at the time of T-cell activation via anti-tumor immunization will lead to greater effector CD8 T cells and greater anti-tumor efficacy.

Public Health Relevance

The ultimate goal of our research has been to develop effective anti-tumor vaccines as treatments for cancer, and prostate cancer in particular. Thus this application is directly relevant to the mission of the National Cancer Institute.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA219154-02
Application #
9503698
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
2017-06-09
Project End
2022-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
McNeel, Douglas G (2018) Therapeutic Cancer Vaccines: How Much Closer Are We? BioDrugs 32:1-7
Zahm, Christopher D; Colluru, Viswa T; McIlwain, Sean J et al. (2018) TLR Stimulation during T-cell Activation Lowers PD-1 Expression on CD8+ T Cells. Cancer Immunol Res 6:1364-1374